This is a continuation of application filed on November 21, 2019 under 35 U.S.C. application serial no. 120 No.: 16/690,282 and is a continuation of US serial no. 16/242,273, filed Jan. 8, 2019, is a separate application with US serial no. Serial no. 15/825,982, filed Nov. 29, 2017, now US Pat. 10,238,666, issued March 26, 2019, is US patent no. 15/370,680, filed Dec. 6, 2016, US Ser. no. 9,855,284, issued Jan. 2, 2018, which is a separate application with U.S. Serial No. Serial no. 15/222,062, filed Jul. 28, 2016, now US Pat. 9,598,459, issued March 21, 2017, US Provisional Patent Application No. 62/282,525, filed Aug. 3, 2015 under 35 U.S.C. § 119(e); US Provisional Patent Application No. 62/220,583, filed September 18, 2015; US Provisional Patent Application No. 62/241,875, filed Oct. 15, 2015; US Provisional Patent Application No. 62/271,038, filed Dec. 22, 2015; US Provisional Patent Application No. Provisional patent application no. 62/296,673, filed Feb. 18, 2016; US Provisional Patent Application No. 62/299,120, filed Feb. 24, 2016; US Provisional Patent Application No. 62/314,046, filed Mar. 28, 2016; US Provisional Patent Application no. 62/339,909, filed May 22, 2016; US Provisional Patent Application No. 62/339,906, filed May 22, 2016; US Provisional Patent Application No. 62/342,103, filed May 26, 2016; US Provisional Patent Application No. 62/342,965, filed May 29, 2016; US Provisional Patent Application No. 62/342,966, filed May 2016. US Provisional Patent Application No. 62/342,967, filed May 29, 2016; US Provisional Patent Application No. filed June 3, 2016; US Provisional Patent Application No. 62/345,095, filed Jun. 3, 2016; US Provisional Patent Application No. 62/349,235, filed Jun. 13, 2016; US Provisional Patent Application No. 62/352,624, filed Jun. 21, 2016; US Provisional Patent Application No. 62/352,611, filed Jun. 21, 2016; LOUSE. provisional patent application no. 62/352,572, filed Jun. 21, 2016; US Provisional Patent Application No. 2016; Provisional patent application no. 62/358,211, filed Jul. 5, 2016; US Provisional Patent Application No. 62/361,125, filed Jul. 12, 2016, the disclosures of which are incorporated herein in their entirety.
Specification Background of the invention
The present invention relates to cortisol blockers (eg, glucocorticoid receptor [GR] antagonists) in the treatment or prevention of viral infection, the treatment of drug-resistant prostate cancer, the treatment or prevention of tumors, and the treatment or prevention of acute or chronic injury or Use in infections associated with disease.
Rapid advances in various technologies, along with advances in travel and globalization, have had a major impact on improving the human condition in the United States and internationally. However, all these advances have proved to be a double-edged sword, allowing the easy spread of invasive species and diseases, either by accident or on purpose. The United States government is actively working to legislate and fund medical countermeasures to address the potential public health threat posed by the introduction of pathogens. Key among those responses are the Bioshield Act of 2004 and the Pandemic and All-Hazards Preparedness Act of 2006, which provide opportunities through the Biomedical Advanced Research and Development Authority (BARDA).
The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), maintains an inventory of emerging infectious diseases and pathogens for prioritization and research guidelines. Pathogens are prioritized from A to C based on characteristics of transmissibility, morbidity, mortality and diagnostics. Additionally, a list of new pathogens and diseases not categorized by priority is included. These lists were used as a springboard to explore a series of compounds developed by Palisades Therapeutics (PT), a division of Pop Test Oncology LLC, that have demonstrated antiviral activity against a variety of human pathogens.
The following sections will provide detailed information on PT150 and PT155 compounds and NIAID-listed viral pathogens that exhibit or are suspected of exhibiting activity. We confirmed this activity both in vitro and in animal models. This activity includes the Zika virus. We believe their level of activity acts as an antiviralflavivirus, and perhaps other RNA viruses, favoring their transfer to clinical testing.
PT-150 is a repurposed drug obtained from a major pharmaceutical company that has a transferable IND that could, if found to be warranted, allow it to be rapidly introduced into the human clinical trial population. The compound has previously completed all preclinical studies leading to an IND, one pivotal Phase 1 human study, and two large Phase 2 human psychotic depression trials. PT-150 has unique properties as an antiviral due to its ability to penetrate sanctuaries such as the brain , thymus and testes. Therefore, it may have the potential to clear the virus from these sites through direct antiviral activity, thereby inhibiting viral replication in infected cells and clearance by apoptosis.
PT-155 is a derivative of PT-150 that has shown greater activity associated with a putative mechanism of action, which may lead to greater efficacy. PT150 requires phase III clinical trials. PT155 will require IND support for safety pharmacology and toxicology studies, and IND support for the CMC program.
PT-150 (formerly known as Org34517) and its derivative molecules PT-155 and PT-156 have at least two general mechanisms of antiviral action against a variety of viruses that infect animals and humans. The initial antiviral effect is mediated by the binding of these molecules to the glucocorticoid response element (GRE) present in the genome of certain viruses. The second is through binding of these molecules to phosphatidylserine (PS), which is present in the envelope of all enveloped viruses.
The mechanism of action by binding to GRE is as follows:
Viruses that infect animals and humans infect cells by placing their genetic material in the cytoplasm and/or nucleoplasm of infected cells. "Response elements" within the genome may contain coding or non-coding regions and respond to molecular signals from the host cell and/or other elements of the virus' own molecular network. Viruses often possess a GRE, a response element that influences glucocorticoid signaling mediated by binding of cortisol (or other glucocorticoids) to the glucocorticoid receptor (GCR).
Viruses that have been identified with GRE include: hepatitis C virus, bovine viral diarrhea virus, Ebola-like virus, hepatitis B virus, murine mammary tumor virus, human immunodeficiency virus 1 (HIV-1), varicella-band herpes zoster virus (varicella; VZV ),Cytomegalovirus(CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or human herpesvirus 8; HHV-8), smallpox virus (variola),vacciniavirus, vaccinia virus, monkey pox virus
Binding of PT-155 and its derivatives (including but not limited to PT-155 and PT-156), which are GCR antagonists, also modulates the viral GRE to directly or indirectly inhibit essential viral functions (including but not limited to replication genes, virus-related protein production, assembly of genetic material and viral proteins into complete viruses, increased genetic diversity, facilitation of active or passive release of viruses from cells and viral infectivity).
In addition, these viruses contain viral DNA transcripts that are proviral, allowing the virus to become latent in isolated cellular compartments in vivo; these proviral DNA genomes are responsible for latent infection when the individual is immunocompromised or suppressed. When the antiviral regimen is interrupted, the latent infection can erupt into full viral replication. Binding of these molecules inactivates this proviral activity by directly inactivating the provirus or by inducing mutations in the proviral genome that trigger p53-mediated apoptosis in host cells. In any case, the virophilic genome is disrupted. Among those sensitive viruses, PT-150, PT-155 and PT-156 and other possible derivatives of these molecules will lead to cure of chronic viral infection.
Antiviral mechanisms of action associated with PS binding are as follows:
PS is normally sequestered in the inner layer of the plasma membrane bilayer, but during apoptosis the mechanisms that normally keep PS in the inner layer are down-regulated, allowing PS to appear on the cell surface. Exposure to PS is a recognition signal for phagocytes to clear dying cells. Several macrophage receptors are involved in the recognition of PS on apoptotic cells, including various scavenger receptors, CD36, CD14, and the PS receptor (PSR). Therefore, PS has the ability to mediate intercellular interactions and act as a ligand for various PS-binding receptors.
Enveloped viruses continuously expose PS on host lipid bilayer membranes. Enveloped viruses take advantage of this exposure to PS to evade attack by the body's immune system and enter phagocytes such as monocytes/macrophages, making its presence in the viral envelope highly suspect as a factor in virus-target cell fusion.
Viruses that infect animals and humans infect cells by placing their genetic material in the cytoplasm and/or nucleoplasm of infected cells. "Response elements" within the genome may contain coding or non-coding regions and respond to molecular signals from the host cell and/or other elements of the virus' own molecular network. Viruses often possess a "glucocorticoid response element" (GRE), a response element that influences glucocorticoid signaling mediated by binding of cortisol (or other glucocorticoids) to the glucocorticoid receptor (GCR).
The combination of this activation leads to a signaling cascade that regulates endogenous host cell GRE as well as viral GRE. Modulation of the viral GRE may directly or indirectly contribute to viral physiology, thereby promoting essential viral functions (including but not limited to gene replication, production of virus-associated proteins, assembly of genetic material and viral proteins into complete viruses, increased genetic diversity, facilitation virus exit from cells Active or passive virus release and virus infectivity.
ORG 34517, PT150, PT155, PT156, PT157, PT158 and TCY1 are members of a class of therapeutic agents designed to block the glucocorticoid receptor (GR), acting as endogenous cortisol antagonists. It is primarily being developed for the treatment of neuropsychiatric disorders characterized by dysregulation of hypothalamic-pituitary-adrenal axis signaling and often higher than normal levels of circulating endogenous cortisol. Of particular note is the completed phase 2 clinical trial for the treatment of psychotic depression. Other possible uses for this class of diseases being investigated include, among others, post-traumatic stress disorder, weight gain in patients requiring long-term antipsychotic treatment, and hospitalization for delirium in the elderly.
Endogenous glucocorticoids are steroids that are mainly produced in the cortex of the adrenal gland. Glucocorticoids are important steroids for intermediate metabolism, immunity, function of the musculoskeletal system, connective tissue and brain. The main glucocorticoid in the body is cortisol. The production and secretion of cortisol is controlled by a complex and highly efficient system involving the hypothalamus, pituitary gland and adrenal glands, the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol secretion has a circadian rhythm of release with a peak in the morning and a trough at midnight.
The creation and secretion of cortisol, the most important glucocorticoid, is controlled by a complex and highly efficient system that includes the hypothalamus, pituitary gland and adrenal glands, the hypothalamus-pituitary-adrenal axis. Cortisol secretion is regulated by the suprachiasmatic nucleus of the hypothalamus, forming a circadian rhythm of release. Time is synchronized with the solar day by weaker changes, which often reflect normal sleep-wake patterns. Therefore, in healthy individuals, cortisol secretion has a 24-hour circadian pattern, with the highest serum levels in the early morning, 3-6 hours after falling asleep, and the lowest levels around midnight. Physical and psychological stressors also activate the secretion of cortisol. Patterns of changes in serum cortisol levels have been observed to correlate with abnormal adrenocorticotropic hormone (ACTH) levels, clinical depression, psychological stress, and physiological stressors such as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion, or extreme temperatures. Cortisol levels and reactivity may also differ from normal levels in older adults and individuals with autism or Asperger syndrome.
Glucocorticoids (GCs), such as cortisol in humans, have several important functions. These include involvement in the regulation of carbohydrate, protein and fat metabolism by signaling the liver to produce glucose and glycogen, adipose tissue to release lipids and fatty acids into the blood, and skeletal muscle to release proteins or amino acids into the blood. GC also reduces bone formation.
GCs also regulate the body's inflammatory response. GC is part of a feedback mechanism in the immune system that suppresses immune activity (ie, inflammation). GCs produce their effects by binding to GCRs. Activated GCR complexes in turn enhance the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and suppress the expression of pro-inflammatory proteins in the cytoplasm by preventing the translocation of other transcription factors from the cytoplasm to the cytoplasm. Nuclei (trans-suppression) (Rhen T and Cidlowski J A. NEJM 2005;353:1711-23).
Treatment with GCR antagonists or active drugs may be helpful in patients with abnormally high cortisol levels (but still maintaining a circadian rhythm), hyperresponsiveness to normal levels, or high nocturnal cortisol levels as a feature of a circadian rhythm disorder. This altered cortisol physiology may be associated with acute or chronic stress (eg, associated with physical or psychological trauma) or with age-related changes in the elderly. Therefore, successful treatment with these drugs often depends on determining circadian cortisol levels (peak levels during the day, such as midday, or measurements taken every 4 or 6 hours over a 24-hour period). This combinatorial salivary cortisol quantification system as a paired GCR antagonist enabling device will identify individuals who would benefit from a GCR antagonist or active drug therapy.
The glucocorticoid receptor (GR) is expressed at high levels in some normal tissues but not in others. Likewise, malignant diseases of different types and sites have variable expression of GR. When present in normal or neoplastic (benign or malignant) tissues, this GR expression can be differentially localized in some or all of their cellular compartments: 1. Stem cells; 2. Progenitors of activated stem cells (so-called "transit amplified") cellular offspring 3. differentiated offspring of activated stem or progenitor cells.
Accordingly, the present invention relates to the use of GR antagonists or agents (eg ORG34517, PT150 - a relatively specific GR antagonist, RU486 - a non-specific GR antagonist, etc.), optionally in combination with at least one other Combination of agents for treatment or prophylaxis of drug-resistant prostate cancer, treatment or prevention of neoplasia, and/or treatment or prevention of infections associated with acute or chronic injury or disease.
ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1 are members of a class of therapeutic agents designed to block the glucocorticoid receptor (GR), acting as endogenous cortisol antagonists. It is primarily being developed for the treatment of neuropsychiatric disorders characterized by dysregulation of hypothalamic-pituitary-adrenal axis signaling and often higher than normal levels of circulating endogenous cortisol. Of particular note is the completed phase 2 clinical trial for the treatment of psychotic depression. Other possible uses for this class of diseases being investigated include, among others, post-traumatic stress disorder, weight gain in patients requiring long-term antipsychotic treatment, and hospitalization for delirium in the elderly. Furthermore, various data suggest GR blockade as a means of promoting the chemosensitivity of target tumors. Preclinical studies have shown remarkable results - slowing down the growth and reversal of breast cancer. In these preclinical trials, the company successfully demonstrated the effectiveness of the chemosensitizer against "triple-negative" cancers of the breast, ovary and prostate.
"Triple-negative" breast cancer is the most difficult type of breast cancer to treat, and patients test negative for estrogen receptors, progesterone receptors, and her-2/neu. Triple negative breast cancer is resistant to chemotherapy. Primary resistance and early resistance are seen in other tumor types, such as liver and ovarian cancer, where there is an unmet medical need for effective treatments. Chemotherapy remains a key method of cancer treatment. Chemosensitizers would help improve the effectiveness of current treatments and possibly improve their side effects. The global cancer market was estimated at $23 billion in 2004 and is expected to grow to at least $61 billion by 2013, a compound annual growth rate of 14.7%.
The present invention provides a low-cost, rapid-response diagnostic system for determining salivary cortisol levels in patients selected as potential candidates for treatment with GCR (glucocorticoid receptor) antagonists, using GCR antagonists or active agents such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof. The inventors have developed a saliva-based cortisol detection diagnostic device that follows the development of ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts as therapeutic agents for various indications. Clinical testing of cortisol levels in patients is an expensive and laborious test, which can be saliva or serum, and samples are collected from patients and sent to a laboratory to await results. To date, the cost and time factors of such testing have been prohibitive due to the inability to determine cortisol levels when needed or monitor changes in cortisol as a measure of response to treatment. By allowing physicians to identify elevated cortisol levels in patients and in turn provide treatment for that elevation at the point of measurement, physicians can identify the best candidates for such treatment. The system also enables continuous monitoring of patients during treatment to assess response to therapy.
The subject invention provides a system in which the device uses a high volume void carrier to absorb a sufficient amount of saliva, which is then placed in a reaction vessel with reagents. The reagent is mixed with the sample, then conjugated with a fluorescent ligand or a pigment-labeled ligand, etc., and placed in a device to determine the cortisol level in the patient's saliva in less than 5 minutes using a portable miniature fluorescent detector Polarized reading probe (in the first case) or lateral flow devices (in the second) are used to measure the amount of substrate in small volumes of liquid by direct or indirect methods.
For example, the readers offer temperature control and on-board mixing in addition to reactive viscosity control to ensure better accuracy and precision.
Invention and method for non-invasive sampling and detection of the presence of biological substances of interest in a test sample, such as saliva or body fluid, which is combined with a buffer system (reagent 1) consisting of a viscosity regulator and a stabilizer in In a reaction vessel, mix the solution, mix the test sample and the mixture of the buffer system with the fluorescently labeled ligand (reagent 2) with the biological substance in the reaction vessel (test solution), mix the solution and detect the change in fluorescence polarization reading of the test solution in the container or the pigment-labeled ligand.
The continued development of this invention led to a new discovery; thiosemicarbazones ORG34517 cannot be dimerized by treatment with sodium hydroxide NaOH. But after thinking about it, it turns out that this is actually more suitable for the goal of eradicating human hepatitis B and immunodeficiency provirus. The key lies in the way it binds to the human glucocorticoid receptor (hGR). It can be shown that the expected dimer does not bind hGR. The thiosemicarbazone from ORG34517 can bind hGR and force nuclear translocation of the ligand-receptor complex. This is important because nuclear translocation is a prerequisite for our mode of action, and the ORG34517-hGR complex itself does not translocate to the nucleus. Furthermore, the thiosemicarbazones of ORG34517 will activate human flavin-containing monooxygenases (hFMO1, hFMO2.1, hFMO3) to reactive sulfenic acid and carbodiimide metabolites. Activation is not via an activation bond in the putative dimer, but via metabolic activation of the human enzyme. In addition, cells infected with human hepatitis B and human immunodeficiency virus show increased oxidative stress, which may lead to increased activation of virus-infected cells. Material PT155 is the complex of choice for in vitro antiviral studies. The present invention relates to glucocorticoid receptor (GCR) antagonists or active agents (such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof) administered by devices for use in Rapid , sensitive, and inexpensive specific quantification of salivary cortisol levels as a surrogate for serum cortisol levels. One objective of the combination of the present invention is to identify patients with abnormal adrenocortical cortisol production or circadian rhythm disturbances as a means of selecting subjects for treatment with potentially beneficial and/or beneficial GCR antagonists or activators. Treatment effects, ie. abnormally high levels (but maintaining the circadian rhythm), hyperreaction to normal levels, high nocturnal cortisol levels as features of circadian rhythm disorders. This rapid, sensitive and inexpensive test can also be used to monitor changes in cortisol levels in response to therapy, as an option for selecting subjects with GCR antagonists or active agents in patients with abnormal adrenal cortex cortisol production or circadian rhythm disorders. Approach Treatment is likely to be beneficial and/or therapeutically effective in patients who have a normal baseline cortisol value at the start of treatment but whose cortisol levels change during treatment suggestive of a response to a GCR antagonist.
Endogenous glucocorticoids are steroids that are mainly produced in the cortex of the adrenal gland. Glucocorticoids are important steroids for intermediate metabolism, immunity, function of the musculoskeletal system, connective tissue and brain. The main glucocorticoid in the body is cortisol. The production and secretion of cortisol is controlled by a complex and highly efficient system involving the hypothalamus, pituitary gland and adrenal glands, the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol secretion has a circadian rhythm of release with a peak in the morning and a trough at midnight.
The creation and secretion of cortisol, the most important glucocorticoid, is controlled by a complex and highly efficient system that includes the hypothalamus, pituitary gland and adrenal glands, the hypothalamus-pituitary-adrenal axis. Cortisol secretion is regulated by the suprachiasmatic nucleus of the hypothalamus, forming a circadian rhythm of release. Time is synchronized with the solar day by weaker changes, which often reflect normal sleep-wake patterns. Therefore, in healthy individuals, cortisol secretion has a 24-hour circadian pattern, with the highest serum levels in the early morning, 3-6 hours after falling asleep, and the lowest levels around midnight. Physical and psychological stressors also activate the secretion of cortisol. Patterns of changes in serum cortisol levels have been observed to correlate with abnormal adrenocorticotropic hormone (ACTH) levels, clinical depression, psychological stress, and physiological stressors such as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion, or extreme temperatures. Cortisol levels and reactivity may also differ from normal levels in older adults and individuals with autism or Asperger syndrome.
Glucocorticoids (GCs), such as cortisol in humans, have several important functions. These include involvement in the regulation of carbohydrate, protein and fat metabolism by signaling the liver to produce glucose and glycogen, adipose tissue to release lipids and fatty acids into the blood, and skeletal muscle to release proteins or amino acids into the blood. GC also reduces bone formation.
GCs also regulate the body's inflammatory response. GC is part of a feedback mechanism in the immune system that suppresses immune activity (ie, inflammation). GCs produce their effects by binding to GCRs. Activated GCR complexes in turn enhance the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and suppress the expression of pro-inflammatory proteins in the cytoplasm by preventing the translocation of other transcription factors from the cytoplasm to the cytoplasm. Nuclei (trans-suppression) (Rhen T and Cidlowski J A. NEJM 2005;353:1711-23).
Treatment with GCR antagonists or active drugs may be helpful in patients with abnormally high cortisol levels (but still maintaining a circadian rhythm), hyperresponsiveness to normal levels, or high nocturnal cortisol levels as a feature of a circadian rhythm disorder. Therefore, successful therapeutic use of this class of drugs depends on determining circadian cortisol levels (peak levels during the day, such as midday, or measurements every 4 or 6 hours over a 24-hour period). This combinatorial salivary cortisol quantification system as a paired GCR antagonist enabling device will identify individuals who would benefit from a GCR antagonist or active drug therapy.
The glucocorticoid receptor (GR) is expressed at high levels in some normal tissues but not in others. Likewise, malignant diseases of different types and sites have variable expression of GR. When present in normal or neoplastic (benign or malignant) tissues, this GR expression can be differentially localized in some or all of their cellular compartments: 1. Stem cells; 2. Progenitors of activated stem cells (so-called transport-enhanced proliferation ") cell progeny; 3. Differentiated progeny of activated stem cells or progenitor cells.
For example, in the GI tract, GR is highly expressed in esophageal squamous epithelium, hepatocytes, and islet cells, but not in other GI epithelia (stomach, small and large intestine, pancreas, and bile ducts). Among the corresponding malignancies arising from these epithelial cells, hepatocellular carcinoma (HCC) and squamous cell carcinoma (SCC) of the esophagus have consistently high GR expression. Gastric adenocarcinoma and colorectal adenocarcinoma showed weak expression of GR.
Dexamethasone (DEX) was found to be an activator of GR binding that confers chemoresistance in esophageal SCC and HCC cells, suggesting that GR expression may be biologically important in some GR-expressing cancers. This not only suggests why DEX or other glucocorticoids cannot be used to treat these malignancies, but also implies that endogenous circulating cortisol itself may actually promote chemoresistance even in the absence of iatrogenic glucocorticoid administration. The same goes for the following. Therefore, these findings suggest that blocking GR within such malignancies may play a role in maintaining or promoting chemosensitivity and/or treating neoplasia by preventing activation of endogenous circulating cortisol.
Accordingly, the present invention relates to GR antagonists or agents (for example, ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof) for the treatment of, for example, esophageal SCC and of HCC. or other Tumors with high GR expression act as a suppressor of endogenous cortisol to promote resistance to chemotherapy. These effects may be present in all tumor cells, or especially when tumors have stem cell or progenitor cell compartments. Therefore, the novel, targeted "cancer stem cell" treatment of the present invention.
In order to avoid the possible negative effects of systemic GR blockade, the present invention further relates to localized tumor therapy with GR antagonists by direct vascular infusion into tumor-feeding vessels or by direct intratumoral injection.
This invention relates to the use of GR antagonists for the treatment of, for example, breast cancer and other types of cancer. The subject invention is based on the observation that inhibition of GR increases the sensitivity of tumor cells. GR antagonists would block anti-apoptotic GR signaling in GR-overexpressing breast cancer cells and subsequently make breast cancer cells more sensitive to conventional and novel cytotoxic therapies (by blocking the GR pro-survival signaling pathway).
All references cited herein are hereby incorporated by reference in their entirety.
Content of the invention
The invention provides a compound selected from the group consisting of:
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- PT155:
or a pharmaceutically acceptable salt thereof;
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- PT156:
or a pharmaceutically acceptable salt thereof;
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- PT157:
or a pharmaceutically acceptable salt thereof;
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- PT158:
or a pharmaceutically acceptable salt thereof;
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- TCY1:
or pharmaceutically acceptable salts thereof, and combinations thereof. The present invention provides a pharmaceutical composition containing a therapeutically effective amount of at least one active agent, wherein said active agent is selected from:
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- PT155:
or a pharmaceutically acceptable salt thereof;
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- PT156:
or a pharmaceutically acceptable salt thereof;
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- PT157:
or a pharmaceutically acceptable salt thereof;
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- PT158:
or a pharmaceutically acceptable salt thereof;
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- TCY1:
or a pharmaceutically acceptable salt thereof; their combination; optionally, at least one additional pharmaceutical active agent; and at least one pharmaceutically acceptable excipient.
The invention provides a pharmaceutical composition whose dosage form is selected from microcapsules, capsules, tablets, implants, lozenges, lozenges, small tablets, temporary or permanent suspensions, injections, ovules, suppositories, wafers, chewable tablets, instant tablets, effervescent tablets, oral or sublingual solids, granules, films, sprays, pills, topical preparations, patches, pellets, pills, powders, abrasives, smart pills, smart capsules, platelets, strips and sachets.
The present invention provides a pharmaceutical composition in dosage form for topical administration and at least one pharmaceutically acceptable excipient. The present invention provides a pharmaceutical composition in dosage form for local administration, wherein said composition is in a form selected from the group consisting of a cream, lotion, gel, oil, ointment, suppository, spray, foam, liniments, aerosols, buccal and sublingual tablets or transdermal devices or patches for absorption through the skin or mucosa.
The subject invention provides a kit for treating or preventing a condition in a patient, a kit containing: (a) a therapeutically effective amount of a pharmaceutical preparation; (b) at least one blister pack; blister with lid; blister card or package; folding top; intravenous (IV) pack, IV pack, or IV container; tray or shrink film containing the pharmaceutical preparation (a) and instructions for the use of the pharmaceutical preparation.
The subject invention provides a method for the treatment and/or prevention of viral diseases in patients, which includes: selecting patients in need of treatment and/or prevention of viral diseases; active means of their combinations and their pharmaceutically acceptable salts, whereby the viral disease is to prevent or eliminate acute viral infection, reduce the intensity of viral infection, shorten the duration of viral infection and accelerate the resolution and healing time of viral infection, accelerate the time to suppression of viral infection, increase the probability of eradication virus and/or reduces the infectivity of viral infection, hepatitis C virus, bovine viral diarrhea virus, Ebola-like virus, hepatitis B virus, murine mammary tumor virus, human immunodeficiency virus 1 (HIV-1), varicella-zoster virus (varicella; VZV) ,Cytomegalovirus(CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or human herpesvirus 8; HHV-8), smallpox virus (variola),vacciniavirus, vaccinia virus, monkey pox virus.
The subject invention provides a method for the treatment and/or prevention of viral diseases in patients, which includes: selecting patients in need of treatment and/or prevention of viral diseases; Active agents in combination with their pharmaceutically acceptable salts, wherein the viral status prevents conversion from acute viral infection to chronic active or latent infection with hepatitis C virus, bovine viral diarrhea virus, Ebola-like virus, hepatitis B virus, murine mammary tumor virus, human immunodeficiency virus 1 (HIV-1), varicella-zoster virus (varicella; VZV),Cytomegalovirus(CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or human herpesvirus 8; HHV-8), smallpox virus (variola),vacciniavirus, vaccinia virus, monkey pox virus.
The subject invention provides a method for the treatment and/or prevention of viral diseases in patients, which includes: selecting patients in need of treatment and/or prevention of viral diseases; A combination of active agents and their pharmaceutically acceptable salts, whereby the viral status should prevent a chronic latent viral infection from becoming active (reactivation), reduce the intensity of viral reactivation, shorten the time of viral reactivation, accelerate viral reactivation Time to resolution and cure, accelerate the time to suppress viral reactivations, increase the likelihood of viral eradication and/or reduce infectious reactivation of viruses: hepatitis C virus, bovine viral diarrhea virus, Ebola-like virus, hepatitis B viruses, murine mammary tumor virus, human immunodeficiency virus 1 (HIV-1), varicella-zoster virus (varicella; VZV),Cytomegalovirus(CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or human herpesvirus 8; HHV-8), smallpox virus (variola),vacciniavirus, vaccinia virus, monkey pox virus.
The present invention provides a method for treating and/or preventing viral disorders in a patient, comprising: selecting a patient in need of treating and/or preventing viral disorders; administration of at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, wherein the viral disorder is inactivation of the underlying proviral genome, elimination ("treatment") of the hepatitis C virus, bovine viral diarrhea virus, chronic Bora-like virus infection, hepatitis B virus, murine mammary tumor virus, human immunodeficiency virus 1 (HIV-1), varicella-zoster virus (varicella; VZV),Cytomegalovirus(CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or human herpesvirus 8; HHV-8), smallpox virus (variola),vacciniavirus, vaccinia virus, monkey pox virus.
The subject invention provides a method for the treatment and/or prevention of viral diseases in patients, which includes: selecting patients in need of treatment and/or prevention of viral diseases; Active means of pharmaceutically acceptable salts, where the viral condition is the prevention or elimination of an acute viral infection, reduce the intensity of the viral infection, shorten the duration of the viral infection, accelerate the resolution and healing time of the viral infection, accelerate the suppression of the duration of the viral infection, increase the probability of eradicating the virus and/or reduce the infectiousness of the viral infection infections. The present invention provides a method in which the viral condition is selected from the group consisting of Ebola virus and Marburg virus (Filoviridae); Ross River virus, Chikungunya virus, Sindbis virus, Eastern equine encephalitis virus (Philoviridae); Envelope Viridae,alfa virus), vesicular stomatitis virus (Rhabdoviridae,vesicular virus), Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus (Arenaviridae,breast virus), West Nile virus, dengue virus, yellow fever virus (Flaviviridae,flavivirus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); Moloney murine leukemia virus (Retroviridae,gama retrovirus); Virus influence A (Orthomyxoviridae); Respiratorni sincicijski virus (Paramyxoviridae, Pneumoviridae,lung virus);vacciniaVirus (poxviridae, chordopoxviridae,Ortopoksvirus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus);California autographNuclear polyhedrosis virus (Baculoviridae, Alphabaculoviridae) (insect virus); Ebola and Marburg viruses (Filoviridae); Semliki forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern/Western/Venezuelan equine encephalitis virus (Togaviridae,alfa virus); rubella virus (German measles) (Togaviridae,Ruby virus); Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae,rabies virus); Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae,breast virus); West Nile virus, Dengue virus, Yellow fever virus, Zika virus, Japanese encephalitis virus, St.flavivirus); human hepatitis C virus (Flaviridae,hepatitis virus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); influenza A/B viruses (Orthomyxoviridae, common "flu" viruses); respiratory syncytial virus (Paramyxoviridae, Pneumoviridae,lung virus); Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae,Henipa virus); virus ospica (Paramyxoviridae, Paramyxovirinae,measles virus); small pox virus (variola) (Poxviridae, Chordopoxvirinae,Ortopoksvirus); human hepatitis B virus (Hepadnaviridae,ortohepatotropni virus); hepatitis D virus (hepatitis D virus) (family not specified,delta virus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus).
The present invention provides a method for the treatment and/or prevention of viral disorders in patients, comprising: selecting a patient in need of treatment and/or prevention of viral disorders; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, wherein the viral disorder is to prevent the acute viral infection from turning into a chronic active or latent infection. The subject invention provides a method in which the viral condition is selected from the group consisting of Ebola virus and Marburg virus (Filoviridae); Ross River virus, Chikungunya virus, Sindbis virus, Eastern equine encephalitis virus (Philoviridae); Envelope Viridae,alfa virus), vesicular stomatitis virus (Rhabdoviridae,vesicular virus), Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus (Arenaviridae,breast virus), West Nile virus, dengue virus, yellow fever virus (Flaviviridae,flavivirus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); Moloney murine leukemia virus (Retroviridae,gama retrovirus); Virus influence A (Orthomyxoviridae); Respiratorni sincicijski virus (Paramyxoviridae, Pneumoviridae,lung virus);vacciniaVirus (poxviridae, chordopoxviridae,Ortopoksvirus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus);California autographNuclear polyhedrosis virus (Baculoviridae, Alphabaculoviridae) (insect virus); Ebola and Marburg viruses (Filoviridae); Semliki forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern/Western/Venezuelan equine encephalitis virus (Togaviridae,alfa virus); rubella virus (German measles) (Togaviridae,Ruby virus); Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae,rabies virus); Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae,breast virus); West Nile virus, Dengue virus, Yellow fever virus, Zika virus, Japanese encephalitis virus, St.flavivirus); human hepatitis C virus (Flaviridae,hepatitis virus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); influenza A/B viruses (Orthomyxoviridae, common "flu" viruses); respiratory syncytial virus (Paramyxoviridae, Pneumoviridae,lung virus); Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae,Henipa virus); virus ospica (Paramyxoviridae, Paramyxovirinae,measles virus); small pox virus (variola) (Poxviridae, Chordopoxvirinae,Ortopoksvirus); human hepatitis B virus (Hepadnaviridae,ortohepatotropni virus); hepatitis D virus (hepatitis D virus) (family not specified,delta virus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus).
The subject invention provides a pharmaceutical composition containing a therapeutically effective amount of any one or more compounds selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; at least one additional active agent selected from a molecule with the potential to bind to viral PS, annexin-5, anti-PS monoclonal or polyclonal antibodies, bavituximab and/or to bind to the viral glucocorticoid response element (GRE), retinone, RU486 or its derivative; and at least one pharmaceutically acceptable carrier; optionally, at least one blister pack; blister with lid; blister card or package; folding top; intravenous (IV) pack, IV pack, or IV container; tray or shrink film containing the pharmaceutical composition and instructions for use of the pharmaceutical composition.
The present invention provides a pharmaceutical composition comprising: a therapeutically effective amount of one or more PT150, PT155, PT156, PT157, PT158, TCY1 and combinations thereof, and pharmaceutically acceptable salts thereof; at least one additional active agent selected from molecules or derivatives that can bind to viral PS, annexin 5, anti-PS monoclonal or polyclonal antibodies, bavituximab and/or can bind to viral glucocorticoid response elements (GRE), retinone and RU486 , cell entry inhibitors, uncoating inhibitors, reverse transcriptase inhibitors, integrase inhibitors, transcription inhibitors, antisense translation inhibitors, ribozyme translation inhibitors, preconditioning and targeting inhibitors, protease inhibitors, assembly inhibitors, release phase inhibitors, immune system modulators and vaccines including but including but not limited to Abacavir, Ziagen, Trizivir, Kivexa/ Epzicom, Acyclovir, Acyclovir, Adefovir, Adamantane Amine, Amprizine, Ampligen, Arbidol, Atazanavir, Atripla, Baravir, Cidofovir, Combivir, Dolutegravir, Darunavir, Delavirdine, didanosine, docosanol, edoxudine , efavirenz, emtricitabine, enfuvirtide, entecavir, Ecoliever, famciclovir , fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, lovelite, maraviroc, morpholidine, mexixadone, nelfinavir, nevirapine, nekvir, nucleoside analogues, novir, oseltamivir (Tamiflu), pegylated interferon alfa-2a, penciclovir, peramivir, pleconal, podophyllotoxin, protease inhibitors, raltegravir, inhibitor reverse transcription enzyme, ribavirin, rimantadine, ritonavir, pyrimidine, saquinavir, sofosbuvir, stavudine, synergist, tea tree oil, telaprevir, tenofo vicrivir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, trimantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, vilamine , zalcitabine, zanamivir, zidovudine and their combinations; at least one pharmaceutically acceptable carrier; and optional, and at least one blister pack; covered blisters; plastic card or package; folding top; intravenous (IV) pack, IV pack, or IV container; a tray or shrink film containing a pharmaceutical composition and instructions for the use of the pharmaceutical preparation.
The present invention provides a method for the treatment and/or prevention of viral disorders in patients, comprising: selecting a patient in need of treatment and/or prevention of viral disorders; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; administration of at least one additional active agent selected from among other molecules that have the potential to bind to the viral glucocorticoid response element (GRE), the retinal A group consisting of a ketone, RU486, and its derivatives, wherein the viral disease prevents or eliminates acute viral infection, reduces the intensity of viral infection, shortens the time of viral infection, accelerates the resolution and treatment time of viral infection and accelerates the time of inhibition of viral infection, increases the probability of viral eradication and/or reduces the infectivity of viral infections, with hepatitis C virus, bovine viral diarrhea virus, Ebola-like virus, virus hepatitis B, murine mammary tumor virus, human immunodeficiency virus 1 (HIV-1), varicella-zoster virus (varicella; VZV),Cytomegalovirus(CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or human herpesvirus 8; HHV-8), smallpox virus (variola),vacciniavirus, vaccinia virus, monkey pox virus.
The present invention provides a method for treating and/or preventing viral disorders in a patient, comprising: selecting a patient in need of treating and/or preventing viral disorders; administration of at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts; administration of at least one additional active agent selected from the group consisting of molecules with the potential to bind viral glucocorticoid response elements (GRE), retinone, RU486 and its derivatives, where the viral status should prevent acute viral infection from becoming chronically active or latent infection hepatitis C virus, virus bovine viral diarrhea, Ebola-like virus, hepatitis B virus, murine mammary tumor virus, human immunodeficiency virus 1 (HIV-1), Varicella-zoster virus (varicella; VZV),Cytomegalovirus(CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or human herpesvirus 8; HHV-8), smallpox virus (variola),vacciniavirus, vaccinia virus, monkey pox virus.
The present invention provides a method for treating and/or preventing viral disorders in a patient, comprising: selecting a patient in need of treating and/or preventing viral disorders; administration of at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts; application of at least one additional active agent selected from molecules with the potential to bind viral glucocorticoid responsive elements (GRE), retinone, RU486 or its derivatives, where the viral status is to prevent chronic latent viral infection from becoming active (reactivation), reduce the intensity of viral reactivation, shorten the time to viral reactivation, accelerate resolution and healing time of viral reactivation, accelerate suppression Time to viral reactivation, increase likelihood of viral eradication and/or decrease infectious viral reactivation of viruses: hepatitis C virus, bovine viral diarrhea virus, Ebola-like virus, hepatitis B virus, oncoviruses mouse mammary glands, human immunodeficiency virus 1 (HIV-1), varicella-zoster virus (varicella; VZV),Cytomegalovirus(CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or human herpesvirus 8; HHV-8), smallpox virus (variola),vacciniavirus, vaccinia virus, monkey pox virus.
The present invention provides a method for treating and/or preventing viral disorders in a patient, comprising: selecting a patient in need of treating and/or preventing viral disorders; administration of at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts; application of at least one additional active agent selected from molecules with the potential to bind viral glucocorticoid responsive elements (GRE), retinone, RU486 or its derivatives, where the viral condition is inactivation of the latent proviral genome, elimination ("treatment") of hepatitis C virus, bovine viral diarrhea virus , Ebola-like virus, hepatitis B virus, murine mammary tumor virus, chronic viral infections with human immunodeficiency virus 1 (HIV-1), varicella-zoster virus (varicella; VZV),Cytomegalovirus(CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or human herpesvirus 8; HHV-8), smallpox virus (variola),vacciniavirus, vaccinia virus, monkey pox virus.
The present invention provides a method for treating and/or preventing a viral condition in a patient, comprising: selecting a patient in need of treatment and/or preventing a viral condition; administering an active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; application of at least one additional active agent selected from molecules with the potential to bind viral PS, annexin-5, anti-PS monoclonal or polyclonal antibodies, the group consisting of bavituximab, wherein the viral condition is prevention or elimination of acute viral infection, to reduce the intensity of viral infection, to reduce the duration of a viral infection, to speed up the time to resolve and cure a viral infection, to speed up the time to control a viral infection, increase the likelihood of eradicating the virus and/or reduce the transmission of the viral infection. The present invention provides a method in which the viral condition is selected from the group consisting of Ebola virus and Marburg virus (Filoviridae); Ross River virus, Chikungunya virus, Sindbis virus, Eastern equine encephalitis virus (Philoviridae); Envelope Viridae,alfa virus), vesicular stomatitis virus (Rhabdoviridae,vesicular virus), Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus (Arenaviridae,breast virus), West Nile virus, dengue virus, yellow fever virus (Flaviviridae,flavivirus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); Moloney murine leukemia virus (Retroviridae,gama retrovirus); Virus influence A (Orthomyxoviridae); Respiratorni sincicijski virus (Paramyxoviridae, Pneumoviridae,lung virus);vacciniaVirus (poxviridae, chordopoxviridae,Ortopoksvirus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus);California autographNuclear polyhedrosis virus (Baculoviridae, Alphabaculoviridae) (insect virus); Ebola and Marburg viruses (Filoviridae); Semliki forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern/Western/Venezuelan equine encephalitis virus (Togaviridae,alfa virus); rubella virus (German measles) (Togaviridae,Ruby virus); Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae,rabies virus); Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae,breast virus); West Nile virus, Dengue virus, Yellow fever virus, Zika virus, Japanese encephalitis virus, St.flavivirus); human hepatitis C virus (Flaviridae,hepatitis virus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); influenza A/B viruses (Orthomyxoviridae, common "flu" viruses); respiratory syncytial virus (Paramyxoviridae, Pneumoviridae,lung virus); Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae,Henipa virus); virus ospica (Paramyxoviridae, Paramyxovirinae,measles virus); small pox virus (variola) (Poxviridae, Chordopoxvirinae,Ortopoksvirus); human hepatitis B virus (Hepadnaviridae,ortohepatotropni virus); hepatitis D virus (hepatitis D virus) (family not specified,delta virus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus)
The present invention provides a method for the treatment and/or prevention of viral disorders in patients, comprising: selecting a patient in need of treatment and/or prevention of viral disorders; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; administration of at least one additional active agent selected from molecules with the potential to bind viral PS, annexin-5, anti-PS monoclonal group A consisting of a clonal or polyclonal antibody, bavituximab, where the viral status serves to prevent an acute viral infection from becoming chronically active or latent infection. The subject invention provides a method in which the viral condition is selected from the group consisting of Ebola virus and Marburg virus (Filoviridae); Ross River virus, Chikungunya virus, Sindbis virus, Eastern equine encephalitis virus (Philoviridae); Envelope Viridae,alfa virus), vesicular stomatitis virus (Rhabdoviridae,vesicular virus), Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus (Arenaviridae,breast virus), West Nile virus, dengue virus, yellow fever virus (Flaviviridae,flavivirus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); Moloney murine leukemia virus (Retroviridae,gama retrovirus); Virus influence A (Orthomyxoviridae); Respiratorni sincicijski virus (Paramyxoviridae, Pneumoviridae,lung virus);vacciniaVirus (poxviridae, chordopoxviridae,Ortopoksvirus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus);California autographNuclear polyhedrosis virus (Baculoviridae, Alphabaculoviridae) (insect virus); Ebola and Marburg viruses (Filoviridae); Semliki forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern/Western/Venezuelan equine encephalitis virus (Togaviridae,alfa virus); rubella virus (German measles) (Togaviridae,Ruby virus); Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae,rabies virus); Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae,breast virus); West Nile virus, Dengue virus, Yellow fever virus, Zika virus, Japanese encephalitis virus, St.flavivirus); human hepatitis C virus (Flaviridae,hepatitis virus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); influenza A/B viruses (Orthomyxoviridae, common "flu" viruses); respiratory syncytial virus (Paramyxoviridae, Pneumoviridae,lung virus); Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae,Henipa virus); virus ospica (Paramyxoviridae, Paramyxovirinae,measles virus); small pox virus (variola) (Poxviridae, Chordopoxvirinae,Ortopoksvirus); human hepatitis B virus (Hepadnaviridae,ortohepatotropni virus); hepatitis D virus (hepatitis D virus) (family not specified,delta virus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus)
The subject invention provides a pharmaceutical preparation containing: at least one active agent selected from PT150, PT155, PT156, PT157, PT158, TCY1 and their combinations, and their pharmaceutically acceptable salts; optionally, at least one adjuvant selected from opiates. The subject invention provides a pharmaceutical composition, wherein the dosage form of the composition is selected from capsules, tablets, smart pill delivery devices and smart capsule delivery devices.
The present invention provides a pharmaceutical preparation containing a therapeutically effective amount of one or more of PT150, PT155, PT156, PT157, PT158, TCY1 and their combinations, and their pharmaceutically acceptable salts; at least one additional therapeutically active agent is selected from molecules that have the potential to bind viral PS, annexin-5, anti-PS monoclonal or polyclonal antibodies, bavituximab and/or bind viral glucocorticoid response elements (GRE), (including but not limited to , retinal ketone and RU486, derivatives thereof; and optionally at least one selected from antiviral drugs, cell entry inhibitors, uncoating inhibitors, reverse transcriptase inhibitors, integrase inhibitors, transcription inhibitors, translation inhibitors (reverse (sense) inhibitors), translation inhibitors (ribozyme ), preprocessing and targeting inhibitors, protease inhibitors, assembly inhibitors, release phase inhibitors, immune system modulators and vaccines, including but not limited to abacavir, Ziagen, Trizivir, Kivexa/Epzicom, Acyclovir, Acyclovir, Adefovir, Amantadine, Amprenavir, Ampligen . , imacitabine, imonavir, idouridine, imiquimod, indinavir, inosine, integrase inhibitors, interferon III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, loverilide, maraviril, morpholino, metaxadone, nelfinavir, nevirapine, nexavir, nucleoside analogs, novir, oseltamivir (tamiflu), peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitor, raltegravir, reverse transcriptase inhibitor, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, sofosbuvir, stavudine, synergistic enhancer, tea tree oil, telaprevir , tenofovir, tenofovir disoproxil, advice ranavir, trifluridine , Trizivir, Tromantadine, Truvada, Valaciclovir (Valtrex), Valganciclovir, Vicriviroc, Vidarabine, Viramidin, Zalcitabine, Zanamivir (Relenza), Zidovudine and their combinations; and at least one pharmaceutically acceptable carrier.
The present invention provides a pharmaceutical composition comprising: i) a first therapeutic agent, which is at least one antiviral agent or a pharmaceutically acceptable salt thereof; ii) another therapeutic agent, wherein at least one is a GCR antagonist. The agent is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; iii) at least one pharmaceutically acceptable carrier; wherein the antiviral agent and the GCR antagonist are each combined as a therapeutically effective amount present to treat or prevent a viral infection in a patient. The invention provides a pharmaceutical preparation, where the antiviral agent is selected from: Abacavir, Ziagen, Trizivir, Kivexa/Epzicom, Acyclovir, Acyclovir, Adefovir, Amantadine, Amantadine, Prunavir, Ampligen, Arbidol, Atazanavir, Atripla, Baravir, Cidofovir, Combivir, Dolutegravir, Darunavir, Delavirdine, Go Hydroxyinosin, docosanol, edoxidine, efavirenz, emtricitabine, enfuvirtide, entecavir, Ecoliever, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphoric flunide, ganciclovir, ibacitabine, imonavir, iodoglycoside, imiquimod, indinavir vir, inosine, integrase inhibitor , interferon III, interferon II, interferon interferon I, interferon, lamivudine, lopinavir, loviride, maraviroc, moxidine, metizazone, nelfinavir, nevirapine, nexavir, nucleoside analogues, novir, oseltamivir (tamiflu), peginterferon alfa-2a, penciclovir, peramivir, Pleconaril, Podophyllotoxin, protease inhibitor, raltegravir, reverse transcriptase inhibitor, ribavirin, rimantadine, ritonavir, pyramid, saquinavir, sofosbuvir, stavudine, synergistic enhancer, tea tree oil, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, Truvada, Valacyclovir (Valtrex), Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir (Relenza), Zidovudine and their combinations.
The present invention provides a pharmaceutical composition comprising: i) a first therapeutic agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts; ii) another therapeutic agent selected from the group consisting of: cholinesterase inhibitors, Aricept, Exelon, Razadyne, memantine and their combinations iii) at least one pharmaceutically acceptable carrier. The present invention provides a pharmaceutical composition comprising: i) a first therapeutic agent, which is at least one antiviral agent or a pharmaceutically acceptable salt thereof; ii) another therapeutic agent, which is selected from PT150, GCR antagonists PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; iii) at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated or manufactured as a liquid, elixir, aerosols, sprays, powders, tablets, pills, capsules, gels, gel tablets, nanosuspensions, nanoparticles, sustained-release dosage forms, or topical formulations , in addition, antiviral agents and GCR antagonists. Each viral infection in the patient is present in an amount that, in combination, is a therapeutically effective amount for the treatment or prevention of the disease. The invention provides a pharmaceutical preparation, where the antiviral agent is selected from: Abacavir, Ziagen, Trizivir, Kivexa/Epzicom, Acyclovir, Acyclovir, Adefovir, Amantadine, Amantadine, Prunavir, Ampligen, Arbidol, Atazanavir, Atripla, Baravir, Cidofovir, Combivir, Dolutegravir, Darunavir, Delavirdine, Go Hydroxyinosin, docosanol, edoxidine, efavirenz, emtricitabine, enfuvirtide, entecavir, Ecoliever, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphoric flunide, ganciclovir, ibacitabine, imonavir, iodoglycoside, imiquimod, indinavir vir, inosin, integrase inhibitor , interferon III, interferon II, interferon interferon I, interferon, lamivudine, lopinavir, loviride, maraviroc, moxidine, metizazone, nelfinavir, nevirapine, nexavir, nucleoside analogues, novir, oseltamivir (tamiflu), peginterferon alfa-2a, penciclovir, Peramivir, Pleconaril, Podophyllotoxin, protease inhibitor, raltegravir, reverse transcriptase inhibitor, ribavirin, rimantadine, ritonavir, pyramid, saquinavir, sofosbuvir, stavudine, synergistic enhancer, tea tree oil, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, Truvada, Valacyclovir (Valtrex), Valganciclovir, Vicriviroc, Vidarabine, Viramidin, Zalcitabine, Zanamivir (Relenza), Zidovudine and their combinations.
The present invention provides a method for treating and/or preventing a viral condition in a patient, comprising: selecting a patient in need of treatment and/or preventing a viral condition; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; administration of at least one additional active agent selected from molecules with the potential to bind viral PS, annexin-5, anti-PS monoclonal panel consisting of clonal or polyclonal antibodies, bavituximab, where the viral status is prevention of chronic latent viral infection from becoming active (reactivation) as would reduce the intensity of viral reactivation, shorten the time to viral reactivation and accelerate the resolution of viral reactivation and the time to cure, accelerate the time to suppress viral reactivation, increase the probability of eradicating the virus and/or reduce the reactivation of the infectious virus.
The present invention provides a method in which the viral condition is selected from the group consisting of Ebola virus and Marburg virus (Filoviridae); Ross River virus, Chikungunya virus, Sindbis virus, Eastern equine encephalitis virus (Philoviridae); Envelope Viridae,alfa virus), vesicular stomatitis virus (Rhabdoviridae,vesicular virus), Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus (Arenaviridae,breast virus), West Nile virus, dengue virus, yellow fever virus (Flaviviridae,flavivirus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); Moloney murine leukemia virus (Retroviridae,gama retrovirus); Virus influence A (Orthomyxoviridae); Respiratorni sincicijski virus (Paramyxoviridae, Pneumoviridae,lung virus);vacciniaVirus (poxviridae, chordopoxviridae,Ortopoksvirus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus);California autographNuclear polyhedrosis virus (Baculoviridae, Alphabaculoviridae) (insect virus); Ebola and Marburg viruses (Filoviridae); Semliki forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern/Western/Venezuelan equine encephalitis virus (Togaviridae,alfa virus); rubella virus (German measles) (Togaviridae,Ruby virus); Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae,rabies virus); Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae,breast virus); West Nile virus, Dengue virus, Yellow fever virus, Zika virus, Japanese encephalitis virus, St.flavivirus); human hepatitis C virus (Flaviridae,hepatitis virus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); influenza A/B viruses (Orthomyxoviridae, common "flu" viruses); respiratory syncytial virus (Paramyxoviridae, Pneumovirinae, Pneumovirusi); Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae,Henipa virus); virus ospica (Paramyxoviridae, Paramyxovirinae,measles virus); small pox virus (variola) (Poxviridae, Chordopoxvirinae,Ortopoksvirus); human hepatitis B virus (Hepadnaviridae,ortohepatotropni virus); hepatitis D virus (hepatitis D virus) (family not specified,delta virus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus)
The present invention provides a method for the treatment and/or prevention of viral disorders in patients, comprising: selecting a patient in need of treatment and/or prevention of viral disorders; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; application of at least one additional active agent selected from molecules with the potential to bind viral PS, annexin-5, anti-PS monoclonal clonal or polyclonal antibody bavituximab and/or binding viral glucocorticoid response element (GRE), retinasin, RU486 or their derivatives, whereby at least one active agent and at least one additional active agent can be used together or sequentially, act additively or synergistically to prevent or treat acute viral infection, prevent acute viral infection from becoming latent or active chronic infection, prevent chronic latent infection from becoming active or eliminate chronic latent infection Viral infection.
The present invention provides a method in which the viral condition is selected from the group consisting of Ebola virus and Marburg virus (Filoviridae); Ross River virus, Chikungunya virus, Sindbis virus, Eastern equine encephalitis virus (Philoviridae); Envelope Viridae,alfa virus), vesicular stomatitis virus (Rhabdoviridae,vesicular virus), Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus (Arenaviridae,breast virus), West Nile virus, dengue virus, yellow fever virus (Flaviviridae,flavivirus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); Moloney murine leukemia virus (Retroviridae,gama retrovirus); Virus influence A (Orthomyxoviridae); Respiratorni sincicijski virus (Paramyxoviridae, Pneumoviridae,lung virus);vacciniaVirus (poxviridae, chordopoxviridae,Ortopoksvirus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus);California autographNuclear polyhedrosis virus (Baculoviridae, Alphabaculoviridae) (insect virus); Ebola and Marburg viruses (Filoviridae); Semliki forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern/Western/Venezuelan equine encephalitis virus (Togaviridae,alfa virus); rubella virus (German measles) (Togaviridae,Ruby virus); Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae,rabies virus); Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae,breast virus); West Nile virus, Dengue virus, Yellow fever virus, Zika virus, Japanese encephalitis virus, St.flavivirus); human hepatitis C virus (Flaviridae,hepatitis virus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); influenza A/B viruses (Orthomyxoviridae, common "flu" viruses); respiratory syncytial virus (Paramyxoviridae, Pneumoviridae,lung virus); Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae,Henipa virus); virus ospica (Paramyxoviridae, Paramyxovirinae,measles virus); small pox virus (variola) (Poxviridae, Chordopoxvirinae,Ortopoksvirus); human hepatitis B virus (Hepadnaviridae,ortohepatotropni virus); hepatitis D virus (hepatitis D virus) (family not specified,delta virus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus).
The present invention provides a method for the treatment and/or prevention of viral disorders in patients, comprising: selecting a patient in need of treatment and/or prevention of viral disorders; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; administration of at least one additional active agent selected from molecules with the potential to bind viral glucocorticoid responsive elements (GRE), retinone, RU486 or its derivatives, which can be used together or sequentially, act in an additive or synergistic manner to prevent or treat acute viral infection, prevent transformation of acute viral infection into latent or active chronic infection and prevention of transformation of chronic latent infection into active infection or elimination of chronic latent viral infection, etc.
The subject invention provides a method in which the viral condition is selected from the group consisting of treating diseases caused by virus-induced or associated damage and disease in tissues (necrosis, inflammation, sclerosis) including, but not limited to: the eye (retina, sclera, lens ), iris, pupil, cornea, macula, retinal vessels, optic nerve), ear (ear canal, middle ear bone, eardrum, Eustachian tube, cochlear nerve, vestibular nerve, semicircular canal, cochlea), nose (nostril, vestibule, turbinate, sinuses), oral cavity and oropharynx (lips, gums, hard and soft palate, salivary glands, uvula, tonsils, adenoids, teeth), central nervous system and related structures (brain, cerebrum, cerebellum, olfactory bulbs, hypothalamus , reticular structure), medulla oblongata, meninges, ventricles, thalamus, pineal gland), peripheral and intestinal nervous system (autonomic, sympathetic, parasympathetic, sensory, ganglion cells, ganglia), skin (epidermis, dermis, accessory structure, sebaceous glands ), hair follicles, stratum corneum, granular cells, acanthocytes, sweat glands), respiratory tract (larynx, trachea, bronchi, bronchioles, lungs, alveoli, pleura), digestive tract (pharynx, esophagus, stomach, small intestine, duodenum, jejunum), ileum, colon, rectum, appendix, anus), liver (intrahepatic and extrahepatic bile ducts, gall bladder, liver, hepatocytes, tubule, Haring's duct), pancreas (endocrine pancreas, exocrine pancreas, pancreatic duct, alveolar duct pancreas), urinary tract (renal cortex, renal tubules, renal pelvis, glomerulus, ureter, bladder, urethra), male reproductive tract (prostate, testis, scrotum, epididymis, vas deferens, glans, prepuce, corpus cavernosum, corpus cavernosum, Cowper's glands), female reproductive system tract (ovary, fimbriae, fallopian tubes, uterus, endometrium, endocervix, endocervical glands, cervix, ectocervix, labia, lips, placenta), endocrine system (pineal physis, pituitary gland, thyroid gland, parathyroid gland, adrenal gland, adrenal cortex, adrenal medulla), cardiovascular system (heart, pericardium, myocardium, endocardium, atrium, ventricle, coronary artery, tricuspid valve, aortic valve, mitral valve, pulmonary valve, aortic valve, arteries, arterioles, capillaries, venules, veins, inferior vena cava, superior vena cava, pulmonary artery, pulmonary vein), musculoskeletal system (bones, tendons, ligaments, skeletal muscles, smooth muscles, fascia) and blood (platelets, erythrocytes, leukocytes and all their precursors) and Marrowbone).
The present invention provides a method for the treatment and/or prevention of viral disorders in patients, comprising: selecting a patient in need of treatment and/or prevention of viral disorders; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; administration of at least one additional active agent selected from the group consisting of virus-binding PS, annexin 5, anti-PS monoclonal or polyclonal antibody Molecules potentially, bavituximab can be used together or sequentially to act in an additive or synergistic manner to prevent or treat acute viral infections, preventing acute viral infection from becoming latent or active chronic infection and preventing chronic latent infection from becoming active Sexual infection or elimination of chronic latent viral infection, thereby treating disease caused by virus or collateral damage, and tissue disease (necrosis, inflammation, sclerosis) , including but not limited to: eye (retina, sclera, lens, iris, pupil, cornea, macula, retinal blood vessels, optic nerve), ear (ear canal, middle ear bone), eardrum, eustachian tube, cochlear nerve, vestibular nerve, semicircular canal, cochlea), nose (nostril, vestibule, turbinate, sinus), oral cavity and oropharynx (lips, gums, hard and soft palate, salivary glands, uvula, tonsils, adenoids, teeth), central nervous system and related structures (brain, cerebrum, cerebellum, olfactory bulbs, hypothalamus, reticular formation, medulla, meninges, ventricles, thalamus, pineal gland), peripheral and enteric nervous system (autonomic, sympathetic, parasympathetic, sensory, ganglion cells, ganglia), skin (epidermis, dermis, accessory structures, sebaceous glands, hair follicles, stratum corneum, granular cells, acanthocytes, sweat glands), respiratory tract (larynx, trachea, bronchi, bronchioles, lungs, alveoli, pleura), digestive tract (pharynx, esophagus, stomach, small intestine, duodenum, jejunum, ileum, large intestine, rectum, appendix, anus), liver (intrahepatic and extrahepatic bile ducts, gall bladder, liver, hepatocytes, tubule, Haring's canal), pancreas ( endocrine pancreas, exocrine pancreas, pancreatic duct, pancreatic alveolar), urinary tract (renal cortex, renal tubules, renal pelvis, glomerulus, ureter, bladder, urethra), male reproductive tract (prostate, testicle, scrotum, epididymis, vas deferens, glans, prepuce, corpus cavernosum, corpus cavernosum, Cowper's gland), female reproductive tract (ovary, fimbria, fallopian tube, uterus, endometrium, cervical canal, endocervical gland, cervix, ectocervix, vagina, lips, placenta), endocrine system (pineal gland, pituitary , thyroid gland, parathyroid gland, adrenal gland, adrenal cortex, adrenal medulla), cardiovascular system (heart, pericardium, myocardium, endocardium, atrium, ventricle, coronary artery, tricuspid valve, aortic valve, mitral valve, pulmonary valve, aorta, artery, arterioles, capillaries, venules, veins, inferior vena cava, superior vena cava, pulmonary artery, pulmonary vein), musculoskeletal system (bones), tendons, ligaments, skeletal muscles, smooth muscles, fascia) and blood (platelets, red blood cells, white blood cells and all their precursors and bone marrow).
The present invention provides a method for the treatment and/or prevention of viral disorders in patients, comprising: selecting a patient in need of treatment and/or prevention of viral disorders; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; administration of at least one additional active agent selected from molecules with the potential to bind viral PS, annexin-5, anti-PS monoclonal clonal or polyclonal antibody bavituximab and/or viral glucocorticoid response element (GRE), retinasin, RU486 or their derivatives, at wherein the active agents can be used together or sequentially to prevent or treat an acute viral infection, preventing an acute viral infection from becoming a latent or active chronic infection, preventing a chronic latent infection from becoming an active infection, or eliminating a chronic latent viral infection, thereby treating a virus-induced or associated tissue damage and disease (necrosis, inflammation, sclerosis), including but not limited to: eye (retina, sclera, lens, iris, pupil, cornea, macula, retinal vessels, optic nerve), ear (ear canal, median bone ear, eardrum, Eustachian tube, cochlear nerves, vestibular nerves, semicircular canals, cochlea), nose (nostrils, vestibule, nasal shells), sinuses), oral cavity and oropharynx (lips, gums, hard and soft palate, salivary glands, uvula, tonsils, adenoids, teeth), central nervous system and related structures (brain, cerebrum, cerebellum, olfactory bulb, hypothalamus, reticular formation, medulla oblongata, meninges, ventricles, thalamus, pineal gland), peripheral and intestinal nerves system (autonomic, sympathetic, parasympathetic, sensory nerves, ganglion cells, ganglia), skin (epidermis, dermis, accessory structures, sebaceous glands, hair follicles, stratum corneum, granular cells, acanthocytes, sweat glands), respiratory tract (larynx, trachea , bronchi, bronchioles, lungs, alveoli, pleura), digestive tract (pharynx, esophagus, stomach, small intestine, duodenum, jejunum, ileum, large intestine, rectum, appendix, anus), liver (intrahepatic and extrahepatic bile ducts, bile bladder, liver, hepatocytes, tubules, Hering's ducts), pancreas (endocrine pancreas, exocrine pancreas, pancreatic ducts, pancreatic acini), urinary tract (kidney cortex, renal tubules, renal pelvis, glomeruli, ureters, urinary bladder, urethra), male reproductive tract (prostate, testicle, scrotum, epididymis, vas deferens, glans, prepuce, corpus cavernosum, corpus cavernosum, Copper's gland), female reproductive tract (ovary, fimbriae, fallopian tube, uterus, endometrium, cervical canal, endocervical canal glands, uterus Cervix, cervix, vagina, lips, placenta), endocrine system (pineal gland, pituitary gland, thyroid gland, parathyroid gland, adrenal gland, adrenal cortex, adrenal medulla), cardiovascular system (heart, pericardium, myocardium, intracardiac membrane, atrium, ventricle, coronary artery, tricuspid valve, aortic valve, mitral valve, pulmonary valve, aorta, artery, arteriole, capillary, venule, vein, inferior vena cava, superior vena cava, pulmonary artery, pulmonary veins), musculoskeletal system (bones , tendons, ligaments, skeletal muscles, smooth muscles, fascia) and blood (platelets, erythrocytes, leukocytes and all their precursors), and bone marrow).
The present invention provides a method for the treatment and/or prevention of viral disorders in patients, comprising: selecting a patient in need of treatment and/or prevention of viral disorders; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; administration of at least one additional active agent selected from molecules with the potential to bind to viral PS annexin-5, anti-PS monoclonal or polyclonal antibodies, bavituximab and/or conjugated viral glucocorticoid response elements (GRE), retinone, RU486 or their derivatives) and one or more antiviral drugs, including but not limited to cell entry inhibitors, decapping inhibitors, reverse transcriptase inhibitors, integrase inhibitors, transcription inhibitors, translation inhibitors (antisense), translation inhibitors (ribozyme), preprocessing and targeting inhibitors, protease inhibitors, assembly inhibitors, release phase inhibitors, immune system modulators and vaccines can be used together or sequentially to prevent or treat acute viral infections in an adjunctive or synergistic manner to prevent acute viral infections from becoming latent or active chronic infections to prevent chronic latent infections from becoming active infection or elimination of chronic latent viral infection, thereby treating disease caused by virus-induced or associated tissue damage and disease (necrosis, inflammation), sclerosis), including but not limited to: eye (retina, sclera, lens, iris, pupil, cornea, macula, retinal vessels, optic nerve), ear (ear canal, middle ear bone, eardrum, Eustachian tube, cochlear nerve, vestibular nerve, semicircular canal, cochlea), nose (nostril, vestibule, turbinate, sinuses), lip cavity and oropharynx (lips, gums, hard and soft palate, salivary glands, villi, tonsils, adenoids, teeth), central nervous system and related structures (cerebrum, cerebellum, cerebellum, olfactory bulbs, hypothalamus, reticular formation, medulla oblongata, cerebral sheaths, ventricles, thalamus, pineal gland), peripheral and enteric nervous system (autonomic, sympathetic, parasympathetic, sensory, ganglion cells, ganglia), skin (epidermis, dermis), adnexal structures, sebaceous glands, hair follicles, stratum corneum, granular cells, acanthocytes, sweat glands), respiratory tract (larynx, trachea, bronchi, bronchioles, lungs, alveoli, pleura), digestive tract (pharynx, esophagus, stomach, small intestine, duodenum, jejunum, ileum, large intestine, rectum, cecum intestine, anus), liver (intrahepatic and extrahepatic bile ducts, gall bladder, liver, hepatocytes, tubules, Herring ducts), pancreas (endocrine pancreas, exocrine pancreas, pancreatic duct, pancreatic alveolus), urinary tract (renal cortex, renal tubule, renal pelvis, glomerulus, ureter, urinary bladder, urethra), male reproductive tract (prostate, testis, scrotum, epididymis, vas deferens, glans, prepuce, corpus cavernosum, corpus cavernosum, Cowper's gland), female reproductive tract (ovary, umbel, fallopian tube , uterus, endometrium, endocervix, endocervical glands, cervix, ectocervix, vagina, lips, placenta), endocrine system (pineal gland, pituitary gland, thyroid gland, parathyroid gland, adrenal gland, adrenal cortex, adrenal medulla), cardiovascular system (heart , pericardium, myocardium, endocardium, atrium, ventricle, coronary artery, tricuspid valve, aortic valve, mitral valve, pulmonary valve, aorta, artery, arteriole, capillary, venule, vein, inferior vena cava, superior vena cava, pulmonary artery, pulmonary vein), musculoskeletal system (bones, tendons, ligaments, skeletal muscles, smooth muscles, fascia) and blood (platelets, erythrocytes, leukocytes and all their precursors and bone marrow).
The subject invention provides a method of treating immunocompetent patients with a mycobacterial infection, comprising: selecting a patient in need of treatment and/or prevention of the condition; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; where it is a mycobacterial infectionMycobacterium tuberculosis(MTB) and leprosy, identified by routine screening in the absence of clinical signs or symptoms of mycobacterial infection, serological studies, in cultured tissue, in tissue biopsy or resection specimens by histochemistry or identified by immunostaining, or manifested by clinical signs or symptoms of mycobacterial infection, suppresses physiological suppression of the immune system mediated by cortisol, which facilitates the immune clearance of the infection.
The present invention provides a method for treating an immunocompetent patient with a mycobacterial infection, comprising: selecting a patient in need of treatment and/or prevention of the condition; administering to the patient at least one selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof, wherein mycobacterial infections include, but are not limited toMycobacterium tuberculosis(mountain bike), leprosy,Mycobacterium avium intracellulare(possible),Mycobacterium kansasii, Mycobacterium slučajno, in the absence of clinical signs or symptoms of mycobacterial infection, as determined by routine screening, serologic studies, in cultured tissue, in tissue biopsy, or resection specimens by histochemical or immunostaining, or in the presence of clinical signs or symptoms of mycobacterial infection , to prevent physiologic suppression of the immune system, mediated by cortisol, which promotes immune clearance of the infection.
The present invention provides a pharmaceutical composition containing: at least one glucocorticoid antagonist selected from PT150, PT155, PT156, PT157, PT158, TCY1 and their combinations, and their pharmaceutically acceptable salts; optionally, antibiotics against mycobacterial infection (including but not limited to rifamycin, isoniazid, pyrazinamide, ethambutol, fluoroquinolones, aminoglycosides, ethionamide, cycloserine, capreomycin, dapsone, clofazimine, minocycline, clarithromycin, macrolides; at least one pharmaceutically acceptable excipient.
The subject invention provides a method for the treatment and/or prevention of addiction in patients, which comprises: selecting a patient in need of treatment and/or prevention of addiction; continuously or intermittently administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof, wherein at least one active agent inhibits Pavlov protein trigger signal tracking, thereby the need for initial and cost-effective use is reduced or eliminated Possible relapse response to signs associated with addictive compounds.
The subject invention provides a method for the treatment and/or prevention of addiction in patients, which includes: selecting patients in need of treatment and/or prevention of addiction; PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof, wherein said at least one active agent prevents the development of Pavlovian signal monitoring, thereby reducing or preventing exposure to routine (recreational or medical) use that progresses to physical dependence.
The subject invention provides a method for the treatment or prevention of patients with Addison's disease, the method comprising: selecting a patient in need of treatment and/or prevention of Addison's disease; administering a pharmaceutical preparation according to the patent claims to the patient32, as a way to prevent or minimize Addison's disease, sustained, high levels of systemic GCR block endogenous physiological cortisol, thereby treating and/or preventing Addison's disease.
The invention provides a method for treating and/or preventing the reactivation of a viral infection in patients, comprising: selecting patients who need to be treated and/or prevented from viral infection; At least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof is administered to the patient.
The invention provides a method for the treatment and/or prevention of reactivation of a latent viral infection in a patient, which includes: selecting patients in need of treatment and/or prevention of a latent viral infection; prior to or receiving a therapeutic dose of glucocorticoid hormone administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, wherein the administration reduces the intensity of virus reactivation to decreased viral reactivation Time to activation, accelerated resolution and cure time of viral reactivation, accelerated time to suppress viral reactivation, increased likelihood of viral eradication, and/or decreased infectivity of viral reactivation.
The present invention provides a method for treating and/or preventing reactivation of a viral infection in a patient, comprising: selecting patients to treat and/or prevent viral infection; At least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof is administered to the patient, wherein the administration reduces the intensity of the viral infection to shorten the duration of the viral infection, to to speed up the resolution and healing time of a viral infection, to speed up the time to control a viral infection, to increase the likelihood of viral eradication, and/or to reduce the contagiousness of a viral infection.
The subject invention provides a method for the treatment and/or prevention of reactivation of a viral infection in patients, comprising: selecting a patient in need of treatment and/or prevention of a viral infection; administering to the patient at least one selected from the active agents of the following group: PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts.
The present invention provides a method for treating and/or preventing dementia in a patient, comprising: selecting a patient in need of treating and/or preventing dementia; administering to the patient at least one active agent selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; administering to the patient at least one additional therapeutic agent selected from the group consisting of cholinesterase inhibitors, Aricept, Exelon, Razadyne and memantine, thereby treating and/or preventing dementia in the patient.
The subject invention provides a pharmaceutical composition that is antagonized by at least one antiviral agent or a pharmaceutically acceptable salt thereof, at least one GCR selected from PT150, PT155, PT156, PT157, PT158, TCY1 and their combinations, agents and pharmaceutically acceptable combinations to prepare their salts and pharmaceutically acceptable carriers.
This invention provides a combination of pharmaceutically active substances, which contains: i) a first therapeutic agent, which is at least one antiviral agent or a pharmaceutically acceptable salt thereof; ii) another therapeutic agent, which is selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts, GCR antagonists as combined products for simultaneous, separate or consecutive use.
The present invention provides a pharmaceutical dosage form, which contains: i) a first therapeutic agent, which is at least one antiviral agent or its pharmaceutically acceptable salt; ii) a second therapeutic agent, which is selected from PT150, PT155, GCR antagonists PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts, wherein the first and second agents are in separate dosage units or in a single dose unit of a combination of therapeutic funds.
The subject invention provides a kit for treating, alleviating or preventing a viral infection condition in a patient in need of such treatment, comprising: (a) a pharmaceutical composition herein; (b) at least one blister pack; covered blister blister card or package; flip top; intravenous (IV) pack, IV pack, or IV container; tray or shrink wrap containing the pharmaceutical preparation (a) and instructions for the use of the pharmaceutical preparation.
The present invention provides a pharmaceutical packaging system containing: i) a first therapeutic agent which is an antiviral agent or a pharmaceutically acceptable salt thereof; ii) another therapeutic agent that is a GCR antagonist or its pharmaceutically acceptable salt Therapeutic agent, wherein the agent for containing said therapeutic dose is selected from the group consisting of the first and second drugs in one dosage form; the first and second doses are packed together in one package or package; the first and second doses are packaged separately in multipacks or packages; blister packs; blisters with lids; or blister cards or packages; wrapped in shrink wrap and releases both medications when one package or packet is opened; multiple packs or blister packs; blister pack with lid or blister card or package; or shrink wrap; blister packaging; tank; and a device in which the doses are separated from each other within the pharmaceutical packaging system.
The subject invention provides a method for the preparation of a pharmaceutical composition, and the method includes combining at least one antiviral agent or a pharmaceutically acceptable salt thereof, at least one selected from PT150, PT155, PT156, PT157, PT158, TCY1, their combination GCR antagonists, and their pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.
The present invention provides a method for treating or preventing a viral infection in a patient, comprising: selecting a patient in need of treatment or prevention of a viral infection; administering to the patient a preparation containing: i) a first therapeutic agent, which is an antiviral Toxic agent or a pharmaceutically acceptable salt thereof; ii) another therapeutic agent such as a GCR antagonist or a pharmaceutically acceptable salt thereof; iii) at least one pharmaceutically acceptable carrier, wherein each antiviral agent and GCR antagonist is present in an amount that in combination is a therapeutically effective amount to treat or prevent a viral infection in a patient.
The subject invention provides a method in which the antiviral agent is selected from the group consisting of: Abacavir, Ziagen, Trizivir, Kivexa/Epzicom, Aciclovir, Acyclovir, Adefovir, Amantadine, Amprenavir, Ampligen, Arbidol, Atazanavir, Atripla, Balavir, Cidofovir, Combivir, Dolutegravir . type III, type II interferon, type I interferon, interferon, lamivudine, lopinavir, lovellitide, maraviroc, morpholino, formazan thionin, nelfinavir, nevirapine, nexavar, nucleoside analogs, novir, oseltamivir (tamiflu). Pegylated interferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, raltegravir, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, pyrilamine, saquinavir, sofosbuvir, stavudine, synergist, tea tree oil, telaprevir, tenofovir, tenofovir disoproxil, tipranavir , Trifluridine, Trizivir, Tromantadine, Truvada, Valacyclovir (Valtrex), Valganciclovir, Vikriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir, Zidovudine and their combinations.
The present invention provides a method wherein the GCR antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The subject invention relates to a method for detecting the presence of biological substances in a test sample which includes the step of providing a test sample consisting of, for example, a sample of saliva or body fluid of a subject, for example a lollipop-shaped device. consisting of a stem-integrated base and a stem-integrated head. The head includes a spongy receiver mount to provide a high void ratio for absorbing suitable saliva, oral fluid or body fluid samples.
Mix the test sample with the buffer system (reagent 1) containing the viscosity regulators and stabilizers in the reaction vessel, mix the solution thoroughly, squeeze all liquid from the sample transfer device into the reagent 1 in the reaction vessel and discard. The sample and buffer reaction vessel is read as a fluorescence polarization blank, then the test sample and buffer mixture is combined with a fluorescently labeled ligand (reagent 2) with the biological species in the reaction vessel, and the solution is mixed to create Additionally, reagent 2 can be delivered to the reaction vessel without further diluting the volume of the test solution.
The present invention provides a method of screening a patient for a disease state suitable for GCR (glucocorticoid receptor) antagonist therapy, which consists of the steps: a) obtaining a test sample from the patient, optionally at a predetermined time, using a test sample collection unit; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measurement of the mixture parameter to determine the blind measurement; d) combining the specified test sample and buffer mixture with a labeled ligand that binds cortisol, whereby the labeled ligand is in the labeling unit, the test solution is produced in the reaction unit; or the test sample and buffer mixture are combined and delivered to a carrier containing a labeled cortisol-binding ligand, wherein the labeled ligand is provided in the labeling unit, generating an assay-immobilized complex in the reaction unit; e) measuring the parameters of the specified test solution or complex; f) comparison of the measured value of the test solution with the blank measured value; g) determination of the patient's circulating cortisol levels; h) comparing the patient's measured cortisol level to a predetermined reference range of cortisol levels, wherein when the cortisol level is elevated relative to the predetermined reference range, then the patient has a condition associated with elevated cortisol, a disease state, and therefore has a disease state that is a potential candidate for GCR antagonist or activator therapy. The present invention also provides a method wherein the test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The invention also provides a method in which the sample is taken from the patient at more than one time, the predetermined time being selected from morning, noon and evening. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the method is determining the circadian cycle of cortisol levels in a patient, and the predetermined time is selected from the group consisting of approximately every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the predetermined reference range is a medical standard reference range. The present invention also provides a method wherein the predetermined reference range is a previously measured level of the patient. The invention also provides a method wherein the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The present invention also provides a method in which said mixture and said mixture are derived using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence energy transfer resonance. Said measurement of said parameter said test solution, fluorescence quenching, lateral flow, fluorescence polarization, etc. means. The present invention also provides a method further comprising the steps of: i) determining elevated cortisol levels in a patient, j) providing treatment for such elevated cortisol levels, wherein the treatment includes a GCR antagonist or agent treatment. The invention also provides a method wherein the patient has altered patterns of cortisol levels that have been observed to be associated with abnormal levels of adrenocorticotropic hormone (ACTH). The subject invention further provides a method in which a patient has abnormal levels of cortisol produced by the adrenal cortex or a disturbed circadian rhythm, as a method of selecting a subject for treatment with a GCR antagonist or agonist, wherein the patient has abnormalities selected from high cortisol levels but maintaining circadian rhythm, hyperreaction to normal levels and high nocturnal cortisol levels as a feature of circadian rhythm disorders. The invention also provides a method wherein the disease state is selected from cancer, clinical depression, psychological and physiological stressors such as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extreme temperature.
The subject invention provides a method for monitoring changes in cortisol levels in response to treatment in patients whose adrenal cortex produces abnormal levels of cortisol, comprising: a) obtaining a test sample from the patient, optionally at a predetermined time, using a test sample collection unit ; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measuring the parameters of the mixture to determine the blind measurement; d) combining the specified test sample and the buffer mixture with the bound cortisol marker - ligand binding, whereby the label-ligand is given in the labeling unit that creates the test solution in the reaction unit; or combining said test sample and buffer mixture and delivering to a carrier containing a label-ligand that binds cortisol, wherein the labeled ligand is in the labeling unit and the test immobilized complex is formed in the reaction unit; e) measurement of test solution or complex parameters; f) comparison of the measured value of the test solution with the blank measured value; g) determining the level of circulating cortisol in the patient based on the measured change; h) administration of GCR antagonists; i) repeating steps a) to f) after treatment; j) determining the level of circulating cortisol in the patient after treatment, wherein when cortisol changes in levels in Response to treatment indicates a response to a GCR antagonist. The present invention also provides a method wherein the test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The invention also provides a method in which samples are taken from a patient over a period of more than one day, and a predetermined time is selected from morning, noon and evening. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method, wherein the method is determining the circadian cycle of cortisol levels in a patient, and the predetermined time is selected from the group consisting of every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the predetermined reference range is a medical standard reference range. The present invention also provides a method wherein the predetermined reference range is a previously measured level of the patient. The invention also provides a method wherein the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The present invention also provides a method in which said mixture and said mixture are derived using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence energy transfer resonance. Said measurement of said parameter said test solution, fluorescence quenching, lateral flow, fluorescence polarization, etc. means.
The subject invention provides a method for monitoring changes in cortisol levels in response to treatment in patients with abnormal levels of cortisol produced by the adrenal cortex and adjusting treatment in response to those changes, which includes: a) receiving from the patient, optionally at a predetermined time, using test sample collection units; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measuring the mixture parameters to determine the blind measurement; d) combining said test sample and buffer mixture Binding to a labeled ligand that binds to cortisol, wherein the labeling ligand is located in the labeling unit that creates the test solution in the reaction unit; or combining the test sample and the buffer mixture and subjecting it to a label containing a cortisol binding carrier ligand, wherein the labeled ligand is provided in the labeling unit, the assay immobilized complex is formed in the reaction unit; e) measurement of the parameter of the specified test solution or complex; f) comparison of the measured value of the test solution with a blank sample g) determine the level of circulating cortisol in the patient based on the measured change; h) give GCR antagonist; i) repeat steps a) to f) after the treatment has been applied; j) determine the patient's post-treatment state of circulating cortisol levels and k) adjust the GCR antagonist or active agent therapy in response to changes in the patient's post-treatment cortisol levels, wherein the adjustment of the GCR antagonist or active agent therapy is to improve the therapeutic effect.
The present invention also provides a method wherein the test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The invention also provides a method in which the sample is taken from the patient at more than one time, the predetermined time being selected from morning, noon and evening. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method, wherein the method is determining the circadian cycle of cortisol levels in a patient, and the predetermined time is selected from the group consisting of every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the predetermined reference range is a medical standard reference range. The present invention also provides a method wherein the predetermined reference range is a previously measured level of the patient. The invention also provides a method wherein the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The present invention also provides a method in which said mixture and said mixture are derived using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence energy transfer resonance. Said measurement of said parameter said test solution, fluorescence quenching, lateral flow, fluorescence polarization, etc. means. The invention further provides a method wherein the GCR antagonist is selected from compounds that are selective for the GCR, compounds that bind nonspecifically to steroid hormone receptors, and compounds that cross-react with both the GCR and other steroid hormone receptors. The invention further provides a method in which the decision to adjust GCR antagonist or agonist therapy is made by a medical professional in response to changes in cortisol levels following treatment. The present invention also provides a method further comprising the step of using a nucleic acid microarray to monitor changes in biomarker expression. The invention further provides a method wherein in a patient with a normal baseline cortisol at the start of treatment and a change in cortisol levels during treatment is indicative of a response to a GCR antagonist. The present invention also provides a method in which a combinatorial system for quantifying salivary cortisol as a device for enabling its paired GCR antagonist will identify patients for whom a GCR antagonist may be beneficial. The present invention also provides a method, wherein the GCR antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof. The subject invention also provides a method wherein the buffer system contains additional components selected from the group consisting of viscosity control agents, stabilizers, and combinations thereof. The present invention also provides a method, wherein the fluorescently labeled cortisol binding ligand is selected from the group consisting of aptamers, antibodies, antibody fragments, receptors, receptor fragments, binding polypeptides, binding peptides, and combinations thereof. The present invention also provides a method wherein a test sample is collected from a patient using a lollipop-like device comprising a handle integral with the base and a head integral with the handle, and further wherein the handle head includes a spongy receiving support to provide high porosity to absorb enough sample.
The subject invention provides a method of treating major depressive disorder in a patient in need thereof by determining whether the patient suffers from major depressive disorder suitable for treatment with a GCR (glucocorticoid receptor) antagonist, comprising the steps of: a) obtaining a test sample, optionally at a predetermined time, using a test sample collection unit; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measurement of the mixture parameter to determine the blind measure; d) the inclusion of the test sample and buffer mixture is combined with a labeled ligand that binds to cortisol, the labeled ligand being in the labeling unit to create a test solution in the reaction unit; or the test sample and buffer mixture are combined and delivered to a carrier containing a labeled cortisol binding ligand, the labeled ligand being provided in the labeling unit, the assay immobilized complex is formed in the reaction unit; e) measurement of the parameter of the specified test solution or complex; f) including the comparison of the measured value of the test solution with the blank measured value; g) determining the cortisol level in the patient's circulation based on the measured change; h) comparison of the measured cortisol level with a predetermined reference range of cortisol levels, where the cortisol level is relative when the predetermined reference range rises, then the patient suffers from major depressive disorder involving elevated cortisol and is therefore eligible for major depressive disorder for treatment GCR (glucocorticoid receptor) antagonist; i) when the patient suffers from At least one GCR antagonist is administered for major depression, a disorder for which treatment with a GCR antagonist or an active substance is appropriate. The present invention also provides a method wherein the test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The invention also provides a method in which the sample is taken from the patient at more than one time, the predetermined time being selected from morning, noon and evening. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method, wherein the method is determining the circadian cycle of cortisol levels in a patient, and the predetermined time is selected from the group consisting of every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the predetermined reference range is a medical standard reference range. The present invention also provides a method wherein the predetermined reference range is a previously measured level of the patient. The invention also provides a method wherein the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The present invention also provides a method in which said mixture and said mixture are derived using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence energy transfer resonance. Said measurement of said parameter said test solution, fluorescence quenching, lateral flow, fluorescence polarization, etc. means. The present invention further provides a method, wherein the GCR (glucocorticoid receptor) antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The subject invention provides a method of treating psychotic depression in a patient in need thereof by determining whether the patient is suffering from psychotic depression amenable to GCR (glucocorticoid receptor) antagonist therapy, comprising the steps of: using a predetermined time for a test sample collection unit; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measuring the parameters of the mixture to determine the blind measurement; d) combining said test sample and buffer mixture with the binding of a labeled ligand that binds cortisol, wherein the labeled ligand is located in the labeling unit that creates the test solution in the reaction unit; or combining the test sample and the buffer mixture and delivering it to a solution containing the labeled cortisol-binding ligand Body Carrier, wherein the labeled ligand is in the labeling unit and the assay-immobilized complex is formed in the reaction unit; e) measurement of test solution or complex parameters; f) comparison of the measured value of the test solution with the blank measured value making a comparison; g) determining the cortisol level in the patient's circulation based on the measured change; h) comparison of the measured cortisol level with a predetermined reference range of cortisol levels, where when the cortisol level is elevated in relation to the predetermined reference range, then the patient suffers from psychotic depression that includes elevated cortisol and is therefore on psychotic depression or active therapy means for which a GCR antagonist or active agent is suitable; i) when the patient suffers from psychotic depression for which the treatment is a GCR antagonist or an active agent in depression, at least one GCR antagonist has been administered. The present invention also provides a method wherein the test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The invention also provides a method in which the sample is taken from the patient at more than one time, the predetermined time being selected from morning, noon and evening. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method, wherein the method is determining the circadian cycle of cortisol levels in a patient, and the predetermined time is selected from the group consisting of every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the predetermined reference range is a medical standard reference range. The present invention also provides a method wherein the predetermined reference range is a previously measured level of the patient. The invention also provides a method wherein the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The present invention also provides a method in which said mixture and said mixture are derived using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence energy transfer resonance. Said measurement of said parameter said test solution, fluorescence quenching, lateral flow, fluorescence polarization, etc. means. The present invention also provides a method, wherein the GCR antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof.
The present invention provides a method of treating stress-induced elevation of cortisol in a patient in need thereof by determining whether the patient has stress-induced elevation of cortisol suitable for treatment with a GCR (glucocorticoid receptor) antagonist, comprising the steps of a) using units to collect a test sample from the patient, optionally in advance certain time; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measurement of the mixture parameter to determine the blind measurement; d) combining the test sample and the buffer mixture with the labeled ligand that binds to cortisol, the labeled ligand being in the labeling unit to create a test solution in the reaction unit; or combining the test sample and buffer mixture and delivering to a carrier containing a labeled cortisol-binding ligand, wherein the labeled ligand is provided in the labeling unit, generating an assay-immobilized complex in the reaction unit; e) measurement of the parameter of the specified test solution or complex; f) comparison of the measurement of the test solution with a blank measurement; g) determining the level of circulating cortisol in the patient based on the measured change; h) comparison of the measured cortisol level with a predetermined reference range of cortisol levels, whereby when cortisol is When the alcohol level is elevated in relation to a predetermined reference range, then the patient suffers from elevated cortisol caused by stress, which refers to elevated cortisol and therefore, he has elevated stress-induced cortisol. Elevated cortisol suitable for therapy with a GCR antagonist or agent; i) administration of at least one GCR antagonist when the patient has stress-induced elevated cortisol suitable for therapy with a GCR antagonist or agent. The present invention also provides a method wherein the test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The present invention also provides a method wherein the stress-related elevation of cortisol is associated with hospitalization, medical treatment, hospitalization, clinical depression, psychological stress, physiological stress, hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion, or temperature extremes. . The invention also provides a method wherein the patient is an elderly person. The invention also provides a method in which the patient has autism or Asperger's syndrome. The invention also provides a method in which the sample is taken from the patient at more than one time, the predetermined time being selected from morning, noon and evening. The invention also provides a method in which samples are taken from a patient on consecutive days. The subject invention also provides a method, wherein the method is determining the circadian cycle of cortisol levels in a patient, and the predetermined time is selected from the group consisting of every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the predetermined reference range is a medical standard reference range. The present invention also provides a method wherein the predetermined reference range is a previously measured level of the patient. The invention also provides a method wherein the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The present invention also provides a method wherein said mixture and said mixture is derived using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence energy transfer resonance. The specified measurement of the specified parameter, the specified test solution, fluorescence quenching, lateral flow, fluorescence polarization, etc. means. The present invention also provides a method, wherein the GCR antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The present invention provides a method of treating PTSD in a patient in need thereof by determining whether the patient suffers from PTSD amenable to treatment with a GCR (glucocorticoid receptor) antagonist, comprising the steps of: a) obtaining a test sample, optionally collected from the patient at a predetermined time using the test sample collection unit; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measuring the mixture parameters to determine the blind measurement; d) combining the test sample and the buffer mixture with the labeled ligand that binds to cortisol, the labeled ligand being in the labeling unit to create a test solution in the reaction unit; or combining the test sample and buffer mixture and delivering to a carrier containing a labeled cortisol-binding ligand, wherein the labeled ligand is in the labeling unit, generating an assay-immobilized complex in the reaction unit; e) measurement of the parameter of the specified test solution or complex; f) comparison of the measurement of the test solution with a blank sample; g) determining the patient's circulating cortisol level based on the measured change; h) comparison of the measured cortisol level with a predetermined reference range of cortisol levels, whereby when cortisol, when the level is elevated in relation to a predetermined reference range, the patient suffers from post-traumatic stress disorder, which includes elevated cortisol, and therefore has post-traumatic stress disorder stress disorder suitable for treatment with a GCR (glucocorticoid receptor) antagonist i) administration of at least one GCR antagonist when the patient suffers from post-traumatic stress disorder suitable for treatment with a GCR antagonist or active agent. The present invention also provides a method wherein the test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The invention also provides a method in which the sample is taken from the patient at more than one time, the predetermined time being selected from morning, noon and evening. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method, wherein the method is determining the circadian cycle of cortisol levels in a patient, and the predetermined time is selected from the group consisting of every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the predetermined reference range is a medical standard reference range. The present invention also provides a method wherein the predetermined reference range is a previously measured level of the patient. The invention also provides a method wherein the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The present invention also provides a method in which said mixture and said mixture are derived using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence energy transfer resonance. Said measurement of said parameter said test solution, fluorescence quenching, lateral flow, fluorescence polarization, etc. means. The present invention also provides a method, wherein the GCR antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof.
The subject invention provides a method of using antipsychotics or antidepressants in a patient who needs it in order to prevent weight gain in the patient, wherein the weight gain is amenable to treatment with a GCR (glucocorticoid receptor) antagonist, which consists of the steps: a) obtaining a test sample from the patient, optionally using the unit to collect the test sample at a predetermined time; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measuring the parameters of the mixture to determine the blank; d) combining the test sample and the buffer mixture with the labeled ligand that binds to cortisol, the labeled ligand being in the labeling unit, to create a test solution in the reaction unit; or combining the test sample and the buffer mixture and delivering it to a carrier containing a labeled cortisol-binding ligand, wherein the labeled ligand is provided in the labeling unit, generating an assay-immobilized complex in the reaction unit; e) measurement of the parameter of the specified test solution or complex; f) comparison of measurements of test solutions to a blank test; g) determining the level of circulating cortisol in the patient based on the measured change; h) comparison of the measured cortisol level with a predetermined reference range of cortisol levels, whereby when the cortisol When the level is elevated in relation to the predetermined reference value range, then the patient's weight gain includes elevated cortisol, which is suitable for GCR antagonist therapy (glucocorticoid receptor); i) when the patient's weight gain is suitable for therapy with a GCR antagonist or an active agent, at least one GCR antagonist is administered. The present invention also provides a method wherein the test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The invention also provides a method in which the sample is taken from the patient at more than one time, the predetermined time being selected from morning, noon and evening. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method, wherein the method is determining the circadian cycle of cortisol levels in a patient, and the predetermined time is selected from the group consisting of every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the predetermined reference range is a medical standard reference range. The present invention also provides a method wherein the predetermined reference range is a previously measured level of the patient. The invention also provides a method wherein the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The present invention also provides a method in which said mixture and said mixture are derived using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence energy transfer resonance. Said measurement of said parameter said test solution, fluorescence quenching, lateral flow, fluorescence polarization, etc. means. The present invention also provides a method, wherein the GCR antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof.
The present invention provides a method of treating Cushing's syndrome in a patient who needs it by determining whether the patient has Cushing's syndrome amenable to treatment with a GCR (glucocorticoid receptor) antagonist, which consists of the steps of: a) taking a test sample from the patient, optionally at a predetermined time, using test sample collection units; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measuring the parameters of the mixture to determine the blind measurement; d) combining said test sample and buffer mixture with a labeled ligand that binds to cortisol, wherein the labeled ligand is located in the labeling unit that creates the test solution in the reaction unit; or combining said test sample and buffer mixture and delivering to a carrier containing a labeled cortisol-binding ligand, wherein the labeled ligand is in the labeling unit, the assay-immobilized complex is formed in the reaction unit; e) measurement of the parameter of the specified test solution or complex; f) comparison of the measurement of the test solution with a blank measurement; g) determination of the patient's circulating cortisol level based on the measured change; h) comparison of the measured cortisol level with a predetermined reference range of cortisol levels, where when cortisol levels are elevated in relation to a predetermined reference range, then the patient has Cushing's syndrome, which includes elevated cortisol, which is suitable for GCR (glucocorticoid receptor) antagonist therapy ); i) when the patient has an adequate GCR For Cushing's syndrome treated with an antagonist or an active agent, at least one GCR antagonist is administered. The present invention also provides a method wherein the test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The invention also provides a method in which the sample is taken from the patient at more than one time, the predetermined time being selected from morning, noon and evening. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method, wherein the method is determining the circadian cycle of cortisol levels in a patient, and the predetermined time is selected from the group consisting of every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. The invention also provides a method in which samples are taken from a patient on consecutive days. The present invention also provides a method wherein the predetermined reference range is a medical standard reference range. The present invention also provides a method wherein the predetermined reference range is a previously measured level of the patient. The invention also provides a method wherein the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The present invention also provides a method in which said mixture and said mixture are derived using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence energy transfer resonance. Said measurement of said parameter said test solution, fluorescence quenching, lateral flow, fluorescence polarization, etc. means. The present invention also provides a method, wherein the GCR antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof.
The subject invention provides a pharmaceutical composition containing: (a) GCR (glucocorticoid receptor) antagonist; (b) pharmaceutical preparation (a), which further contains at least one pharmaceutically acceptable excipient (c) pharmaceutical preparation (a) or (b), where the pharmaceutical preparation is formulated or produced as a liquid, elixir, aerosol, spray, powder, tablet, pill, capsule, gel formulation, gel tablet, nanosuspension, nanoparticle, sustained release dosage form or topical formulation. The subject invention provides a method for treating weight gain in patients selected from major depressive disorder, psychotic depression, stress-induced elevated cortisol, post-traumatic stress disorder, use of antipsychotics and antidepressants, or patients suffering from. of such treatment which involves the administration of a pharmaceutical preparation to a patient.
The subject invention provides a kit for the treatment, amelioration or prevention of a disease selected from major depressive disorder, psychotic depression, stress-induced cortisol elevation, post-traumatic stress disorder, use of antipsychotics and prevention of weight gain in the patient's condition. Antidepressants or patients with Cushing's syndrome in need of such treatment, consisting of: (a) a pharmaceutical preparation; (b) at least one blister pack; blister with lid; blister cards or packages; folding lid; IV injection (IV) packs, N pack or IV container; a tray or shrink film containing the pharmaceutical preparation (a) and instructions for the use of the pharmaceutical preparation.
The invention provides a product consisting of a blister pack; blister with lid; blister cards or packages; folding lid; intravenous (N) pack, IV pack or N container; pharmaceutical composition and instructions for use of pharmaceutical composition pallets or shrink film. The present invention also provides a method, wherein the GCR (glucocorticoid receptor) antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The subject invention provides a method of treating a neoplasia characterized by the expression of a glucocorticoid receptor in a patient in need of such treatment, comprising: administering to said animal or human a therapeutically effective amount of at least one therapeutic agent for the neoplasia and each GCR (glucocorticoid receptor) ) antagonists are selected from group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts. The present invention also provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered as agents that directly affect tumor growth, independent of other therapeutic modalities applied, are used to relieve, relieve , or heal. The present invention also provides a method wherein the therapeutic agent for the neoplasia is radiation. The present invention also provides a method wherein the treatment for the neoplasia is a biotherapeutic. The present invention also provides a method wherein the therapeutic agent for the neoplasia is a chemotherapeutic agent. The present invention also provides a method wherein the therapeutic agent for neoplasia is a radionuclide. The present invention also provides a method wherein the neoplasia is selected from the group consisting of hepatocellular carcinoma, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, squamous cell carcinoma or adenocarcinoma of the head and neck, colorectal cancer, kidney cancer, brain cancer, prostate cancer Small and non-small cell lung cancer, bladder cancer, bone or joint cancer, uterine cancer, cervical cancer, multiple myeloma, malignant diseases of hematopoiesis, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, skin cancer, melanoma, squamous cell carcinoma, leukemia , lung cancer, ovarian cancer, stomach cancer, Kaposi's sarcoma, laryngeal cancer, endocrine cancer, thyroid cancer, parathyroid cancer, pituitary cancer, adrenal gland cancer and their combinations. The present invention also provides a method in which a neoplasia expresses a multidrug resistance gene when GR is activated by binding endogenous cortisol. The present invention also provides a method in which when GR is activated by binding to endogenous cortisol, the neoplasia expresses gene proteins for cell survival pathways, including inhibition of apoptosis. The present invention also provides a method in which neoplastic expression of genes responsible for epithelial-mesenchymal transition and maintenance of cell shape is inhibited when GR is activated by binding endogenous cortisol. The invention further provides a method wherein the neoplasia expresses genes involved in signal transduction pathways, lipid/fatty acid metabolism, inflammation and macrophage regulation, transcriptional regulation and chromatin remodeling, and cellular metabolic pathways. The present invention also provides a method wherein tumor stem cells (TSC) express GR and blockade of GR by PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof results in anti-TSC therapy. The present invention also provides a method in which a TSC expresses a multidrug resistance gene when GR is activated by endogenous cortisol binding. The present invention also provides a method in which TSC express gene proteins for cell survival pathways, including inhibition of apoptosis, when GR is activated by binding to endogenous cortisol. The present invention also provides a method in which TSC expression of genes responsible for epithelial-mesenchymal transition and maintenance of cell shape is suppressed when GR is activated by binding of endogenous cortisol. The present invention also provides a method in which TSC express genes involved in signal transduction pathways, lipid/fatty acid metabolism, inflammation and macrophage regulation, transcriptional regulation and chromatin remodeling, and cellular metabolic pathways. The invention further provides a method wherein the neoplasia is ER/GR+ chemoresistant breast cancer. The present invention also provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered for GR blockade with reduced toxicity and side effects when administered systemically. The present invention also provides a method wherein PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered systemically by oral or intravenous route. The present invention also provides a method wherein PT150, PT155, PT156, PT157, PT158, TCY1 and combinations thereof and pharmaceutically acceptable salts thereof are targeted to tumors by intra-arterial infusion to reduce systemic side effects of GR blockade. The present invention also provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered to achieve cure or remission of a tumor. The present invention also provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered to achieve a reduction in tumor burden to increase the efficiency of subsequent surgical resection. The present invention also provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered to achieve a reduction in tumor burden so that inoperable tumors can be resected.
The present invention provides a method for treating neoplasia in a patient, comprising targeted delivery of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof, wherein when GR is activated by binding, neoplastic expression of multidrug resistance genes via endogenous cortisol. The present invention also provides a method in which a HCC patient is not a candidate for surgical intervention because the tumor is too large or invades the liver anatomy in a manner that precludes resection, delivery of PT150, PT155, PT156, PT157, PT158, TCY1, in combination with On and its pharmaceutically acceptable salts are used before ablation or chemotherapy to shrink the tumor and make it resectable. The present invention also provides a method where HCC is present in cirrhosis of the liver and the patient is not suitable for transplantation due to large tumor volume, administering PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof to obtain Tumors easily ablated or treated with chemotherapy to shrink the tumor and make the patient eligible for a liver transplant. The present invention also provides a method in which HCC is present in cirrhosis of the liver and the patient is a candidate for transplantation, by administering PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, so that the tumors are readily ablated for control therapy. tumors while patients are still on the waiting list for a liver transplant.
The present invention provides a method of low-toxic chemoprevention by targeted liver infusion for patients with established forms of cirrhosis who are at high risk of developing HCC, including those with precancerous lesions diagnosed by biopsy or radiology. Patients, including targeted delivery of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, to intrahepatic lesions where targeted delivery of ORG g34517 to intrahepatic lesions prevents the occurrence of HCC. The invention also provides a method in which a HCC patient is ineligible for surgery. The present invention also provides a method wherein the HCC is located in a location where surgical or ablative intervention is not possible. The present invention also provides a method in which the cirrhosis of a patient with HCC is too severe for a partial hepatectomy to be performed safely. The invention also provides a method in which the HCC patient is in a stage of chronic liver disease too early for transplantation. The invention also provides a method where the HCC is too advanced for local treatment. The present invention provides a method for the treatment of HCC, which consists of: a) targeted delivery of PT150, PT155, PT156, PT157, PT158, TCY1 and their combinations and their pharmaceutically acceptable salts to intrahepatic lesions, wherein the targeted delivery of PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts improve the outcome of localized chemical ablation therapy of intrahepatic damage. The invention also provides a method in which the treatment helps the patient to become eligible for a liver transplant.
The present invention provides a method of low-toxic chemoprevention by targeted liver infusion for patients with established forms of cirrhosis who are at high risk of developing HCC, including those with precancerous lesions diagnosed by biopsy or radiology. Patients, including targeted delivery of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof to intrahepatic lesions, wherein targeted delivery of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof salt prevents the occurrence of HCC. The present invention further provides a method wherein the neoplasia is eSCC.
The present invention provides a method of treating eSCC in patients with inoperable eSCC, wherein systemic or targeted administration of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof enables the tumor to respond or be treated by ablation or chemotherapy as palliative.
The subject invention provides methods of treating eSCC in patients with inoperable eSCC, wherein systemic or targeted administration of PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts renders the tumor sensitive to ablation or chemotherapy to reduce tumors and improve resectability. The present invention also provides a method wherein the tumor therapeutic agent is a chemotherapeutic agent, including but not limited to gemcitabine, paclitaxel, carboplatin, cisplatin, and 5-fluorouracil. The present invention further provides a method wherein the therapeutically effective amount of glucocorticoid is about 100 to 400 micrograms/kg body weight per day when administered intravenously.
The subject invention provides a method of treating a neoplasia in an animal or human in need of such treatment, wherein said neoplasia is characterized by glucocorticoid receptor expression and is further characterized by multidrug resistance genes or other stem cell-related genes. survival rate of tumor stem cells [0203] when GR is activated by endogenous cortisol binding, the method includes: a) administering to said animal or human a therapeutically effective amount of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; b) administering a therapeutically effective amount of at least one therapeutic agent for neoplasia to an animal or human, wherein the therapeutically effective amount of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof is an amount sufficient to induce tumor stem cell sensitivity to at least one tumor therapeutic agent. The present invention also provides a method wherein the therapeutic agent for the neoplasia is radiation selected from external radiation or radionuclide therapy. The present invention also provides a method wherein the treatment for the neoplasia is a biotherapeutic. The present invention also provides a method wherein the therapeutic agent for the neoplasia is a chemotherapeutic agent. The present invention also provides a method wherein the therapeutic agent for neoplasia is a radionuclide. The present invention also provides a method wherein the neoplasia is selected from the group consisting of hepatocellular carcinoma, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, squamous cell carcinoma or adenocarcinoma of the head and neck, colorectal cancer, kidney cancer, brain cancer, prostate cancer Small and non-small cell lung cancer, bladder cancer, bone or joint cancer, uterine cancer, cervical cancer, multiple myeloma, malignant diseases of hematopoiesis, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, skin cancer, melanoma, squamous cell carcinoma, leukemia , lung cancer, ovarian cancer, stomach cancer, Kaposi's sarcoma, laryngeal cancer, endocrine cancer, thyroid cancer, parathyroid cancer, pituitary cancer, adrenal gland cancer and their combinations. The present invention also provides a method in which a neoplasia expresses a multidrug resistance gene when GR is activated by binding endogenous cortisol.
The present invention provides a pharmaceutical composition for the treatment of neoplasia in a patient characterized by expression of glucocorticoid receptors, comprising: a) a therapeutically effective amount of at least one therapeutic agent for neoplasia; b) GCR (glucocorticoid receptor) antagonists selected from PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts; c) optionally, at least one pharmaceutically acceptable carrier. The present invention also provides a method, wherein the therapeutic agent for the neoplasia is selected from the group consisting of chemotherapeutic agents, biotherapeutic agents, radionuclide agents, and combinations thereof. The present invention also provides a method wherein the neoplasia is selected from the group consisting of hepatocellular carcinoma, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, squamous cell carcinoma or adenocarcinoma of the head and neck, colorectal cancer, kidney cancer, brain cancer, prostate cancer Small and non-small cell lung cancer, bladder cancer, bone or joint cancer, uterine cancer, cervical cancer, multiple myeloma, malignant diseases of hematopoiesis, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, skin cancer, melanoma, squamous cell carcinoma, leukemia , lung cancer, ovarian cancer, stomach cancer, Kaposi's sarcoma, laryngeal cancer, endocrine cancer, thyroid cancer, parathyroid cancer, pituitary cancer, adrenal gland cancer and their combinations. The invention also provides a method wherein the neoplasia is chemoresistant ER-GR+ breast cancer. The present invention also provides a method in which a neoplasia expresses a multidrug resistance gene when GR is activated by binding endogenous cortisol. The present invention also provides a method in which the chemotherapeutic agent is selected from the group consisting of: busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine (DTIC), nitrogen mustard (nitrogen mustard), melphalan carmustine (BCNU), lomustine (CCNU) . , Dexamethasone A, Tamoxifen, Fulvestrant, Anastrozole, Letrozole, Megestrol Acetate, Bicalutamide, Flutamide, Leuth Propyrelin, goserelin, L-asparaginase and retinoic acid, gemcitabine, paclitaxel, carboplatin, 5-FU and their combinations.
The subject invention provides a diagnostic kit consisting of the following components: a) a unit for collecting a sample for detection; b) buffer system unit; c) reaction unit; d) sticker unit, where the components are in blister packaging; blister with cover; Blister card or package; folding top; tray or shrink wrap and instructions for using the kit. The subject invention also provides a test sample collection unit, wherein the test sample collection unit includes a handle integrated with the base and a head integrated with the handle. The present invention also provides a test sample collection unit, wherein the tip includes a sponge-like carrier container sufficient to provide a high void ratio to absorb sufficient samples of saliva, oral fluid, or body fluid. The present invention further provides a buffer system unit, wherein the buffer system unit contains an additional component selected from the group consisting of viscosity regulators, stabilizers, and combinations thereof. The present invention also provides a reaction unit, wherein the reaction unit is adapted to be incorporated into a fluorescence polarization reader. The present invention also provides a labeling unit, wherein the labeling unit comprises a cortisol-binding fluorescent labeling ligand, wherein the cortisol-binding fluorescent labeling ligand is selected from the group consisting of aptamers, antibodies, antibody fragments, receptors, receptors, body fragments, binding polypeptides, binding peptides and their combinations. The present invention also provides a diagnostic kit in which the reader provides on-board temperature control and mixing to aid in controlling the reaction viscosity to ensure better accuracy and precision. The present invention also provides a diagnostic kit, where the reader is a small portable device for measuring the fluorescence polarization of a liquid sample by direct or indirect methods. The present invention also provides a diagnostic kit wherein the system is also capable of continuously monitoring the patient during treatment to assess response to treatment.
The present invention provides a method for treating or preventing addiction, addiction-induced anxiety and/or withdrawal symptoms, said method comprising administering to a patient in need of such treatment at least one therapeutically effective amount of a sugar corticosteroid receptor antagonist. The present invention provides a method in which at least one glucocorticoid receptor antagonist and/or active agent is in the pharmaceutical formulation. The present invention provides a method wherein the glucocorticoid receptor antagonist and/or active agent is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The subject invention provides a method for the treatment or prevention of addiction, addiction-induced anxiety and/or withdrawal symptoms in patients in need, comprising: administering a composition comprising: i) a first therapeutic agent that is a GCR antagonist, or a pharmaceutically acceptable salt thereof; ii) at least one or possibly more additional therapeutic agents selected from anxiolytics, antidepressants, antipsychotics or other psychotropic drugs and their combinations; iii) at least one pharmaceutically acceptable carrier wherein the first and second therapeutic agents are present in an amount that in combination is a therapeutically effective amount for the treatment or prevention of addiction, addiction-induced anxiety and/or withdrawal symptoms.
The present invention provides a method in which the second therapeutic agent is selected from at least one anxiolytic, at least one antidepressant and at least one antipsychotic and combinations thereof, wherein at least one anxiolytic is selected from prazola, bromazepam, diazepam, lorazepam, clonazepam, temazepam, oxazepam, flunitrazepam , triazolam, chlordiazepoxide, flurazepam, estazol Citalopram, nitrazepam and their pharmaceutically acceptable salts, isomers and mixtures; and/or at least one selected from the group consisting of citalopram, escitalopram oxalate, fluoxetine, fluvoxamine, and antidepressants rozoxetine, sertraline, dapoxetine; venlafaxine, duloxetine; harmaline, iproniazid, isocarboxazid, nialamide, pargyline, phenelzine, selegiline, toloxatone, tranylcypromine, brofaromine, moclobemide; amitriptyline, amoxapine, butyline, clomipramine, desipra my, dibenzazepine, doxepin, doxepin, imipramine, isoprindol, lofepramine, melitracen, nortriptyline, opiramol, protriptyline, trimipramine; maprotiline, mianserin, nefazodone, trazodone and their pharmaceutically acceptable salts, isomers and combinations, and/or at least one selected from the group consisting of haloperidol, droperidol, fenperidol, triperidol, mepirone, renperone, azapelone, domperidone, risperidone Ketone tranquilizers, chlorpromazine, fluphenazine , perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, pericazine, promethazine, triflupromain azine, levomepromazine, promethazine, pimozide, c janamide, chlorprofixol, clopentixol, flupentixol thiothiophene, chlorothixene, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, iloperidone, zotepine, sertindole, lurasidone, aripipr Azole and their pharmaceutically acceptable salts, isomers and combinations.
The present invention provides a method wherein the GCR antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The subject invention provides a method for treating or preventing addiction, addiction-induced anxiety and/or withdrawal symptoms in a patient comprising the steps of: a) obtaining a test sample from the patient using a set of test samples, optionally in a predetermined time unit; b) combining said test sample with a buffer system to form a mixture in the reaction unit; c) measuring the parameters of the mixture to determine the blank; d) combining said test sample and buffer mixture with bound cortisol label-ligand, wherein the labeling ligand is in the labeling unit, the test solution is created in the reaction unit; or combining said test sample and buffer mixture and delivering to a carrier containing a labeling ligand that binds cortisol, wherein the labeled ligand is in the labeling unit and the test immobilized complex is formed in the reaction unit; e) measurement of test solution or complex parameters; f) comparison of the measured value of the test solution with the blank measured value; g) determination of the cortisol level in the patient's circulation based on the measured change; h) comparison of the measured cortisol level with a predetermined reference range of cortisol levels, whereby when the cortisol level is elevated in relation to the predetermined reference range, the patient has elevated cortisol, therefore suitable for treatment with a GCR (glucocorticoid receptor) antagonist; i) when the patient is suitable for treatment with a GCR antagonist or active substance, administering at least one GCR antagonist, thereby treating or preventing the patient's addiction, addiction-induced anxiety and/or withdrawal symptoms.
The present invention provides a method in which a test sample from a patient is selected from the group consisting of saliva, blood, plasma, serum, urine, other body fluids, and combinations thereof. The subject invention provides a method in which the sample is taken from the patient once, selected between morning, noon and evening. The present invention provides a method in which samples are taken from a patient on multiple occasions and predetermined times are selected to determine the nature of the cortisol circadian rhythm (including its possible interruption or elimination) consisting of morning, noon and night. The present invention provides a method in which samples are taken from a patient on consecutive days. The subject invention provides a method wherein the method is determining the circadian cycle of cortisol levels in a patient at predetermined times selected from the group consisting of every hour, every 4 hours, every 6 hours, every 8 hours, and every 12 hours. A watch. The subject invention provides a method in which the predetermined reference range is a medical standard reference range. The present invention provides a method in which the predetermined reference range is the patient's previously measured level. The invention provides a method in which the ligand can be detectably labeled with a moiety selected from radioisotopes, fluorophores, fluorescence quenchers, enzymes, affinity tags, and epitope tags. The subject invention provides a method in which said mixture and said mixture are performed using a method selected from spectroscopic, photochemical, radiochemical, biochemical, enzymatic, immunochemical, chemical shift labeling, surface plasmon resonance, fluorescence resonance, energy transfer, measurement of the specified test parameters, solutions, quenching agents fluorescence, lateral flow and fluorescence polarization.
The present invention provides a method wherein the GCR (glucocorticoid receptor) antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The present invention provides a test kit for the treatment or prevention of addiction, anxiety and/or withdrawal symptoms caused by addiction, comprising: (a) containing at least one therapeutically effective amount of a glucocorticoid receptor antagonist and a pharmaceutical composition/or active agent; (b) ) at least one blister pack; blister with lid; blister card or package; folding top; intravenous (IV) pack, IV pack, or IV container; trays or shrink wraps of the preparation and instructions for use of the pharmaceutical preparation to treat or prevent addiction, addiction-induced anxiety and/or withdrawal symptoms.
The subject invention provides a product for the treatment or prevention of addiction, addiction-induced anxiety and/or withdrawal symptoms, consisting of a blister pack; blister with lid; blister cards or packages; folding lid; intravenous (IV) packs, IV packs or IV containers; trays or shrink wraps containing pharmaceutical preparations containing at least one glucocorticoid receptor antagonist and/or active agent, and for the treatment or prevention of addiction, Instructions for anxiety and/or withdrawal symptoms caused by addiction.
The present invention provides a method of treating bone fractures and/or bone-related injuries, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one glucocorticoid receptor antagonist and/or active agent. The present invention provides a method in which at least one glucocorticoid receptor antagonist and/or active agent is in the pharmaceutical formulation. The present invention provides a method wherein the GCR (glucocorticoid receptor) antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof. The present invention provides a method in which a GCR antagonist is administered intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intrathecally, intravitreally, vaginally, intrarectally, intratumorally, intramuscularly, intraperitoneally, intraocularly, subcutaneously, subconjunctivally. , intracapsular, mucosal, intrapericardial, intraumbilical, intraocular, oral, topical, topical, by inhalation, by injection, infusion, continuous infusion, local perfusion, direct application during surgery, catheter, lavage or catheterization, immersion, absorption or adsorption. The present invention provides a method, the method comprising administering a pharmaceutical composition to tissue surrounding a fracture. The invention provides a method in which administering a pharmaceutical composition comprises injecting the pharmaceutical composition into tissue surrounding a bone fracture. The present invention provides a method wherein the glucocorticoid receptor antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The subject invention provides a kind of kit for the treatment of fractures and/or injuries related to bones, and includes: (a) a pharmaceutical composition containing at least one glucocorticoid receptor antagonist and/or an active agent in a therapeutically effective amount (b) at least one blister pack; blister pack with lid; blister card or packet; folding top; intravenous (IV) pack, IV pack, or IV container; Instructions for use tray or shrink wrap of pharmaceutical composition for bone-related and/or bone-related injuries.
The subject invention provides a product of manufacture for the treatment of fractures and/or injuries related to bones, consisting of a blister pack; blister with lid; blister cards or packages; folding lid; of intravenous (IV) packaging, IV. pack or IV container; tray or shrinkable package containing a pharmaceutical composition containing at least one glucocorticoid receptor antagonist and/or active agent, and instructions for use in the treatment of bone fractures and/or bone-related injuries.
The present invention provides a method of treating or preventing osteoporosis, whether caused by stress or associated with unregulated or elevated cortisol in the elderly, wherein said method includes administering to a patient in need of such treatment at least one glucocorticoid receptor antagonist and/or an active glucocorticoid receptor antagonist. A therapeutically effective amount of the agent. The present invention provides a method in which at least one glucocorticoid receptor antagonist and/or active agent is in the pharmaceutical formulation.
The present invention provides a method wherein the glucocorticoid receptor antagonist and/or active agent is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof. The present invention provides a method in which the GCR antagonist is administered intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intranasally, intrarectally, intramuscularly, subcutaneously, orally, topically, topically, by inhalation, by injection, by infusion, by continuous administration by infusion, by local by infusion, direct application during surgery, catheter, lavage or catheterization, immersion, absorption or adsorption.
The subject invention provides a kit for the treatment or prevention of osteoporosis, whether stress-induced or associated with cortisol dysregulation or elevation in the elderly, comprising: (a) a combination of drugs (b) at least one blister pack, covered blisters; blister cards or packages; folding covers; intravenous (IV) pack, IV pack, or IV container; a tray or shrink wrap containing a pharmaceutical composition (a) and instructions for using the pharmaceutical composition for the treatment or prevention of stress-induced osteoporosis.
The subject invention provides a product for use in the treatment or prevention of osteoporosis, whether stress-induced or associated with unregulated or elevated cortisol in the elderly, consisting of a blister pack, a blister with a lid, a blister card or packet, a flip-top lid; intravenous (IV) pack, IV pack, or IV container; tray or shrinkable package containing a pharmaceutical preparation containing at least one glucocorticoid receptor antagonist and/or active substance, and instructions for use in the treatment or prevention of osteoporosis, whether stress-induced or associated with cortisol dysregulation or elevation in the elderly.
The subject invention provides a method of improving function after stem cell transplantation in a patient in need of such treatment, comprising the steps of: providing stem cells, whether embryonic stem cells, stem cells derived from embryonic stem cells or their differentiated progeny, induced pluripotent stem cells or their progeny, fetal stem cells or their differentiated progeny, postnatal (adult) stem cells or their differentiated progeny, or tissues derived from any of these, by treating the stem cells or differentiated stem cell-derived progeny with at least one GCR antagonist for the preparation of the transplant and introduction of treated stem cells into the patient.
The present invention provides a method wherein the glucocorticoid receptor antagonist and/or active agent is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof. The present invention provides a method in which the treated stem cells are administered intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intrathecally, intravitreally, intravaginally, intrarectally, intratumorally, intramuscularly, intrapericularly toneally, intraocularly, subcutaneous, subconjunctival, intracapsular, mucosal, intrapericardial, intraumbilical, intraocular, oral, topical, local, by inhalation, by injection, infusion, continuous infusion, local infusion, administered directly during surgery, catheter, lavage or catheterization, immersion, absorption or adsorption.
The present invention provides a pharmaceutical composition for improving the function of mammalian stem cells after transplantation, comprising: a therapeutically effective amount of treated stem cells, whether embryonic stem cells, stem cells derived from embryonic stem cells or their differentiated progeny, induced pluripotent stem cells or their progeny, fetal stem cells or their differentiated progeny, postnatal (adult) stem cells or their differentiated progeny, or tissues derived from any of these, and a pharmaceutically acceptable medium or carrier.
The subject invention provides a method for reducing rejection of a transplanted organ and/or improving graft function and survival, comprising the steps of: providing an organ for transplantation; treatment of organs with a GCR antagonist before transplantation; and organ implantation to patients who need this treatment. The present invention provides a method wherein the glucocorticoid receptor antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof. The present invention provides a method for reducing post-transplant rejection and/or improving graft function and survival comprising treating a patient in need of such treatment with a GCR antagonist. The present invention provides a method wherein the glucocorticoid receptor antagonist and/or active agent is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The subject invention provides a method in which a GCR antagonist is administered to a transplanted organ intravascularly, intraarterially, intravenously or into tissue or by submerging all or part of the organ prior to transplantation.
The subject invention provides a type of kit for reducing post-transplant rejection and/or improving graft function and survival rate, comprising: (a) a pharmaceutical composition comprising at least one glucocorticoid receptor in a therapeutically effective amount of antagonist; (b) preservation of the decision body.
The subject invention provides a type of kit for reducing post-transplant rejection and/or improving graft function and survival rate, comprising: (a) a pharmaceutical composition comprising at least one glucocorticoid receptor in a therapeutically effective amount of antagonist; (b) at least one blister pack; blister with lid; blister card or package; folding cover; intravenous (IV) pack, IV pack, or IV container; tray or shrink wrap containing the drug (a) Composition and directions for use of the pharmaceutical preparation to reduce post-transplant rejection.
The subject invention provides a product of manufacture for reducing post-transplant rejection comprising a blister pack; blister with lid; blister cards or packages; folding lid; intravenous (IV) pack, IV pack or IV container; trays or shrink packs of compositions containing at least one glucocorticoid receptor antagonist and instructions for reducing post-transplant rejection and/or improving graft function and survival after transplantation.
The present invention provides a method of improving wound healing and preventing excessive scarring in a patient in need thereof comprising administering to a mammal a therapeutically effective amount of a glucocorticoid receptor antagonist. The present invention provides a method wherein the glucocorticoid receptor antagonist is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof. The present invention provides a method in which a wound is treated with a glucocorticoid receptor antagonist, wherein the glucocorticoid receptor antagonist and/or active agent is administered intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intrathecally, intravitreally, intravaginal, intrarectal, intratumoral, intramuscular, intraperitoneal, intraocular, subcutaneous, subconjunctival, intracapsular, mucosal, intrapericardial, intraumbilical, intraocular, oral, local, topical, inhalation, injection, infusion, continuous infusion, local infusion, direct administration during surgery, by catheter, lavage or catheterization operation, immersion, absorption or adsorption or local application of antagonist-impregnated bandages, gauze or sutures.
The present invention provides a pharmaceutical composition for promoting wound healing and preventing excessive scarring, comprising: a therapeutically effective amount of a glucocorticoid receptor antagonist selected from PT150, PT155, PT156, PT157, PT158, TCY1 and combinations thereof, and pharmaceutically acceptable salts and pharmaceutically acceptable media or carriers.
The present invention provides a pharmaceutical composition for the treatment or prevention of drug-resistant prostate cancer, comprising: (a) a therapeutically effective amount of at least one selected from ARN-509, flutamide, nilutamide, enzalutamide, bicalutamide, ketozole androgen receptor antagonists, abiraterone, abiraterone acetate , oterone, finasteride, dutasteride, bexosteramide, isosteramide, turostamide, episteride, dexamethasone, prednisone, leuprolide, goserelin, triptorelin, torelin group, estrogen, MDV3100, cyproteroneacetate, spironolactone, flutamide, hydroxyflutamide, and combinations (b) a therapeutically effective amount of at least one GCR (glucocorticoid receptor) antagonist selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof and combinations thereof; (c) optionally, to at least one pharmaceutically acceptable carrier.
The present invention provides a kit for the treatment or prevention of treatment-resistant prostate cancer, comprising: (a) a therapeutically effective amount of at least one GCR (glucocorticoid receptor) antagonist selected from the group consisting of PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and their pharmaceutically acceptable salts and combinations thereof; (b) a therapeutically effective amount of at least one androgen receptor antagonist selected from the group consisting of: ARN-509, flutamide, nilutamide, enzalutamide, bicalutamide, ketozole, abiraterone, abiraterone acetate, olterone, finasteride, dutasteride, bexosteramide, isosteramide, tolosteramide, episterol, dexamethasone, prednisone, leuprolide, goserelin, triptorelin, tourelin, estrogen, MDV3100, cyproterone acetate, spironolactone, flutamide, hydroxyflu tamide and their combinations; (c) optionally, at least one pharmaceutically acceptable carrier; (d) at least one blister pack; blister; blister card or package; folding top; intravenous (IV) pack, IV pack, or IV container; tray or shrink wrap containing a pharmaceutical composition (a) and use of the pharmaceutical composition for the treatment or prophylaxis of treatment-resistant prostate Cancer Guidelines.
The subject invention provides a product for use in the treatment or prophylaxis of drug-resistant prostate cancer consisting of a blister pack; blister with lid; blister cards or packages; folding lid; intravenous (IV) pack, IV pack, or IV container; a tray or shrink film containing a pharmaceutical composition for which protection is required1And instructions for use of the pharmaceutical preparation for the treatment or prevention of drug-resistant prostate cancer.
The subject invention provides a method for treating or preventing drug-resistant prostate cancer in a patient in need of such treatment or prevention, comprising: administering to said patient a therapeutically effective amount of each of: (a) treating an effective amount of at least one selected androgen receptor antagonist from the group that consists of ARN-509, flutamide, nilutamide, enzalutamide, bicalutamide, ketozole, abiraterone, albino acetate biraterone, oterone, finasteride, dutasteride, bexosteramide, isosteramid, tulusteramide, alpresteramide, dexamethasone, prednisone, leu prox Relin , goserelin, triptorelin, collective relin, estrogen, MDV3100, cyproterone acetate, spironolactone, flutamide, hydroxyflutamide and their combinations; (b) a therapeutically effective amount of at least a GCR (glucocorticoid receptor) antagonist selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, pharmaceutically acceptable salts thereof, and combinations thereof. The present invention provides a method, wherein the GCR (glucocorticoid receptor) antagonist is PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered as agents that directly affect tumor growth, independent of other applied therapeutic modalities, to alleviate, mitigate or cure. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered systemically by oral or intravenous route. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are targeted to tumors by intra-arterial infusion to reduce systemic side effects of GR blockade. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered to achieve cure or remission of a tumor. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered to achieve a reduction in tumor burden to increase the efficiency of subsequent surgical resection. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered to achieve tumor burden reduction, thereby rendering inoperable tumors resectable.
The present invention provides a pharmaceutical composition for the treatment of neoplasia in a patient in need thereof, comprising: (a) a therapeutically effective amount of at least one selected from 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl ]-methyl]-2H-phthalazin-1-one (compound B, i.e. olaparib), 4-iodo-3-nitrobenzamide (Iniparib), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole -4-carboxamide (AB T-888), 8-fluoro-2-{4-[(methylamino)methyl]-phenyl}-1,3,4,5-tetrahydro-6H-azepino-[5 ,4,3 -cd]indol-6-one (AG014699), 4-methoxy-carbazole (CEP 9722), 2-[4-[(3S)-piperidin-3-yl]phenyl [indazole-7-carboxamide hydrochloride (MK 4827) , and 3-aminobenzamide, Iniparib, Olaparib, Rucaparib, Veliparib, CEP-9722, MK4827, BMN-673, A pharmaceutically acceptable salt thereof, and a combination thereof (b) at least one GCR (glucocorticoid) selected from PT150, PT155, PT156, PT157 , PT158, TCY1, combination thereof and pharmaceutically acceptable salts thereof (hormone receptor) antagonists; (c) optionally, at least one pharmaceutically acceptable carrier.
The present invention provides a kit for the treatment or prevention of neoplasia, comprising: (a) a therapeutically effective amount of at least one selected from 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]-methyl]- 2H-phthalazin-1-one (compound B, Olaparib), 4-iodo-3-nitrobenzamide (Iniparib), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazol-4-carboxamide (AB T-888), 8-fluoro-2-{4-[(methylamino)methyl]-phenyl}-1,3,4,5-tetrahydro-6H-azepino-[5,4,3- cd]indole- 6-one (AG014699), 4-methoxycarbazole (CEP 9722), 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide hydrochloride (MK 4827) and 3-aminobenzamide, Iniparib, Olaparib, Rucaparib, Veliparib, CEP-9722, MK4827, BMN-673, their pharmaceutically acceptable salts and their combination; (b) a therapeutically effective amount of at least one GCR (glucocorticoid receptor) antagonist selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof; (c) optionally, at least one pharmaceutically acceptable carrier; (d) at least one blister pack; blister with lid; blister card or package; flip top intravenous (IV) pack, IV pack or IV container; tray or shrink wrap containing the pharmaceutical composition (a) and instructions for using the pharmaceutical composition for the treatment or prevention of neoplasia. The subject invention provides a product for the treatment or prevention of neoplasia consisting of a blister pack; blister with lid; blister cards or packages; folding lid; intravenous (IV) pack, IV pack or IV container; drawers or shrink wraps of pharmaceutical compositions12and instructions for use of the pharmaceutical preparation for the treatment or prevention of neoplasia.
The present invention provides a method for treating or preventing neoplasia in a patient in need of such treatment or prevention, comprising: administering to said patient: (a) a therapeutically effective amount of at least one selected from the group consisting of 4 [[ 3 ] PARP inhibitor-[ 4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]-meth-yl]-2H-phthalazin-1-one (Compound B, i.e. olaparib), 4-iodo-3-nitrobenzamide ( Iniparib), 2 -[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazol-4-carboxamide (ABT-888), 8-fluoro-2-{4-[(methylamino)methyl]-phenyl}-1,3 ,4,5-tetrahydro-6H-azepino-[5,4,3-cd]indol-6-one (AG014699), 4-methoxycarbazole (CEP 9722), 2-[4-[(3S)-piperidin-3 -yl]phenyl]indazole-7-carboxamide hydrochloride (MK 4827) and 3-aminobenzamide, Iniparib, Olaparib, Rucaparib, Veliparib, CEP-9722, MK4827, BMN-673, their pharmaceutically acceptable salts and their combinations; (b) a therapeutically effective amount of at least one GCR (glucocorticoid receptor) antagonist or active agent selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; (c) optionally, at least one pharmaceutically acceptable carrier. The present invention provides a method, wherein the GCR (glucocorticoid receptor) antagonist is PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered as agents that directly affect tumor growth, independent of other applied therapeutic modalities, to alleviate, mitigate or cure. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered systemically by oral or intravenous route. The invention provides a method in which the neoplasia is selected from the group consisting of adenocarcinoma of the head and neck (including salivary glands and oral cavity), gastrointestinal tract (including pharynx, esophagus, stomach, small intestine, colon, anus), lung (including hepatocellular carcinoma), cholangiocarcinoma and mixed tumors), extrahepatic biliary tract and gall bladder, pancreas (including ductal and acinar types), genitourinary tract (ovary, fallopian tube, endometrium, cervix and vagina, ureter, bladder, testis, epididymis, prostate) and skin accessories; head and neck (including salivary glands and oral cavity), gastrointestinal tract (including pharynx, esophagus, anus), lung cancer, intrahepatic and extrahepatic biliary system (including gall bladder), pancreas, urogenital tract (including diaphragm, vagina cervix, ureter, bladder, testes, epididymis, prostate) and skin appendages; germ cell tumors (including malignant teratoma, embryonal carcinoma, ovarian stromal tumor, yolk sac tumor, seminoma, choriocarcinoma); sarcoma (including leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, liposarcoma, chondrosarcoma, fibrosarcoma, Ewing's sarcoma, malignant schwannoma, alveolar soft tissue sarcoma, clear cell sarcoma, synovial sarcoma, osteosarcoma); malignant diseases of the central nervous system (including astrocytoma, oligodendroglioma, glioblastoma, medulloblastoma); salivary gland malignant diseases (including adenoid cystic carcinoma, adenosquamous carcinoma, clear cell carcinoma, cystadenocarcinoma, mucoepidermoid carcinoma); mixed carcinoma (including hepatocellular cholangiocarcinoma, carcinosarcoma, mixed neuroblastoma, gangliocytoma, Wilms tumor); renal cell carcinoma; neuroendocrine carcinoma; thyroid cancer (including papillary, follicular, medullary, anaplastic); Parathyroid carcinoma, pituitary carcinoma, adrenal carcinoma (including adrenocortical carcinoma, pheochromocytoma) and their combinations. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are targeted to tumors by intra-arterial infusion to reduce systemic side effects of GR blockade. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered to achieve cure or remission of a tumor. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered to achieve a reduction in tumor burden to increase the efficiency of subsequent surgical resection. The present invention provides a method in which PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are administered to achieve tumor burden reduction, thereby rendering inoperable tumors resectable.
The present invention provides a pharmaceutical composition for the treatment or prevention of infection associated with an acute or chronic injury or disease in a patient in need thereof, comprising: (a) a therapeutically effective amount of at least one selected from the group consisting of: GCR (glucocorticoid receptor) antagonists: PT150 , PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts; (b) optionally, at least one pharmaceutically acceptable carrier.
The subject invention provides a method of treating or preventing an infection associated with an acute or chronic injury or disease in a patient in need of such treatment, comprising: administering to said animal or human a therapeutically effective amount of each of: (a) a therapeutically effective amount of at least one GCR antagonist (glucocorticoid receptor) selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; (b) optionally, at least one pharmaceutically acceptable carrier.
The invention provides a method of treating or preventing infection associated with an acute or chronic injury or disease, the method comprising administering at least one therapeutically effective amount of a glucocorticoid receptor to a patient in need of such treatment antagonist.
The present invention provides a method in which at least one glucocorticoid receptor antagonist and/or active agent is in the pharmaceutical formulation.
The present invention provides a method wherein the glucocorticoid receptor antagonist and/or active agent is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The present invention provides a method wherein the acute or chronic injury or disease is selected from the group consisting of vascular events, stroke, cardiac arrest, acute limb infarction/battlefield trauma, traumatic limb, hip, brain injury, post-operative trauma, major orthopedic, Thoracic, Abdominal, Neurosurgery.
The present invention provides a kit for the treatment or prevention of infection associated with an acute or chronic injury or disease, comprising at least one blister pack; blister pack with lid; blister card or package; folding top; intravenous (IV) pack, IV pack, or IV container; a tray or shrink film containing a pharmaceutical composition for which protection is required24And instructions for the use of a pharmaceutical preparation for the treatment or prevention of infection associated with an acute or chronic injury or disease.
The subject invention provides a product for the treatment or prevention of infection associated with an acute or chronic injury or disease, comprising blisters, capped blisters, blister cards or packs, flip-tops, intravenous (IV) packs, IV bags or IV containers; a tray or shrink film containing a pharmaceutical composition containing a pharmaceutical composition according to requirements24And instructions for the use of a pharmaceutical preparation for the treatment or prevention of infection associated with an acute or chronic injury or disease.
The present invention provides a pharmaceutical composition for the treatment or prevention of short-term memory impairment in patients in need thereof, comprising: (a) a therapeutically effective amount of at least one GCR (glucocorticoid) selected from PT150 hormone receptor) antagonists, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; (b) optionally, at least one pharmaceutically acceptable carrier.
The present invention provides a method for treating or preventing impaired short-term memory in a patient in need thereof, comprising: administering to an animal or human a therapeutically effective amount of each of: (a) a therapeutically effective amount of at least A GCR (glucocorticoid receptor) antagonist selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof; (b) optionally, at least one pharmaceutically acceptable carrier.
The present invention provides a kit for the treatment or prevention of infection associated with an acute or chronic injury or disease, comprising at least one blister pack; blister pack with lid; blister card or package; folding top; intravenous (IV) pack, IV pack, or IV container; a tray or shrink film containing a pharmaceutical composition for which protection is required32And instructions for the use of a pharmaceutical preparation for the treatment or prevention of infection associated with an acute or chronic injury or disease.
The subject invention provides a product for the treatment or prevention of infection associated with an acute or chronic injury or disease, comprising blisters, capped blisters, blister cards or packs, flip-tops, intravenous (IV) packs, IV bags or IV containers; a tray or shrink film containing a pharmaceutical composition containing a pharmaceutical composition according to requirements32And instructions for the use of a pharmaceutical preparation for the treatment or prevention of infection associated with an acute or chronic injury or disease.
The invention provides the use of the composition of the invention in the manufacture of a medicament for the treatment of the indications described herein.
According to a further embodiment, the present invention provides for the use of the above pharmaceutical composition in an effective amount for medicine, most preferably as medicine for the treatment of a disease or condition in a subject.
According to another embodiment, the subject invention provides the use of the above pharmaceutical composition and at least one additional therapeutic agent in an effective amount in a medicament, most preferably as a medicament for the treatment of a disease or condition associated with a disease in the subject.
The subject invention provides a method of treating or preventing infection following an ischemic stroke, said method comprising administering to a patient in need of such treatment at least one therapeutically effective amount of a glucocorticoid receptor antagonist.
The present invention provides a method in which at least one glucocorticoid receptor antagonist and/or active agent is in the pharmaceutical formulation.
The present invention provides a method wherein the glucocorticoid receptor antagonist and/or active agent is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The subject invention provides a method of treatment or prevention of infection secondary to injury to the central nervous system in a patient in need thereof, which consists of administering at least one therapeutically effective amount of a GCR antagonist.
The present invention provides a method wherein the CNS damage is selected from the group consisting of stroke, neuronal damage due to head trauma, epilepsy, pain, migraine, mood disorders, schizophrenia, neurodegenerative diseases, depression, anxiety, psychosis, high blood pressure, or heart disease. arrhythmia or their combination.
The invention provides a kit for the treatment or prevention of infection after an ischemic stroke, comprising: (a) a pharmaceutical composition comprising at least one therapeutically effective amount of a glucocorticoid receptor antagonist; (b) at least one blister pack; blister with lid; blister card or package; folding top; intravenous (IV) pack, IV pack, or IV container; a pharmaceutical preparation containing (a) and for use in the treatment or prevention of ischemic stroke.
The present invention provides a product for the treatment or prevention of infection after an ischemic stroke consisting of a blister pack; blister with lid; blister cards or packets; folding lid; intravenous (IV) pack, IV pack or IV container; a tray or shrink wrap containing a pharmaceutical composition containing at least one glucocorticoid receptor antagonist, and instructions for using the pharmaceutical composition to treat or prevent infection after ischemic stroke.
The present invention provides a method for reducing infarct severity and improving long-term outcome after ischemic stroke, said method comprising administering at least one therapeutically effective amount of a glucocorticoid receptor antagonist to a patient in need of such treatment.
The present invention provides a method in which at least one glucocorticoid receptor antagonist and/or active agent is in the pharmaceutical formulation.
The present invention provides a method wherein the glucocorticoid receptor antagonist and/or active agent is selected from PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof.
The subject invention provides a method of treatment or prevention of infection secondary to injury to the central nervous system in a patient in need thereof, which consists of administering at least one therapeutically effective amount of a GCR antagonist.
The present invention provides a method for improving the long-term outcome secondary to central nervous system injury in a patient in need thereof comprising the administration of at least one GCR antagonist.
The present invention provides a method wherein the CNS damage is selected from the group consisting of stroke, neuronal damage due to head trauma, epilepsy, pain, migraine, mood disorders, schizophrenia, neurodegenerative diseases, depression, anxiety, psychosis, high blood pressure, or heart disease. arrhythmia or their combination.
The present invention provides a kit for reducing infarct severity and improving long-term outcome after ischemic stroke, comprising: (a) a pharmaceutical composition comprising at least one GCR antagonist; (b) at least one blister pack, blister card or package; flip-top; intravenous (IV) pack, IV pack, or IV container; Pharmaceutical preparations containing (a) and pharmaceutical combinations useful in the treatment or prevention of infection following ischemic stroke Container or shrink wrap with instructions for use.
The subject invention provides a product of manufacture for reducing infarct severity and improving long-term outcomes after ischemic stroke, including blister packs; blisters with lids; blister cards or packages; folding tops; intravenous (IV) packs, IV packs or IV containers; tray or shrink wrap containing a pharmaceutical composition containing at least one glucocorticoid receptor antagonist, and instructions for using the pharmaceutical composition to treat or prevent infection after ischemic stroke.
The present invention provides a glucocorticoid receptor antagonist selected from PT150, PT155, PT156, PT157, PT158, TCY1 and combinations thereof and pharmaceutically acceptable salts thereof, used for the preparation and treatment or prevention of diseases or patients such as the Conditions described herein. The present invention provides a pharmaceutical composition, which contains a glucocorticoid receptor antagonist selected from PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts, for the preparation of the use of a local therapeutic drug for the treatment and/or prophylaxis of a disease or condition as described here in the patient. The subject invention provides a method for treating and/or preventing a disease or disorder as described herein in a patient, the method comprising: selecting a patient in need of treatment and/or prevention of said disease or disorder as described herein; administering a composition of the invention to a patient in a therapeutically effective amount, thereby treating and/or preventing said disease in said patient.
The invention will be described with the help of the following drawings, in which like reference numerals refer to like elements, and in which:
Detailed description of the invention
This invention relates to, for example, glucocorticoid receptor antagonists (optionally in combination with another agent) for the treatment or prophylaxis of drug-resistant prostate cancer, the treatment or prevention of neoplasia and/or the treatment or prophylaxis of acute or chronic prostate cancer Use in infections associated with cancer. injury or illness.
As used herein, the term "effective amount" refers to a therapeutic amount sufficient to result in the prevention of the development, recurrence, or onset of a disease or condition such as a neoplasia or infection and one or more symptoms wherein the preventive effect of another therapy is enhanced or enhanced, reducing severity, duration of a disease or condition such as a neoplasia or infection, ameliorating one or more symptoms of a disease or condition such as a neoplasia or infection, preventing progression of a disease or condition such as a neoplasia or infection, causing a disease or condition such as regression of a neoplasia or infections, and/or enhancing or improving the therapeutic effect of another therapy. An amount is "effective" as used herein when the amount provides an effect in the subject. As used herein, the term "effective amount" refers to an amount of a compound or composition sufficient to significantly induce a positive benefit, including the benefits set forth herein alone or in combination, but low enough to avoid serious side effects, i.e., given within the skill of the art Within the reasonable judgment of the staff, a reasonable balance of benefits and risks. Effective amounts, as well as dosages and frequency of administration, can be readily determined by those skilled in the art in accordance with their knowledge and standard methods based only on routine experimentation of this disclosure.
As used herein, the term "pharmaceutically acceptable" means approved by a federal or state government regulatory agency, or listed in the US Pharmacopoeia, European Pharmacopoeia, or other recognized pharmacopoeia for use in animals, and especially in humans.
As used herein, the terms "prevent", "prevent" and "prevent" in the context of administering treatment to a subject refer to preventing or inhibiting the recurrence, onset and/or progression of a disease or condition, such as neoplasia, viral infection, latent viral infection or its symptoms in a subject resulting from the administration of a therapy (eg, a prophylactic or therapeutic agent) or a combination of therapies (eg, a combination of prophylactic or therapeutic agents).
As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, the term "patient" refers to animals, preferably mammals such as non-primates (such as cows, pigs, horses, cats, dogs, rats, etc.) and primates (such as monkeys and humans). , most good to be human. In some embodiments, the subject is a non-human animal, such as a farm animal (eg, a horse, pig, or cow) or a pet (eg, a dog or cat). In specific embodiments, the subject is an elderly person. In another embodiment, the subject is an adult. In another embodiment, the subject is a human child. In yet another embodiment, the subject is a human child.
As used herein, the terms "therapy" and "therapy" may refer to any method, composition and/or agent or condition useful in the prevention, treatment and/or management of a disease, such as a neoplasia or viral infection, or or more symptoms.
As used herein, the terms "treat", "treatment" and "treatment" in the context of administering therapy to a subject refer to reducing or inhibiting the progression and/or duration of a disease or condition, for example as a result of neoplasia or a viral infection, reducing or alleviating the severity diseases or conditions, such as neoplasia or infection, and/or alleviation of one or more symptoms as a result of the administration of one or more therapies.
As used herein, the term "about" when referring to a value or amount of mass, weight, time, volume, concentration or percentage is intended to encompass a variation of ±20% in some embodiments, ±10% in some embodiments, in some embodiments it is ±5% of the specified amount, in some embodiments it is ±1%, in some embodiments it is ±0.5%, in some embodiments it is ±0.1% of the specified amount, as such variations are suitable for carrying out the disclosed method.
As used herein, ranges may be expressed as from "about" one particular value and/or to "about" another particular value. It is also understood that there are many values disclosed herein and that each value is also disclosed herein as being "about" that particular value in addition to the value itself. For example, if the value "10" is published, then "about 10" is also published. It is also understood that each unit between two specific units is also published. For example, if 10 and 15 are published, then 11, 12, 13 and 14 are also published.
The term "androgen antagonist" refers to drugs that prevent androgens from exerting their biological effects on reactive tissues. These drugs alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell surface, or affecting androgen production. Androgen antagonists may be prescribed to treat a number of diseases and conditions. In men, these drugs are most often used to treat prostate cancer. In women, these drugs are used to lower the level of the male hormone that causes symptoms of hyperandrogenism. The presence of androgen antagonists in the environment has become a matter of concern. Many industrial chemicals, insecticides and insecticides have antiandrogenic effects. Non-limiting examples of androgen antagonists include, but are not limited to, allyl estradiol, oxydolone, oxalone acetate, bicalutamide, steroids, antiandrogens, medroxyprogesterone (MPA), cyproterone ketone, cyproterone acetate (CPA), dienogest, flutamide, nilutamide, spironolactone, α-reductase inhibitors , dutasteride, finasteride, salts thereof, gold nanoparticles thereof, combinations thereof, etc. In some embodiments of the present invention, examples of androgen antagonists include, but are not limited to, α-bicalutamide gold nanoparticles or β-bicalutamide gold nanoparticles.
The present invention relates to the use of GR antagonists (eg ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and pharmaceutically acceptable salts) as therapeutic agents for preventing anxiety and withdrawal side effects caused by addiction. for wound healing and transplantation, for the prevention or treatment of stress osteoporosis and for rapid healing of bone-related injuries, and regenerative therapy.
The present invention relates to a low-cost rapid response diagnostic system for determining salivary cortisol levels in patients selected as potential candidates for GCR (glucocorticoid receptor) antagonist therapy using GCR antagonists such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1 their combinations and pharmaceutically acceptable salts. A rapid, sensitive and inexpensive test can be used to identify patients with abnormal cortisol production or circadian rhythm disturbances, as a method of selecting subjects in whom treatment with GCR antagonists or agonists may be beneficial and/or curative, and can also be used for monitoring change in cortisol levels in response to treatment.
As used herein, the term "agent" refers to any molecule, compound, methodology, and/or substance useful in the prevention, treatment, management, and/or diagnosis of a viral infection or cancer. Non-limiting examples of cancer therapy include chemotherapy, radiation therapy, hormone therapy, antiangiogenic therapy, targeted therapy, and/or biological therapy, including immunotherapy and surgery.
As used herein, the term "cancer cell" refers to a cell that acquires a characteristic set of functional capabilities during its development, including the ability to evade apoptosis, self-sufficiency in growth signals, insensitivity to opposing growth signals, tissue invasion/metastasis, significant growth potential, and/or sustainable angiogenesis. The term "cancer cell" includes precancerous and malignant cancer cells.
As used herein, the term "cancer stem cell" refers to a cell that can be the progenitor of a highly proliferative cancer cell. Cancer stem cells have the ability to regrow tumors, as evidenced by their ability to form tumors in immunocompromised mice, and they often form tumors when subsequent serial transplants of immunocompromised mice occur. Cancer stem cells tend to grow slowly compared to most tumors; that is, they are usually dormant. In some, but not all, embodiments, the cancer stem cells may represent about 0.1 to 10% of the tumor.
As used herein, the term "diagnostic agent" refers to any molecule, compound and/or substance used in the diagnosis of a disease or condition. Non-limiting examples of diagnostic agents include antibodies, antibody fragments, or other proteins, including those conjugated to detectable reagents. As used herein, the term "detectable reagent" refers to any molecule, compound and/or substance that can be detected by any method available to those skilled in the art. Non-limiting examples of detectable agents include dyes, gases, metals or radioisotopes. As used herein, diagnostic agent and "imaging agent" are equivalent terms.
In one embodiment of the invention, a therapeutic amount is effective to achieve one, two, three or more outcomes after administration of one, two, three or more therapies: (1) stabilization, reduction or elimination of the cancer stem cell population; (2) stabilization, reduction or elimination of the cancer cell population; (3) stabilization or reduction of tumor or neoplastic growth; (4) disorders of tumor formation; (5) eradication, removal or control of primary, regional and/or metastatic cancer; (6) reduction of mortality; (7) increase disease-free, recurrence-free, progression-free and/or overall survival, duration or rate; (8) response rate, duration of response (9) reduction in hospitalization rates; (10) shortened length of hospital stay; (11) tumor size remains unchanged, does not increase, or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%; ( 12) increased number of patients in remission; (13) increased length or duration of remission; (14) reduced cancer recurrence rate; (15) prolonged time to cancer recurrence; (16) improvement in cancer-related symptoms and/or quality of life.
As used herein, the term "predetermined reference range" refers to a reference range for a particular biological entity (eg, cortisol) for a subject or population of subjects. Each laboratory may establish its own reference ranges for each specific assay, or standard reference ranges for each assay may be available and used locally, regionally, nationally, or worldwide, or may be patient-specific. In a specific embodiment, the term refers to a reference range for the amount of cortisol in a patient or sample from a patient. In another specific embodiment, the term refers to a reference range for the amount of cortisol in a patient or patient sample.
As used herein, the term "therapeutic agent" refers to any molecule, compound, and/or substance used for the purpose of treating and/or managing a disease or disorder. Examples of therapeutic agents include, but are not limited to, proteins, immunoglobulins (eg, multispecific Ig, single-chain Ig, Ig fragments, polyclonal antibodies and fragments thereof, monoclonal antibodies and fragments thereof), peptides (eg, peptide receptors, selectins), binding proteins , biologics, chemospecific drugs, chemotoxic drugs (eg, anticancer drugs), proliferation-based therapies, radiotherapy, chemotherapy, anti-angiogenic drugs, and small molecule drugs.
As used herein, the terms "therapy" and "therapy" may refer to any method, composition and/or agent or condition useful in the prevention, treatment and/or management of a disease, such as cancer or a viral infection, or one or more than symptoms. In certain embodiments, the terms "therapy" and "therapy" refer to chemotherapy, small molecule therapy, radioimmunotherapy, toxin therapy, prodrug-activating enzyme therapy, biological therapy, antibody therapy, surgical therapy, hormone therapy, immunotherapy, therapy, antiangiogenic therapy , targeted therapy, epigenetic therapy, demethylation therapy, histone deacetylase inhibitor therapy, differentiation therapy, radiation therapy or a combination of the above and/or other therapies, can be used to prevent, control and/or treat cancer or one or more of its symptoms. As used herein, the terms "treatment", "treatment" and "treatment" in the context of administering therapy to a subject refer to reducing or inhibiting the progression and/or duration of a disease or condition, for example cancer or a viral infection, reducing or alleviating the severity of a disease or conditions, such as cancer, and/or alleviating one or more symptoms as a result of one or more therapies. In particular embodiments, such terms refer to one, two, or three or more outcomes following administration of one, two, three, or more therapies: (1) Stabilization of the cancer stem cell population (2) Stabilization, reduction, or elimination of the cancer cell population; (3) Stabilizing or reducing the growth of tumors or neoplasms; (4) Disorders of tumor formation; (5) Eradication, removal or control of primary, regional and/or metastatic cancer; (6) reduction of mortality; (7) ) increase in disease-free, relapse-free, progression-free and/or overall survival, duration or rate; (8) response rates, duration of response, or increase in the number of patients with response or remission; (9) reduced hospitalization rates; (10) shortened length of hospital stay; (11) tumor size remained unchanged, did not increase, or increased by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%; (12 ) The number of patients in remission is increasing. In certain embodiments, such terms relate to stabilizing or reducing the cancer stem cell population. In some embodiments, such terms relate to stabilizing or reducing the growth of cancer cells. In some embodiments, such terms relate to stabilizing or reducing the cancer stem cell population and reducing the cancer cell population. In some embodiments, such terms refer to the stabilization or reduction of tumor growth and/or formation. In some embodiments, such terms relate to eradicating, removing, or controlling (eg, minimizing or delaying the spread of cancer) a primary, regional, or metastatic cancer. In some embodiments, such terms relate to reduced mortality and/or increased survival in a patient population. In further embodiments, such terms refer to an increase in response rate, durability of response, or number of patients responding or in remission. In some embodiments, such terms relate to reducing the hospitalization rate of the patient population and/or reducing the length of stay of the patient population.
The present invention relates to, for example, the use of glucocorticoid receptor antagonists in, for example, preventive treatment against infections after stroke, and use for the preparation of drugs and/or pharmaceutical preparations for preventive treatment against infections after stroke. The incidence of respiratory tract infection after stroke is 1-33%, and the incidence of urinary tract infection is 2-27%. These infections have a major impact on morbidity and mortality. The 30-day mortality rate for patients with pneumonia was 27%, compared with 4% for stroke patients without pneumonia. In addition, stroke patients with pneumonia had higher levels of disability than those without pneumonia, leading to increased medical costs and reduced quality of life. Prevention or treatment of infections after stroke is ethically and medically desirable. Antibiotics for the prevention and treatment of post-stroke infections are currently being tested.
The term "early post-stroke prevention, treatment against infections" refers to the initiation of treatment within 72 hours after the onset of stroke.
glucocorticoid receptor
Glucocorticoid receptors are ubiquitously distributed and expressed in many cultured cell lines, and therefore the control of gene expression by glucocorticoids has been extensively studied as a model of transcriptional regulation.
Many glucocorticoid-responsive transcription factors, including murine mammary tumor virus (MMTV) (Ringold et al., 1975; Parks et al., 1974), murine and human metallothionein (Eager et al., 1981; Karin et al. ., 1980 ), rat α2M globulin (Kurtz et al., 1977), and rat and human growth hormone (Spindler et al., 1982; Evans et al., 1982; Robins et al., 1982) Genes have been identified. The DNA sequences mediating the transcriptional stimulation of several of these genes were mapped. For MMTV, these sequences are discrete genomic regions upstream of the transcription start site that appear to function independently of orientation and position (Chandler et al., 1983; Ostrowski et al., 1984). Steroid/receptor complexes appear to bind to these regulatory sequences, and purified receptors have been used to define specific binding sites (Govinda et al., 1982; Scheidereit et al., 1983; Pfahl, 1982; Payvar et al., 1983). . The ability of the glucocorticoid response element (GRE) to change its position and orientation yet retain promoter inducibility suggests that it resembles a class of cis-acting regulatory sequences called enhancers (Chandler et al., 1983). First discovered in viruses and subsequently in cellular genes, these sequences are required for efficient transcription in vivo (Laimonis et al., 1982; Benoist et al., 1981; Baerji et al., 1983). It has been suggested that enhancers are recognized by trans-acting factors that mediate regulatory effects through tissue-specific transcriptional control. Although enhancers are not well characterized, the glucocorticoid receptor serves as an example of these putative gene activators.
It is widely believed that unbound glucocorticoid receptors (GRs) reside in the cytoplasm and that hormone activation leads to nuclear accumulation and gene activation. (Gasc, J.-M. & Baulieu, E. E. (1987) in Steroid Hormone Receptors: Their Intracellular Localisation, ed. Clark, C. R. (Ellis Horwood Ltd., Chichester, England), pp. 233-250; Beato, M. (1989) Cell 56, 335-344; Carson-Jurica, M. A., Schrader, W. T. & OMalley, B. W. (1990) Endocr. Rev. 11, 201-220; Gronemeyer, H. (1993) Steroid hormone action, Parker, ed. , M. G. (Oxford University Press, New York), pp. 94-117; Tsai, M. J. and OMalley, B. W. (1994) Annu. Rev. Biochem. 63, 451-486; Akner, G., Wikstrom, A. C. & Gustafsson, J. J. A. (1995) J. Steroid Biochem. Mol. Biol. 52, 1-16), and references therein. However, little is known about the mechanisms involved in the nuclear translocation and targeting of steroid receptors to chromatin regulatory sites. Previously, it has been difficult to distinguish the ability of a given receptor mutant or given receptor/ligand combination to participate in various processes such as receptor activation, nuclear translocation, sequence-specific binding, and promoter activation.
The glucocorticoid receptor (GR) is expressed in a subset of ERalpha-positive and -negative human breast cancers, as well as in other malignancies such as some ovarian, hepatocellular, and esophageal squamous cell carcinomas. In vitro and in vivo experiments have shown that GR activation in ER-negative precancerous mammary epithelial cells and cancer cells triggers cell survival pathways under stress conditions that usually induce significant cell death (eg, chemotherapy, radiotherapy, growth factor deprivation).
The glucocorticoid receptor (GR), present in glucocorticoid-responsive cells, resides in the cytosol in an inactive state until stimulated by an agonist. Upon stimulation, the glucocorticoid receptor translocates to the nucleus where it specifically interacts with DNA and/or proteins and regulates transcription in a manner responsive to glucocorticoids. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NFkappa-B. This interaction results in inhibition of API- and NFkappa-B-mediated transcription and is thought to be responsible for part of the anti-inflammatory activity of endogenous glucocorticoids. In addition, glucocorticoids may also exert physiological effects independent of nuclear transcription. Biologically relevant glucocorticoid receptor agonists include cortisol and corticosterone. There are many synthetic glucocorticoid receptor agonists, including dexamethasone, prednisone, and prednisolone.
Glucocorticoid receptor antagonists
Glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding and triggering GR-mediated events, including transcription. RU486 is an example of a non-selective glucocorticoid receptor antagonist.
Compounds with high binding affinity to glucocorticoid receptors and additionally high in vivo antiglucocorticoid activity while having, for example, low androgenic and progestogenic activity are disclosed in US Pat. US patent no. . ORG 34517 (PT150) is an example of a compound with high binding affinity to the glucocorticoid receptor combined with low androgenic and progestogenic activity, shows specificity and high binding affinity to the glucocorticoid receptor, and is very active in vivo, showing great antiglucocorticoid activity. These compounds lack appreciable affinity for mineralocorticoid, progesterone, estrogen, and androgen receptors, indicating no significant side effects.
ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1 and combinations thereof and pharmaceutically acceptable salt derivatives of the present invention can be used for the prevention and treatment of glucocorticoid-dependent diseases or symptoms, such as Cushing's syndrome, diabetes, glaucoma, sleep disorders, depression, anxiety, atherosclerosis, hypertension, obesity, osteoporosis and withdrawal symptoms from narcotics and their mixtures.
Preferred compounds according to the invention are ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts. Preferred active agents according to the invention are ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts.
GR antagonists from the following structural classes are presented: octahydrophenanthrene, spirocyclic dihydropyridine, triphenylmethane and diaryl ether, chromene, dibenzylaniline, dihydroisoquinoline, pyrimidinedione, nitrogen polynaphthalenes and arylpyrazoloazinaphthalenes. Examples of glucocorticoid receptor antagonists include, but are not limited to, mifepristone, RU486, 11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxyl-4,9 Estradien-3-one, 17β-hydroxy-17α-19-(4 -methylphenyl)androsta-4,9(11)-dien-3-one-4α(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9, 10, 10 α (R)-o-ctahydro-phenanthrene-2,7-diol and 4.alpha.(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4 α,9, 10, 10 α(R)-octahydro-phenanthrene-2,7-diol and (11β,17β)-11-(1,3-benzodioxo-5-yl)-17-hydroxy-17-(1-propynyl) ester -4,9-dien-3-one. Examples include, but are not limited to, beclomethasone, betamethasone, budesonide, ciclesonide, flunisolide, fluticasone, mifepristone, mometasone, and triamcinolone. In a further example, it could be CORT 0113083 or CORT 00112716.
Examples of steroid glucocorticoid receptor antagonists include, but are not limited to, mifepristone, cortisol, dexamethasone-oxetanone, 19-deoxycorticosterone, 19-norprogesterone, 21-methylsulfonate, acid cortisol; Dexamethasone-21-mesylate, 11(-(4-dimethylaminoethoxyphenyl)-17(-propynyl-17(-hydroxy-4,9-estradien-3-one, and 17(-hydroxy-17(-19-(4-methylphenyl) )androsta-4,9(11)-dien-3-one.
Examples of non-steroidal glucocorticoid receptor antagonists include, but are not limited to, N-(2-[4,4',441-trichlorotrityl]oxyethyl)morpholine; 1-(2[4,4',4"-trichlorotrityl]oxyethyl)-4-(2-hydroxyethyl)piperazine dimaleate; N-([4,4',4"]-trichloro trityl)imidazole; 9-(3-mercapto-1,2,4-triazolyl)-9-phenyl-2,7-difluorofluorenone; 1-(2-chlorotrityl)-3,5-dimethylpyrazole; 4-(morpholinomethyl)-A-(2-pyridyl)benzhydryl alcohol; 5-(5-Methoxy-2-(N-methylamino)Formyl)-phenyl)dibenzocyclopentadiol; N-(2-chlorotrityl)-L-prolinol acetate; 1-(2-chlorotrityl)-1,2,4-triazole; 1,S-bis(4,4',4″-trichlorotrityl)-1,2,4-triazole-3-thiol; 4. Alpha (S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4.alpha,9,10,10 alpha(R)-octahydro-phenanthrene-2,7-diol ("CP 394531"), 4alpha (S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4.alpha .,9,10,10alpha(R)-oc-tahydro-phenanthrene- 2,7-di alcohol ("CP-409069"), trans-(1R,2R)-3,4-dichloro-N-methyl-N-[2-l-pyrrolidinyl)cyclohexyl]benzene-acetamide, Buma Zocin, ethyl ketone cyclozocine and naloxone.
The specificity of ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts, for GR blockade, in relation to other related steroid hormone receptors such as estrogen and progesterone receptors) without significant cross-linking, eliminating possibility of significant toxicity and side effects. In fact, in all the significant Phase I and II clinical trials that have been conducted with PT150 compounds, none have been found. Because the drug is intended to be administered in limited doses over time, consistent with the typical intermittent dosing strategy of chemotherapeutic agents, GR blockade also does not result in significant changes in HPA axis function, and the HPA axis rapidly returns to baseline post-drug.
Fabric 34517/Pt150
The (-)-enantiomers PT150 (ent-PT150) and PT155 (ent-PT155) represent the corresponding unnatural enantiomers of the steroid moieties in PT155, PT156, PT157 and PT158. We claim the unnatural (-)-enantiomer of the steroid moiety in PT155, PT156, PT157, and PT158 and all possible steroid diastereomers as subject to this scope.
platinum 153
PT153 is an inclusion complex of one molecule of ORG34517 (guest) and two molecules of ORG34517 thiosemicarbazone (host). PT153 is produced by refluxing ORG34517 in 90% (v/v) aqueous ethanol with excess thiosemicarbazide [H2N-NH-(C=S)-NH2]. The product is precipitated by adding water or by freezing.
In-depth analysis of the reaction products showed that the product PT153 consists of two molecules of ORG34517 thiosemicarbazone and one molecule of unreacted ORG34517, as well as ethanol (1.52×) and water (1.25×) solvents, which cannot be removed by prolonged vacuum drying On calcium chloride (CaCl2):
The thiosemicarbazone moiety of ORG34517 is a cis/trans stereoisomeric mixture [(Z/E)-mixture] with 71.8% (E)-stereoisomers (trans) and 28.2% (Z)-stereoisomers of the construct (cis):
protonska NMR (1H-NMR) spectra clearly distinguish the three molecular species contained in PT153 [(E)-thiosemicarbazone, (Z)-thiosemicarbazone, ORG34517]. Elemental analysis (combustion analysis of elemental CHNS/O content) clearly confirms this composition:
(E/Z)-thioamide group (H2N—C═S) is known as thiosemicarbazone. The nature of the clathrate will be revealed in the discussion of the structure of PT154.
An important feature of PT153 is its strong electrostatic properties in powder form. PT153 powder has strong induction magnetism and there are significant difficulties in grinding, crushing and dosing. As it landed, dust flew from each vane. Taken together, this magnetism of PT153 presents significant difficulties for drug formulation. As will be shown, the PT154 does not exhibit this unusual phenomenon at this power.
PT154
PT154 is a purified clathrate consisting of one molecule of ORG34517 (guest) and two molecules of ORG34517 thiosemicarbazone (host).
To synthesize the putative dimer, PT153 was treated with a molar excess of aqueous sodium hydroxide (NaOH) in acetone at room temperature. The product PT154 was precipitated by adding water and freezing. The model reaction for this experiment was the dimerization of retinoic acid thiosemicarbazone published in 2011.
In-depth analysis of the reaction products showed that the product PT154 was composed of two molecules of ORG34517 thiosemicarbazone and one molecule of unreacted ORG34517 with the solvent ethanol (1×), diacetone alcohol (0.24×) and water (0.8×), which could be obtained in anhydrous calcium chloride (CaCl2)).Diacetone alcohol is produced from the reaction solvent acetone [2H3C-(C=O)-CH3→ (tall3C)2C(OH)-CH2-(C=O)-CH3]. Diacetone alcohol is a relatively non-toxic solvent and is also a natural product in weeds (Achnatherum resplendent, Poaceae; synonymsHe's a tough guy).
The ORG34517 thiosemicarbazone moiety in PT154 was analyzed as exactly the same cis/trans stereoisomeric mixture as in PT153 [(Z/E)-mixture with 71.8% (E)-stereoisomer (trans) and 28.2% (Z)-stereoisomer ( cis) )].
protonska NMR (1H-NMR) spectra clearly separated the three molecular species contained in PT154 [(E)-thiosemicarbazone, (Z)-thiosemicarbazone, ORG34517] (see Experimental section). Elemental analysis (combustion analysis of elemental CHNS/O content) clearly confirms this composition:
This striking analogy between PT154 and PT153 is significant because complete dissolution, alkali treatment, and precipitation almost always result in changes in stereoisomeric composition and ratio. Additionally, the sodium salt should be formed from the ORG34517 thiosemicarbazone. These changes did not happen at all. This strongly suggests the formation of a complex (clathrate) of ORG34517 in the ORG34517 thiosemicarbazone molecular lattice. ORG34517 Thiosemicarbazone has a thiourea group known for its ability to form macromolecular clathrates9-11 (view, expert)., the so-called clathrates. Therefore, it was hypothesized that PT153 and PT154 are actually stable clathrates of one molecule of ORG34517 (guest) and two molecules of ORG34517 thiosemicarbazone (host).
The reason for this assumption is that (i) PT153 and PT154 are completely similar in composition, although PT153 is treated with base and reprecipitated to produce PT154, (ii) the thiourea structural elements in PT153 and PT154 form the thiourea clathrate inclusion compound methylenetetramine and thiourea as an example (ratio 1:2)11, and (iii) according to Nobel laureate Heinrich Wieland, the presence of steroid inclusion complexes such as cholesterol (guest) and deoxycholate (host).
The most appropriate explanation for the interaction of one molecule of ORG34517 (guest) with two molecules of ORG34517 thiosemicarbazones (host) is the published analysis of testosterone with hippuric acid (or phenylcarbamate, acetanilide, acetamide) Observation of complex formation (all in a 1:2 ratio).-(acetyloxy)androst- 5-en-17-one] forms a complex with hippuric acid (the ratio of the two is 1:2). This means that 3-keto-Δ4- Steroids such as ORG34517 can form addition compounds with amides (or thioamides) that represent compounds in a 1:2 ratio.
It is interesting that complexes of thiourea with pyridine halides (2:1)14,15Ferroelectric/dielectric properties can be demonstrated in the case of pyridinium iodide/thiourea (1:2)15.This could be the explanation for the electrostatic/magnetic properties of PT153.
PT155 PT155: ⅓(11β,17β)-17-Hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-dien-3-one (ORG34517 ) ×(2EZ)-2-{(11β,17β)-17-hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-diene - 3-podjedinica} hydrazinemethylsulfonamide [71.8% (E), 28.2% (Z)] hemihydrate × ¾ acetone × ⅛ ethanol (PT155)
PT155 is an inclusion complex of choice, for example, one molecule of ORG34517 (guest) to three molecules of ORG34517 thiosemicarbazone (host). In an exemplary embodiment, the ratio of ORG34517 thiosemicarbazone to ORG34517 is, for example, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1.
In experiments designed to drive the reaction towards ORG34517 thiosemicarbazone, the reflux time was doubled from 30 minutes to 1 hour. Only clathrates similar to those contained in PT153 and PT154 were isolated. ORG34517 thiosemicarbazone and ORG34517 were concluded to interact strongly with each other, as previously described. The ORG34517 thiosemicarbazone portion of PT155 is a (Z/E)-mixture with 71.8% (E)-stereoisomer and 28.2% (Z)-stereoisomer. This material, PT155, is the compound of choice for in vitro antiviral studies. Metabolic activation of ORG34517 thiosemicarbazones contained in PT153-155:
S-oxidation by human flavin monooxygenase (hFMO).
As we all know, thiosemicarbazone compounds, such as thiacetazone (paracetamide benzaldehyde thiosemicarbazone), are cheap second-line anti-tuberculosis drugs, discovered by Nobel laureate Gerhard Domagk in 1946, can be replaced by yellow monooxygenase (hFMO1, hFMO2. 1, hFMO3 ) bioactivation of the element is converted into sulfenic acid (R—S—OH), sulfinic acid [R—(S=O)—OH] and carbodiimide derivatives (R—N=C=N—H)23, 24:
Both sulfinic acid and carbodiimide derivatives are active antituberculosis metabolites. Sulfinic acid (bottom left) does not form carbodiimides and is an inactive metabolite. In particular, carbodiimide derivatives can react with amino acid residues in target proteins, for example,Mycobacterium tuberculosis, or with human hepatic/extrahepatic glutathione R-SH thiols/thiols for metabolic detoxification:
Therefore, ORG34517 thiosemicarbazone will be bioactivated by hFMO (S-oxidation) in the same way as thiaphene upon consumption of molecular oxygen (O2) and will be able to bind covalently after transfer to HBV and HIV proviral GRE DNA hGR core of host cells. The thiosemicarbazone moiety in ORG34517 thiosemicarbazone can be oxidized by hFMO (hFMO1, hFMO2.1, hFMO3) and molecular oxygen on sulfinic acid to form ORG34517 thiosemicarbazone carbodiimide, which can be co-catalyzed by hGR Transported into the host cell nucleus: hGR subunit 1 -( ORG34517 thiosemicarbazone carbodiimide)=hGR subunit 2-ORG34517. The carbodiimide moiety is added to the amino group of the proviral GRE DNA, creating an N-amidinohydrazone (amihydrazone) group, which induces damage to the proviral DNA.
Human flavin-dependent monooxygenases (hFMO) (EC 1.14.13.8) are the second most important monooxygenase in humans, the other well-known type being cytochrome P450 monooxygenase (CYP450 monooxygenase enzyme). Both are microsomally localized and molecular oxygen (O2) dependent, and hFMO also requires the cofactors flavin-adenine dinucleotide (FAD) and nicotinamide-adenine dinucleotide phosphate (NADPH), whereas CYP450 monooxygenases are heme-dependent. hFMO1 is mainly expressed in the human kidney, and small amounts are also expressed in the small intestine and lung. hFMO2 is expressed at very high levels in human lung and kidney and at lower levels in liver and small intestine28. hFMO3 and hFMO5 are highly expressed in human liver, but also in lung and, to a lesser extent, in human kidney. hFMO4 is mainly expressed in the kidneys, and to a lesser extent in the liver and small intestine. hFMO5 is also expressed at high levels in the small intestine. FMO2 is also expressed in the human brain, but at a low level (<1% of the lung).
Slightly revised quote: "hFMOs oxidize nucleophilic chemicals and drugs containing heteroatoms, usually converting them to harmless, polar metabolites that are readily excreted. Sometimes, however, FMOs bioactivate chemicals that are the active substance that can cause toxicity. Most of the interindividual variation in hFMOs is due to genetic variation and allelic variation, and splicing variation may contribute to the observed interindividual and interethnic variation in hFMO-mediated metabolism Similar to cytochrome P450 Compared to monooxygenases (CYP450 monooxygenases), hFMOs are less likely to be induced and inhibited, and for drugs that are mainly metabolized hFMOs, potential adverse drug interactions are minimized. These properties can be useful for drug design, and Discovery offers advantages, and by incorporating hFMO detoxification pathways into drug candidates, more drug-like materials may emerge. Although there are no exhaustive examples, physiological factors may affect hFMO function, which may have implications for hFMO clinically and in human disease. A role in has an impact."
The magnetism exhibited by the PT155 is electrostatic, which is called the triboelectric effect. Triboelectrification (also known as triboelectrification) is a type of contact electrification in which a material becomes charged upon frictional contact with another material. Rubbing fur against glass or combing hair with a comb creates triboelectricity. Most of everyday static electricity is due to friction. The polarity and strength of the generated charges vary depending on the material, surface roughness, temperature, stress and other properties.
PT-156
PT156: 1/17(11β,17β)-17-Hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propin-1-yl)estra-4,9-dien-3-one (ORG34517)×(2EZ)-2-{(11β,17β)-17-hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propin-1-yl)estra-4,9 -dien-3-ylidene}-N-phenylhydrazinmethylsulfonamide [74.1% (E), 25.9% (Z)] 11/17 hydrate (PT156)
PT156: 11/17 ORG34517 4-phenylthiosemicarbazone containing traces of ORG34517
In an exemplary embodiment, PT156 is (2EZ)-2-{(11β,17β)-17-hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propane alkyn-1-yl)ester - 4,9-dien-3-ylidene}-N-phenylhydrazinecarbothioamide does not exist (11β,17β)-17-Hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl) estra-4,9-dien-3-one (ORG34517). In an exemplary embodiment, the ratio of PT156 to ORG34517 is 30:1, 20:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9 :1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.
Elemental analysis confirmed the results obtained by 1H NMR spectroscopy:
PT156 is formed by refluxing ORG34517 in 90% (v/v) aqueous ethanol with a slight excess of 4-phenylthiosemicarbazide [H2-N-NH-(C=S)-NH-C6H5]. The product was precipitated by adding water and freezing. Analysis of the reaction products showed that the inventive PT156 contained 17 1 unreacted molecules of ORG34517 and solvent water (17 11×), which could not be removed by prolonged vacuum drying with anhydrous calcium chloride (CaCl2). ORG34517 4-Phenylthiosemicarbazone is part of a cis/trans mixture of stereoisomers [(Z/E)-mixture] with 74.1% (E)-stereoisomer (trans) and 25.9% (Z)-stereoisomer (cis).
Metabolic activation of the ORG34517 4-phenylthiosemicarbazone contained in PT156: para-oxidation by human cytochrome P450 monooxygenase
It is well known that acetanilide is oxidized by the human cytochrome P450 monooxygenase isoenzyme 1A2 (CYP1A2) at the para position of the phenyl ring to form paracetamol (paracetamol)29, which is further oxidized by CYP3A4 to N-acetyl-p-phenyl quinone imine:_
Similarly, PT156 activates CYP1A2 and CYP3A4 in T lymphocytes to:
Similarly, PT156 activates CYP1A2 and CYP3A4 in T lymphocytes to:
This represents an additional activation mechanism for the PT156 that is neither achievable nor built into the PT155. This is particularly important for the potential treatment of acquired immunodeficiency syndrome (AIDS) with PT compounds, as only very low levels of human flavin monooxygenase (only hFMO4 and hFMO5) can be detected in human blood lymphocytes. PT156 can be activated in human T lymphocytes even in the absence of human flavin-containing monooxygenase, since microsomal cytochrome P450 isozymes 1A2 and 3A4 are readily detected in human blood lymphocytes. Historically, the overall metabolism of acetanilide was elucidated by Brodie and Axelrod in 1948.
Pt-157
platinum 158 ⅓(11β,17β)-17-Hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-dien-3-one—(2) -2-{(11β,17β)-17-hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-dien-3-ylidene} Hydrazine carbothioamide [71.8% (E), 28.2% (Z)]-bis[6-amino-2-oxo-3-(β-D-ribofuranosyl)-2,3-dihydropyrimidin-1-ium-1 -yl]methanediamine monohydrochloride x ½ acetone (PT158)
In an exemplary embodiment, the PT-158 is:
Material:
-
- PT155 (.C28H30O4×C29H33N3O3S×¾C3H6O×.C2H5OH×½H2O) [Pop Test Oncology LLC, Cliffside Park, N.J., USA; first series synthesized by Andreas J. Kesel on Thursday, October 8, 2015; w (n/n). 99% (1H NMR and elemental analysis)]
- TCY-1 (C19H26N6O10×HCl×1.25 H2O) [synthesized by Andreas J. Kesel and Subotu, 26. prosinca 2015.; w (n/n). 99% (1H NMR and elemental analysis)]=bis(cytidin-3-ium-3-yl)methandide monohydrochloride×1.25 H2O=bis[6-amino-2-oxo-3-(â-D-ribofuranosyl); -2 ,3-dihydropyrimidin-1-ium-1-yl]methanediamine hydrochloride × 1.25 H2O
Description: PT155 (M=705.49 g/mol, 151 mg, 214.0356 μmol) and TCY-1 (M=557.42 g/mol, 121 mg, 217.0715 μmol) (the whole mixture was M= 1270.82 g/mol before drying) Weigh carefully and mix thoroughly with a spatula to obtain a solid powder. The mixture was then carefully dried over CaCl2 in vacuo to give PT158 as a pale yellow amorphous powder.
Connection: PT158
Molecular formula: (.C28H30O4×C29H33N3O3S)×(C19H26N6O10×HCl)×½C3H6O
Molecular weight: 1211.11 g/mol
Yield: 260 mg (100%)
'H NMR: 0.41 (3H, s; 18-CH3, (E)-TSC*), 0.42 (1.18 H, s; 18-CH3,
(DMSO-d6, ppm) (Z)-TSC**), 0,44 (1,393 H, s; 18-CH3, ORG34517), 1,20-2,77 (m; steroidi CH i CH2), 1,83 (5,58 H, br s; R—C≡C—CH3 metil, sve tri vrste), 2,09 (4,18 H, s; aceton CH3), 3,57 (dd, 2 H; 2J=−11,9 Hz, 3J= 2,2 Hz; H-5', pro-R, TCY-1), 3,68 (dd, nerazriješeno, 2H; 2J=−12,2 Hz; H-5', pro-S, TCY-1), 3,86 (dt, 2 H; 3J=5,6 Hz, 3J=2,6 Hz; H-4', TCY-1), 3,95 (t, 2 H; 3J=5,1 Hz; H-3', TCY-1), 4,00 (t, 2H, 3J=4,5 Hz; H-2', TCY-1), 4,28 (0,393 H, m; 11a-CH, (Z)-TSC), 4,30 (IH, d; 3J (H,H) = 7,1 Hz; 11a-CH, (E)-TSC), 4,38 (0,464 H, d; 3J (H,H)=7,1 Hz; 11a-CH, ORG34517), 5,08-5,16 (1,857 H+4 H, br m; 17a- OH, sve tri vrste; 3'-OH, 5'-OH, TCY-1), 5,42 (br s, 2 H; 2'-OH, TCY-1), 5,66 (0,464 H, s; 4 -CH, ORG34517), 5,74 (d, 2H; 3J=3,8 Hz; H-l', TCY-1), 5,86 (1H, s; 4-CH, (E)-TSC), 5,94 (d, 2H; 3J=7,7 Hz; H-5, TCY-1), 5,97 (3,716 H, br s; O-CH2-O benzobisoksazol, sve tri vrste), 5,97 (0,393 H, s; 4-CH, (Z)-TSC ), 6,60 (1,858 H, d; 3J(H,H) = 7,7 Hz; 5'-CH benzobisoksazol, sve tri vrste), 6,67 (0,393 H, s; 2'-CH benzobisoksazol, (Z)-TSC), 6,77 (1,464 H, s; 2'-CH benzobisoksazol, (E)-TSC i ORG34517), 6,79 (0,393 H, m; 6'-CH benzobisoksazol, (Z)-TSC), 6,79 (1,464 H, d; 3J (H, H) = 8,3 Hz; 6'-CH benzobisoksazol, (E)-TSC i ORG34517), 7,51 (0,393 H, br s; NH2, HA, (Z)-TSC), 7,57 (1 H, br s NH2, HA, (E)-TSC), 7,92 (br s, 2 H; 4-NH2, HA, TCY-1), 7,97 (0,393 H, br s; NH2, HB, (Z)-TSC), 8,08 (IH, br s; NH2, HB, (E)-TSC), 8,09 (d, 2 H; 3J = 7,7 Hz; H-6, TCY-1), 8,48 (br s, 2 H; 4- NH2, HB, TCY-1), 10,05 (IH, br s; N-H, (E)-TSC), 10,42 (0,393 H, br s; NH, (Z)-TSC), 13,00 (br s, 1H; hidroklorid, TCY-1). *,** (E ili Z)-TSC=(E ili Z)-tiosemikarbazon.
TCY-1 Bis(cytidin-3-ium-3-yl)methandide monohydrochloride×1,25 H2O=bis[6-amino-2-oxo-3-(β-D-ribofuranosyl)-2,3-dihydropyrimidin-1-ium- 1- base] methane diamine hydrochloride × 1.25 H2O (TCY-1)
In the example embodiment, TCY1 is:
In exemplary embodiments, TCY1 is an HIV integrase inhibitor. Due to the essential role of HIV integrase in viral infections, especially HIV infection, it is an attractive target for the discovery of new therapies. The compounds of the present invention exhibit advantages over previously disclosed integrase inhibitors, such as increased potency, metabolic stability, increased therapeutic index, or other pharmaceutical properties.
The methods, compounds, compositions and uses described herein may be specifically directed to the inhibition of HIV integrase in patients in need thereof. Such methods and uses prevent, treat or delay the onset of AIDS in mammals in need thereof. The present invention also includes the compounds of the present invention described herein and/or their pharmaceutically acceptable salts, hydrates, solvates, tautomers, optical isomers, E-isomers, Z-isomers and the body or their combination for, as a medicine for and/or for the preparation of a medicine for inhibiting HIV integrase, preventing or treating HIV infection, or preventing, treating or delaying the onset of AIDS.
The compounds of this invention may also be used in combination with one or more drugs used in the treatment of HIV infection or AIDS. Because the compounds of the present invention can be HIV integrase inhibitors, such compounds can also be used for rescue therapy in patients whose virus has mutated and become resistant to other drugs. Such inhibitors target a unique step in the retroviral life cycle and can therefore be used in combination with other types of HIV drugs to minimize viral adaptation.
Material:
-
- Cytidine [Sigma-Aldrich Corp., St. Louis, MO, USA, Batch Number: BCBN7660V; w (n/n)=99.9% (HPLC, area %), =+29.7° (c=9 in H2O), = +33.0° (c=2 in H2O), m.p. 210-220°C (decomposition.)]20D][a20D][a
- Crystallization of thymol (5-methyl-2-isopropylphenol). Ph.D. Euro. 1997 [Caesar & Loretz (Caelo) GmbH, Hilden, Germany, lot no: 24252173; residue after evaporation <0.05% (m/m)]
- 3% (m/m) dihydrogen peroxide (H2O2) in water [according to DAC/NRF (Deutscher Arzneimittel-Codex/Neues Rezeptur-Formularium), NRF monograph 11.103] with orthophosphoric acid (H3PO4) in water [0.0588% ( m / m) 85% (m/m) H3PO4 in water; this corresponds to a final concentration of 0.05% (m/m) H3PO4 in a stable H2O2 solution (the solution shows a pH of 5.0 at =19.8°C)]
- 10.27 M [32% (m/m)] Hydrochloric acid pre-analysis [AppliChem, Darmstadt, Germany, lot number: 3A001639; w (m/m) = 33.09% (titration), bromide <0.005%, phosphate < 0.00005%, sulfate <0.0001%, As <0.000001%, Fe <0.00002%, heavy metals (Ni, Pb, Zn)<0.000005%]
- Preliminary analysis of ethyl acetate [AppliChem GmbH, lot number: 0000518022; w (n/n) = 99.9 % (GC), w (H20) = 0.01 % (m/m) (Karl Fischer titration), ethanol <0.1 %, methanol <0.02%, methyl acetate<0.02%, trace elements (Cr, Fe, Ni, Pb, Zn, P, S, K, Mg)<0.00001%, Si<0.00002%, Na<0.0002%, non-volatile substances <0.001%, acidity/alkalinity <0.0005 meq/g]
instructions:
Cytidine (M=243.22 g/mol, 10.355 g, 42.5746 mmol), carbon source thymol Ph. Eur. 1997 (M=150.22 g/mol, 6.228 g, 41.4592 mmol) and sodium bicarbonate NaHCO3 (3.646 g, 43.3996 mmol) was suspended in 90% (v/v) aqueous ethanol (100 ml). An aqueous solution of 3% (w/w) dihydrogen peroxide (H2O2) [48 ml, 1.440 g H2O2 (M = 34.01 g/mol) 42.3405 mmol] was then added at room temperature (RT, θ = 15.6 °C). Solid sodium hydroxide grains NaOH (2.064 g, 51.6000 mmol) and water (80 mL) were added with stirring. During 10 minutes of stirring at room temperature, the suspension turned light purple. Then heat the suspension at 40-50 °C for 5 minutes (heat gun) until all solids are dissolved. Let the solution stand at room temperature for 5 minutes. Then quench the reaction by adding 10.27 M [32% (m/m)] aqueous hydrochloric acid (9.20 mL, 94.4840 mmol). The color changes from purple to pale yellow. A floating yellow oil quickly formed. The solution (pH 4-5) of floating yellow oil is cooled to +0-2°C for 2 hours. The mixture was then frozen at -25°C for 2.5 hours. Sodium hydroxide (520 mg, 13.0000 mmol) dissolved in water (3 mL) was then added (color changed to violet). The mixture was then frozen at -25°C for 30 minutes. Then 10.27 M [32% (m/m)] analytical hydrochloric acid in water (3.00 mL, 30.8100 mmol) was added with stirring (color changed to yellow). The mixture was then frozen at -25°C for 105 minutes. Sodium hydroxide (740 mg, 18.5000 mmol) dissolved in water (5 mL) was then added. The yellow solution was extracted with analytical ethyl acetate (EtOAc, 100 ml). Separate the aqueous phase and freeze at -25 °C for 55 h (2 days 7 h). The precipitated white, highly odorous (cheese-like) crystalline product (1.932 g) was filtered and dried in vacuo over CaCl 2 .
Connection: TCY-1
Molecular formula: C19H26N6O10×HCl×1.25 H2O
Molecular weight: 557.42 g/mol
Prinos: 1.932 g (16%)
Elemental analysis: Calculated: C 40.94%, H 5.33%, N 15.08%, O 32.29%;
Discovery: C 39.31%, H 5.56%, N 15.26%, O 32.08%, C 39.43%;
'H-NMR: 3.57 (dd, 2H; 2J=-12.2 Hz, 3J=3.2 Hz; H-5'),
(DMSO-d6, ppm) pro-R), 3,68 (dd, 2 H; 2J=-12,2 Hz, 3J=3,2 Hz; H-5', pro-S), 3,86 (dt, 2 H; 3J=5,4 Hz, 3J=3,0 Hz; H-4'), 3,95 (t, 2 H; 3J=5,1 Hz; H-3'), 3,99 (m, 2 H; H-2'), 5,07 (br s, 2 H; 3'-OH), 5,15 (br s, 2 H; 5'-OH), 5,41 (br s, 2 H; 2'-OH), 5,74 (d, 2 H; 3J=3,8 Hz; H- l'), 5,93 (d, 2H; 3J=7,7 Hz; H-5), 7,89 (br s, 2H; 4-NH2, HA),
Test method: HIV-1 reverse transcriptase (RT) replication by TCY-1
HIV-1let（=HIV-1Bruce=LAV-1; The origin and identity of HIV-1let) was tested in primary [freshly donated from healthy (tested HIV-negative, HBV-negative, and HCV-negative) blood donors and isolated by single-phase Ficoll-Hypaque centrifugation] human peripheral blood mononuclear cells (PBMCs) for drug evaluation. A parameter of antiviral activity was the decrease in RT activity in the cell supernatant after Triton X-100-mediated lysis of released virions, as determined by [5alpha-3H]dTTP (5alpha-tritiated thymidine 5'-triphosphate) is incorporated into poly(rA)⋅poly(dT) under the guidance of the RNA template poly(rA)⋅oligo(dT). It should be noted that this assay does not detect inhibition of RT by the potential RT inhibitors themselves, but rather indirectly quantifies the amount of HIV-1 released in the supernatant. A detailed test method was published by Schinazi et al., based on the old test system of Spiro et al. The experiments were performed in triplicate and statistically processed by analyzing the regression curve (r2decisive factor). The RT inhibitor AZT (zidovudine, 3'-azido-3'-deoxythymidine; RETROVIR™) was used as a positive control. Cytotoxicity of the tested compounds on PBMC was determined using CellTiter 96® AQ as described by Stuyver et al.LiquidOne Solution Cell Proliferation Assay (Promega Corp., Madison, WI). Briefly, phenazine ethosulfate (PES) coupled reduction of the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) Purple, water-soluble formazan was measured in live, undamaged cells.
antiviral activity
PT150, formerly known as ORG34517, was originally developed by Organon as a treatment for major depressive disorder (Gallagher & Young, 2006). In 2007, it was acquired by Schering-Plough, then by Merck & Co., and finally in December 2010 by Pop Test Cortisol LLC. As ORG34517, it has undergone two phases of safety clinical trials:
PT155 was developed based on PT150 with the observation that thiosemicarbazones show significant antiviral activity, including activity against hepatitis C virus and Zaire Ebola virus (Kesel, 2011; Kesel et al., 2014).
Mechanism
The 3' UTR is critical for viral replication in the host and interacts with a number of host proteins (Roby, 2014), including Mov34, which has been shown to be involved in transcription and translation in mice (Ta & Vrati, 2000). The gene product PMSD7 (Mov34-related gene) is a subunit in the proteasome. Mov34 has been shown to bind to the Japanese encephalitis virus genome (Ta & Vrati, 2000). Changes in the proteasomal processing of NF-κB are a major regulatory point for the production of pro-inflammatory cytokines and the control of the immune response; microbial and viral pathogens have been documented to alter this pathway to facilitate infection (Rahman & McFadden, 2011). Furthermore, Mov34 contains an MPN domain that is highly conserved among eukaryotic initiation factors of the 3A family (Asano, 1997; Sanches, 2007).
Without being bound by any theory, one possible mechanism of action of compounds PT150 and PT155 derives from their activity as glucocorticoid receptor (GR) antagonists. The GR agonist dexamethasone and the GR antagonist mifepristone (RU38486) have been shown to interact with Mov34 in HIV-1 infection ( Ramanathan et al., 2002 ) and promote or inhibit nuclear translocation. Disruption of Mov34-like proteins with the 3'-UTR region of Zika and possible other interactionsflavivirus, inhibits viral replication and negates sfRNA-mediated cellular events that are required for successful viral infection. Patents for antiviral compositions against human hepatitis C virus WO 2004/112720 A2 ND US 2007/0259844 A1 (Kim 2004; Kim, 2007) further support this hypothesis.
result justification for readiness
PT150 is a new class of therapeutic agents designed to block the glucocorticoid receptor (GR), which acts as an antagonist of endogenous cortisol. PT150 or (11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one is first choice Sexual GR antagonists have been studied in a phase I program in healthy human subjects (ClinicalTrials.gov, NCT00226278) regarding their safety, tolerability, and pharmacodynamic/pharmacokinetic profile. In the first study on humans, it did not show an inhibitory effect. It is significantly more selective for GR than mifepristone (RU486). The binding rates of PT150 and mifepristone to cytosolic GR were 365% and 193%, respectively, however, values for the cytosolic progesterone receptor (PR) were 6.4% and 36%, respectively. This shows a selectivity ratio (GR/PR) of 57 for PT150 compared to 5.4 for mifepristone. In the rat pregnancy termination test, 4 mg/kg twice daily−1po PT150 i 1-2 mg kg−1After mifepristone it gave similar results (almost 100% embryo loss), confirming that PT150 has lower anti-pregnancy activity compared to mifepristone. Thus, the specificity of PT150 for GR blockade, without significant cross-binding to other related steroid hormone receptors (such as the estrogen receptor and the progesterone receptor), eliminates the possibility of significant toxicity and side effects. Compared with mifepristone, PT150 was able to block GR translocation induced by corticosterone. This suggests that PT150 is a true competitive GR antagonist without partial agonist activity (Peeters et al., 2008).
GR expression did not show any prognostic value in Kaplan-Meier analysis of survival and residual survival or overall survival of patients with ovarian cancer (Woenchhaus et al., 2006). Nevertheless, administration of GC and apoptosis-inducing chemotherapy to ovarian cancer patients suppressed cell death and activation of anti-apoptotic genes SGK1, MKP1/DUSP1 and caspase inhibitor cIAP2 in ovarian tissue, suggesting that chemotherapy resulted in an overall reduction of drug effectiveness (Runnebaum & Bruning, 2005; Melhem et al., 2009).
Virus test results
The following viruses extracted from the NIAID pooled list of pathogens areflavivirusAmong them, PT150 and PT155 have therapeutic potential.
Issues with blurred activities in existing test results
Two issues have been identified with past test results that we believe are masking antivirus results. First, many of the cell lines used for testing are immortal cell lines. Second, not all cell lines tested contained active glucocorticoid receptors that play a role in the interactions of the compounds for antiviral activity.
Phase II clinical trial of patients treated with PT150 at a dose of 900 mg daily for 2 weeks without significant side effects of cytotoxicity. However, cytotoxicity appears in in vitro models. PT reveals that PT150 has value as a chemosensitizer in cancer therapy. Therefore, it has a pronounced effect on cancer cells. Unfortunately, this includes most cell lines used for in vitro testing.
For example, differences in cytotoxicity were observed when PT150 was used in Zika assays in HeLa cells (a breast tumor-derived cell line), HUH7 (a liver tumor cell line), and HFF (human foreskin fibroblasts of non-tumor origin). The cytotoxicity of 50% of primary human foreskin fibroblasts was much higher than 150 μM, and these cells are very sensitive sensors of human tissue toxicity.
Cell lines derived from Vero (Vero, Vero 76, Vero E6) do not contain the human glucocorticoid receptor since they are derived from the African green monkey (Ethiopian Chlorella) kidney epithelial cells. they don't even containgreen pineGlucocorticoid receptors (Dreyer et al., 1989) and were shown to be completely unresponsive to dexamethasone. Therefore, forflavivirusNot surprisingly. We believe that the choice of cell line masked the potentially positive results of the PT150 and PT155 tests. Retesting in a cell line containing glucocorticoid receptors (preferably human receptors) can give the activity of the compound
Sexual transmission of the Zika virus
Several studies have shown that the Zika virus can be sexually transmitted through semen. RNA viruses can be detected in semen up to 62 days after the onset of infection. (Hill et al., 2016; Mansuy et al., 2016; McCarthy, 2016). Not only does this allow the virus to have an arthropod vector-independent route of infection, but it also exceeds current WHO guidelines for unprotected sex within 30 days of returning from an endemic area (Turmel et al., 2016).
The persistence of Zika virus in semen presents an opportunity for clinical testing in the arena, which avoids the problem of birth defects in testing pregnant women or women who want to conceive.
ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts and other GCR-antagonist molecules must therefore also interfere with the function of the viral GRE and can be used as follows: administration of ORG34517, PT150, PT155 , PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof or other GCR antagonist molecules before or during physical, social, emotional or psychological stress conditions that result in elevated circulating cortisol to reduce or prevent reactivation of latent viral infections;
ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof, or other GCR antagonist molecules before or during physical, social, emotional, or psychological stress states that lead to increased circulating Cortisol administration to reduce or prevent susceptibility to viral infections;
Before using ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts or other GCR antagonist molecules in individuals, or receiving therapeutic doses of glucocorticoids to reduce or prevent latent viral reactivation of infection;
Prior to the use of ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts or other GCR antagonist molecules in individuals or receiving therapeutic doses of glucocorticoids to reduce or prevent viral susceptibility infection.
Administration of ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof or other GCR antagonist molecules to an individual during reactivation of a latent viral infection to reduce the magnitude of viral reactivation, to reduce the length of viral reactivation to accelerate the time to resolution and cure of viral reactivation, to accelerate the time to suppression of viral reactivation, to increase the likelihood of viral eradication, and/or to reduce the infectivity of viral reactivation;
Administration of ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts or other GCR antagonist molecules to an individual during an acute viral infection reduces the intensity of the viral infection, shortens the duration of the viral infection, to accelerate the resolution time and curing a viral infection, to speed up the time to control the viral infection, to increase the likelihood of eradicating the virus, and/or to reduce the infectivity of the viral infection.
Administration of ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof or other GCR antagonist molecules before or during travel to a viral environment to reduce or prevent susceptibility to a virus Viral infection
By interfering with the function of GRE viruses, ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations, their pharmaceutically acceptable salts and other GCR antagonist molecules, tissue damage can be prevented or reduced in form, but not Limitations are limited to direct viral cytotoxicity, immune-mediated destruction of virus-infected cells and tissues, and malignant transformation.
ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof and other GCR antagonist molecules can be combined with other antiviral agents that target the virus (ie, molecules that specifically bind to viral molecules) and interfere with viral physiology) in cases of acute infection, reactivation of latent viral infection or active chronic viral infection.
ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts and other GCR antagonist molecules can be combined with other non-specific antiviral drugs (ie immune system modulators with non-specific action) Use specifically for regulation viral physiology) in cases of acute infection, reactivation of latent viral infection or active chronic viral infection.
viral status
Families of viruses that infect humans (some of which also infect animals) include: Adenoviridae, Papillomaviridae, Polyomaviridae, Herpesviridae, and Poxviridae. These include, but are not limited to: adenovirus, herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster virus, Epstein-Barr virus,Cytomegalovirus, human herpesvirus type 8, human papillomavirus, BK virus, JC virus, chicken pox and small pox.
Hepadnaviridae, including but not limited to hepatitis B virus.
Parvoviridae, including but not limited to humansmouth virusiparvovirusB19.
Astroviridae, Caliciviridae, Picornaviridae, Coronaviridae, Flaviviridae, Retroviridae, Togaviridae, Hepadnaviridae. To uključuje, ali nije ograničeno na ljudeAstrovirus, Norwalk virus,coxsackie virus, Hepatitis A,Poliovirus, rinovirus, severe acute respiratory syndrome virus (SARS), hepatitis C virus, yellow fever virus, dengue virus, West Nile virus, rubella virus, hepatitis E virus
Arenaviridae, Bunyaviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae and Rhabdoviridae. This includes, but is not limited to, influenza virus, Guanarito virus, Junina virus, Lassa virus, Machupo virus, Sabia virus, Simian-Congo hemorrhagic fever virus, Ebola virus, Marburg virus, measles virus, mumps virus, parainfluenza virus, respiratory syncytial virus virus, humanmetapneumovirus, Hendra virus, Hippa virus, rabies virus,
Reoviridae include but are not limited toToravirus, Orbivirus, Coltivirus, Banna virus.
Virus hepatitis D.
Other viruses that infect animals include:
Rhabdoviridae, including but not limited to vesicular stomatitis virus.
Picornaviridae, including but not limited to foot-and-mouth virus,
Pestiviridae include but are not limited to classical swine fever and bovine viral diarrhea.
The family Arteriviridae includes, but is not limited to, equine arteritis virus, porcine reproductive and respiratory syndrome virus, elevated lactate dehydrogenase virus, and simian hemorrhagic fever virus.
Coronaviridae include but are not limited to infectious bronchitis virus, infectious gastroenteritis coronavirus, bovine coronavirus, feline coronavirus, canine coronavirus, hepatitis A virus,
Orbiviridae include, but are not limited to, Berne virus, Breda virus.
Orthomyxoviridae include, but are not limited to, avian influenza virus, swine influenza virus.
The Reoviridae family includes but is not limited to bluetongue viruses.
The Circoviridae family includes, but is not limited to, chicken anemia virus, porcine circovirus-1, porcine circovirus-2, psittaci beak and feather disease virus, pigeon circovirus, canary circovirus, and goose circovirus.
Asfarviridae includes but is not limited to African swine fever virus.
Retroviridae include but are not limited to avian leukosis virus, Rous sarcoma virus, murine mammary tumor virus, murine leukemia virus, feline leukemia virus, bovine leukemia virus, cutaneous sarcoma leukoplakia virus, simian and feline immunodeficiency virus, simian foam virus.
The Flaviviridae family includes, but is not limited to, tick-borne encephalitis virus, Japanese encephalitis virus, St. Louisa, Israeli turkey meningoencephalomyelitis virus, Sitiawan virus, Wesselsbron virus and looping disease virus.
Paramyxoviridae include but are not limited to canine distemper virus, swine distemper virus, cetacean virusmeasles virus, Newcastle disease virus, rinderpest virus.
Most of the identified enveloped viruses susceptible to PS interception are RNA viruses:
Ebola and Marburg viruses (Filoviridae); Ross River virus, Chikungunya virus, Sindbis virus, Eastern equine encephalitis virus (Togaviridae,alfa virus), vesicular stomatitis virus (Rhabdoviridae,vesicular virus), Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus (Arenaviridae,breast virus), West Nile virus, dengue virus, yellow fever virus (Flaviviridae,flavivirus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); Moloney murine leukemia virus (Retroviridae,gama retrovirus); Virus influence A (Orthomyxoviridae); Respiratorni sincicijski virus (Paramyxoviridae, Pneumoviridae,lung virus)
Confirmed enveloped DNA viruses susceptible to PS interception are:
vacciniaVirus (poxviridae, chordopoxviridae,Ortopoksvirus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus);Virus nuklearne poliedroze Autographa californica(Baculoviridae, Alphabaculoviridae) (virus insekata)
Expected important enveloped RNA viruses susceptible to PS interception are: Ebola virus and Marburg virus (Filoviridae); Semliki Forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern/Western/Venezuelan equine encephalitis virus (Togaviridae,alfa virus); rubella virus (German measles) (Togaviridae,Ruby virus); Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae,rabies virus); Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae,breast virus); West Nile virus, Dengue virus, Yellow fever virus, Zika virus, Japanese encephalitis virus, St.flavivirus); human hepatitis C virus (Flaviridae,hepatitis virus); human immunodeficiency virus type 1 (Retroviridae,lentivirus); influenza A/B viruses (Orthomyxoviridae, common "flu" viruses); respiratory syncytial virus (Paramyxoviridae, Pneumoviridae,lung virus); Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae,Henipa virus); virus ospica (Paramyxoviridae, Paramyxovirinae,measles virus)
The expected PS that will intercept sensitive enveloped DNA viruses are:
Small pox (variola) virus (Poxviridae, Chordopoxvirinae,Ortopoksvirus); human hepatitis B virus (Hepadnaviridae,ortohepatotropni virus); hepatitis D virus (hepatitis D virus) (family not specified,delta virus); herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus);HumanityCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus)
Thus, binding of anti-PS molecules to PS viral envelopes would interfere with acute infection with any of the above viruses, as well as acute reactivation of latent chronic viral infection (in those PS-tagged viruses that can maintain latency), or chronic infection with any of the above viruses Viral infection with active viral replication.
Therefore, the antiviral effect of PT150, PT155, PT156, PT157, PT158, TCY-1 or any other derivative may act on any viral infection through more than one mechanism of action, either by binding to GRE (with all possible antiviral activity) or acting on additive or synergistic way on PS (with all the above possible antiviral activities).
virus gripe
PT150 and PT155 had antiviral activity against influenza A virus replication at higher concentrations (EC50>>10 μM). PT150 is more efficient than PT155
This antiviral activity is probably dependent on the human glucocorticoid receptor-a (hGRa), since PT150 is more active than PT155, which is reasonably considered to be a weaker glucocorticoid antagonist than PT150, since PT155 is a related compound of PT150 oxime shown (ORG36174). Both compounds were more effective against avian influenza A (H5N1) virus than pandemic influenza A (H1N1) virus of swine origin.
The probable mechanism of action of PT150 is the capture of Hsp90 to a non-nuclear translocation complex (PT150-hGRa-Hsp90) in the host cytosol. Therefore, the amount of free Hsp90 available for assembly of the influenza A virus polymerase complex and trafficking to the core is reduced by PT150 and, to a lesser extent, also by PT155, resulting in an antiviral effect.
Furthermore, inhibition of Hsp90 with small molecule drugs (eg, geldanamycin/radiol derivatives) represents an established antitumor chemotherapy strategy. Hsp90 client proteins (more than 300 cellular proteins are currently known to be Hsp90 clients) are important for cancer growth and malignant transformation. PT compounds, especially PT150, target Hsp90 indirectly by trapping it in an inactive complex with the α isoform of the human glucocorticoid receptor. This in turn leads to reduced availability of Hsp90 protein, a client protein required for stable cancer cell growth, maintenance of malignant cell phenotype, tumor angiogenesis, tumor spread and metastasis.
rift valley fever
PT150 and PT155 have antiviral activity against RVF virus replication in relatively low concentrations (EC50≈10 μM). PT150 is about as active as PT155. This antiviral activity is apparently independent of the human glucocorticoid receptor alpha (hGRa), since Vero 76 cells do not express this receptor, nor do they even express any monkey glucocorticoid receptors.
The mechanism of action is likely to be inhibition of virus-cell fusion, since the RVFV glycoprotein GC contains a binding pocket for lipophilic compounds.
The observation that RVFV accessory proteins (the 78-kDa protein, NSm1, NSm2, and NS) are dispensable for virus replication in vitro, and the hypothesis that PT compounds do not interact with large RNA-dependent RNA polymerase L and nucleocapsid protein N. Other expression products genes are unknown, therefore PT compounds should bind GN and/or GC RVFV envelope transmembrane glycoprotein mediates receptor binding and fusion
PT compounds are not expected to bind to the nucleocapsid N protein, since the RVFV N protein has no hydrophobic binding site, only a central RNA-binding core (and therefore positively charged) and alternately charged N- and C-termini.
A binding pocket for highly lipophilic compounds is described in the X-ray crystal structure of the RVFV GC protein. GC is a fusion-capable glycoprotein, representing the fusion glycoproteins of type II viruses.
Poliovirus
PT150 and PT155 have antiviral activityPoliovirusType 3 replication at low concentrations (EC50≈1-5 μM). The PT155 is slightly more active than the PT150
Polio is an ancient disease (see picture).PoliovirusIt can infect neurons and cause neuromuscular paralysis.
The term "polio" is used to identify the disease caused by any of the three serotypesPoliovirus.Describes two basic patterns of polio infection: mild disease that does not involve the central nervous system (CNS), sometimes called abortive polio, and severe disease that affects the CNS, which may be paralytic or nonparalytic.
PT150 and PT155 have antiviral activityPoliovirusType 3 replication at low concentrations (EC50≈1-5 μM). The PT155 is slightly more active than the PT150
This antiviral activity is apparently independent of the human glucocorticoid receptor-a (hGRa), as Vero 76 cells do not express this receptor, nor do they express any monkey glucocorticoid receptors. The mechanism of action is probably inhibitionPoliovirusCapsid removal, such as PT150, fits the picornavirus VP1 capsid protein hydrophobic pocket binder model well, as does the 'canyon binder' compound 40, aryldone, disoxaril, WIN 58084, pleconaril and pyrodavir. For models that hydrophobically bind PT150 in the human VP1 pocketrinovirus14 See below. A similar PT150 is expected to be suitable forPoliovirusHydrophobic pocket of capsid protein type 3 VP1.
hepatitis virus
ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1 are a new class of therapeutic agents designed to block the glucocorticoid receptor (GR), acting as endogenous cortisol antagonists. The main development path to date has been the treatment of neuropsychiatric disorders characterized by dysregulation of the hypothalamic-pituitary-adrenal axis, often associated with higher than normal circulating levels of endogenous cortisol.
Other possible uses include oncology, viral infections, and other neuropsychiatric disorders, including post-traumatic stress disorder, weight gain in patients requiring long-term antipsychotic treatment, and inpatient confusion in the elderly.
Human hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) integrate their retroviral DNA into the genome of the human host. Current antiretroviral drug regimens fail to directly target these intrachromosomal heterogeneous genomes, resulting in persistence of viral genetic information. Both HBV and HIV-1 contain a glucocorticoid response element (GRE) in their proviral DNA genome. The subject invention describes a potent glucocorticoid antagonist that binds to the human glucocorticoid receptor subtype alpha (hGR-alpha), translocates to the nucleus via nuclear receptor dimers, and is capable of covalently inactivating HBV and HIV intragenic and exonic viral GREs. 1. The glucocorticoid antagonist ORG34517 dimeric thiosemicarbazone derivative described in this invention represents the first published antiviral agent capable of eradicating human immunodeficiency virus and hepatitis B provirus from human hosts. The anti-HBV effects of dimeric thiosemicarbazone derivatives of the glucocorticoid antagonist ORG34517 may be mediated by hGR-α because the HBV genome contains at least two hGR-α transactivation targets (GREs). The glucocorticoid antagonist ORG34517 dimer derivative of thiosemicarbazone binds to hGR-α, which is transported (glucocorticoid antagonist ORG34517 dimer derivative of thiosemicarbazone)-ligand hGR-α through the core pore complex to In the core genome of HBV, the ligand hGR-α complex binds to GREs, and finally, the cotransported glucocorticoid antagonist ORG34517 dimeric thiosemicarbazone derivative transfers to HBV DNA and is transthiocarbamylated Covalent modification of amine-containing nucleobases (cytosine, guanine, adenine). This may also occur with host cell GREs, but we think there is selectivity for exonic GREs, which is not typical for human genomes, since viral intronic GREs are less incorporated into chromatin than host cell GREs. Clear epigenetic regulation of remodeling events. Human GREs are found in promoter regions upstream of the transcription start site, with a few exceptions found in introns of human genes. Furthermore, it should be mentioned that human GRE is in most cases imperfect (GRE sequence degenerate), i.e. their sequence does not match the given perfect GRE consensus sequence. Despite these imperfect GRE sites, their response to glucocorticoids was preserved.
GRE 4 has been proposed as a target of dimeric thiosemicarbazone derivatives of the glucocorticoid antagonist ORG34517 because the 5'-LTR GRE is only a partially functional negative enhancer (silencer) of HIV-1 gene expression, while the vif gene GRE-4 has been shown to function fully as an enhancer of gene transcription for HIV.
Covalent modification of HIV-1letThe gene vif derivative of the glucocorticoid antagonist ORG34517 dithiosemicarbazide, which has a mechanism of action very similar to that already described for HBV ayw, causes loss of HIV-1letFunction of protein Vif (Vif=viral infectivity factor). Vif proteins are intrinsic retroviral inhibitors of the human antiretroviral defense system dependent on the human innate enzyme 3G (APOBEC3G) editing mRNA of human apolipoprotein B. Therefore, Vif failed to protect HIV-1 (-)-cDNA from the cytidine deaminase enzymatic activity of the host APOBEC3G (mutation dC→ dU).
Covalent "capture" of proviral DNA by HBV or HIV-1 is expected to induce p53-mediated apoptosis through DNA damage signaling mechanisms sensed by the p53 tumor suppressor protein and/or other DNA damage-induced sensing mechanisms [e.g. Dysregulated telangiectasia and Rad3-related protein (ATR)]. Through apoptosis induced by proviral DNA damage, the virus host organism can be continuously cleared of proviral heterologous DNA integrated into the host genome.
Dimeric thiosemicarbazone derivatives of the glucocorticoid antagonist ORG34517 were synthesized by constructing thiosemicarbazone ORG34517 [ORG34517 and equimolar thiosemicarbazones were refluxed in 90% (v/v) aqueous ethanol for 20 min], followed by treatment (in acetone, room temperature) with sodium hydroxide (NaOH, previously dissolved in water). These transactions are based on general procedures already described in the literature and known to those skilled in the art.
The heretofore claimed compounds of the invention may also be active against human hepatitis C virus (HCV), as shown by published proof-of-concept studies. Mechanism of antiviral action of the glucocorticoid antagonist thiosemicarbazone dimeric derivative ORG34517 and the thiosemicarbazone intermediate ORG34517 against human hepatitis C virus subtype 1b strain Con1 (HCV-1b Con1 proposed). It is essentially clear that it cannot be mediated by hGR-α because HCV does not contain any DNA stages in its life cycle. Since the anti-HCV-1b activity of the thiosemicarbazones described in this invention was determined using the HCV RNA replicon cell line Huh7ET (luc-ubi-neo/ET), it encodes only the non-structural HCV proteins NS3, NS4A, NS4B, NS5A and NS5B, the inhibitory effect of the thiosemicarbazone drugs described in the present invention should be limited to these five genes and/or gene products. Thiosemicarbazone drugs (5,6-dimethoxyindan-1-one thiosemicarbazone, DMI-TSC) have been reported to target bovine viral diarrhea virus type 1 (BVDV-1 strain NADL,Flaviridae, Pestiviruses) NS5B protein RNA-dependent RNA polymerase (RdRp). BVDV-1 is generally considered a suitable surrogate for HCV because bothFlaviviridaePolyprotein sequences are closely related (maximum sequence identity 39%)
Since the compounds claimed in this invention may also be active against EBOV Zaire 1976 Mayinga, a published proof-of-concept study showed that a triple sequence alignment between BVDV-1 NADL NS5B RdRp, HCV-1b Con1 NS5B RdRp and EBOV Zaire 1976 Mayinga VP40 membrane associated matrix proteins are included in this invention. Compounds similar to those claimed in the present invention are inhibitors of octamerization of the membrane-associated matrix protein VP40 of EBOV Zaire 1976 Maying, an event essential for replication of EBOV Zaire 1976 Maying.
The present invention provides treatment of EBOV Zaire infection with the glucocorticoid antagonist ORG34517 thiosemicarbazone dimer derivative or the ORG34517 thiosemicarbazone intermediate, which are two embodiments of the present invention, since the method described herein is known to those skilled in the art.
The present invention provides a combination of ORG34517 dimeric thiosemicarbazone derivatives and other antiviral and anti-inflammatory compounds in a kit for the treatment or amelioration of a condition selected from HBV infection, HIV infection, and Ebola virus infection.
Cytosolic nuclear receptors translocate to the nucleus after ligand binding
Nuclear receptor ligand dimers bind to cognate hormone-responsive element DNA
Glucocorticoids bind to human glucocorticoid receptor subtype a/b (hGR-a/b)
hGR-a ligand/bdimer binds to glucocorticoid response element (GRE) DNA
PT155 is metabolically activated by flavin-containing monooxygenase (hFMO) via S-oxidation of the thiosemicarbazone moiety of PT155
The PT155 carbodiimide metabolite acts as a ligand for homodimeric hGR-a/b, half of which binds to ORG 34517, and the ligand complex translocates to the nucleus:
hGR subunit 1-(ORG 34517 carbodiimide derivative)=hGR subunit 2—ORG 34517
hGRa/b-(PT155 carbodiimide metabolite) complex binds to GRE in intrachromosomal HBV or HIV-1 proviral DNA
Thus, HBV or HIV-1 host DNA integrated proviral GRE DNA is covalently inactivated by amidrazone linkage
Covalently captured HBV or HIV-1 proviral DNA is expected to induce p53-mediated apoptosis through DNA damage signaling mechanisms sensed by the p53 tumor suppressor protein and/or other DNA damage-induced sensing mechanisms. Ataxia vasodilation and Rad3-related protein (ATR)]
Through proviral DNA damage-induced apoptosis, the viral host organism can continuously clear proviral heterologous DNA integrated from the host genome
Human hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) integrate irreversibly transcribed DNA proviruses into the human host genome. Current antiretroviral drug regimens fail to directly target these intrachromosomal heterogeneous genomes, resulting in persistence of viral genetic information
Existing HAART therapies target reverse transcriptase (HBV, HIV), protease (HIV) and integrase (HIV) proteins. These treatments do not cure
In a proof-of-concept study, the PT155 retinone analog compound was shown to be effective against HBV, HIV-1, HCV, and the human herpesviruses HHV-3, HHV-6, and HHV-8 (herpesviridae)
The antiviral activity of retinoids is fully related to the presence of intragenic and exonic GRE in the essential viral genes of retinoid-sensitive viruses
The glucocorticoid antagonist ORG34517 thiosemicarbazone derivative PT155 described in this presentation may be the first reported antiviral agent capable of eradicating human immunodeficiency virus and hepatitis B provirus from human hosts.
The human hepatitis C virus (HCV) RNA polymerase NS5B protein shares a common thiosemicarbazone binding motif
HCV-1b Con1 NS5B domain finger/toe RdRp motif I, 139-MAKNEV-144 (fully conserved hepatitis virus aa residues in bold), identified as a thiosemicarbazone binding motif
Structurally different thiosemicarbazones are active as inhibitors of HCV replication in a proof-of-concept study
PT155 has also been proposed as an HCV inhibitor
HIV PT150 and PT155 against the LAI strain of human immunodeficiency virus type 1 (Retroviridae,lentivirus)
RESULTS: PT150 and PT155 were highly effective against human immunodeficiency virus type 1 (HIV-1) strain LAI (HIV-1)let) in primary human peripheral blood mononuclear cells (PBMCs) consisting of T lymphocytes, B lymphocytes and monocytes. (=HIV-1let（=HIV-1Bruce=LAV-1 in primary [donated fresh from healthy (tested HIV-1 negative, HBV negative and HCV negative) blood donors and isolated by single-phase Ficoll-Hypaque centrifugation] human peripheral blood mononuclear cells (PBM) were Assess for the presence of drugs. The parameter of antiviral activity was the reduction of reverse transcriptase (RT) activity in the cell supernatant after Triton X-100-mediated lysis of released virions, via [5alpha-3H]dTTP (5alpha-tritiated thymidine 5'-triphosphate) is incorporated into poly(rA)⋅poly(dT) under the guidance of the RNA template poly(rA)⋅oligo(dT). It should be noted that this assay does not detect inhibition of RT by the potential RT inhibitors themselves, but rather indirectly quantifies the amount of HIV-1 released in the supernatant. A detailed test method was published by Schinazi et al., based on the old test system of Spiro et al. The experiments were performed in triplicate and statistically processed by analyzing the regression curve (r2decisive factor). The RT inhibitor AZT (zidovudine, 3'-azido-3'-deoxythymidine; RETROVIR™) was used as a positive control. Cytotoxicity of the tested compounds on PBMC was determined using CellTiter 96® AQ as described by Stuyver et al.LiquidOne Solution Cell Proliferation Assay (Promega Corp., Madison, WI). Briefly, the phenazine ethosulfate (PES) coupled reduction of the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) was measured purple formazan in intact cells.
Mechanism of action: The antiretroviral effects of PT150 and PT155 are mediated by the DNA glucocorticoid response element (GRE) present in the HIV-1Lm prolentivirus as a heterogeneous genomic prolentiviral DNA sequence integrated into the nucleochromosomal genome of the human host:
Cytosolic nuclear receptors translocate to the nucleus after ligand binding
Nuclear receptor ligand dimers bind to cognate hormone-responsive element DNA
Glucocorticoids bind to human glucocorticoid receptor alpha subtype (hGR-α)
Liganded dimers of hGRalpha bind to DNA glucocorticoid response elements (GREs)
The glucocorticoid nuclear receptor targets GRE DNA
HIV-1letProviral (9229 nt) contains four GREs: GRE 1-4
HIV-1letGRE 4 in the vif gene is located in the exon of the vif gene
HIV-1letProviral DNA contains 4 recognized GREs (GRE 1, GRE 2, GRE 3, GRE 4)
GRE 1 (-264 to -259), GRE 2 (-6 to -1) and GRE 3 (+15 to +20) within the 5'-long terminal repeat (5'-LTR)
PT155 is metabolically activated by flavin-containing monooxygenase (hFMO) through sulfur oxidation of the thiosemicarbazone moiety of PT155.
The PT155 carbodiimide metabolite binds as a ligand to the hGRalpha homodimer, half with PT150, and the ligand complex translocates to the nucleus:
hGRalpha subunit 1-(PT155 carbodiimide metabolite)≡hGRalpha subunit 2-PT150
The hGRalpha-(PT155 carbodiimide metabolite) complex binds to GRE in intrachromosomal HIV-1 proviral DNA
Consequences of capture of proviral DNA by PT155 carbodiimide derivatives:
Covalently captured HIV-1 proviral DNA is predicted to induce p53-mediated apoptosis through DNA damage signaling mechanisms sensed by the p53 tumor suppressor protein and/or other DNA damage-induced sensing mechanisms [e.g. ataxia telangiectasia and Rad3-related protein (ATR)]
Through proviral DNA damage-induced apoptosis, the viral host organism can continuously clear proviral heterologous DNA integrated from the host genome
Without being bound by any theory, it is believed that the human immunodeficiency virus (HIV) integrates its retroviral DNA into the genome of the human host. Current antiretroviral drug regimens fail to directly target these intrachromosomal heterogeneous genomes, resulting in persistence of viral genetic information. Existing HAART therapies target reverse transcriptase, protease and integrase proteins. There is no cure with these treatment options. In a proof-of-concept study, the PT155 analog compound retinone was shown to be effective against HBV, HIV-1, HCV, and human herpesviruses HHV-3, HHV-5, HHV-6, and HHV-8 (herpesviridae) Antiviral activity of flavonoids is entirely related to the presence of intragenic and intra-exonic GRE in essential viral genes of retinoid-sensitive viruses. The glucocorticoid antagonist PT155 described in this presentation may be the first reported antiviral agent capable of eradicating human immunodeficiency provirus from a human host.
Metabolic activation of PT150 thiosemicarbazones contained in PT155: S-oxidation by human flavin-containing monooxygenases (hFMO): It is well known that thiosemicarbazones such as thiacetazone (para-acetamibenzaldehyde thiosemicarbazone) have been discovered as inexpensive second-line drugs against tuberculosis by Bell Gerhard Domagk , winner in 1946, is bioactivated by flavin-containing monooxygenases (hFMO1, hFMO2.1, hFMO3) to sulfenic acid (R—S—OH), sulfenic acid [R—(S=O)—OH ], and carbodiimide derivatives (R-N=C=N-H). Metabolites of sulfinic acid and carbodiimide are active antituberculosis metabolites. Sulfinic acid does not form carbodiimides and is an inactive metabolite. In particular, carbodiimide metabolites can react with amino acid residues in target proteins, for example,Mycobacterium tuberculosis, or with human hepatic/extrahepatic glutathione R-SH thiol groups for metabolic detoxification:
Therefore, PT155 will consume molecular oxygen (O2), and can covalently bind to HBV and HIV proviral GRE DNA after being translocated into the host cell nucleus by hGRalpha.
Human flavin-dependent monooxygenases (hFMO) (EC 1.14.13.8) are the second most important monooxygenase in humans, the other well-known type being cytochrome P450 monooxygenase (CYP450 monooxygenase enzyme). Both are located in microsomes and depend on molecular oxygen (O2), and hFMO also requires the cofactors flavin-adenine dinucleotide (FAD) and nicotinamide-adenine dinucleotide phosphate (NADPH), whereas CYP450 monooxygenases are heme-dependent. hFMO1 is mainly expressed in the human kidney, and small amounts are also expressed in the small intestine and lung. hFMO2 is expressed at very high levels in the human lung and kidney, and at lower levels in the liver and small intestine. hFMO3 and hFMO5 are highly expressed in human liver, but also in lung and, to a lesser extent, in human kidney. hFMO4 is mainly expressed in the kidneys, and to a lesser extent in the liver and small intestine. hFMO5 is also expressed at high levels in the small intestine. hFMO2 is also expressed in the human brain, but at a low level (<1% of the lung).
Slightly modified quote: "hFMOs oxidize nucleophilic chemicals and heteroatom-containing drugs, usually converting them to harmless, polar metabolites that are readily excreted. Sometimes, however, FMOs bioactivate the chemically active substance that can cause toxicity. Most interindividual variation in hFMO is due to genetic variation and allelic variation, and splicing variation may contribute to the observed interindividual and interethnic variation in hFMO-mediated metabolism Similar to cytochrome P450 Compared to monooxygenases (CYP450 monooxygenases), hFMOs are less likely to be induced and inhibited, and for drugs that are mainly metabolized by hFMOs , potential adverse drug interactions are minimized. These properties may be useful for drug design, and Discovery offers advantages, and incorporating hFMO detoxification pathways into drug candidates may yield more drug-like materials. Although there are no exhaustive examples, physiological factors may affect hFMO function, which may have implications for hFMO clinically and in human disease. A role in has an impact."
Impact of PT155 structure on nuclear receptor binding - nuclear translocation is crucial for the biological role of PT155: PT150 does not support nuclear translocation of the PT150-hGRalpha complex. It is an antagonist that competes with cortisol only in the cytosol. Therefore, to achieve our goal of targeting HBV and HIV proviruses residing in eukaryotic nuclear chromatin, we must perform nuclear translocation. Nuclear translocation of the glucocorticoid-hGR complex is structure-dependent. RU38486 (RU486, mifepristone) The RU486-hGRalpha complex translocates to the nucleus, since RU486 is a partial hGRalpha agonist. The residual agonist potency of RU486 is sufficient to induce nuclear translocation. The latter property can be seen as strictly dependent on the conformation of hGRalpha protein bound to RU486, which still enables steroid receptor coactivator 2 (SRC-2) [= nuclear receptor coactivator 2 (NCoA-2), = glucocorticoid receptor-interacting protein 2 ( GRIP2), =transcription intermediate factor 2 (TIF-2)] or SRC-1 binding is required for nuclear targeting. These conformational inductions of the RU486 hGRalpha protein structure are shown [next page, top and bottom].
From these considerations of the three-dimensional structure of the hGRalpha protein, it can be concluded that the previously hypothesized dimer is indeed unable to bind hGRalpha because it is too large to fit into the pocket of the hGRalpha ligand-binding domain (LBD). It certainly does not cause nuclear translocation.
Zika virus iflavivirus
this oneflavivirusThe family Flaviviridae are single-stranded (+) RNA viruses. Other important pathogens from the Flaviviridae family include hepatitis C, yellow fever, West Nile encephalitis, St. Louisa, Japanese encephalitis and dengue fever. They are transmitted by vectors (mosquitoes or ticks) and usually cause a mild flu-like infection that lasts less than a week. this oneflavivirusWithin their 3' untranslated regions (UTRs) is a unique set of secondary structures that play a role in their replication and ability to generate subgenomesflavivirus(sfRNA) when digested by host exonucleases. sfRNAs are of particular interest because they are thought to play a role in altering host metabolic pathways by altering host mRNA stability, RNAi, and DICER activity (Roby, 2014). sfRNA has been implicated in altering the immune response to promote viral pathogenicity (Chang et al., 2013) and recently identified a potential link between Zika virus, cerebellar malformations, and Guillain-Barré syndrome (Ricketson & Lyons-Weiller, 2016).
The Zika virus originated in West Central Africa and spread to parts of Africa, Asia and Micronesia in the early 2000s. When the virus began to spread rapidly in Brazil (2015), the introduction to the Americas attracted attention. Numerous concurrent cases have shown that Zika virus causes microcephaly and other birth defects in the fetuses of pregnant women (Johannson et al., 2016; Malkki, 2016) and an additional risk of increased incidence of Guillain-Barré syndrome (Cao-Lormeau et al., 2016). .; Paploski, 2016).
Microcephaly is caused by genetic and environmental factors. Genetic factors are estimated to occur in 1:30-50,000 live births, while environmental factors are more common and are estimated to occur in 1:10,000 live births. A link between Zlka and cerebellar malformations was discovered in Brazil in 2015 (Moron et al., 2016; Saiz et al., 2016; Slavov et al., 2016), and although the data are preliminary and difficult to correlate, it seems se da situation In 2015, the prevalence of microcephaly in the northeastern states of Brazil increased 4-5 times (Butler, 2016). The main risk seems to coincide with infection in the first trimester; Cauchenez et al. (2016) modeled case data in French Polynesia and estimated a 47.5-fold increased risk of microcephaly in early pregnancy if Zika virus infection occurs.
The CDC reported 3,988,076 births in the United States in 2014 (CDC Vital Statistics Report, 2015). The number of monthly births in the United States remains fairly constant, with the highest months being July and August each year (Live Science, 2010). Extrapolating data from 2006, 56.64% of children in 2016 will be conceived between March and September when Zika-infected mosquitoes spread across the country. Thus, 2,258,846 newborns would be exposed to an increased risk of microcephaly in the coming year. Using the 1:10,000 ratio as a guideline, this means that microcephaly in the United States could increase by 9.3% in the coming year.
Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system. The cause of GBS is unknown, but it has been shown to follow a bacterial or viral infection. Inappropriate stimulation of the immune system by certain infections is thought to be key to the induction of GBS. GBS is treated with plasmapheresis or immunoglobulin therapy to reduce its duration and severity. Glucocorticoid therapy, available for other autoimmune diseases, has been shown to increase the severity of GBS.
To date, only one study (Cao-Lormeau et al., 2016) has shown that Zika virus is the causative agent of GBS. Yung and Thoon (2016) modeled the increased risk of GBS after Zika virus infection using data collected from French Polynesia in 2015. They reported that the incidence of GBS increased from a baseline of 0.24 per 1000 to 0.41 per 1000. This corresponds to a 21-fold increased risk of GBS.
Frenzen (2008) using CDC data from 2004 calculates the annual health care cost of GBS in the US to be $1.7 billion per year. CDC data from 2015 put the incidence of GBS in the US at approximately 1:100,000. Mortality from GBS has been estimated in several studies by Alshekhlee et al. (2008) 2.58% and 3.9% respectively (van den Berg, 2013), but the differences can be large due to differences in demographics such as age and access to health care. Extrapolation of these statistics provides a very frightening scenario of a rapidly expanding Zika virus-infected population triggering a cascade of responses that affect GBS caseloads, health care costs, and mortality.
Side effects in patients receiving glucocorticoids with GBS are of particular interest to the compounds of this invention since they not only exhibit in vitro antiviral activity but also glucocorticoid antagonism. This means that PT150 and PT155, which have already been shown to be safe in phase II human clinical trials, may not only be able to treat the infection, but also reduce the risk and/or severity of GBS-infection.
PT150 (formerly known as ORG34517) is active against Flaviviridae, including Zika and yellow fever viruses, and possibly against some Picornaviridae such asPoliovirusThe proposed mechanism of action is as follows: PT150 is a known, clinically proven, potent and selective glucocorticoid receptor antagonist. Most Flaviviridae (excluding generaflavivirus) and all Picornaviridae contain an internal ribosome entry site (IRES), a 5'-noncoding region (5'-NCR) at the 5'-end of their (+)-ssRNA genomes. This IRES is in turn required for translation by the human host cell ribosome of the viral (+)-ssRNA genome into a polyprotein (which is cleaved by the host cell and virus-encoded proteases to produce the mature viral protein)
However, there is also a highly conserved non-coding region (NCR) at the 3'-end of the (+)-ssRNA genome, and the 3'-NCR exhibits a highly conserved RNA stem-loop secondary structure (refs. 22, 23) (See below)
The 3'-NCR binds several host cell proteins, one of which is hVIP/Mov34, which is the correspondingflavivirusDissemination (transcription/replication). hVIP/Mov34 (human Vpr-interacting protein) is a member of the eukaryotic initiation factor 3A (eIF3) family (ref. 26) and is required for the 3'-NCR of Flaviviridae to control replication (the exact role of replication in Flaviviridae is currently unknown and needs to be elucidated ). This is particularly shown in the 3'-NCR of Japanese encephalitis virus (JEV), a typicalflavivirusLike the Zika virus.
The Mov34 homologue serves as the S12 subunit of the 26S proteasome p40 (the proteasome is the "waste bin" of the human cell, it degrades all overused, misfolded and "proteasome"-like proteins Mov34 is a component of the eukaryotic initiation factor 3 (eIF3) complex: eIF3 subunit F p47 (37.5 kDa) and eIF3 subunit H p40 (39.9 kDa).Therefore, the Mov34-like protein appears to be a multifunctional HIV-1 vpr accessory gene product protein Vpr essential for life interacts with the human Mov34 protein, so Mov34 is named: human Vpr interacting protein (hVIP/Mov34). Mov34 is associated with the G2/M phase transition of the mammalian cell cycle, implying that the hVIP/Mov34 protein is essential for the transition from G2 to M phase of human cell division. The carboxy-end hVIP/Mov34 is critical for HIV-1-Vpr interaction and glucocorticoid-mediated signaling This defines a key interaction between the human Mov34 protein and the human glucocorticoid receptor alpha.
In the absence of Vpr or HIV-1 infection, full-length hVIP/Mov34 is expressed in the cytoplasm. However, the cytoplasmic localization pattern of the full-length hVIP/Mov34 protein shifted to a distinct nuclear localization pattern in cells expressing hVIP/Mov34 and HIV-1 Vpr. In contrast, Vpr did not change the localization pattern of hVIP/Mov34 mutants whose carboxy-terminal domain was deleted. The movement of hVIP/Mov34 supports previous work showing that Vpr triggers the activation of the glucocorticoid receptor complex. Dexamethasone was observed to mobilize hVIP/Mov34 to the nucleus, while mifepristone (RU38486) inhibited this effect. Interestingly, expression of the hVIP/Mov34 carboxy-terminal mutant was unresponsive to Vpr and unresponsive to dexamethasone. These data suggest that the carboxy-terminal domain of hVIP/Mov34 is critical for mediating the hVIP/Mov34-Vpr interaction and its hGRa response. These results support the idea that hVIP/Mov34 is a member of a complex array of translocating nucleoplasmic proteins regulated by HIV-1 infection and hGRalpha. Mov34 protein from mouse brain interacts with the 3'-noncoding region (3'-NCR) of Japanese encephalitis virus. Therefore, since Mov34 is the hGRa-binding partner, the flavivirus 3'-NCR is regulated by the human glucocorticoid receptor and is therefore susceptible to inhibition by glucocorticoid antagonists. Flaviviruses require Mov34 for optimal replication in human cells. The glucocorticoid antagonist mifepristone (RU38486) has been shown to inhibit Mov34 function in the context of HIV-1 infection. PT150 and possibly PT155 bind to the human glucocorticoid receptor alpha subtype (hGRalpha) as antagonists. The human glucocorticoid receptor subtype b (hGRb) is an inactive receptor. hGRa, the ligand for PT150 and/or PT155, is also an inactive complex bound by Hsp90, which in turn sequesters the human protein Mov34. This results in a blockageflavivirusReplication because Mov34 cannot bind the 3'-noncoding region (3'-NCR) of yellow fever and Zika virus. PT150 and PT155 act via the hVIP/Mov34 protein toflavivirus3′-noncoding region, also the origin of the subgenomeflavivirusRNA (sfRNA) is important for pathogenicity and immune evasion. Protein hVIP/Mov34 regulates human glucocorticoid receptor a and binds proteins hGRa and HIV-1 Vpr. The hVIP/Mov34 protein is required for optimal flavivirus replication and host pathogenicity, a role that requires binding of hVIP/Mov34 to the 3'-NCR and 3'-NCR-derived sfRNA. The hVIP/Mov34 protein binds toflavivirus3'-NCR and sfRNA, the exact mode of binding and further details remain unknown
PT155 inhibits more effectively than PT150flavivirusReplication, such as PT155 and HIV-1 replication.
Filoviridae is a family of the order Monogaviridae
Filoviridae include (2014):
belongs toMarburg virus: Marburg virus, virus vrane
belongs toebola virus: Tay Forest virus, Reston virus, Sudan virus, Ebola virus, Bundibugyo virus
belongs toVirus cuva: Lloviu virus
Filoviridae are single-stranded enveloped, non-segmented, negative-sense RNA viruses [(−)-ssRNA viruses]
Filoviridae show similarities with Rhabdoviridae, Paramyxoviridae and Boersviridae. Together they founded the Order Mononegavirales.
Compounds retinone (RTZ) and PT155 have the structural elements (lipophilic core/thiosemicarbazone head) required to inhibit octamerization of the EBOV matrix protein VP40 and loop-mediated RNA binding
RTZ has been shown to act as an in vitro inhibitor of EBOV replication in Vero cells.
RTZ inhibits the octamerization of the EBOV matrix protein VP40
Here we now show that PT155 also acts as an in vitro inhibitor of EBOV replication and, like RTZ, can act by inhibiting EBOV VP40 matrix protein octamerization and RNA binding in Vero cells (the first mechanism of action against filagoviruses).
In addition, PT150 and PT155 also antagonize Hsp90 in hGRa-expressing cells (another mechanism of action against filoviruses).
Results: Compound PT155 was highly active compared to the first Zika virus isolate (MR766) obtained in 1947 from rhesus monkey 766 in the Zika forest (Uganda). This activity was observed in HuH-7 cells of human hepatocellular carcinoma (HCC, hepatoma), established by Nakabayashi & Sato in 1982 from a liver tumor of a 57-year-old Japanese man). In cells that do not express functional human glucocorticoid receptor-alpha (hGRalpha), PT155 is generally inactive against Zika virus MR766. This strongly suggests that hGRalpha is involved in the antiviral activity of PT155 against Zika virus MR766.
Presumed mechanism of action: most Flaviviridae (excluding generaflavivirus) and all Picornaviridae contain an internal ribosome entry site (IRES), a 5'-noncoding region (5'-NCR) at the 5'-end of their (+)-ssRNA genomes. This IRES is in turn required for ribosomal translation of the viral (+)-ssRNA human host cell genome into a polyprotein that is cleaved by host cell- and virus-encoded proteases to produce mature viral proteins. However, there is also a highly conserved non-coding region (NCR) at the 3'-end of the (+)-ssRNA genome, and the 3'-NCR has a highly conserved RNA stem-loop secondary structure.
The 3'-NCR binds several host cell proteins, one of which is hVIP/Mov34, which is the correspondingflavivirusDissemination (transcription/replication). hVIP/Mov34 (human Vpr-interacting protein) is a member of the eukaryotic initiation factor 3A (eIF3) family and is required for the 3'-NCR of Flaviviridae to control replication (3'-NCR in Flaviviridae replication. The exact role is currently unknown and remains to be elucidated ). This is particularly shown in the 3'-NCR of Japanese encephalitis virus (JEV), a typicalflavivirusLike the Zika virus.
A glucocorticoid receptor (GR) agonist (dexamethasone) and a glucocorticoid antagonist (mifepristone, RU38486) interact with hVIP/Mov34. Specifically, GR agonists stimulate the translocation of hVIP/Mov34 into the nucleus, while mifepristone inhibits this translocation. Therefore, mifepristone may act as an hVIP/Mov34 antagonist, and this antagonism may inhibit Flaviviridae replication, as described in U.S. Pat. Patent No. Application forhepatitis virusHuman hepatitis C virus, through a detailed mechanism that is not yet understood.
Vero cell derivatives (Vero, Vero 76, Vero E6) do not contain human glucocorticoid receptors since they are derived from African green monkeys (Chlorocebus aethiops, Cercopithecus aethiops) kidney epithelial cells. they don't even containgreen pineGlucocorticoid receptor and Vero cells did not respond to dexamethasone. Therefore, in all Vero cell derivatives (Vero, Vero 76, Vero E6), the antiviral effect of PT155 against Flaviviridae would be masked.
hVIP/Mov34 protein can beflavivirusThe key to replication, infectivity and pathogenicity and antiflaviviral activity of PT compounds. The Moloney murine leukemia provirus insertion-disrupted protein of 36 kDa is correctly named:
The murine (mouse) gene Mov34 was first discovered in 1987 during mutational analysis of Moloney murine leukemia virus (MoMLV) proviral insertion mapping in mice: Retrovirus and mouse insertion mutation: Mov 34 Proviral point integration leads to early embryonic death
The murine (mouse) Mov34 gene was further studied in 1990, including chromosomal mapping of the human Mov34 ortholog: Molecular analysis of the Mov 34 mutation: transcripts disrupted by proviral integration in miceDrosophilaThe murine (mouse) gene Mov34 was cloned and sequenced in 1991 for a lethal mutation. The Mov34 homolog acts as the S12 subunit of the 26S proteasome p40 (the proteasome is the "waste bin" of the human cell, it breaks down all overused, misfolded and "proteasome" proteins)
Mov34-like proteins are components of the eukaryotic initiation factor 3 (eIF3) complex: eIF3 subunit F p47 (37.5 kDa) and eIF3 subunit H p40 (39.9 kDa)
Therefore, the Mov34-like protein appears to be a multifunctional HIV-1 vpr accessory gene product protein Vpr that is essential for life by interacting with the human Mov34 protein, thus Mov34 was named: human Vpr interacting protein (hVIP/Mov34). Mov34 is associated with the G2/M phase transition of the mammalian cell cycle, implying that the hVIP/Mov34 protein is essential for the transition from G2 to M phase of human cell division.
The carboxy terminus of hVIP/Mov34 is critical for HIV-1-Vpr interaction and glucocorticoid-mediated signaling. This defines a key interaction between the human Mov34 protein and hGRalpha.
In the absence of Vpr or HIV-1 infection, full-length hVIP/Mov34 is expressed in the cytoplasm. However, the cytoplasmic localization pattern of the full-length hVIP/Mov34 protein shifted to a distinct nuclear localization pattern in cells expressing hVIP/Mov34 and HIV-1 Vpr. In contrast, Vpr did not change the localization pattern of hVIP/Mov34 mutants whose carboxy-terminal domain was deleted. The movement of hVIP/Mov34 supports previous work showing that Vpr triggers the activation of the glucocorticoid receptor complex. Dexamethasone was observed to mobilize hVIP/Mov34 to the nucleus, while mifepristone (RU38486) inhibited this effect. Interestingly, expression of the hVIP/Mov34 carboxy-terminal mutant was unresponsive to Vpr and unresponsive to dexamethasone. These data suggest that the carboxy-terminal domain of hVIP/Mov34 is critical for mediating the hVIP/Mov34-Vpr interaction and its hGRalpha response. These results support the idea that hVIP/Mov34 is a member of a complex array of translocating nucleoplasmic proteins regulated by HIV-1 infection and hGRalpha. Mov34 protein from mouse brain interacts with the 3'-noncoding region (3'-NCR) of Japanese encephalitis virus. Therefore, since Mov34 is a binding partner of hGRalpha, the flavivirus 3'-NCR is regulated by the human glucocorticoid receptor and is therefore susceptible to inhibition by glucocorticoid antagonists. Flaviviruses require Mov34 for optimal replication in human cells. The glucocorticoid antagonist mifepristone (RU38486) has been shown to inhibit Mov34 function in the context of HIV-1 infection. PT155 binds human glucocorticoid receptor alpha isoform (hGRalpha) as an antagonist [human glucocorticoid receptor alpha isoform (hGRalpha) is an inactive ligand-independent receptor]. hGRalpha, a ligand of PT155, is also an inactive complex bound by Hsp90, which in turn sequesters the human protein Mov34. This results in a blockageflavivirusReplication because Mov34 cannot bind the 3'-noncoding region (3'-NCR) of yellow fever and Zika virus.
The hVIP/Mov34 protein binds the highly secondary structured RNA stem loopflavivirus3'-NCR:
The hVIPAVIov34 protein interacts with the subgenome derived from the 3'-noncoding region (3'-NCR)flavivirusRNA (sfRNA) produced by human host cell exoribonuclease XRN1 (5'→3'-exoRNase)
Summary of the mechanism of action of PT155flavivirusCongeners of yellow fever virus and Zika virus:
PT155 acts via the hVIP/Mov34 protein onflavivirus3′-noncoding region, also the origin of the subgenomeflavivirusRNA (sfRNA) is important for pathogenicity and immune evasion
hVIP/Mov34 protein regulates hGR□ and binds hGRalpha and HIV-1 Vpr proteins
The hVIP/Mov34 protein is essential for optimal flavivirus replication and host pathogenicity, which requires binding of hVIP/Mov34 to 3'-NCR-derived sfRNA and 3'-NCR
hVIP/Mov34 protein bindingflavivirus3'-NCR and sfRNA, the exact mode of binding and further details remain unknown
PT155 inhibits more effectively than PT150flavivirusReplication, such as PT155 and HIV-1 replication
Aktivnost PT150 and and PT155 and PT155 iflavivirusReplication can only be demonstrated in cells expressing the human glucocorticoid receptor-α
Finding the hVIP/Mov34 cofactor: Because the HIV-1 Vpr protein acts as a coactivator for hGRalpha and is dependent on hVIP/Mov34 for this coactivator function, it is likely that hVIP/Mov34 similarly requires a cofactor to bind the Zika virus 3'- NCR se binds to hGRalpha. Basic Local Alignment Search Tool (BLAST®) BLASTP 2.3.1+ pair is inactive for replication of dengue virus type 2 New Guinea C (NGC) strain in HuH-7 cells expressing hGRalpha, including PT155. a search for viral protein products with the largest sequence differences between Zika virus MR766 and dengue virus type 2 NGC was performed. This is expected to generate the hVIP/Mov34 cofactor required to recruit hGRalpha to the 3'-NCR of Zika virus, since this putative Zika virus cofactor is predicted to be non-functional in dengue type 2. This in turn could explain the inactivity of compounds PT, including PT155, with dengue virus type 2.
Flavivirus nonstructural protein 2A (NS2A) was found to show the least similarity or evolutionary conservation between Zika virus and dengue virus type 2. The absolute amino acid identity is only 29%, compared to 56% for the total polyprotein. This clearly indicates that the Zika virus NS2A protein is involved in the antiviral effect of PT155. The inactivity of PT compounds against dengue virus type 2 is due to the lack of affinity of PT compounds for the different NS2A proteins of dengue virus type 2.
This concordance was demonstrated by a report that showed that the flavivirus NS2A protein was associated with the correspondingflavivirus3'-NCR. In a recent comprehensive listing of all viral and host cytokines known to bindflavivirus3'-NCR, hVIP/Mov34 and NS2A have all been assigned as high-affinity ligands for the flavivirus 3'-NCR
PT155 and PT156 against human hepatitis C virus (Flaviridae,hepatitis virus) HuH-7 clone B (genotype 1a) replicates
RESULTS: PT155 and PT156 are active in the subgenomic replicon of human hepatitis C virus (HCV) genotype 1a (HCV-1a) HuH-7 cell-derived by C. M. Rice et al. in 2000. Establish. The sequence of this replicon is based on the genome of HCV-1a (isolate H77). PT156 was more active than PT155, while PT150 showed only marginal activity compared to HCV-1a (isolate H77) replication of the subgenomic RNA replicon of HuH-7 cells.
Mechanism of action: The effects of PT155 and PT156 on the hepatitis virus are mediated by the motif of thiosemicarbazone and 4-phenylthiosemicarbazone:
Human hepatitis C virus (HCV)-dependent RNA polymerase (RdRp) NS5B protein shares a common thiosemicarbazone binding motif.
HCV-1a (isolate H77) NS5B fingertip/finger RdRp motif I, which represents the thiosemicarbazone binding motif.
5,6-dimethoxyindan-1-one thiosemicarbazone (DMI-TSC) has been reported to inhibit bovine viral diarrhea virus type 1 (BVDV-1 strain NADL, Flaviviridae,Pestivirus) NS5B RdRp.
In a proof-of-concept study, structurally different thiosemicarbazones were found to be active as inhibitors of HCV genotype 1b (HCV-1b) (isolate Con1) RNA replication.
The anti-hepatitis pharmacophore in PT155 and PT156 is thiosemicarbazone or 4-phenylthiosemicarbazone.
Regarding the antiviral mechanism of action of PT155 and PT156 with the replication of the RNA subgenomic replicon of HCV-1a (isolate H77) HuH-7 cells, it is clear that it cannot be mediated by the glucocorticoid receptor because HCV does not contain a DNA phase in its life cycle. Recently, thiosemicarbazone (DMI-TSC) was reported to be active against bovine viral diarrhea virus type 1 (BVDV-1 strain NADL, Flaviviridae,Pestivirus) NS5B RdRp protein. BVDV-1 is generally considered a suitable surrogate for HCV because the two Flaviviridae polyprotein sequences are closely related (maximum sequence identity 32%) (see Appendix 1). Since the anti-HCV-1a activity of PT155 and PT156 was determined using a subgenomic replicon derived from HCV-1a (isolate H77) HuH-7 cells, which encodes only the nonstructural HCV proteins NS3, NS4A, NS4B, NS5A and NS5B, PT155 and PT156 must be limited to these five genes and/or gene products (proteins).
Implications of antiviral chemotherapy for hepatitis C infection: HCV is one of the main causes of chronic hepatitis, cirrhosis and hepatocellular carcinoma. According to the World Health Organization, approximately 2.2% of the world's population is infected with HCV, with more than a million new cases each year. Furthermore, 27% of these infected individuals eventually developed cirrhosis, and 25% of them eventually developed hepatocellular carcinoma. HCV is a positive-sense RNA virus that exhibits great genetic heterogeneity and high levels of resistance to antiviral drugs in vivo and in vitro. Therefore, the genetic variation of HCV represents a major problem for global public health.
Essentially, PT156 successfully targets the human HCV RNA-dependent RNA polymerase protein NS5B, a "hard" target involved in viral RNA replication ["hard" targets represent intracellular aspects; "soft" targets represent indispensable and compensable extracellular aspects of the viral life cycle, such as attachment/entry/fusion inhibitors (or neuraminidase inhibitors)]. This makes PT156 a potent antihepadnaviral compound worthy of further investigation.
Binding of phosphatidylserine
PS (serine cephalin) is an important lipid of the inner membrane in all human cells. PS stands for phospholipid, along with phosphatidylcholine (lecithin) and phosphatidylethanolamine (cholamin-cephalin). PS consists of 1,2-diacylglycerophospho-L-serine. 1,2-diacylglycerol-3-phosphate is also known as phosphatidic acid, hence the name "phosphatidyl". PS is usually only exposed on human cells in the case of apoptosis (programmed cell death, "voluntary cell suicide"). Enveloped viruses continuously expose PS on host lipid bilayer membranes. Enveloped viruses use this exposure to PS to evade attacks by the body's immune system and gain access to phagocytes such as monocytes/macrophages.
3-O-sn-phosphatidyl-L-serine (PS)
The structure of a typical PS, as shown in the figure, the 1-O position is stearic acid and the 2-O position is docosa-4,7,10,13,16,19-hexenoic acid. This represents the major serine cephalin derived from bovine brain. The composition of fatty acids in the 1-O and 2-O positions varies, depending, for example, on the type of cell. The polar head group (phosphoserine) is negatively charged. The phosphate anion charge and the cationic charge of the ammonium group neutralize each other. Therefore, PS has a net negative charge at physiological pH 7.4.
Sn-phosphatidylcholine (PC)
The structure of a typical PC, as shown in the figure, the 1-O position is stearic acid and the 2-O position is linoleic acid. This represents the main lecithin from egg yolk and human cell membranes. The composition of fatty acids in the 1-O and 2-O positions varies, depending on e.g. about the station type. The polar head group (phosphorylcholine) is zwitterionic. The phosphate anion charge and the cationic charge of the ammonium group neutralize each other. Therefore, PC is net neutral at physiological pH 7.4. Both ORG34517 and PT155 are associated with PS but not PC. Weak (stereospecific!) binding to PC was observed only for the PT155 component (E)-ORG34517 thiosemicarbazone, which was included in the three-component PT155 mixture. Therefore, PS binding of ORG34517 and PT155 is selective. Binding of ORG34517 and PT155 to PS was observed in PS micelles and PS non-micelles. The three components of PT155 [two (E/Z)-ORG34517 thiosemicarbazones and residual (original) ORG34517] were easily separated in a TLC run.
Most of the identified enveloped viruses susceptible to PS interception are RNA viruses:
Ebola and Marburg viruses (Filoviridae) | Ross River virus, Chikungunya virus, Sindbis virus, Eastern equine encephalitis virus (Togaviridae,alfa virus) | Vesicular stomatitis virus (Rhadoviridae,vesicular virus)|Amaparí virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus (Arenaviridae,breast virus)|West Nile virus, dengue virus, yellow fever virus (Flaviviridae,flavivirus) | Human immunodeficiency virus type 1 (Retroviridae,lentivirus) Moloney murine leukemia virus (Retroviridae,gama retrovirus) | Virus influence A (Orthomyxoviridae) | Respiratorni sincicijski virus (Paramyxoviridae), Pneumovirinae, Pneumovirusi)
Confirmed enveloped DNA viruses susceptible to PS interception are:
vacciniaVirus (poxviridae, chordopoxviridae,Ortopoksvirus)|Herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus)|humanCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus)|California autographVirus nuklearne poliedroze (Baculoviridae, Alphabaculoviridae) (virus insekata)
Important enveloped RNA viruses expected to be susceptible to PS interception are (significant human viruses are highlighted in red):
Ebola and Marburg viruses (Filoviridae) | Semliki Forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern/Western/Venezuelan equine encephalitis virus (Togaviridae,alfa virus) | Rubella virus (German measles) (Togaviridae,Ruby virus)|Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae,rabies virus)|Amapari virus, Pichindé virus, Tacaribe virus, Junín virus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae,breast virus)|West Nile Virus, Dengue Virus, Yellow Fever Virus, Zika Virus, Japanese Encephalitis Virus, St. Louisa, tick-borne encephalitis virus, Ohm hemorrhagic fever virus, Kisanur forest virus (flavivirus division,flavivirus)|Human hepatitis C virus (Flaviridae,hepatitis virus) | Human immunodeficiency virus type 1 (Retroviridae,lentivirus) | Influenza A/B (Orthomyxoviridae, common "flu" viruses) | Respiratory syncytial virus (Paramyxoviridae), Pneumovirinae, Pneumovirusi)|Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae, Henipavirusi)|Virus ospica (Paramyxoviridae, Paramyxovirinae,measles virus)
Expected enveloped DNA viruses susceptible to PS interception are:
Small pox (variola) virus (Poxviridae, Chordopoxvirinae,Ortopoksvirus)|Human hepatitis B virus (Hepadnaviridae,ortohepatotropni virus)|Hepatitis D virus (hepatitis D virus) (family not specified,delta virus)|Herpes simplex virus tip 1, herpes simplex virus tip 2 (Herpesviridae, Alphaherpesvirinae,simple virus)|humanCytomegalovirus(Herpesviridae, Betaherpesvirinae,Cytomegalovirus)
norovirus
norovirusIt infects humans and many other mammals, causing severe gastroenteritis.norovirusIt causes approximately 90% of abacterial gastroenteritis outbreaks worldwide (Lindesmith et al., 2003).norovirusIt has also been isolated from many other species including pigs, cattle, sheep and mice. Zoonotic potentialnorovirusLargely unstudied, it may represent a reservoir from which new strains can emerge (Thorne & Goodfellow, 2014). There is currently no vaccine and there is a great need for treatments that can shorten the course of the disease, the severity of symptoms, the period of infection and the loss of productivity and life.
this onenorovirusThe VP1 protein is unstable during capsid assembly and requires the host protein Hsp90 to assemble mature virions. Vaschist et al. (2012) showed that geldanamycin binds to Hsp90 and inhibits itnorovirusAssemble and sprout. Hsp90 forms a complex with GRα in the host cytosol and is therefore, according to the predicted stoichiometry, sensitive to the action of hGRα antagonists such as compounds PT15x:
[hGRα-PT150-(Hsp90)n]rice(n=1,2, . . ;rice=2)
The compounds of the invention have shown activity in both humans and micenorovirus, which suggests a wider applicationnorovirusIn veterinary medicine, research applications involving mice and human medical applications.
Results: PT150 is highly active on the replication of the self-replicating RNA replicon of HG23 cells derived from human norovirus HuH-7 [Norovirus (humannorovirus) genotype 1 (GT1), original isolate 1968., Hu/NV/Norwalk virus/1968/US (GenBank: M87661.2)].
Mechanism of action: In 2015, Vashist et al proposed heat shock protein 90 (Hsp90) as a therapeutic target for norovirus. The mechanism is apparently dependent on the glucocorticoid receptor, such as PT150, as a high-affinity ligand of the human glucocorticoid receptor-alpha (hGRalpha),norovirusReplicon RNA replicates while PT155 is mildly active and PT156 is inactive. PT150 can reduce the availability of Hsp90 by trapping Hsp90 in a transcriptionally inactive dimer complex:
[hGRalpha-PT150-(Hsp90)n]rice(n=1,2,. . . ;rice=2)
this onenorovirusThe capsid protein VP1 is a highly unstable protein that must be protected by the molecular chaperone Hsp90 to survive in the host cell cytoplasm. If Hsp90 is trapped by PT150 in an inactive complex with hGRalpha, thennorovirusVP1 is rapidly degraded by an unknown mechanism. Vashist et al. This has been proven by the use of geldanamycin derivatives. Geldanamycin and Hsp90, 17-allylamino-17-demethoxygeldanamycin [and water-soluble geldanamycin derivatives used in this study such as: 17-{N-[2-(dimethylamino)ethyl]amino}-17-demethoxygeldanamycin] binds, inhibitsnorovirusAssemble and sprout.
In conclusion, PT150 reduces the availability of norovirus Hsp90 by trapping Hsp90 in an inactive complex [hGRalpha-PT150-(Hsp90)n]m (n=1, 2, ...; m=2). This prevents the stabilization of the sensitive viral capsid protein VP1 and leads to the degradation of this component of the viral capsid by an unknown mechanism. result,norovirusAssembly and budding are abolished by the high-affinity hGRalpha ligand PT150.
The importance of antiviral chemotherapynorovirusInfection: PrototypenorovirusNorwalk virus was first described in 1972 as the cause of an outbreak of acute gastroenteritis in an elementary school in Norwalk, Ohio, USA. Norovirus is now recognized as the leading cause of gastroenteritis in developed and developing countries. Transmission is mainly through the fecal-oral route,norovirusInfections are usually acute self-limited gastrointestinal infections.norovirusGastroenteritis has recently been identified as an important cause of morbidity and mortality in immunocompromised individuals and can lead to long-term persistent disease.norovirusInfection is also associated with much more important clinical outcomes: necrotizing enterocolitis, infantile seizures, encephalopathy, intestinal pneumatosis, and disseminated intravascular coagulation, to name a few. In developing countries, an estimated 200,000 deaths of children under 5 are caused bynorovirusinfections, which were recently reported to be the second leading cause of gastroenteritis-related deaths in the United States, typically killing 797 people annually. Despite their significant impact, noroviruses remain one of the least characterized groups of RNA viruses, mainly because human noroviruses have not yet been grown efficiently in cell culture despite numerous attempts.
Noroviruses are members of the Caliciviridae family of small positive-sense RNA viruses, currently divided into five genera:Vesivirus、Lagovirus、Nebovirus、Sapovirusinorovirus.members of the genusnorovirusiSapporo virusIt can infect humans and cause gastroenteritis. belongs tonorovirusthey are divided into at least five genotypes (GT1-5). Genotypes GT1, GT2, and GT4 infect humans and cause acute gastroenteritis, but noroviruses have also been isolated from many other species, including pigs (GT2), cattle and sheep (GT3), and mice (GT5). A novel was recently publishednorovirusThe identification of a representative new GT6 genotype in domestic dogs with diarrhea was proposed. To date, zoonotic diseasesnorovirusNo infections have been reported, but there is clear evidence of the possibility of transmission. For example, human norovirus can infect germ-free piglets, and there is serological evidence of human norovirus in pigs. Although antibodies to norovirus GT6 have been found in veterinarians, it has not been determined whether the infection results in clinical disease. Additional research is needed to further clarify the zoonotic potential of norovirus and whether animals are hosts for the possible emergence of new strains.
addiction
The present invention provides therapeutic compositions and methods for alleviating addiction. This invention makes PT150 (formerly known as ORG34517) or its derivatives (eg, PT-155, PT-156, PT-157) a potent and selective corticosteroid antagonist for preventing signs and symptoms of physical withdrawal when taken addictively during withdrawal from an addictive compound or near withdrawal. The mechanism underlying this effect is that central nervous system (CNS) pathways that control body withdrawal depend on the binding of cortisol or other glucocorticoids. When blockade is established by administration of PT150 or its derivatives (eg, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof), the pathway is blocked and physical withdrawal symptoms are not produced. A broad field of addiction research has confirmed that corticosteroids appear to play an important role in other aspects of addictive behavior and mechanisms. They play a key role in facilitating the transition from recreational (or medical use of opioids) to compulsive use (ie, use fueled by physical dependence). The terminology for this change is tricky, but in simple terms, object tracking in animal models suggests that animals are paying more attention and exhibiting behaviors that are directly related to access to a rewarding substance. For example, when a rat presses a lever to receive food pellets containing opioids, the rat first focuses on the food delivery door and, among other things, scratches the door. However, when physical dependence occurs with repeated exposure to opioids, animals shift their attention and behavior to the stimulus that predicts drug delivery, the lever. This is called "following the flag".
For example, a similar human condition is an alcoholic who initially experiences rewarding thoughts and subjective feelings while drinking. With continued heavy drinking, the body becomes dependent. At this point, the cues of alcohol (which may include, for example, drinking buddies, bar signs, emotional stress or tension, the time of day or week when alcohol is usually consumed) provide the addict with a "reward" similar to actual drug abuse. This is a key sign that physical dependence has occurred. A number of animal studies and others investigating the transfer of these findings to humans have shown that increases in circulating corticosteroids are at least highly correlated with sign monitoring.
Dementia
According to the Alzheimer's Association, dementia is not a specific disease. It is an umbrella term that describes a set of symptoms associated with a decline in memory or other thinking skills that is severe enough to impair a person's ability to perform daily activities. Alzheimer's disease accounts for 60% to 80% of cases. Vascular dementia, which occurs after a stroke, is the second most common type of dementia.
Glucocorticoid receptor activity stimulated by the steroid hormone corticosterone disrupts neuronal function in the rodent hippocampus, a brain region critical for learning and memory formation in all mammals, and is known to occur in patients with Alzheimer's disease or major depressive disorder. The work that has been done has shown that such effects are dependent on over-activation of glucocorticoid receptors (GR; a consequence of hypercortisolemia) and subsequent enhancement of glutamate receptors via transcription and/or effects on receptor subunit turnover levels. The fact that Namenda® (memantine), a federally approved drug for the treatment of Alzheimer's disease, is a short-acting glutamate receptor inhibitor (reviewed in Zhou et al. 2016), supports these findings. Evidence for the role of receptors in brain preparation is decreasing.
The evidence discussed above also suggests that GR modulation may represent a therapeutic target in dementia, as hypothesized by Dhikav and Anand (2007), although clinical studies have not confirmed this possibility and selective GR antagonists or agonists have not been used, such as ORG34517 PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof. Subchronic treatment with the non-selective GR/progesterone receptor antagonist mifepristone prevents episodic memory loss in a mouse model of Alzheimer's disease. However, the lack of pharmacological specificity observed with mifepristone does not allow an unambiguous examination of GR signaling in this setting.
The study examined the effect of selective and competitive inhibition of GR using PT150 or PT155 on corticosteroid-induced neuronal loss in the hippocampus using a validated organotypic slice culture model. Rat hippocampal culture slices were surgically harvested and maintained in vitro for 5 days before experiments. After 5 days, transfer slice cultures to treatment wells containing corticosterone (0.1-1 µM) or corticosterone vehicle (peanut oil) for 5 consecutive days of treatment. Portions of these cultures, including corticosterone-exposed and untreated cultures, were also co-exposed to PT150 or PT155 (1–100 nM) in cell culture medium for 5 days. After 5 days, cultures were harvested to measure cytotoxicity (propidium iodide uptake and neuron-specific nucleoprotein immunoreactivity) and glutamate receptor density, or were exposed to the glutamate receptor agonist NMDA for 24 hours. In the latter culture, measurements of cytotoxicity and receptor density were assessed after exposure to NMDA. Exposure to corticosterone at concentrations greater than 1 nM for 5 days was shown to induce cytotoxicity in the cornu ammonis layer 1 pyramidal cells, which was attenuated by simultaneous exposure to PT150 and PT155. This cell layer is a region critical for memory formation in mammals and is known to degenerate in dementia. PT150 and PT155 were found to have effects on cell integrity in corticosterone-naive cultures. Furthermore, exposure to corticosterone enhances the NR2B subunit of ionotropic glutamate receptors and significantly enhances the neurotoxicity of NMDA itself, suggesting that elevated steroid hormone receptor-mediated glutamate signaling in brain regions contributes to important memory formation.
The subject invention provides requirements for methods of use and requirements for preparations of substances and preparations. In a specific embodiment, the present invention provides a composition containing a therapeutically effective amount of a GR antagonist (PT150 or PT155) and at least one cholinesterase inhibitor (Aricept, Exelon, Razadyne) and an additional therapeutic agent (name) for at least one of amantadine.
Amyloid beta (Aβ or Abeta) refers to a peptide of 36-43 amino acids that is closely associated with Alzheimer's disease as a major component of amyloid plaques found in the brains of Alzheimer's patients. These peptides are derived from amyloid precursor protein (APP), which is cleaved by β and γ secretases to produce Aβ. Ap is formed after sequential cleavage of amyloid precursor protein (APP), a transmembrane glycoprotein of unclear function. APP is cleaved by the proteolytic enzymes α-, β- and γ-secretase; Aβ protein is produced by the sequential action of β and γ-secretase. Aβ molecules can aggregate and form flexible soluble oligomers, which can exist in multiple forms. Certain misfolded oligomers (called "seeds") can induce other Aβ molecules to also adopt a misfolded oligomeric form, resulting in a chain reaction similar to prion infection. The seeds, or the resulting amyloid plaques, are toxic to nerve cells. Another protein associated with Alzheimer's disease, tau, also forms such misfolded prion-like oligomers, and there is some evidence that misfolded Aβ can induce tau misfolding.
Triboelectric PT155 can form nanomagnets in the brains of Morbus Alzheimer's disease, which leads to the destruction of aggregates of Aβ amyloid fibrils, more or less restoring brain function. Since Alzheimer's fibrils themselves are highly structured aggregates with an order of polarization, electromagnetic fields can be induced in the brain. The polarization order (orientational polarization of permanent dipoles) of Alzheimer's Aβ fibrils can be disrupted by inserting nanomagnetic materials into the Aβ supramolecularly ordered β-sheet, allowing them to be degraded by the proteasome.
Nanomagnets are submicron systems that exhibit spontaneous magnetic order (magnetization) at zero applied magnetic field (remanence). The small size of nanomagnets prevents the formation of magnetic domains. The magnetization dynamics of sufficiently small nanomagnets (usually unimolecular magnets) at low temperatures exhibit quantum phenomena such as macroscopic spin tunneling. At higher temperatures, random thermal fluctuations in magnetization (superparamagnetism) represent a limitation for the use of nanomagnets for permanent information storage.
autism
Autism is a neurodevelopmental disorder characterized by impaired social interaction, verbal and nonverbal communication, and limited and repetitive behavior. Parents usually notice these signs during the first two years of their child's life. These signs usually develop gradually, although some children with autism reach their developmental milestones at a normal pace and then regress. Diagnostic criteria require that symptoms become apparent in early childhood, usually before the age of three. Although autism is highly heritable, researchers suspect that environmental and genetic factors are to blame. In rare cases, autism is closely related to factors that lead to birth defects. Controversy surrounds the environmental rationale for other proposals. Autism affects information processing in the brain by changing the way nerve cells and their synapses are connected and organized; how this happens is not well understood. In DSM V, it is one of three disorders recognized in autism spectrum disorder (ASD), the others being Asperger's syndrome (lack of cognitive development and speech delay) and Pervasive Developmental Disorder, Not Otherwise Specified (often abbreviated as PDD-NOS ). , is diagnosed when the full range of criteria for autism or Asperger's syndrome is not met.
Triboelectrically charged PT155 can form nanomagnets in the brains of people with autism, resulting in unknown effects on nerve cells (neurons). Cortisol levels are believed to be elevated in autism spectrum disorders
Therapeutic preparations and procedures for the treatment and prevention of tuberculosis
Tuberculosis (TB) tops the list of infectious diseases worldwide, associated with 1.5 million deaths and 9.6 million infections in 2014. Tuberculosis kills one in three HIV-positive patients, with an estimated 480,000 cases of MDR-TB worldwide (WHO, 2016). There is no effective vaccine against tuberculosis. Existing chemotherapy drugs have a wide range of side effects and require long-term treatment to be successful, thus reducing the likelihood of drug resistance (Gillespie & Murphy, 2011; Korb et al., 2016).
pathogenic factor,Mycobacterium tuberculosis, using multiple strategies to manipulate the host immune response to enhance and evade clearance. After phagocytization by macrophages,Mycobacterium tuberculosisAvoid destruction by blocking full phagosome activation and altering the behavior of signaling molecules that regulate inflammation and adaptive immunity (Russell, 2007; Sasindran & Torrelles, 2011; Korb et al., 2016). Immunosuppressive effects of the Toll-like receptor (TLR) family using tumor necrosis factor alpha (TNF-α) and glucocorticoids (GC).
Antagonism of the GC pathway offers a potential way to alter the cellular behavior of infected cells to promote a prolonged immune response and clearance of tuberculosis (Brown et al., 1993; Bottasso, 2007).
combination therapy
Compositions and methods for the treatment of GC-responsive disorders, including, for example, as therapeutic agents for the prevention or addiction-induced anxiety and withdrawal side effects, for wound healing and transplantation, for the prevention or treatment of stress-induced osteoporosis, and Rapid Bone Healing This invention provides a related injury and regenerative therapy in subjects.
Embodiments of the present invention provide methods of treating a GC-reactive condition in a subject comprising administering a GR antagonist in combination with at least one additional therapeutic agent selected from at least one anxiolytic, at least one anxiolytic depressant, and at least one sedative. and combinations thereof, wherein at least one anxiolytic is selected from the group consisting of alprazolam, bromazepam, diazepam, lorazepam, clonazepam, temazepam, oxazepam Pan, flunitrazepam, triazolam, chlordiazepoxide, flurazepam, estazolam, nitrazepam and pharmaceutically acceptable salts, isomers and mixtures thereof that; and/or at least one selected from the antidepressants citalopram, escitalopram oxalate, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine; venlafaxine and duloxetine; harmaline, iproniazid, isocarboxazid, nialamide, pargyline, phenelzine, selegiline, toloxatone, trani cypromine, brofaromine, moclobemide; doxepin, doxepin, imipramine, isoprindol, lofepramine, melitracene, nortriptyline, opiramol, protriptyline, trimipramine; maprotiline, mianserin, nefazodone, trazodone and their pharmaceutically acceptable salts, isomers and combinations and/or at least one selected from haloperidol, droperidol, fenperidol, Tranquilizers triperidol, mepirone, renperone, azapelone, domperidone, risperidone, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, pericazine, promethazine, triflupromazine, levomepromazine, promethazine, pimozide, cyanamide, chlorprofixene, clopentix Tonne, flupentixol, thiothiophene, chlorothixene, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, iloperidone, zotepine , sertindole, lurasidone, aripiprazole and their pharmaceutically acceptable salts, isomers and combinations, in a therapeutically effective amount. In certain embodiments, the agents are administered in the same dosage form. In certain embodiments, the therapeutic agents are administered separately.
In a particular embodiment, the present invention provides a composition comprising a therapeutically effective amount of a GR antagonist and at least one selected from at least one anxiolytic, at least one antidepressant, and at least one antipsychotic. Additional therapeutic agents and their combinations, wherein at least one anxiolytic is selected from the group consisting of alprazolam, bromazepam, diazepam, lorazepam, clonazepam, temazepam, oxazepam, flunitrate Zepam, triazolam, chlordiazepoxide, flurazepam, estazolam, nitrazepam and their pharmaceutically acceptable salts , isomers and mixtures; and/or to at least one selected from citalopram, the antidepressant escitalopram oxalate, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine; venlafaxine and duloxetine; harmaline, iproniazid, isocarboxazid, nialamide, pargyline, phenelzine, selegiline, toloxatone, tranylcypromine, brofaromine, moclobemide; Doxepin, imipramine, isoprindol, lofepramine, melitracen, nortriptyline, opiramol, protriptyline, trimipramine; maprotiline, mianser Lin, nefazodone, trazodone and their pharmaceutically acceptable salts, isomers and combinations and/or at least one selected from haloperidol, droperidol, fenoperidol, triperidol Tranquilizers of , mepirone, renperone, azaperone, domperidone, risperidone, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, perricazine, promethazine, triflupromazine, levomepromazine, promethazine, pimozide, cyanamide, chlorprothixene, clopentixol, dropperidone thioxanthene, thiothiophene, zhuklotixene, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, imperidone ketone, zotepine, sertindole, lurasidone, aripiprazole and their pharmaceutically acceptable salts, isomers and combinations.
In certain embodiments, the agents are in the same dosage form. In certain embodiments, the therapeutic agents are in separate dosage forms.
The phrase "combined administration" as used herein refers to any form of administration of one or more GR antagonists and at least one additional therapeutic agent selected from at least one anxiolytic, at least one antidepressant, and at least one sedative and combinations thereof, wherein at least an anxiolytic is selected from the group consisting of alprazolam, bromazepam, diazepam, lorazepam, clonazepam, temazepam, oxazepam, flunitrazepam, triazolam, chlordiazepoxide, flurazepam, estazolam, nitrazepam and pharmaceutically acceptable salts, isomers and mixtures thereof; and/or at least one selected from the group consisting of citalopram antidepressants Pram, escitalopram oxalate, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine; venlafaxine and duloxetine; harmaline, iproniazid, isocarboxazid, nialamide, pargyline, phenelzine, selegiline, toloxatone, tranylcypromine, brofaromine, moclobemide; Ping, doxepin, imipramine, isoprindol, lofepramine, melitracen, nortriptyline, opiramo, protriptyline, trimipramine; maprotiline, rice anserine, nefazodone, trazodone and pharmaceutically acceptable salts, isomers and combinations thereof and/or at least one selected from haloperidol, droperidol, fenperidol and triperidol Tranquilizers Lido, mepirone, renperone, azaperone, domperidone, risperidone, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoroperazine, mesoridazine, pericasin, promethazine, triflupromazine, levomepromazine, promet hazine, pimozide and pharmaceutically acceptable salts, isomers and combinations thereof, in therapeutically effective amounts. In certain embodiments, the agents are in the same dosage form. In certain embodiments, the therapeutic agents are in separate dosage forms.
addiction and withdrawal
The present invention relates to methods and compositions for the treatment and alleviation of symptoms associated with substance abuse and abstinence. The subject invention relates to methods and preparations for the treatment of addiction to, for example, alcohol, drugs, caffeine, sugar, food, nicotine, opiates and/or marijuana.
Substance dependence and abuse is a multifactorial neurological disorder. Repeated exposure to various endogenous and exogenous substances over time leads to changes in neurotransmission circuits and adaptations of postreceptor signaling cascades. This modification of neurons has multiple effects. Among them, the ability of natural rewards to activate reward pathways is reduced, resulting in reduced motivation and mood and increased compulsive behavior that compensates for physiological changes.
Although the common perception behind addiction is a "reward loop," pleasure is not necessarily a strong motivator for people to become addicted. Instead, addictive behaviors stem from a strong desire to manage and/or avoid the anxiety that occurs when someone experiences withdrawal.
Traditional treatment of substance addictions, such as benzodiazepine abuse, is based on cognitive behavioral therapy or pharmacotherapy, or a combination thereof. However, traditional treatments fail because they do not address the changes in physiochemistry that occur as a result of addiction. As a result, conventional treatments to control withdrawal symptoms and cravings for addictive substances have limited success and often have unwanted side effects.
Therefore, there is a need for improved methods and compositions for preventing dependence and physical dependence on addictive substances. There is also a need for improved treatments to control cravings and withdrawal symptoms caused by substance abuse.
Accordingly, the present invention provides methods and compositions for preventing dependence and physical dependence on addictive substances. Also provided are methods and compositions for improved treatment of craving and withdrawal symptoms caused by substance abuse.
The present invention relates to the use of cortisol blockers (glucocorticoid receptor [GR] antagonists) as therapeutic agents and in combination with diagnostic agents in the prevention or side effects of addiction-induced anxiety and withdrawal.
The compounds of the invention can be administered enterally or parenterally. A mixture with pharmaceutically suitable excipients, for example as described in the standard reference Gennaro et al., Remington's Pharmaceutical Sciences. The compounds can be compressed into solid dosage units such as pills, tablets, or processed into capsules or suppositories. The compounds may also be administered in the form of solutions, suspensions, emulsions, eg as injections or eye drops, or as sprays, eg as nasal sprays, via pharmaceutically acceptable liquids. For the manufacture of dosage units such as tablets, common additives such as fillers, colorants, polymer binders and the like are considered. In general, any pharmaceutically acceptable additive that does not interfere with the function of the active compounds can be used. Suitable carriers with which the composition may be administered include lactose, starch, cellulose derivatives and the like or mixtures thereof used in appropriate amounts.
The compounds of this invention can be administered orally, topically, intravenously, and the like. The compounds can be administered in the form of solutions, suspensions or emulsions with pharmaceutically suitable liquids. The compounds may also be formulated as a patch, ointment or may be enclosed in devices for topical application to the skin.
The subject invention reflects the role of endogenous glucocorticoids (GC) in withdrawal from abuse and addiction (hereinafter referred to as "drugs" or "drugs", including but not limited to alcohol, nicotine, caffeine, cocaine) (including crack cocaine),marihuana, amphetamines (including meth), opioids and opioid analogs (including heroin, oxycodone, hydrocodone, hydromorphone, methadone), dextromethorphan, benzodiazepines, ecstasy (MDMA), GHB, barbiturates, khat, kratom, PCP, LSD, ketamine, cactus, mescaline , psilocybin, hallucinogens,sage, antidepressants, anxiolytics 5 drugs, sleep aids, anti-allergy drugs.
Increased circulating GC levels may be related to direct elevated effects of substance abuse or stress-related increases in GC in response to neuropsychiatric and physiological stress withdrawal.
The present invention relates to the co-administration of selective GC receptor antagonists, such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutical use during the active intoxication phase of drug use. Acceptable salts, pre-drug or post-drug withdrawal to reduce neuropsychiatric and physical withdrawal symptoms such as anxiety, hallucinations, restlessness, depression, delirium tremens, chills, tremors, tremors, akathisia, restlessness, restless legs syndrome, musculoskeletal pains, cramps, chills, weakness.
The present invention relates to a single dose of a GC receptor antagonist or continuous administration of a GC receptor antagonist for hours, days, weeks or months for the prevention and/or treatment of drug withdrawal symptoms.
Co-administration of this invention with anxiolytics and antidepressants may be considered for better control of episodic, sudden attacks of anxiety or depression. Periodic co-administration of this invention with anxiolytics and/or antidepressants.
The subject invention can also be used for the diagnosis of specific substances, namely alcohol, cocaine, caffeine, nicotine, etc. (for example, diagnostic tests using saliva, blood, plasma, serum, urine or tears as substrates). Specific levels of these components are monitored in individuals to prevent anxiety and withdrawal.
The present invention may also be used with cortisol diagnostics (eg, diagnostic tests using saliva, blood, plasma, serum, urine, or tears as substrates) to determine which individuals have elevated circulating cortisol or dysregulated cortisol and therefore may most likely benefit from administration of GC receptor antagonists.
The subject invention can be packaged for use alone, as a single dose (prescription or over-the-counter), as a limited number of time-limited doses in packages designed to specifically guide self-administration, and in conjunction with medication or a cortisol diagnostic test (using saliva, blood, plasma , serum, urine or tears as a substrate) for self-administration or application by a healthcare worker or technician.
androgen receptor antagonist
The compositions and methods of the invention may also employ one or more androgen receptor antagonists, for example in combination with a glucocorticoid receptor antagonist of the invention. For example, the invention provides at least one glucocorticoid receptor antagonist in combination with at least one androgen receptor antagonist, such as ARN 509 (4-{7-[6-cyano-5-(trifluoromethyl)-3-pyridinyl]-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]oct-5-yl}-2-fluoro-N-methylbenzamide). ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements, and unlike bicalutamide, ARN-509 does not exhibit agonist properties in the presence of AR overexpression.
Another example of an antiandrogen is bicalutamide, which has the chemical name (R,S)-N-(4-cyano-3-(4-fluorophenyl sulfonyl)-2-hydroxy-2-methyl-3-(trifluoromethyl)propanamide, flutamide ( trade name Eulexin), nilutamide (trade name Anandron and Nilandron) and bicalutamide (trade name Casodex) are nonsteroidal "pure" antiandrogens;5 - alpha-reductase inhibitors such as finasteride (trade name Proscar and Propecia), dutasteride (trade name Casodex and Avodart), bexosteramide, isosteramide, tulosteramide, and epristamide are antiandrogens because they block the conversion of testosterone to dihydrotestosterone (DHT); spironolactone (trade names Aldactone and Spirotone), a synthetic 17-spironolactone corticosteroid; cyproterone acetate ketone (trade names Androcur, Climen, Diane 35 and Ginette 35) is an anabolic steroid, a powerful antiandrogen that also has progestogenic properties.Hydroxyflutamide.
In some embodiments, steroidal or non-steroidal androgen receptor antagonists include, but are not limited to, flutamide, hydroxyflutamide, enzalutamide, bicalutamide, nilutamide, or a hydroxysteroid dehydrogenase inhibitor.
In one embodiment, the androgen receptor antagonist is enzalutamide (trade name Xtandi®, Astellas Pharma US, Inc.), also referred to herein as MDV3100, chemical name 4-(3-(4-cyano-3-) (trifluoromethyl)phenyl ) -5,5-dimethyl-4-oxo-2-thioamino-oxazolin-1-yl)-2-fluoro-N-toluamide.
The compositions and methods of the invention may also employ one or more androgen receptor antagonists, for example in combination with a glucocorticoid receptor antagonist of the invention. Androgen receptor antagonists can be selected from, for example, flutamide, nilutamide, enzalutamide, bicalutamide, ketozole, abiraterone, abiraterone acetate, oteronide, finarutamide, andramine, dutasteride, bexosteramide, isosteramide, tulosteramide, episteramine, dexamethasone, prednisone, leuprolide, gosera elin , triptorelin, Trirelin, Estrogen, MDV3100, Cyproteroneacetate, Spironolactone, Flutamide, Hydroxyflutamide, Enzalutamide and their combinations.
The selective androgen receptor (AR) antagonists contained herein are useful in a variety of conditions and diseases such as, but not limited to, male contraception; treatment of various androgen-related disorders such as hypersexuality and gender deviation; treatment including benign conditions including benign prostatic hyperplasia, acne vulgaris, androgenic alopecia and hirsutism; intentionally preventing or suppressing virilization in the case of transgender women undergoing sex reassignment treatment; antineoplastic agents and palliative, adjuvant or neoplastic agents for prostate cancer Adjuvant hormone therapy; reduces the incidence of prostate cancer and prevents or causes regression of prostate cancer.
Prostate cancer is one of the most common cancers in men worldwide and the leading cause of cancer death in men in the United States. Androgen receptor antagonist drugs, such as flutamide and bicalutamide, were originally designed to avoid the side effects of HT, but androgen agonism has been observed with hydroxyflutamide (the active form of flutamide) and bicalutamide. A composition of the present invention is a combination of a GCRA and, for example, an androgen receptor antagonist, which can be used to alleviate any condition associated with inappropriate activation of the androgen receptor. Besides prostate cancer, other examples of such conditions include acne, hirsutism, seborrhea, excess sebum, and alopecia. In order to exhibit the above therapeutic properties, the compound must be administered in an amount sufficient to inhibit the activation of the androgen receptor. In a typical embodiment, the compound is applied topically, which is particularly useful for hirsutism, alopecia, acne and hypersebum. Androgens have a powerful effect on hair loss, stimulating hair growth by prolonging the hair growth cycle (anagen phase) and increasing the size of hair follicles. Androgens are not required for scalp hair growth, but paradoxically, androgens are required for scalp hair loss in genetically predisposed individuals (androgenic alopecia), in which anagen duration and follicle size gradually decline. The composition of the present invention can also be used topically to reduce the production of seborrhea, more specifically to reduce seborrhea (oily skin), which can be used to reduce acne topically.
Poly(ADP-ribose) polymerase (PARP)
The compositions and methods of the invention may also employ one or more PARP inhibitors, for example in combination with a glucocorticoid receptor antagonist of the invention. Poly (ADP-ribose) polymerase (PARP) is also known as poly (ADP-ribose) synthase and poly ADP-ribosyltransferase. PARP catalyzes the formation of monomeric and polymeric (ADP-ribose) polymers that can attach to cellular proteins (and themselves), thereby altering the activity of those proteins. This enzyme plays a role in transcriptional regulation, cell proliferation and chromatin remodeling (see D'amours et al., Biochem., 342:249268, 1999).
Poly(ADP-ribose) polymerase plays an important role in promoting DNA repair, controlling RNA transcription, mediating cell death, and regulating immune responses. These actions enable PARJP inhibitors to target a wide range of diseases. (Virag L. et al., Pharmacol. Rev. 2002 54(3):375-429). In various preclinical cancer models and human clinical trials, PARP inhibitors have been shown to improve radiation and chemotherapy by increasing cancer cell apoptosis, limiting tumor growth, reducing metastasis, and prolonging the survival of tumor-bearing subjects. (WO 2007-084532; Donawho C.K. et al., Clin Cancer Res 2007 13(9):2728-37; Kummar S. et al., J Clin Oncol. 2009 27(16):2705-11).
PARP contains an N-terminal DNA-binding domain, an automodification domain and a C-terminal catalytic domain. Various cellular proteins interact with PARP. The N-terminal DNA-binding domain contains two zinc finger motifs. Transcription enhancer factor-1 (TEF-1), retinoic acid X receptor a, DNA polymerase a, X-ray repair cross complementation factor-1 (XRCC1), and PARP itself interact with PARP in this domain. The automodification domain contains the BRCT motif, which is one of the protein-protein interaction modules. This motif, originally found at the C-terminus of BRCA1 (breast cancer susceptibility protein 1), is present in various proteins associated with DNA repair, recombination and cell cycle checkpoint control. Octameric transcription factor 1 (Oct-1), yin-yang (YY)1, and ubiquitin-conjugating enzyme 9 (ubc9), which contain a POU homology domain, can interact with this BRCT motif in PARP.
More than 15 members of the PARP gene family exist in mammalian genomes. The PARP family of proteins and poly(ADP-ribose) glycohydrolase (PARG) degrade poly(ADP-ribose) to ADP-ribose, are involved in a variety of cellular regulatory functions, including DNA damage response and transcriptional regulation, and are involved in carcinogenesis and biology cancer. Several PARP protein families have been identified. Tankyrase was found to be an interacting protein of telomere regulatory factor 1 (TRF-1) and is involved in telomere regulation. Vault PARP (VPARP), a component of the Vault complex, functions as a nuclear-cytoplasmic transporter. PARP-2, PARP-3 and 2,3,7,8-tetrachlorodibenzo-p-dioxin inducible PARP (TiPARP) have also been identified. Therefore, poly(ADP-ribose) metabolism may be involved in various cellular regulatory functions.
A member of this gene family is PARP-1. The PARP-1 gene product is expressed at high levels in the nucleus and its activation depends on DNA damage. PARP-1 is believed to bind to DNA single- or double-strand breaks (DSBs) via its amino-terminal DNA-binding domain. This binding activates the carboxy-terminal catalytic domain and results in the formation of an ADP-ribose polymer on the target molecule. PARP-1 itself is a target for poly ADP-ribosylation due to its centrally located automodification domain. Ribosylation of PARP-1 results in the dissociation of the PARP-1 molecule from DNA. The whole process of association, ribosylation and dissociation takes place very quickly. It has been proposed that this transient binding of PARP-1 to sites of DNA damage results in the recruitment of the DNA repair machinery or may inhibit recombination long enough to recruit the repair machinery.
The source of ADP-ribose for the PARP reaction is nicotinamide adenosine dinucleotide (NAD). NAD is synthesized in cells where cellular stores of ATP are stored, so a high level of activation of PARP activity can quickly lead to depletion of cellular energy stores. Induction of PARP activity has been shown to lead to cell death, which correlates with depletion of cellular NAD and ATP pools. PARP activity is induced during many oxidative stress or inflammatory processes. For example, during reperfusion of ischemic tissue, reactive nitric oxide is produced, leading to the generation of additional reactive oxygen species, including hydrogen peroxide, peroxynitrate, and hydroxyl radicals. These latter species can directly damage DNA, and the resulting damage induces the activation of PARP activity. In general, sufficient activation of PARP activity appears to lead to depletion of cellular energy stores and cell death. A similar mechanism is thought to operate during inflammation when endothelial and proinflammatory cells synthesize nitric oxide, leading to oxidative DNA damage and subsequent activation of PARP activity in surrounding cells. Cell death resulting from PARP activation is thought to be a major contributor to the extent of tissue damage resulting from ischemia-reperfusion injury or inflammation.
PARP (poly ADP-ribose polymerase) is involved in a variety of DNA-related functions, including cell proliferation, differentiation, apoptosis, DNA repair, and effects on telomere length and chromosome stability (d'Adda di Fagagna et al., Nature Gen , 23( 1): 76-80, 1999). Excessive activation of PARP induced by oxidative stress depletes NAD+ and thus ATP, ultimately leading to cellular dysfunction or necrosis. This cellular suicide mechanism is associated with cancer, stroke, myocardial ischemia, diabetes, diabetes-related cardiovascular dysfunction, shock, traumatic CNS injury, arthritis, colitis, allergic encephalomyelitis, and various other forms of inflammation associated with a pathological mechanism. PARP has also been shown to associate and regulate the function of several transcription factors.
PARP inhibitors
Suitable PARP inhibitors for use in the compositions and methods of the invention include, but are not limited to, 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]-methanol [[(2R )-2- methylpyrrolidin-2-yl]-1H-benzimidazol-4-carboxamide (ABT-888), 8-fluoro-2-{4-[(methylamino)methyl]-phenyl}-1,3,4, 5-tetrahydro-6H -azepino-[5,4,3-cd]indol-6-one (AGO 14699), 4-methoxycarbazole (CEP 9722), 2-[4-[(3S)-piperidin-3-yl]phenyl]indole azole -7-carboxamide hydrochloride (MK 4827) and 3-aminobenzamide or their pharmaceutically acceptable salts. In some embodiments, the glucocorticoid receptor antagonists described herein, such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salt compositions thereof, are combined with poly ADP-ribose polymerase (PARP) inhibitors ( eg BSI201, Olaparib (AZD-2281), ABT-888, AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT-673, 3-aminobenzamide). Other examples of PARP inhibitors include pharmacological inhibitors of the enzyme poly ADP-ribose polymerase (PARP). Suitable PARP inhibitors may be iniparib, olaparib, rucaparib, veliparib or CEP 9722.
PARP inhibitors currently in clinical trials include: Iniparib (Sanofi), Olaparib (AstraZeneca), Rucaparib (Pfizer), Veliparib (Abbott), CEP-9722 (Cephalon), MK4827 (Merck), BMN-673 (Biomarin), and others.
refractory prostate carcinoma
The subject invention provides a method of treating and/or prophylaxis of drug-resistant prostate cancer in a patient in need of such treatment and/or prevention, comprising: administering to the patient a therapeutically effective amount of a GCR (glucocorticoid) as shown herein as an exemplary receptor), in combination with, for example, neoplasia therapy, including, for example, androgen receptor (AR) antagonists. Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer death in men in North America and Europe. New treatments are needed for the prevention and treatment of advanced and metastatic prostate cancer. Nutritional factors, particularly high protein and calcium intake, and the metabolic syndrome are known to alter the risk and progression of prostate cancer, but the molecular mechanisms by which diet is associated with prostate cancer are not well understood. There is also a link between prostate cancer and bone metabolism. Osteocalcin (OC) encodes a vitamin K-dependent hormone primarily produced by osteoblasts/osteocytes in bone, which regulates energy metabolism, and is also ectopically expressed in some prostate cancers with a tendency to metastasize to bone. Polymorphisms in OC are also associated with prostate cancer progression. Recent evidence has also identified a link between the bone transcription factor Runx2 and advanced prostate and breast cancer, as demonstrated by the effects of Runx2 ablation by RNA interference to suppress cell migration and invasive properties and prevent metastatic bone disease. Bone-secreted OC can directly target prostate cancer cells. Finally, androgen deprivation therapy is the mainstay of drug therapy for prostate cancer, but androgen ablation is often ineffective in controlling prostate cancer progression, and castration-resistant metastatic disease, especially bone, becomes incurable. Accumulating evidence indicates the existence of a putative androgen-sensing membrane receptor that mediates the rapid, non-genomic effects of androgens, which may also be involved in prostate cancer growth and metastasis. Nevertheless, a better understanding of the molecular mechanisms underlying nutritional risk factors, OC effects and androgen resistance in prostate cancer may reveal clues to possible new molecular targets that regulate prostate cancer growth and progression.
Neoplasia, cancer, neoplasm, proliferative disease, malignancy and its metastases
The present invention provides a method of treating neoplasia in a patient in need thereof, comprising: administering to the patient a therapeutically effective amount of a GCR (glucocorticoid receptor) antagonist, as exemplified herein, such as ORG 34517, PT150, PT155, PT156 , PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, optionally in combination with, for example, a neoplasia therapeutic. The term "neoplasia" as used herein also refers to tumors, proliferative diseases, malignant diseases and their metastases. Examples of cancerous diseases are head and neck adenocarcinoma (including salivary glands and oral cavity), gastrointestinal tract (including pharynx, esophagus, stomach, small intestine, colon, anus), lung, liver (including hepatocellular carcinoma, cholangiocarcinoma and mixed tumors). ), liver External biliary tract and gallbladder, pancreas (including ductal and acinar types), genitourinary tract (ovary, fallopian tube, endometrium, cervix and vagina, ureter, bladder, testis, epididymis, prostate) and skin appendages; head and neck (including salivary glands and oral cavity), gastrointestinal tract (including pharynx, esophagus, anus), lung cancer, intrahepatic and extrahepatic biliary system (including gall bladder), pancreas, genitourinary tract (including endometrium, cervix, vagina, ureters , bladder, testicles, epididymis, prostate) and skin appendages; germ cell tumors (including malignant teratoma, embryonal carcinoma, ovarian stromal tumor, yolk sac tumor, seminoma, choriocarcinoma); sarcomas (including leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, liposarcoma, chondrosarcoma, fibrosarcoma, Ewing sarcoma, malignant Schwannoma, alveolar soft tissue sarcoma, clear cell sarcoma, synovial sarcoma, osteosarcoma); malignancies of the central nervous system (including astrocytoma, oligodendroglioma, gliblastoma, adenoinoine syloma); carcinoma, cystadenocarcinoma, mucoepidermoid carcinoma); mixed cancers (including hepatocellular cholangiocarcinoma, carcinosarcoma, mixed neuroendocrine carcinoma, adenosquamous carcinoma); hepatocellular carcinoma; blastic malignant tumors (including hepatoblastoma, neuroblastoma, neuroblastoma, gangliocytoma) a, Wilms tumor); renal cell carcinoma; neuroendocrine carcinoma; thyroid cancer (including papillary, follicular, medullary, anaplastic); carcinoma of the parathyroid gland, pituitary gland, adrenal gland (including adrenocortical carcinoma, pheochromocytoma) and their combinations.
cancer therapy
Any therapy (eg, therapeutic or preventive agent) that is useful, has been used, is currently being used, or can be used for the prevention, treatment and/or control of cancer can be used for the prevention, treatment and/or control of cancer according to the method of this invention Patients with neoplasia and/or cancer stem cells. Further, such neoplasia and/or cancer stem cell monitoring may be used in combination with any cancer therapy of the invention. Therapies (eg, therapeutic or prophylactic agents) include, but are not limited to, peptides, polypeptides, fusion proteins, nucleic acid molecules, small molecules, mimetics, synthetic drugs, inorganic molecules, and organic molecules. Non-limiting examples of cancer therapy include chemotherapy, radiation therapy, hormone therapy, antiangiogenic therapy, targeted therapy, and/or biological therapy, including immunotherapy and surgery. In some embodiments, a prophylactic and/or therapeutically effective regimen includes administration of a combination of therapies. In some embodiments, ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof may be administered as an agent for the treatment or prevention of neoplasia. In certain embodiments, RU486 (mifepristone) can be administered as an agent for the treatment or prevention of neoplasia.
Examples of cancer therapy include, but are not limited to: acivicin; arubicin; alcodazole hydrochloride; actracin; penicillin; aldesleukin; amsacrine; anastrozole; anthracycline; anthramicin; asparaginazu; aspirin; azacitidine (Vidaza); azetepu; bisantrene hydrochloride; bisnafid dimesylate; bisphosphonates (e.g. pamidronate (Aredria), klodronate (Bonefos), zoledronska kiselina (Zometa), alendronate (Fosamax), etidronate, ibandoat, simadronate, risedronate and tiludronate); bezelesin; bleomycin sulfate; brekvinar sodium; bromide; sulfamil; actinomycin; calsterone; amide; timer carboplatin; carmustine; carbicin hydrochloride; carotene; sidiphenol; chlorambucil; cyclomycin; cisplatin; cladribine; kristenol mesylate; cyclophosphamide; cytarabine (Ara-C); dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine (Dacogen); Sredstvo za metiliranje, deksormaplatin; deazavanine; demethylguanine mesylate; dikinon; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate sol; dromostanolone propionate; diazoxamicin; edatrexate; eflornithine hydrochloride; EphA2 inhibitor; elsamitrucin; enloplatin; protection; epipropidine; epirubicin hydrochloride; ; Erubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; ethoprine; fadrozole hydrochloride; amine; foksuridin; fludarabine phosphate; fluorouracil; flucitabine; Bixing; ifosfamide; imofozine; imatinib mesilate (Gleevec, Glivec); interleukin II (including recombinant interleukin II, ili rIL2), interferon alfa-2a; interferon alfa-2b; interferon α-n1; interferon α-n3; interferon beta-I a; interferon γ-I b; isoproplatin; irinotecan hydrochloride; lanreotide acetate; ); letrozole; leuprolide acetate; lirozol hydrochloride; lomexol sodium; lomustine; loxoantrone hydrochloride; human milk protein; maytanzin; dušikov iperit hydrochloride; siplizumab (MedImmune Inc.; international publication br. WO 02/098370, which is here in its entirety included in the reference)); megestrol acetate; melengestrol acetate; melphalan; menogalil; mercaptopurine; methotrexate; methotrexate sodium; metropin; meturedepa; mifepristone; meteon mitocarcinoma; mitomycin; mitomycin tan; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogamicin; tissue 345 17 Omaplatin; Oxaliplatin; thiourea oxide; taxol; aspartase; puromycin; pentastin; pebramycin sulfate; superphosphamide; brobroxol; thiofloxacin; pyrrole anthraquinone hydrochloride; pramicin; plomestan; sodium porphyrin; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofuran; sodium sparsom cin; spirogermanijev hydrochloride; spiromustine; spiroplatin; streptomycin; streptozotocin; sulfadiazine; taxomycin; tikogalen sodium; tegafur; loksantrakinone; temoporfin; teniposide; troxidone; testosterone; thiamin; thioguanine; thiotepa; tiazofurin; tirapazamine; toremiphene citrate; trixolone acetate; trimetrexate phosphate; trimethopterin; trimethotrexate glucuronate; Triptorelin; Tobuzol hydrochloride; Uracil iperit; Urepa; Vapreotide; Verteporfin; Vinblastine sulfate Vincristine sulfate; Vinblastine sulfate; Vinblastine sulfate; Platinum; Genostatin; Zorubicin hydrochloride.
癌症治疗的其他例子包括但不限于：20-epi-1,25 二羟基维生素 D3； 5-乙炔尿嘧啶；阿比特龙；阿柔比星;酰基富烯；癸二酚；青霉素;阿地白介素； ALL-TK拮抗剂；六甲胺；氨莫司汀；胺氧嘧啶;氨磷汀；氨基乙酰丙酸；氨柔比星；安吖啶;阿那格雷;阿那曲唑;穿心莲内酯;血管生成抑制剂；拮抗剂D；拮抗剂G；安泰瑞克;抗背侧化形态发生蛋白-I；抗雄激素，前列腺癌；抗雌激素;抗肿瘤素；反义寡核苷酸；阿非迪霉素甘氨酸盐；凋亡基因调节剂；细胞凋亡调节剂；嘌呤酸； ara-CDP-DL-PTBA；精氨酸脱氨酶；阿苏分泌;阿他美坦;阿曲莫司汀； axinastatin 1;阿司他丁 2；阿司他丁 3；阿扎司琼；氮杂毒素；氮杂酪氨酸；浆果赤霉素 III 衍生物；巴拉诺;巴马司他； BCR/ABL拮抗剂；苯并二氢呋喃；苯甲酰星孢菌素； β-内酰胺衍生物； β-丙氨酸；倍他霉素 B；桦木酸； bFGF 抑制剂；比卡鲁胺；比生群;双氮丙啶基精胺；比萘敏;双司烯A；比泽莱辛;放气；溴吡胺;布多他坦；丁硫氨酸亚砜亚胺；钙泊三醇；钙磷蛋白C；喜树碱衍生物；金丝雀痘 IL-2；卡培他滨；甲酰胺-氨基-三唑；羧胺三唑； CaRest M3；卡恩 700；软骨衍生抑制剂；胡萝卜素;酪蛋白激酶抑制剂 (ICOS)；栗精胺；天蚕素B；西曲瑞克；二氢卟酚；氯喹喔啉磺胺；西卡前列素;顺式卟啉；克拉屈滨；氯米芬类似物；克霉唑;考利斯霉素A；考利斯霉素B；考布他汀A4；康普他汀类似物；芹菜素; crambescidin 816；克里斯那醇;隐藻素8；隐藻素A衍生物； curacin A;环戊蒽醌类；环铂;环霉素;阿糖胞苷；细胞溶解因子；细胞抑素;达克昔单抗；地西他滨；脱氢蛋白B；地洛瑞林；地塞米松;右磷酰胺；右雷佐生；右维拉帕米；地亚醌; didemnin B;双氧水;二乙基去甲精胺；二氢-5-氮杂胞苷；二氢紫杉醇，二恶霉素；二苯基螺莫司汀；多西紫杉醇；二十二烷醇；多拉司琼；多西氟尿苷；屈洛昔芬；屈大麻酚;多卡霉素 SA；依布硒啉;生态氮芥；雪草碱；依瑞科洛单抗；氟胺嘧啶;榄香烯;艾特福尔；表柔比星;爱普立特；雌莫司汀类似物；雌激素激动剂；雌激素拮抗剂；依他硝唑;磷酸依托泊苷；依西美坦；法卓唑;法扎拉宾；芬维A胺；非格司亭；非那雄胺;氟哌啶醇；氟唑斯汀；氟甾酮;氟达拉滨;盐酸氟柔诺新；福芬宁;福美坦；福三星;福莫司汀；钆泰克萨弗林；硝酸镓；加洛西他滨;加尼瑞克；明胶酶抑制剂；吉西他滨;谷胱甘肽抑制剂； HMG CoA 还原酶抑制剂（例如，阿托伐他汀、西立伐他汀、氟伐他汀、莱斯科、lupitor、洛伐他汀、瑞舒伐他汀和辛伐他汀）； hepsulfam;调蛋白；六亚甲基双乙酰胺；金丝桃素;伊班膦酸；伊达比星;艾多昔芬;艾德拉曼通;伊莫福新；伊洛司他；咪唑并吖啶酮；咪喹莫特；免疫刺激肽；胰岛素样生长因子-1 受体抑制剂；干扰素激动剂；干扰素；白细胞介素；碘苯胍；碘柔比星; ipomeanol, 4-iroplact;伊索拉定;异苯唑; isohomhalicondrin B;伊他司琼；茉莉内酯;卡哈拉利德 F； lamellarin-N三乙酸酯；兰瑞肽；来霉素;来诺司亭；硫酸香菇多糖；瘦素;来曲唑;白血病抑制因子；白细胞α干扰素；亮丙瑞林+雌激素+黄体酮；亮丙瑞林;左旋咪唑； LFA-3 TIP（Biogen, Cambridge, MA；国际公开号 WO 93/0686 和美国专利号 6,162,432）；利阿唑;线性多胺类似物；亲脂性双糖肽；亲脂性铂化合物；赖索林胺 7；洛铂; lombricine;洛美曲索；洛尼达明;洛索蒽醌；洛伐他汀；洛索立宾；勒托替康；镥泰克萨弗林；溶血茶碱；裂解肽；麦坦辛;甘露抑素A；马立马司他；母乳蛋白；马斯平;基质溶酶抑制剂；基质金属蛋白酶抑制剂；美诺加利；麦巴龙；米瑞林;蛋氨酸酶；甲氧氯普胺； MIF抑制剂；米非司酮；米替福新；米莫司汀；不匹配的双链 RNA；米妥瓜酮；米托内醇;丝裂霉素类似物；米托那非;丝裂霉素成纤维细胞生长因子皂草素；米托蒽醌；莫法罗汀;莫格司亭；单克隆抗体，人绒毛膜促性腺激素；单磷酰脂A+分枝杆菌细胞壁sk；莫匹达莫；多重耐药基因抑制剂；基于多种肿瘤抑制因子 1 的疗法；芥末抗癌剂；菌过氧化物 B；分枝杆菌细胞壁提取物；咪唑啉酮； N-乙酰地那林； N-取代的苯甲酰胺；那法瑞林; nagrestip;纳洛酮+喷他佐辛；纳帕文;萘酚;那托司亭;奈达铂；新柔比星；奈立膦酸;中性内肽酶；尼鲁米特；尼沙霉素;一氧化氮调节剂；氮氧化物抗氧化剂；硝氮磷; O6-苄基鸟嘌呤；奥曲肽；奥昔酮；寡核苷酸；奥那司酮；甲氧嘧啶;口服细胞因子诱导剂；奥马铂；奥沙酮;奥沙利铂;奥霉素;紫杉醇;紫杉醇类似物；紫杉醇衍生物；帕劳胺;棕榈酰根瘤菌素；帕米膦酸；人参三醇；帕诺米芬； parabactin;帕齐利汀；门冬酶；紫地碱;戊聚糖多硫酸钠；喷司他丁;戊唑;全氟隆;过磷酰胺；紫苏醇；吩嗪霉素；乙酸苯酯；磷酸酶抑制剂；匹西巴尼；盐酸毛果芸香碱；吡柔比星；吡氨嘧啶;维生素A；维生素B；纤溶酶原激活剂抑制剂；铂络合物；铂化合物；铂-三胺络合物；卟啉钠；泊菲霉素；强的松;丙基双吖啶酮；前列腺素 J2；蛋白酶体抑制剂；基于蛋白 A 的免疫调节剂；蛋白激酶 C 抑制剂；蛋白激酶 C 抑制剂，微藻；蛋白酪氨酸磷酸酶抑制剂；嘌呤核苷磷酸化酶抑制剂；红紫素;吡唑并吖啶；吡哆醇化血红蛋白聚氧乙烯；英国皇家空军拮抗剂；雷替曲塞;雷莫司琼； ras法尼基蛋白转移酶抑制剂； ras抑制剂； ras-GAP 抑制剂； retelptine去甲基化；铼 Re 186 依替膦酸盐；根瘤菌素；核酶； RII 视黄酰胺；罗列酰亚胺;罗希妥金；罗姆肽;罗喹美司； rubiginone B1;红木酚;香叶酚；圣托平；萨尔中国大学；肌醇A；沙格司亭； Sdi 1模拟物；司莫司汀；衰老衍生抑制剂 1；有义寡核苷酸；信号转导抑制剂；信号转导调制器； γ 分泌酶抑制剂，单链抗原结合蛋白；西唑呋喃；索布佐生；硼酸钠;苯乙酸钠；溶剂醇；生长调节素结合蛋白；索纳敏；斯帕福酸；穗霉素D；螺莫司汀；脾胃素;海绵抑素1；角鲨胺；干细胞抑制剂；干细胞分裂抑制剂； stipiamide;溶基质素抑制剂；磺胺嘧啶;超活性血管活性肠肽拮抗剂；苏拉迪斯塔；苏拉明;苦马豆素；合成糖胺聚糖；他莫司汀； 5-氟尿嘧啶；亚叶酸；他莫昔芬甲基碘;牛磺莫司汀；他扎罗汀；替考加仑钠；替加氟；碲吡喃；端粒酶抑制剂；替莫泊芬；替莫唑胺；替尼泊苷;四氯十氧；四氮唑胺;沙利巴斯汀；硫珊瑚碱；血小板生成素;血小板生成素模拟物；胸腺法新;胸腺生成素受体激动剂；胸腺三聚糖;促甲状腺激素；锡乙基紫红素；替拉扎明；二氯化钛；头孢;托瑞米芬；全能干细胞因子；翻译抑制剂；维甲酸;三乙酰尿苷；曲西林；三甲蝶呤;曲普瑞林;托烷司琼；图甾醇;酪氨酸激酶抑制剂；酪氨酸蛋白酶； UBC 抑制剂；乌苯美司；泌尿生殖窦源性生长抑制因子；尿激酶受体拮抗剂；伐普肽；瓦里奥林 B；载体系统，红细胞基因治疗；沙利度胺；维拉雷醇；维胺; verdins;维替泊芬；长春瑞滨；长春沙汀；抗整合素抗体（例如，抗整合素 avb3vorozol; zanotedon; ziniplatin; zirasubb; i zinostatin stimalamer.
A non-limiting list of compounds that can be used to target cancer stem cells includes: interleukin 3 receptor (IL-3R) and CD123 inhibitors (including peptides, peptide conjugates, antibodies, antibody conjugates, antibody fragments, and antibody fragment conjugates that target the IL-3R or CD123 ); cantharidin; norcantharidine and its analogues and derivatives; Notch pathway inhibitors, including γ-secretase inhibitors; sonic hedgehog/smooth pathway inhibitors, including ring dopamine and its analogs; CD96 antibodies; certain NF-kB/proteasome inhibitors, including parthenolide and its analogs; certain triterpenoids, including triptolide; certain mTOR inhibitors; targeting compounds and antibodies directed at the urokinase receptor; penicillins; certain inosine monophosphate dehydrogenase (IMPDH) inhibitors; PPAR-alpha and PPAR-gamma agonists and antagonists (including pioglitazone, tesaslitazar, muraglitazar, peliglitazar, lobeglitazone, balaglitazone, ragaglitazar, rosiglitazone, farglitazar, sodeiglitazar, reglitazar, naveglitazar, oxeglitazar, metaglitase, netoglitazone, darglitazone, englitazone, thiazolidinediones, aleglitazone, eglitazone, rivoglitazone, troglitazone, imiglitazar and sipoglitazar); telomerase inhibitors; EpCAM (ESA) antibodies; GSK-3 beta agonists and antagonists (including lithium, 6-bromoerythrine-3'-oxime (BIO), TDZD8); Inhibitors of the Wnt pathway, including frizzled or small molecule antibodies that inhibit Disheveled/Frizzled or β -catenin; anti-CD20 antibodies and conjugates (eg, Rituxan, Bexxar, Zevalin) for multiple myeloma or melanoma New uses; anti-CD133 antibodies; anti-CD44 antibodies; IL-4 antibodies; certain differentiation agents such as versnarinone; CD33 targeting compounds, such as antibodies or betulinic acid; small molecules or antibodies against SDF-1; small molecules or antibodies against the multidrug resistance pump; survivin inhibitors; XIAP inhibitors; small molecules targeting Bc1-2; CLL-1 antibodies; and furin inhibitors (such as cucurbitacin).
An additional non-limiting list of compounds that may also be used to target cancer and/or cancer stem cells include: i) antibodies, antibody fragments, and proteins that are naked or conjugated to therapeutic moieties that target specific cell surfaces target cancer stem cells, or ii ) small molecules known in the art, including molecules that can be further optimized (e.g., by chemistry) or identified using cancer stem cell-based screening (e.g., molecules that determine whether a compound interferes with proliferation) or by standard detection methods Cancer stem cell viability, cellular surface and intracellular targets include (not limited to): Rex1 (Zfp42), CTGF, activin A, Wnt, FGF-2, HIF-1, AP-2gamma, Bmi-1, nucleotidedestemin, hiwi, Moz -TIF2, Nanog, beta- arrestin-2, Oct-4, Sox2, stella, GDF3, RUNX3, EBAF, TDGF-1, noda1, ZFPY, PTNE, Evi-1, Pax3, Mcl-1, c-kit, Lex -1, Zfx, lactadherin, aldehyde dehydrogenase, BCRP, telomerase, CD133, Bc1-2, CD26, Gremlin and FoxC2.
In some embodiments, the therapy is an immunomodulator. Non-limiting examples of immunomodulators include protein agents such as cytokines, peptide mimetics and antibodies (eg, human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, polyclonal antibodies, Fvs, ScFvs, Fab or F(ab) 2 fragments or epitope-binding fragments ), nucleic acid molecules (eg antisense nucleic acid molecules and triple helices), small molecules, organic and inorganic compounds. Specifically, immunomodulators include, but are not limited to, methotrexate, leflunomide, cyclophosphamide, cyclophosphamide, Immuran, cyclosporine A, minocycline, azathioprine, antibiotics such as FK506 (tacrolimus), methylprednisolone (MP), corticosteroids, steroids, mycophenolate mofetil, rapamycin ( sirolimus), mizoribine, deoxyspergualine, brequinar, dinitrile amides (eg leflunomide), T-cell receptor modulators, cytokine receptor modulators and mast cell modulators. Additional examples of immunomodulators can be found, for example, in paragraphs 259-275 of US Publication No. 2005/0002934 Al, which is incorporated herein by reference in its entirety. In one embodiment, the immunomodulator is a chemotherapeutic agent. In an alternative embodiment, the immunomodulator is an immunomodulator other than the chemotherapeutic agent. In some embodiments, the therapy used in accordance with the invention is not an immunomodulator.
In some embodiments, the one or more therapies are anti-angiogenic agents. Non-limiting examples of antiangiogenic agents include proteins, polypeptides, peptides, fusion proteins, antibodies (eg, human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, polyclonal antibodies, Fvs, ScFvs, Fab fragments, F(ab)2 fragments, and antigenic antibodies) . their binding fragments), such as antibodies that specifically bind TNF-α, nucleic acid molecules (eg antisense molecules or triple helices), organic molecules, inorganic molecules and small molecules that reduce or inhibit angiogenesis. Additional examples of anti-angiogenic agents can be found, for example, in paragraphs 277-282 of US Publication No. 2005/0002934 Al, which is incorporated by reference in its entirety. In other embodiments, the therapy is not an anti-angiogenic agent.
In certain embodiments, the one or more therapies are alkylating agents, nitrosoureas, antimetabolites and anthracyclines, topoisomerase II inhibitors, or mitosis inhibitors. Alkylating agents include, but are not limited to, busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, decarbazide, mechlorethamine, melphalan, and temozolomide. Nitrosoureas include, but are not limited to, carmustine (BCNU) and lomustine (CCNU). Antimetabolites include, but are not limited to, 5-fluorouracil, capecitabine, methotrexate, gemcitabine, cytarabine, and fludarabine. Anthracyclines include, but are not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, and mitoxantrone. Topoisomerase II inhibitors include, but are not limited to, topotecan, irinotecan, etopiside (VP-16), and teniposide. Inhibitors of mitosis include, but are not limited to, taxanes (paclitaxel, docetaxel) andEvergreenAlkaloids (vinblastine, vincristine and vinorelbine). In some embodiments of the invention, the treatment comprises administration of cantharidin or an analog thereof. The invention includes the use of agents that target cancer stem cells. In certain embodiments, the agents act alone. In other embodiments, the agent is directly or indirectly associated with another therapeutic moiety. Non-limiting examples of therapeutic moieties include, but are not limited to, alkylating agents, antimetabolites, plant alkaloids, cytotoxic agents, chemotherapeutic agents (eg, steroids, cytarabine, fluorouracil, methotrexate, aminopterate, mitomycin C, demecolchicum, etoposide, mithramycin, calicheamicin, CC- 1065, chlorambucil or melphalan), radionuclides, therapeutic enzymes, cells Factors, toxins, including plant toxins, fungal toxins, bacterial toxins (eg deglycosylated ricin A chain, ribosome inactivating protein, α-parscin, aspergillin, restrictocin, ribonuclease, diphtheria toxin,Pseudomonasexotoxins, bacterial endotoxins or the lipid A part of bacterial endotoxins), growth regulators and RNases. In some embodiments, the reagent used is a marker binding reagent, e.g. antigen to the cancer stem cell. In a specific embodiment, the agent binds an antigen expressed at a higher level on cancer stem cells than on normal stem cells. In a specific embodiment, the agent specifically binds a cancer stem cell antigen that is not a normal stem cell. In other embodiments, the one or more therapies are agents that bind markers to cancer stem cells. In one embodiment, the reagent that binds to a marker on a cancer stem cell is an antibody or an antibody or antibody fragment conjugated to a therapeutic moiety.
For example, in a specific embodiment, the agent specifically binds the IL-3 receptor (IL-3R). In some embodiments, the IL-3R binding agent is an antibody or antibody fragment specific for IL-3R. In some embodiments, antibodies or antibody fragments are chemically or recombinantly conjugated to therapeutic moieties (eg, chemotherapeutic agents, toxins of plant, fungal, or bacterial origin, radionuclides) using a linker to achieve a cell-killing response. In certain embodiments, the antibody, antibody conjugate, antibody fragment, or antibody fragment conjugate binds to the alpha subunit of IL-3R (ie, the CD123 antigen). In other embodiments, the antibody, antibody conjugate, antibody fragment, or antibody fragment conjugate binds IL-3R and comprises both alpha and alpha. and .beta. subunit. Methods for making anti-IL-3R antibodies and anti-IL-3R antibody mimetics are described in U.S. Pat. patent no. LOUSE. patent no. 6,733,743 B2, the entire contents of which are incorporated herein by reference.
In other embodiments, the agent that binds to a marker on the cancer stem cell is a ligand. In some embodiments, the ligand is a cytokine that binds to a cytokine receptor on the cancer stem cell. In a specific embodiment, the ligand is interleukin 3 (IL-3), which can be conjugated to a therapeutic moiety, including a chemotherapeutic agent, a toxin of plant, fungal or bacterial origin, or a radionuclide. In one embodiment, the prophylactic and/or therapeutic therapy or regimen of the IL-3-conjugate may be in the form of a recombinant fusion protein, wherein the conjugate is a toxin and the toxin is a protein, such as diphtheria toxin. Methods for the preparation and isolation of IL-3-diphtheria toxin fusion protein (IL3DT) are described in Frankel et al., "Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias," Leukemia 14:576 (2000 ) and Urieto et al., Protein Expression and Purification 33:123-133 (2004), the disclosure of which is incorporated by reference in its entirety.
In certain embodiments, the antibody or fragment thereof that binds the marker to the cancer stem cell is substantially non-immunogenic in the treated subject. Methods of obtaining non-immunogenic antibodies include, but are not limited to, chimeric antibodies, humanized antibodies, and isolation of antibodies from the same species as the subject being treated. Antibodies or fragments thereof that bind markers in cancer stem cells can be generated using techniques known in the art. See, e.g., §§ 539-573 of U.S. Publication no. 2005/0002934, which is incorporated by reference in its entirety.
In some embodiments, the treatment includes using X-rays, gamma rays, and other radiation sources to destroy cancer stem cells and/or cancer cells. In particular embodiments, radiation therapy is administered as external beam radiation or teletherapy, in which radiation is directed from a remote source. In other embodiments, radiation therapy is administered as internal therapy or brachytherapy, wherein the radiation source is placed in the body in close proximity to cancer stem cells, cancer cells, and/or tumor masses.
In some embodiments, the therapy used is a proliferation-based therapy. Non-limiting examples of such therapies include chemotherapy and radiation therapy as described above.
Currently available therapies and their dosages, routes of administration, and recommended uses are known in the art and are described, for example, in the Physician's Desk Reference (60th ed., 2006).
In a specific embodiment, cyclic therapy involves administering a first cancer therapeutic agent for a specified period of time, followed by a second cancer therapeutic agent for a specified period of time, optionally followed by a third cancer therapeutic agent for a specified period of time, and so on AND sequentially administering repeated, i.e., cyclically, to reduce the development of resistance to cancer therapy, to avoid or reduce side effects of cancer therapy, and/or to improve the effectiveness of cancer therapy.
When two prophylactically and/or therapeutically effective regimens are administered to a subject at the same time, the term "concurrently" is not limited to administering the anticancer therapeutics at exactly the same time, but rather means that they are administered to the subject sequentially within a time interval, so that they may act together ( eg act synergistically to provide increased benefit compared to administration by other means). For example, anticancer therapeutic agents can be administered simultaneously or sequentially in any order at different time points; however, if not administered simultaneously, they should be administered close enough in time to achieve the desired therapeutic effect, preferably in a synergistic manner. The combination anticancer therapeutics can be administered separately, in any suitable form and by any suitable route. When the components of a combination anticancer therapeutic are not administered in the same pharmaceutical composition, it is understood that they may be administered in any order to a subject in need thereof. For example, a first prophylactic and/or therapeutically effective regimen may be (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours , 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or before 12 weeks), at the same time or subsequently (eg 5 minutes, 15 minutes ), 30 minutes , 45 minutes , 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks , 8 weeks or 12 weeks later) another anticancer drug is administered to a subject in need. In various embodiments, the cancer treatment agent is administered at 1 minute intervals, 10 minute intervals, 30 minute intervals, less than 1 hour intervals, 1 hour intervals, 1 to 2 hour intervals, 2 to 3 hour intervals hours, 3 to 4 hours. hourly intervals Hourly interval of application at intervals of 4 to 5 hours, at intervals of 5 to 6 hours, at intervals of 6 to 7 hours, at intervals of 7 to 8 hours, at intervals of 8 to 9 hours, at intervals of 9 hours to 10 hours, at an interval of 10 hours to An interval of 11 hours Hours, at intervals from 11 to 12 hours, with intervals not longer than 24 hours or not longer than 48 hours. In one embodiment, the anticancer drug is administered at the same visit. In another embodiment, the combination cancer therapeutics are administered at intervals of 1 minute to 24 hours.
In specific embodiments, combination therapies share the same mechanism of action. In another specific embodiment, each combination therapy has a different mechanism of action.
Treat or prevent infections associated with an acute or chronic injury or illness
The present invention provides a method of treating or preventing an infection associated with an acute or chronic injury or disease in a patient in need thereof, comprising: administering to the patient a therapeutically effective amount of a GCR (glucocorticoid receptor) antagonist, as exemplified herein, e.g., ORG34517 , PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts, alone or in combination with, for example, another agent. In particular, the present invention can be used to minimize life-threatening complications, including complications of surgery or clinical interventions, in humans resulting from burns, shock, stroke, heart attack, or other bodily events that result in cell, tissue, or organ injury, which is due to trauma. Soldiers wounded on the battlefield or civilians wounded at the scene of a natural disaster or terrorist attack are situations where this treatment could be useful.
The invention is suitable for protecting, preserving or stabilizing vital organs such as the heart and brain, other nerve tissues and cells, kidney tissue, lung tissue, muscle tissue, liver and other tissues in the body.
In one embodiment, the invention provides a method for reducing damage to cells, tissues or organs in the body following trauma by administering to the body a composition comprising: (i) a glucocorticoid receptor antagonist and optionally (ii) another agent.
The term "trauma" is used here in its broadest sense to refer to a serious or severe injury, wound or shock to the body. Trauma can be the result of unintentional physical damage (or injury) to the body, such as a traffic or industrial accident, childbirth, surgery, heart attack, stroke, burns, complications from surgery or other medical interventions. Trauma can be the result of physical injury, whether in or out of hospital. Trauma is often associated with in-hospital (eg, hospital emergency rooms), during emergency evacuation, or out-of-hospital settings where the trauma occurs (eg, domestic or industrial accidents, traffic accidents, battlefields, and terrorist attacks. Trauma treatment may also include resuscitation in many cases Example Sexual injuries include, for example, burns, shock, stroke, heart attack, or other physical events, including complications of surgery or clinical interventions due to trauma Soldiers injured on the battlefield or at the scene of a natural disaster or terrorist attack Civilians are situations in which such treatment may be useful. The invention provides a method of treating or preventing infection associated with an acute or chronic injury or disease, the method comprising administering a minimum therapeutically effective amount of a glucocorticoid receptor antagonist.
The activity of GR agonists and their changes in cellular function are variable and depend on complex intracellular molecular signals specific to cells and tissues. Among the cells with receptors for glucocorticoids are stem and progenitor cells of all tissues and organs in the body. Therefore, the binding of these molecules to normal "intra-tissue" stem cells and to the progeny of these stem cells (so-called "transit-amplified" progenitors) results in various cell- and tissue-specific effects, inhibiting or enhancing stem cell and progenitor cell function. it includes activation, proliferation, migration and differentiation, all depending on the tissue/organ in question.
GR antagonists or agents, such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof, will thus block GR-agonist activation in a tissue-specific manner. the function of some stem/progenitor cells and inhibiting the function of others. GR antagonists will have beneficial effects in certain clinical settings where regenerative medicine approaches can be used to treat disease and heal wounds, including: improving post-transplant function of autologous stem cell transplantation (depending on the source tissue and/or target tissue).
Reduction of the perioperative effects of catabolic stress hormones associated with surgery or other physical trauma (eg war injuries) where the acute or chronic injury or disease is selected from vascular events, stroke, cardiac arrest, acute limb infarction accident/battlefield trauma, limb trauma , Hip, Brain injury, Trauma after surgery, Major orthopedics, Thoracic, Abdominal, Neurosurgery.
Systemic GR blockade is not appropriate, but direct topical application of ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts to the site of injury/trauma (eg to prevent wound dehiscence) either by direct injection or intravascular by infusion (for internal organ injuries) would be useful.
central nervous system injury
The subject invention provides a method for treating or preventing damage to the central nervous system in a patient in need thereof, comprising: administering to the patient a therapeutically effective amount of a GCR (glucocorticoid receptor) antagonist, as exemplified herein, e.g., ORG34517, PT150 , PT155 PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts, alone or in combination with, for example, another agent. Conditions suitable for treatment according to the present invention include, for example, epilepsy, pain syndromes, neurodegenerative diseases (including motor neuron disease, myelopathy, radiculopathy, and disorders of the sympathetic nervous system), dementia, cerebrovascular disorders, movement disorders, cerebral trauma, cranial nerve disorders, neuropsychiatric disorders and other diseases Neuropathy (including viral neuropathy, diabetes-related neuropathy, Guillain-Barré syndrome, dysproteinemia, transthyretin-induced neuropathy, and carpal tunnel syndrome). As used herein, seizure disorders include complex partial seizures, simple partial seizures, secondary generalized partial seizures, generalized seizures (including absence, grand mal seizures (tonic-clonic), status epilepticus, tonic, atonic, myoclonus), neonatal and infantile spasms , drug-induced seizures, trauma-induced seizures and febrile seizures and other specific epilepsy syndromes such as juvenile myoclonic epilepsy, Lennox-Gastaut, medial temporal lobe epilepsy, frontal lobe nocturnal epilepsy, progressive epilepsy with mental retardation and progressive myoclonic epilepsy such as seizures associated with mass lesions of the central nervous system.
Pain syndromes include, for example, headache (eg, migraine, tension and cluster headaches), acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain and inflammatory pain, drug-induced neuropathic pain, causalgia, pain, complex pain, regional pain type I and II syndrome and reflex sympathetic dystrophy (RSDS).
Neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, ALS, spinal muscular atrophy, prion-related diseases of muscular dystrophy, cerebellar ataxia, Riedrich's ataxia, SCA, Wilson's disease, RP, Gullian Barre syndrome, adrenoleukodystrophy, Menke's Sx, Cerebral autosomal dominant arteriopathy with subcortical infarction (CADASIL), Charcot Marie Tooth neurofibromatosis, von-Hippel Lindau, fragile X, spastic paraplegia, tuberous sclerosis, Wardenburg syndrome, spinal motor atrophy, Tay-Sachs, Sandoff disease, familial spastic paraplegia, myelopathy, neurological Root disease, encephalopathy associated with trauma, radiation, drugs, and infection, and disorders of the sympathetic nervous system (eg, Shy Drager (familial autonomic disorder), diabetic neuropathy, drug-induced neuropathy, and alcoholic neuropathy).
Dementias include Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, Huntington's disease and MCI.
Cerebrovascular disorders suitable for treatment in accordance with the present invention include cerebrovascular disease and stroke (eg, thrombotic, embolic, thromboembolic, hemorrhagic [including AVM and berry aneurysm], venoconstrictive and venous).
Movement disorders include Parkinson's disease, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, and Tourette syndrome. Brain trauma as used herein includes traumatic brain and spinal cord injury as well as radiation brain injury. Cranial nerve disorders include trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, and Bell's palsy.
Neuropsychiatric disorders including panic syndrome, generalized anxiety disorder, all types of phobias, mania, manic depression, hypomania, unipolar depression, depression, stress disorder, post-traumatic stress disorder, somatoform disorders, personality disorders, psychoses and schizophrenia) and substance dependence/addiction ( eg alcohol, psychostimulants (eg crack, cocaine, speed, methamphetamine), opioids and nicotine) and drug-induced mental illness.
Other neuropathy diseases that can be treated with the compositions and methods described herein include Guillain-Barré, diabetes-related neuropathy, dysproteinemia, transthyretin-induced neuropathy, neuropathy associated with HIV, herpes viruses (including herpes zoster), or other neuropathy associated with viral infections, lyme disease, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis neuropathy, cranial multiple neuritis, heavy metal neuropathy, transition metal neuropathy, drug-induced neuropathy, postmeningitis syndrome, postpolio syndrome, prion disease and radiation-related neurological syndrome. Other diseases amenable to treatment by the present invention include fatigue syndromes (eg, chronic fatigue syndrome and fibromyalgia), ataxia syndromes, olivopontocerebellar degeneration, striatonigral degeneration, and brain axonal damage.
The invention is particularly useful in the treatment of neuropsychiatric disorders such as depression, agitation, anxiety, epilepsy such as grand mal seizures, status epilepticus, treatment and prevention of migraine, Alzheimer's disease, Parkinson's disease and traumatic brain and spinal cord injuries.
Furthermore, the higher doses achieved by this invention are expected to be particularly important for dementias including Alzheimer's disease, Parkinson's disease and vascular dementia, pain syndromes including headache and migraine, epilepsy, movement disorders and traumatic brain injury.
In addition, the ease of use and convenience of the dosage forms offered have been developed to be administered once daily or administered less frequently in therapeutically effective amounts from the start of treatment, which is important in the treatment of diseases including Alzheimer's disease and Parkinson's disease. It has value in dementia, epilepsy, pain syndrome and cerebrovascular diseases.
Improved memory and/or performance. Situational stress can lead to elevated levels of circulating cortisol, which in turn impairs short-term memory formation. For example, student testing periods in high school, college, and graduate school, as well as professional certification and licensing exams, can lead to such stress and thus lead to self-defeating cortisol-related learning deficits that can impair learning-based memory and lead to Expect worse test results. The invention is particularly useful for the treatment and/or prevention of short-term memory impairment, for example, single or sequential administration of a glucocorticoid blocking compound or composition of the invention before and during testing, which will prevent inhibition of short-term memory -term memory formation, to improve learning and subsequent performance test.
Immunomodulatory effect
The pharmaceutical preparation of this invention may additionally contain one or more excipients to further increase its immunomodulatory effect, such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts, alone or in combination with immune system modulators (eg, EL-1R antagonists) for prophylaxis of trauma with high risk of bacterial infection (eg, wound infection, pneumonia, colitis, pyelonephritis, liver and spleen abscesses) and sepsis after or after illness-related systemic immunosuppression Enabled are new preparations and methods that advantageously use compounds with a newly defined immunomodulatory function, or compounds with the ability to mimic that immunomodulatory function, or combinations of such compounds. For the purposes of this disclosure, the terms "immunomimetic", "immunomodulator", "immunomodulator", "immunomodulator", "immune control agent", "immunosuppressant", "immunosuppressant", etc. refer to the response of the secretory immune system (ie, dimeric /polymeric IgA and pentameric IgM) mediated by newly discovered Poly-Ig receptors or Poly-Ig-like receptors to newly discovered cancer cells in most cases Inhibition of growth (ie, proliferation) via receptors (also classified as Fc-like receptors), not immune function of the immune system, which is usually based on antibody/antigen recognition. In this context, the terms "immunomodulation" or "immunopotentiation" refer specifically to these cytostatic immunoglobulins that modulate or enhance the secretory immune system. The term "immunomimetic" refers to a substance that can act in a similar way to an immunoglobulin inhibitor of cell growth (eg, tamoxifen). However, in some contexts, references to "natural immunosuppressants", "immunopotentiators", "immunomodulators", "immune system", "immunotherapy" and "immune response", etc., where the terms are intended to have conventional meanings and the context so dictates, in particular when describing methods, compounds and preparations from the state of the art. Reference is made below to conventional definitions or "new" meanings, or both, where appropriate. The compounds of this invention, such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts or derivatives thereof defined in accordance with the synergistic effect of this invention, and as stated above above mentioned, excipients which may be optionally included in the pharmaceutical composition of the present invention are preferably thereby achieved. Depending on the different types of excipients, different mechanisms can be considered in this sense. In general, any substance that affects the immune system in the form of a "danger signal" (LPS, GP96, etc.) The immune stimulation produced by the agent is amplified and/or targeted. Particularly preferred adjuvants are cytokines, such as monokines, lymphokines, interleukins or chemokines, which additionally stimulate the innate immune response, such as IL-1, IL-1, IL-2, IL-3, IL-4 receptor antagonists, IL-5, IL-6, EL-7, IL-8, EL-9, ELIO, IL-12, EL-13, EL-14, EL-15, EL-16, IL-17, EL-18, IL -19, EL-20, EL-21, EL-22, DL-23, EL-24, IL-25, EL-26, EL-27, EL-28, EL-29, EL-30, EL- 31 , EL-32, EL-33, INF-alpha, EFN-beta, INF-gamma, GM-CSF, G-CSF, M-CSF, LT-beta or TNF-alpha, hGH and other growth factors.
The pharmaceutical preparation of this invention may additionally or alternatively contain any other compound known for its binding affinity to the human Toll-like receptors TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7 (as a ligand), TLR8, TLR9, TLR10, or due to of its binding to murine Toll-like receptors TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 or TLR13 Affinity (as a ligand).
immune inflammatory disease
Another aspect of the present invention relates to the use of the compounds and/or combinations of the present invention as therapeutic agents for the prevention and/or treatment of immunoinflammatory diseases. The term "immunoinflammatory disease" encompasses a variety of conditions, including autoimmune diseases, proliferative skin diseases, and inflammatory skin diseases. Immune-inflammatory diseases lead to the destruction of healthy tissue through inflammatory processes, dysregulation of the immune system and unwanted cell proliferation. Examples of immunoinflammatory diseases are acne vulgaris; acute respiratory distress syndrome; Addison's disease; allergic rhinitis; allergic intraocular inflammatory disease, inflammation of small blood vessels associated with antineutrophil cytoplasmic antibodies (ANCA); ankylosing spondylitis; arthritis, asthma; atherosclerosis; atopic dermatitis; autoimmune hepatitis; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease; Bell's palsy; bullous pemphigoid wounds; cerebral ischemia; chronic obstructive pulmonary disease; liver cirrhosis; Cogan syndrome; contact dermatitis; chronic obstructive pulmonary disease; Crohn's disease; Cushing's syndrome; dermatomy itis; Diabetes mellitus; Discoid lupus erythematosus; Eosinophilic fasciitis; erythema nodosum; exfoliative dermatitis; fibromyalgia; focal glomerulosclerosis; focal segmental glomerulosclerosis; giant cell arteritis; gout; gouty arthritis; transplantation medicine against the host; hand eczema; allergic purpura; herpes in pregnancy; hirsutism; idiopathic keratoscleritis; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; immune thrombocytopenic purpura inflammatory bowel disease or gastrointestinal disease, inflammatory skin disease; lichen planus; lupus nephritis; lymphomatous tracheobronchitis; macular edema; multiple sclerosis; myasthenia gravis; my ositis; non-specific fibrotic lung disease; osteoarthritis; pancreatitis; pemphigoid pregnancy; pemphigus vulgaris; periodontitis; polyarteritis nodosa; polymyalgia rheumatica; scrotal pruritus; pruritus/inflammation, psoriasis; psoriatic arthritis; cytoplasm of lung tissue; rheumatoid arthritis; relapsing polychondritis; rosacea caused by sarcoma ooidosis; Rosacea due to scleroderma; rosacea caused by Sweet's syndrome; systemic lupus erythematosus rosacea caused by urticaria; rosacea caused by pain associated with shingles; sarcoidosis; scleroderma; segmental glomerulosclerosis; septic shock syndrome; shoulder tendonitis or bursitis; Sjogren's syndrome; Steele's disease; death of brain cells from a stroke; Sweet's disease; systemic lupus erythematosus; systemic sclerosis; Takayasu arteritis; temporal arteritis; toxic epidermal necrolysis; transplant rejection and transplant rejection syndromes; tuberculosis; type 1 diabetes; ulcerative colitis; uveitis; vasculitis; and Wegener's granulomatosis.
As used herein, "non-cutaneous inflammatory conditions" include, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease. "Inflammatory skin disorder" or "inflammatory skin disease" means a disease selected from the group consisting of psoriasis, punctate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, acute febrile neutrophilic dermatosis, eczema, steatotic eczema, hyperhidrotic eczema, vesicular palmoplantar eczema, inflammatory disorders acne vulgaris, atopic dermatitis, contact dermatitis, allergic contact dermatitis, dermatitis myositis, exfoliative dermatitis, hand eczema, acne, rosacea, rosacea caused by sarcoidosis, rosacea caused by scleroderma, rosacea caused by Sweet's syndrome, systemic lupus erythematosus rosa cea , urticaria, rosacea caused by pain associated with herpes zoster, Sweet disease, neutrophilic hidradenitis, impetigo asepticum, drug eruption, seborrheic dermatitis, pityriasis rosea, cutaneous Kikuchi disease, pruritic urticarial papules and macules gravidarum, Stevens-Johnson syndrome and toxic epidermal necrolysis, tattoo reaction, Wells syndrome (eosinophilic cellulitis), reactive arthritis (Reiter's syndrome), gut-related dermatosis-arthritic syndrome, rheumatoid neutrophilic dermatosis, neutrophilic hidradenitis, dorsal neutrophilic dermatosis, plasma cell balanitis, balanoposthitis, Behcet's disease, erythema annulare centrifugal, erythema persistent dyspigmentation, erythema multiforme, granuloma annulare, hand dermatitis, lichen glossy, lichen planus, lichen sclerosus and lichen atrophic, lichen simplex chronicum, lichen acanthus, nummular dermatitis, pyoderma gangrenosum, sarcoidosis, subcorneal pustular dermatosis, urticaria and acantho sis lytic dermatosis.
"Proliferative skin disease" refers to a benign or malignant disease characterized by accelerated cell division in the epidermis or dermis. Examples of proliferative skin diseases are psoriasis, atopic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinoma of the skin, lamellar ichthyosis, epidermosporiosis, analytical hyperkeratosis, precancerous keratosis, acne, and seborrheic dermatitis. As will be appreciated by those skilled in the art, a particular disease, disorder or condition may be characterized by proliferative and inflammatory diseases of the skin. An example of such a disease is psoriasis.
Symptoms and signs of inflammation associated with specific conditions include: Rheumatoid arthritis: associated joint pain, swelling, warmth, and tenderness; generalized and morning stiffness; insulin-dependent diabetes; Complications, including: retinopathy, neuropathy, nephropathy; coronary artery disease, peripheral vascular disease and cerebrovascular disease; autoimmune thyroiditis: weakness, constipation, difficulty breathing, edema of the face, hands and feet, peripheral edema, bradycardia; multiple sclerosis: - spasms, blurred vision, dizziness, weakness, paresthesia; uveoretinitis: reduced night vision, loss of peripheral vision; lupus: joint pain, rash, photosensitivity, fever, muscle pain, edema of hands and feet, abnormal urine analysis (hematuria, cylindrical urine, proteinuria), glomerulonephritis, cognitive impairment, vascular thrombosis, pericarditis; scleroderma: Raynaud's disease; swelling of hands, arms, legs and face; thickening of the skin; pain in fingers and knees, swelling and stiffness, gastrointestinal dysfunction, restrictive lung disease; pericarditis; kidney failure; other arthritic conditions with an inflammatory component, eg rheumatoid spondylitis, osteoarthritis, suppurative arthritis and polyarthritis: - fever, pain, swelling, tenderness; other inflammatory disorders of the brain such as meningitis, Alzheimer's disease, AIDS dementia encephalitis: - photophobia, memory loss of cognitive functions; other inflammatory conditions of the eye such as retinitis: vision loss; inflammatory skin conditions such as eczema, other dermatitis (e.g. atopic dermatitis, contact dermatitis), psoriasis, ultraviolet radiation (sunlight, etc.) Inflammatory bowel diseases such as Crohn's disease, ulcerative colitis: pain, diarrhea, constipation, rectal bleeding , fever, arthritis; asthma: difficulty breathing, wheezing; other allergic diseases, such as allergic rhinitis: sneezing, itching, runny nose associated with acute trauma, such as brain injury after a stroke - loss of sensation, loss of movement, loss of cognition; myocardial ischemia Damage to heart tissue: - pain, difficulty breathing; lung injury, as occurs in respiratory distress syndrome in adults: difficulty breathing, hyperventilation, reduced oxygenation, pulmonary infiltrates; inflammation with infection, such as sepsis syndrome, septic shock, toxic shock syndrome: fever, respiratory failure, tachycardia, hypotension, leukocytosis; other inflammatory conditions associated with certain organs or tissues, for example: (ii) appendicitis: - fever, pain, tenderness, leukocytosis; (iii) gout: - Pain, tenderness, swelling and erythema in the affected joints, elevated serum and/or uric acid; (iv) Inflamed gallbladder: abdominal pain and tenderness, fever, nausea, leukocytosis; (v) Congestive heart failure: difficulty breathing, wheezing, peripheral edema; (vi) Type II diabetes: end-organ complications including cardiovascular, ocular, renal, and peripheral vascular disease; (vii) Pulmonary (pulmonary) fibrosis (viii) Vascular disorders such as atherosclerosis and restenosis: - pain, loss of sensation, weak pulse, loss of function; (ix) Syndromes leading to graft rejection Immunity: - Pain, tenderness, fever.
neurodegenerative disease
Another aspect of the present invention relates to the use of the compounds and/or combinations of the present invention as therapeutic agents for the prevention and/or treatment of neurodegenerative diseases. Examples of active agents include, for example, ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof.
The invention generally relates to the fields of neurology and psychiatry and methods of protecting the cells of the central nervous system of mammals from damage or injury. Various injuries or traumas to the central nervous system (CNS) or peripheral nervous system (PNS) produce profound and long-lasting neurological and/or psychiatric symptoms and disorders. One form this can take is the progressive death of neurons or other central nervous system (CNS) cells, known as neurodegeneration or neuronal degeneration. For example, neuronal degeneration due to; Alzheimer's disease, multiple sclerosis, cerebrovascular insult (CVA)/stroke, traumatic brain injury, spinal cord injury, optic nerve degeneration such as ischemic optic neuropathy or degenerative retinal disorders and other central nervous system disorders are a big problem. medical and public health problem due to high morbidity and frequency of long-term consequences. Animal studies and clinical trials have shown that amino acid transporters (especially glutamate), oxidative stress and inflammatory responses have a strong influence on cell death in these conditions. After injury or ischemic injury, damaged neurons release large amounts of the neurotransmitter glutamate, which is excitotoxic to surrounding neurons. Glutamate, a negatively charged amino acid, is an excitatory synaptic transmitter in the mammalian nervous system. Although glutamate concentrations in nerve endings can reach the millimolar range, its extracellular concentration is kept low to prevent neurotoxicity. It has been observed that glutamate can be toxic to neurons if present in high concentrations. The term "excitotoxicity" has been used to describe the cytotoxic effects of glutamate (and other such excitatory amino acids) on neurons when administered at high doses.
Patients with any type of injury or damage to the central (CNS) or peripheral (PNS) nervous system, including the retina, may benefit from neuroprotective approaches. Such injury to the nervous system may manifest as sudden injury or acute injury to the nervous system, such as acute neurodegenerative disease, including but not limited to: acute injury, hypoxia-ischemia, or a combination thereof resulting in neuronal cell death or damage. Acute injury includes, but is not limited to, traumatic brain injury (TBI), including blunt, blunt or penetrating traumatic brain injury, focal brain trauma, diffuse brain injury, spinal cord injury, intracranial or without limitation, spinal cord contusion, penetrating, injury by shearing, compression or tearing or whipped and shaken baby syndrome).
In addition, hypoxia or ischemia in general can cause acute injury such as hypoxia and/or ischemia, including but not limited to cerebrovascular insufficiency, cerebral ischemia or cerebral infarction (including cerebral ischemia or infarction caused by embolism occlusion and thrombosis), retinal ischemia (diabetic or otherwise), glaucoma, retinal degeneration, multiple sclerosis, toxic and ischemic optic neuropathy, reperfusion following acute ischemia, perinatal hypoxic-ischemic injury, cardiac arrest, or intracranial hemorrhage of any kind (including but not limited to epidural, subdural, subarachnoid, or intracerebral hemorrhage).
Trauma or damage to nervous system tissue can also manifest as more chronic and progressive neurodegenerative diseases, such as those associated with progressive neuronal cell death or damage over time, including but not limited to Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), chronic epilepsy associated with neurodegeneration, motor neuron disease (atrophic lateral muscular sclerosis), multiple sclerosis, degenerative ataxia, corticobasal degeneration, ALS-Parkinson's disease-dementia complex Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies (including multiple system atrophy), primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease or spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, bulbar and pseudobulbar palsy, spinal cord and bulbar spine muscular atrophy (Kennedy disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach disease, Sandhoff disease, familial spasticity, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, familial autonomic dysfunction (Riley-Day syndrome) or prion diseases (including but not limited to Creutzfeldt-Jakob disease, Gerstmann-Strussler-Scheinker disease, Kuru disease, or fatal familial insomnia).
In addition, trauma and progressive damage to the nervous system can occur in a variety of psychiatric disorders including, but not limited to, progressive, exacerbating forms of bipolar or schizoaffective disorder or schizophrenia, impulse control disorders, obsessive-compulsive disorder (OCD), conduct disorders, temporal lobe epilepsy, and changes in personality disorders. In a preferred embodiment, the compounds and/or compositions of the present invention will be used to provide neuroprotection in diseases involving trauma and progressive damage to the nervous system in various psychiatric disorders. These disorders were selected from: schizoaffective disorder, schizophrenia, impulse control disorder, obsessive-compulsive disorder (OCD), and personality disorder.
In addition, trauma and injury can lead to disorders associated with marked and widespread memory loss, including but not limited to age-related dementia, vascular dementia, diffuse white matter disease (Binswanger disease), neurologic dementia associated with endocrine dementia, degenerative or metabolic dementia of origin, head trauma and diffuse brain injury, boxing dementia or frontal lobe dementia, including but not limited to Pick's disease.
Other conditions associated with neuronal damage include, but are not limited to, those associated with chemical, toxic, infectious, and radiation damage to the nervous system, including the retina, damage during fetal development, prematurity at birth, hypoxia-ischemia, injury, or neuropathy (including selected multifocal , sensory, motor, sensorimotor, autonomic, sensory-autonomic, or demyelinating neuropathies (including but not limited to Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy) or neuropathy secondary to infection, inflammation, immune disorder, substance abuse, drug therapy , toxins, trauma (including but not limited to compression, crushing, laceration or laceration trauma), metabolic disorder (including but not limited to endocrine or paraneoplastic), Charcot-Marie-Tooth disease (including but not limited to, types 1a , 1b, 2,4a or 1-X), Friedreich's ataxia, metachromatic white matter deficiency, Refsum's disease, adrenomyeloneuropathy, ataxia-telangiectasia, Djerine-Sottas (including but not limited to type A or B), Lambert-Eaton syndrome, or cranial nerve disease).
An additional indication is cognitive impairment. The term "cognitive disorder" means anxiety disorders, delirium, dementia, amnesia, dissociative disorders, eating disorders, mood disorders, schizophrenia, psychosis, sexual and gender identity disorders, sleep disorders, somatoform disorders, acute stress agitation disorder, OCD-OCD, Panic disorder, post-traumatic stress disorder, specific phobia, social phobia, substance withdrawal delirium, Alzheimer's disease, Creutzfeldt-Jakob disease, head trauma, Huntington's disease, HTV disease, Parkinson's disease, Pick's disease, learning disorder, motor skills disorder, developmental coordination disorder , communication disorder, speech disorder, pervasive developmental disorder, Asperger's disease, autism, child disintegration disorder, Rett syndrome, pervasive developmental disorder, attention deficit/hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, pica, rumination disorder, tic disorder, chronic motor or vocal tic disorder, Tourette syndrome, elimination disorder, fecal incontinence, enuresis, selective mutism, separation anxiety disorder, separation amnesia, depersonalization disorder, dissociative fugue, dissociative identity disorder, anorexia nervosa, bulimia nervosa, bipolar affective disorder, bipolar disorder schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorder, comorbid psychotic disorder, delusions, hallucinations, substance-induced psychotic disorder, orgasmic disorder, sexual pain disorder, dyspareunia, vaginismus, sexual dysfunction, paraphilias, sleep disorders, breathing-related sleep disorders, disorders circadian rhythm, hypersomnia, insomnia, narcolepsy, insomnia, parasomnia, nightmare disorders, sleep phobias, sleep disorders, parasomnia, dysmorphic disorders, and alcohol, hypolotic disorders, pain in pain, pain in disorder, hypoholzine, hypoholzine, hypoholtoria, disorders in conversion, hypochitamines, hypoholzia, conversion disorders, hypochichondria, sick leave - Disorders related to caffeine,marihuanaRelated Disorders, Cocaine-Related Disorders, Hallucinogen-Related Disorders, Inhalation-Related Disorders, Nicotine-Related Disorders, Opioid-Related Disorders, Phencyclidine-Related Disorders, Abuse, Persistent Amnesia, Intoxication, Withdrawal.
The term "bipolar and clinical disorders" will refer to adjustment disorders, anxiety disorders, delirium, dementia, amnestic and other cognitive disorders, disorders usually first diagnosed in childhood (for example), childhood or adolescence, dissociative disorders (such as is dissociative amnesia, depersonalization disorder, dissociative fugue and dissociative identity disorder), eating disorders, delusional disorders, impulse control disorders, mental disorders due to general medical illness, mood disorders, other conditions that may be the focus of clinical attention, personality disorders, schizophrenia and other psychiatric disorders, sexual and gender identity disorders, sleep disorders, somatoform disorders, substance-related disorders, generalized anxiety disorders (eg, acute stress disorder, post-traumatic stress disorder), panic attacks, phobias, agoraphobia, OCD, stress, acute stress disorder , anxiety neurosis, nervousness, phobias, PTSD, PTSD, abuse, OCD, manic depression phobia, specific phobia, social phobia, adjustment disorder with anxiety features.
Disorders that are usually first diagnosed in infancy, childhood, or adolescence include: intellectual retardation, learning disabilities, math disabilities, dyslexia, written expression disorder, motor skill disorder, developmental coordination disorder, communication disorder, expressive language disorder, speech disorder, Mixed Receptive - Expressive Language Disorder, Stuttering, Pervasive Developmental Disorder, Asperger's, Autism, Childhood Disintegrative Disorder, Rett Disorder, Pervasive Developmental Disorder, Attention Deficit/Hyperactivity Disorder (ADHD), Conduct Disorder, Oppositional Defiant Disorder, Childhood Binge Eating Disorder, or early childhood, rumination disorder, tic disorder, chronic motor or vocal tic disorder, Tourette's syndrome, elimination disorder, fecal incontinence, enuresis, selective gender mutism, separation anxiety disorder, reactive attachment disorder in infancy or early childhood, stereotypic movement disorder.
Examples of drug-related disorders are: alcohol-related disorders, amphetamine-related disorders, caffeine-related disorders,marihuanarelated disorders, cocaine-related disorders, hallucinogen-related disorders, inhalation disorders, nicotine-related disorders, opioid-related disorders, mental disorders, psychoses, phencyclidine-related disorders, abuse, persistent amnesia, anxiety disorders, persistent sexual dementia, addiction, intoxication, toxic delirium, mood disorders, psychotic withdrawal, withdrawal delirium, sexual dysfunction, sleep disorder.
The term "neuroprotection" as used herein refers to; inhibiting, preventing, ameliorating or alleviating the severity of dysfunction, degeneration or death of nerve cells, axons or their supporting cells in the central or peripheral nervous system of mammals, including humans. These include the treatment or prevention of neurodegenerative diseases; prevention of excitotoxicity or mitigation of cytotoxic effects of compounds (eg, excitatory amino acids such as glutamate; toxins; or prophylactic or therapeutic compounds that have immediate or delayed cytotoxic side effects, including but not limited to immediate or delayed induction of apoptosis in patients in need).
As used herein, the term "patient in need of treatment with a neuroprotective drug" refers to any patient currently suffering or likely to suffer from any of the above syndromes or conditions, or any condition for which the patient's current clinical status or prognosis may benefit from neuroprotective agents Prevent the development, spread, worsening or increased resistance to treatment of any neurological or psychiatric disease.
As used herein, the term "treatment" or "cure" refers to any successful prevention or amelioration of an injury, pathology or condition, including any objective or subjective parameter, such as amelioration; remission; reducing the symptoms or increasing the patient's tolerance of an injury, pathology or disease; slowing down the rate of degeneration or decay; making the last bit of degeneration less exhausting; or improving the subject's physical and mental health. Treatment or relief of symptoms may be based on objective or subjective parameters; including the results of physical, neurological and/or psychiatric evaluations.
In some embodiments, the present invention provides methods of neuroprotection. In certain embodiments, these methods include administering a therapeutically effective amount of a composition and/or combination of the present invention to a patient who has not yet shown clinical signs or symptoms of overt injury or damage to nervous system cells, but may have suffered from nervous system injury or trauma, or due to certain known biochemical or genetic predispositions, or due to the discovery of validated biomarkers for one or more of these diseases, are exposed to a high risk of developing neuronal damage.
Accordingly, in some embodiments, the methods and compositions of the present invention are directed to neuroprotection in subjects at risk of developing neuronal damage for which clinical evidence has not yet been established. This patient may simply be at "higher risk," as determined by identifying any factors in the subject's or his family, medical history, physical examination, or testing that indicate a higher than average risk of developing a level of neuronal damage. Accordingly, a determination by any available means that a patient may be at "higher risk" can be used to determine whether a patient should be treated with the methods of the invention.
Accordingly, in an exemplary embodiment, recognized screening methods may be used to identify subjects who may benefit from treatment with the methods and compositions and/or combinations of the invention to determine risk factors for neuronal damage. These screening methods include, for example, routine examinations to identify risk factors including, but not limited to, head trauma, blunt or penetrating, central nervous system infection, bacterial or viral, cerebrovascular disease, including but not limited to stroke, brain tumor, cerebral edema, cysticercosis, porphyria, metabolic encephalopathy, drug withdrawal including but not limited to sedative-hypnotics or alcohol withdrawal, history of perinatal abnormalities including hypoxia at birth or birth of any type Injury, cerebral palsy, difficulty in learning disabilities, ADHD, febrile seizures in children, history of status epilepticus, family history of epilepsy or any seizure-related disorder, inflammatory brain diseases including lupus, drugs directly or through the placenta, intoxication, including but not limited to cocaine poisoning, consanguinity of parents and treatment with neurotoxic drugs, including psychotropic drugs.
Among patients without clinical signs or symptoms, identification of patients who may benefit from neuroprotective drug therapy may be based on various "surrogate markers" or "biomarkers."
As used herein, the terms "surrogate marker" and "biomarker" are used interchangeably to refer to any anatomical, biochemical, structural, electrical, genetic, or chemical marker that can be reliably associated with the present presence or future development of neuronal damage. Indicators In some cases, brain imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET), can be used to determine whether a subject is at risk of neuronal damage. Biomarkers suitable for use in the methods of the invention include, but are not limited to: sclerosis, atrophy or volume loss in the hippocampus or marked medial temporal sclerosis (MTS) or similar relevant anatomical structures as determined by MRI, CT or other imaging techniques Pathology; detecting molecular species such as proteins or other biochemical biomarkers such as elevated levels of ciliary neurotrophic factor (CNTF) or elevated serum levels of neuronal degradation products in the patient's blood, serum or tissue; or Additional evidence from surrogate markers or biomarkers suggests that patients should be treated with neuroprotective drugs.
It is expected that more such biomarkers will be developed in the future using different detection technologies. Any such markers or indicators of the presence of neuronal damage or possible future development (as the latter term is used herein) can be used in the methods of the invention to determine the need for treatment with the compounds and methods of the invention.
Determining that a subject has or may be at risk of neuronal damage also involves, for example, a medical evaluation that includes a detailed medical history, physical examination, and a series of relevant blood tests. It may also include an electroencephalogram (EEG), CT, MRI, or PET scan. Increased risk of neuronal damage or injury can also be determined by genetic testing, including gene expression profiling or proteomic techniques. For psychiatric disorders that can be stabilized or improved by neuroprotective drugs, such as bipolar disorder, schizoaffective disorder, schizophrenia, impulse control disorders, etc., the above tests may also include a check of the current status and a detailed follow-up of the patient's medical history Symptoms such as symptoms mood disorders and psychiatric symptoms over time and in relation to other treatments the patient may have received over time, such as life charts. These and other specialized and routine methods allow clinicians to select patients in need of treatment using the methods and formulations of the invention. In some embodiments of the invention, compounds and/or compositions suitable for practicing the invention will be administered alone or simultaneously with at least one or more other compounds or therapeutic agents, for example with other neuroprotective drugs or anti-inflammatory agents. Medicines for epilepsy, anticonvulsants. In these embodiments, the invention provides methods of treating or preventing neuronal damage in patients. The method includes the steps of administering to a patient in need of treatment an effective amount of a compound and/or composition disclosed herein and an effective amount of one or more other compounds or therapeutic agents capable of providing neuroprotection or treating or preventing seizures, or epileptogenesis or the ability to enhance the neuroprotective effects of the compounds of invention.
As used herein, the term "combination administration" of a compound, therapeutic agent, or known drug with a combination of the present invention means that the drug and compound(s) are administered at a time when both the known drug and/or Combination would have a therapeutic effect. In some cases, this therapeutic effect is synergistic. Such concomitant administration may include simultaneous (i.e. simultaneous), prior or subsequent administration of the drug in relation to the administration of the composition and/or combination of the invention. Those skilled in the art will have no difficulty in determining the appropriate time, order, and dosage of administration of a particular agent of the invention.
One or more other compounds or therapeutic agents may be selected from compounds having one or more of the following properties: antioxidant activity; NMDA receptor antagonist activity, enhancing endogenous GABA inhibition; NO synthase inhibitor activity; ability to bind iron, such as iron chelators; calcium binding abilities, such as Ca(II) chelators; zinc binding capabilities, such as Zn(II) chelators; effectively blocking sodium or calcium ion channels or opening the patient's central nervous system Ability to channel potassium or chloride ions.
diseases of the heart and blood vessels
Another aspect of the present invention relates to the use of compounds and/or combinations of the present invention such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof as therapeutic agents for the prevention and/or cure of diseases hearts. Heart disease is a general term used to describe many different heart diseases. For example, coronary artery disease, the most common form of heart disease, is characterized by constriction or narrowing of the arteries that supply the heart with oxygen-rich blood and can lead to myocardial infarction, the death of part of the heart muscle. Heart failure is a disease caused by the inability of the heart to pump sufficient amounts of blood through the body. Heart failure is not a sudden, sudden stop of the heart, but develops slowly, usually over many years, as the heart gradually loses its ability to pump blood effectively. Risk factors for heart failure include coronary artery disease, hypertension, valvular heart disease, cardiomyopathy, heart muscle disease, obesity, diabetes, and/or a family history of heart failure.
Examples of cardiovascular diseases and conditions are: aneurysm, stable angina, unstable angina, angina, angioedema, aortic stenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventricular dysplasia, arterial cirrhosis, arteriovenous malformation, atrial fibrillation, Behcet's syndrome, bradycardia, cardiac tamponade, cardiac hypertrophy, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, carotid stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Ebstein malformation, Eisenmenger syndrome, cholesterol embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart disease, heart disease, congestive heart failure , heart valve disease, heart attack, epidural hematoma, subdural hematoma, Hippel-Lindau disease, congestion, hypertension, pulmonary hypertension, cardiac hypertrophy, left ventricular hypertrophy, right ventricular hypertrophy, hypoplastic left heart syndrome, hypotension, intermittent claudication, ischemic heart disease , Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, prolonged QT syndrome, mitral valve prolapse, moyamoya disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular disease, phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud's disease, Sneddon's syndrome, superior vena cava syndrome, syndrome X, tachycardia, Takayasu's arteritis, hereditary hemorrhagic telangiectasia telangiectasia, temporal arteritis, tetralogy of Fallot, thromboangiitis obliterans, thrombosis, thromboembolism, tricuspid atresia, varicose veins, vascular disease, vasculitis, vasospasm, ventricular fibrillation, Williams syndrome, peripheral vascular disease, varicose veins and leg ulcers, deep vein thrombosis, Wolff-Parkinson-White syndrome.
Vascular disease is usually the result of reduced perfusion of the vasculature or physical or biochemical damage to blood vessels.
Peripheral vascular disease (PVD) is defined as a blood vessel disorder that usually manifests as narrowing of blood vessels in the extremities. There are two main types of these disorders, functional disorders that do not involve vascular defects but are caused by stimuli such as cold, stress or smoking, and organic disorders that result from structural defects in the vascular system, such as arterial atherosclerotic lesions, local inflammation or trauma. This leads to blockage of blood vessels, abnormal blood flow and ultimately tissue ischemia.
A clinically significant form of PVD is peripheral arterial disease (PAD). PAD is usually treated with angioplasty and stenting or arterial bypass surgery. The clinical picture depends on the location of the blocked vessel. For example, narrowing of the arteries that supply blood to the intestines can cause severe postprandial pain in the lower abdomen because the blocked blood vessels cannot meet the increased oxygen demand for digestion and absorption. In severe cases, ischemia can lead to intestinal necrosis. Likewise, PAD of the legs causes intermittent pain, usually in the lower leg, that comes and goes with activity. Known as intermittent claudication (IC), the disorder can progress to persistent pain at rest, ischemic ulceration, and even amputation.
Peripheral vascular disease also manifests as renal atherosclerotic stenosis, which can lead to renal ischemia and renal dysfunction.
Vascular diseases and their complications One disease that is very common is diabetes. Diabetes causes a number of physiological and anatomical abnormalities, the most prominent of which is the body's inability to use glucose properly, resulting in hyperglycemia. Chronic diabetes can lead to complications of the vascular system, including atherosclerosis, abnormalities of large and medium-sized blood vessels (macroangiopathy), and abnormalities of small blood vessels (microangiopathy), such as arterioles and capillaries. Patients with diabetes have an increased risk of developing one or more foot ulcers due to established long-term complications of the disease, including impaired nerve function (neuropathy) and/or ischemia. Tissue ischemia is a key factor leading to diabetic foot ulcers.
In addition to macrovascular disease, skin perfusion in diabetics is additionally compromised in at least two other ways. Firstly, due to involvement of non-ductal arteries that are adversely affected by the atherosclerotic process, and secondly, and perhaps more importantly, due to disturbed microcirculation control mechanisms (small blood vessel disease). Typically, when a part of the body suffers some form of trauma, that part of the body experiences increased blood flow as part of the body's healing mechanisms. This naturally increased blood flow response is significantly reduced when both small vessel disease and ischemia are present, as is the case in many diabetics. This fact, together with the tendency of diabetics to form blood clots (thrombosis) in the microcirculatory system during periods of poor blood flow, is considered an important factor in the pathogenesis of ulcers.
Neuropathy is a general term that describes a disease process that leads to dysfunction of the nervous system and is one of the main complications of diabetes, and there are no well-established therapeutic approaches either for symptomatic treatment or for preventing the progressive decline of neurological functions.
Thickened and leaky capillaries caused by diabetes mainly affect the eyes (retinopathy) and kidneys (nephropathy). Thickened and leaky capillaries caused by diabetes are also associated with skin and nervous system disorders (neuropathy).
Eye diseases associated with diabetes include nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, diabetic maculopathy, glaucoma, and cataracts.
Other diseases, although not known to be associated with diabetes, have similar physiological effects on the peripheral vasculature. Such diseases include Raynaud's syndrome, CREST syndrome, autoimmune diseases such as erythema, rheumatoid disease, etc.
As used herein, the term "peripheral vascular disease" includes any peripheral vascular disease, including peripheral neuropathy and autonomic neuropathy. Examples of "peripheral vascular disease" include peripheral arterial disease, such as chronic arterial occlusion, including arteriosclerosis, arteriosclerosis obliterans, and thromboangiitis obliterans (Burger's disease), macrovascular disease, microvascular disease, diabetes mellitus, thrombotic venous phlebitis, venous paralysis, Raynaud's disease, Raynaud's syndrome, CREST syndrome, vibration health hazards, Sudeck's syndrome, intermittent claudication, cold extremities, paresthesias in extremities, sensitivity to cold, Meniere's disease, Mei Nière syndrome, numbness, loss of sensation, anesthesia, pain at rest, causalgia (burning pain ), peripheral circulatory dysfunction, neurological dysfunction, motor dysfunction, motor paralysis, diabetic peripheral circulation disorder, lumbar spinal stenosis, diabetic neuropathy, shock, erythema, rheumatoid, rheumatoid arthritis and other autoimmune diseases, autonomic neuropathy, diabetic autonomic neuropathy, autonomic dysregulation, orthostatic hypotension, erectile dysfunction, female sexual dysfunction, retrograde ejaculation, bladder disease, neurogenic bladder, poor vaginal lubrication, exercise intolerance, cardiac denervation, heat intolerance, sweating to taste, diabetic complications, hyperglycemia, hypoglycemia fainting, hypoglycemia without Reac glaucoma , neovascular glaucoma, cataract, retinopathy, diabetic retinopathy, diabetic macular degeneration, retinal artery occlusion, central retinal artery occlusion, retinal vein occlusion, macular edema, age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, chorioretinopathy, neovascular maculopathy, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epithelitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal detachment, ulcer cornea, conjunctival ulcer, chronic nummular cornea Thygeson's keratosis, progressive Mooren's ulcer, skin lesions, skin ulcers, including foot ulcers, diabetic ulcers, ulcers in ulcers, ulcers, postoperative ulcers, ulcerative ulcers, Posstpe induced ulcers, frostbite (cold injury ), frostbite, gangrene and sudden gangrene, angina pectoris/vasculitis variant, coronary arteriosclerosis (chronic ischemic heart disease, asymptomatic ischemic heart disease, atherosclerotic cardiovascular disease), myocardial infarction, heart failure, congestive heart failure and painless ischemic heart disease, pulmonary edema , hypertension, pulmonary hypertension, portal hypertension, diabetic nephropathy, pressure ulcer, kidney failure.
formula
The compounds and preparations of the invention, such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, may be administered at a dose of less than 400 mg/day. In some embodiments, the compounds and compositions of this invention are administered at a dose of about 1 mg/day, about 2 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg drug/day , about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 60 mg/day, about 70 mg/day about 80 mg/day, about 90 mg/day, about 100 mg/day, about 120 mg/day, about 125 mg/day, about 140 mg/day, about 150 mg/day, about 160 mg/day, About 175 mg/ day, About 180 mg/day, About 190 mg/day, About 200 mg/day, About 225 mg/day, About 250 mg/day, About 275 mg/day, About 300 mg/day, About 325 mg/day, about 350 mg/day, about 375 mg/day, about 400 mg/day, about 425 mg/day, about 450 mg/day, about 475 mg/day, or about 500 mg/day. In some embodiments, a compound of the invention is administered at a dose of less than 1 mg/day, less than 2 mg/day, less than 5 mg/day, less than 10 mg/day, less than 15 mg/day, less than 20 mg /day, less than 25 mg/day, less than 30 mg/day, less than 35 mg/day, less than 40 mg/day, less than 45 mg/day, less than 50 mg/day, less than 60 mg/ day mg/day, less than 70 mg/day, less than 80 mg/day, less than 90 mg/day, less than 100 mg/day, less than 120 mg/day, less than 125 mg/day, less than 140 mg/day, less than 150 mg/day, less than 160 mg/day, less than 175 mg/day, less than 180 mg/day, less than 190 mg/day, less than 200 mg/day, less than 225 mg /day to day, less than 250 mg/day, less than 275 mg/day, less than 300 mg/day, less than 325 mg/day, less than 350 mg/day, less than 375 mg/day, less than 400 mg/day, less than 425 mg/day, less than 450 mg/day, less than 475 mg/day or less than 500 mg/day. In some embodiments, compounds of the invention are administered in doses greater than 1 mg/day, greater than 2 mg/day, greater than 5 mg/day, greater than 10 mg/day, greater than 15 mg/day, greater than 20 mg /day, more than 25 mg/day, more than 30 mg/day, more than 35 mg/day, more than 40 mg/day, more than 45 mg/day, more than 50 mg/day, more than 60 mg/ day, more than 70 mg/day, more than 80 mg/day, more than 90 mg/day, more than 100 mg/day, more than 120 mg/day, more than 125 mg/day, more than 140 mg/day , more than 150 mg/day, more than 160 mg/day, more than 175 mg/day, more than 180 mg/day, more than 190 mg/day, more than 200 mg/day, more than 225 mg/day, more than 250 mg/day, more than 275 mg/day, more than 300 mg/day, more than 325 mg more than 350 mg/day, more than 375 mg/day, more than 400 mg/day, more than 425 mg /day, more than 450 mg/day, more than 475 mg/day or more than 500 mg/day.
The compounds and preparations of the invention can be administered enterally or parenterally. A mixture with pharmaceutically suitable adjuvants, for example, as described in the standard reference Gennaro et al., Remington's Pharmaceutical Sciences. The compounds can be compressed into solid dosage units such as pills, tablets, or processed into capsules or suppositories. The compounds may also be administered in the form of solutions, suspensions, emulsions, eg as injections or eye drops, or as sprays, eg as nasal sprays, via pharmaceutically acceptable liquids.
For the preparation of dosage units, e.g. tablets, common additives such as fillers, dyes, polymer binders and the like come into play. In general, any pharmaceutically acceptable additive that does not interfere with the function of the active compounds can be used. Suitable carriers with which the composition may be administered include lactose, starch, cellulose derivatives and the like or mixtures thereof used in appropriate amounts.
The activity of GR agonists and their changes in cellular function are variable and depend on complex intracellular molecular signals specific to cells and tissues. Among the cells with receptors for glucocorticoids are stem and progenitor cells of all tissues and organs in the body. Therefore, the binding of these molecules to normal "intra-tissue" stem cells and to the progeny of these stem cells (so-called "transit-amplified" progenitors) results in various cell- and tissue-specific effects, inhibiting or enhancing stem cell and progenitor cell function. it includes activation, proliferation, migration and differentiation, all depending on the tissue/organ in question.
GR antagonists or agents, such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof, will thus block GR-agonist activation in a tissue-specific manner. the function of some stem/progenitor cells and inhibiting the function of others. GR antagonists will have beneficial effects in certain clinical settings where regenerative medicine approaches can be used to treat disease and heal wounds, including: improving post-transplant function of autologous stem cell transplantation (depending on the source tissue and/or target tissue).
Reduction of the perioperative effects of catabolic stress hormones associated with surgery or other physical trauma (eg war injuries) where the acute or chronic injury or disease is selected from vascular events, stroke, cardiac arrest, acute limb infarction accident/battlefield trauma, limb trauma , Hip, Brain injury, Trauma after surgery, Major orthopedics, Thoracic, Abdominal, Neurosurgery.
Systemic GR blockade is not appropriate, but direct topical application of ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts to the site of injury/trauma (eg to prevent wound dehiscence) either by direct injection or intravascular by infusion (for internal organ injuries) would be useful.
cortisol
The estimated daily rate of cortisol production in normal subjects varies between 4-15 mg/m2 per day, or, according to recent studies, between 9 and 11 mg/m2 per day. In order to adequately describe the 24-hour change in serum cortisol levels, the day can be divided into, for example, four phases. Stage 1 is a period of at least 6 hours of secretory activity 4 hours before and 2 hours after sleep onset. Stage 2 refers to the 3rd to 5th hour of sleep, when there is an initial nocturnal secretory onset. Phase 3 is the main secretory phase that lasts 4 hours during the last 3 hours of sleep and the first hour after waking. Phase 4 is an 11-hour phase of intermittent secretory activity during which serum cortisol levels slowly decline.
In the study by Mah et al. (Clinical Endocrinology (2004) 61, 367-375) describes the circadian rhythm of serum cortisol in normal subjects. Peak levels of around 400-800 mmol/l, around 150-300 mmol/l and around 150 mmol/l were observed at 6 am, 2 pm and 9 pm, with the lowest levels around midnight. In this study, endogenous cortisol levels were observed to peak within 30 minutes of waking. In order to mimic circadian rhythms, Mah et al. A three-day regimen of hydrocortisone is recommended, where the first dose is taken on an empty stomach with breakfast delayed by 1-3 hours, and the second two doses are taken 15-60 minutes before a meal. A recent review by Czock et al also recommends a three-times-daily regimen. (Clin. Pharmacokinet (2005) 44, 61-98) Because of the short half-life of hydrocortisone, a twice-daily regimen is preferable to a once-daily regimen for prednisolone.
cortisol test
To date, the lack of rapid response and inexpensive cortisol assays has prevented the use of GCR antagonists or agonists (eg, ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof). A link to a cortisol pretest for clinical trials of GCR antagonists would prevent the ability to select patients most likely to receive therapeutic benefit from the compound when used clinically. The subject invention provides affordable real-time cortisol testing (eg.
PopTest Cortisol), which will enable the successful completion of clinical trials of this class of drugs and lay the foundations for their future intended therapeutic use.
Conditions that can be systemically treated using, for example, a correlative salivary cortisol quantification assay and GCR antagonists or agents (eg, ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof) include Ali but not limited to the following:
Major Depressive Disorder (MDD).
MDD is a psychiatric disorder with a lifetime prevalence of approximately 8%. One of the most consistent findings in psychiatry is that patients with major depressive disorder show alterations in the hypothalamic-pituitary-adrenal (HPA) axis. A significant proportion of patients with depression show hypersecretion of cortisol, which is manifested by elevated cortisol concentrations in plasma, cerebrospinal fluid and saliva, and increased free cortisol in urine. Furthermore, many depressed patients show a marked inability to turn off endogenous cortisol release after exogenous challenge with the potent synthetic glucocorticoid dexamethasone (the so-called dexamethasone non-inhibitor) (Gold P. W., et al. Clinical and biochemical manifestations of depression in humans: relationship to the neurobiology of stress, New England J. Med. 319, 413-420, 1988). This "subgroup" of severely impaired patients is often those whose depression has become a life-threatening condition requiring hospitalization.
Other HPA axis abnormalities found in depressed patients are increased cortisol response to corticotropin, decreased corticotropin response to CRH (corticotropin-releasing hormone), and enlarged adrenal and pituitary glands (associated with For review, see Holsboer, F. and Barden, N .: Endocrine Reviews 1996, 17, 187-205).
These observations have been interpreted to suggest a causal relationship between HPA axis dysfunction and the pathology of depression (Murphy, B.E.P.J. of Steroid Biochem. and Mol. Biol. 1991, 38, 537-559). The therapeutic efficacy of classical antidepressants has been shown to precede or coincide with the recovery of a disrupted HPA axis in depression (Holsboer and Barden, 1996, supra). It is hypothesized that any intervention that restores this HPA dysfunction may have antidepressant effects.
One type of such intervention whose studies support the impression that HPA axis function and high circulating cortisol are the main drivers of major depressive disorder is the use of glucocorticoid synthesis inhibitors, as shown in patients with Cushing's syndrome, a condition in which high cortisol levels result from adrenal dysfunction. (due to a pituitary tumor or a secondary tumor, both of which produce ACTH which is a cortisol secretagogue). Depressive symptoms associated with Cushing's disappeared relatively quickly when cortisol levels returned to normal. Such treatment may include removal of unwanted tumors or treatment with cortisol synthesis inhibitors such as metyrapone, ketoconazole, or aminoglutethimide (Murphy, B. E. P, Steroids and Depression. J. Steroid Biochem & Mol. Biol 38, 537-558, 1991). , recent clinical trials have shown that cortisol synthesis inhibitors can be used to improve depressive symptoms in patients with treatment-resistant severe non-Cushing's depression (Murphy, B. E. P, Can. J. Psych. 43, 279-286, 1998; see also US Patent No. 4,814,333 (Ravaris, C.L.)).
Another type of intervention is the use of direct GCR antagonists, which have more specific pharmacological effects than synthetic inhibitors and can help restore HPA activity. To study the antidepressant activity of the nonselective glucocorticoid receptor antagonist RU 486 (mifepristone; Murphy, B. E. P. et al. J. Psychiat. Neurosc. 18, 209-213, 1993), a small pilot clinical study. Recently (Nemeroff, C., Remeron Scientific Expert Meeting, Budapest, March 29 - April 1, 2001) a continuation of this phase IIB study showed that the number of responders and efficacy changes according to the Brief Psychiatric Rating Scale (50 mg -33% change; 600 mg-40% change and 1200 mg-52% change), psychiatric treatment increased with increasing mifepristone daily dose. These data suggest that higher doses of glucocorticoid receptor antagonists and/or active agents are associated with greater clinical efficacy.
However, the rate of non-response to standard treatment is as high as 50%. (Connolly KR, Drugs. 2011; 71: 43-64.) Additional intervention is often required to bring patients into remission. Various augmentation and combination strategies have been described in the literature for patients with difficult-to-treat primary MMD.
As noted above, despite clear evidence that at least a subset of MDD patients have significant HPA axis dysfunction, the use of drugs that modulate the HPA axis in these patients has not been studied. Biological symptoms indicative of HPA axis hyperactivity have been reported with great consistency. At the same time, there is substantial evidence of an association between HPA axis function and treatment response, with high HPA axis activation at baseline or after treatment being associated with poorer response to SSRI therapy or greater risk of relapse.
Preclinical studies have shown that the type of HPA axis dysfunction seen in affective disorders can attenuate the neurochemical effects of selective serotonin reuptake inhibitor (SSRI) antidepressants. In contrast, concomitant administration of GR antagonists enhanced the neurochemical effects of SSRIs in animals with normal HPA axis function. These data provide a mechanistic basis for the enhancement strategy of GR antagonists and suggest that this strategy may be effective in patients with and without HPA axis dysfunction.
A small pilot clinical trial was conducted to investigate the antidepressant activity of the non-selective glucocorticoid receptor antagonist RU 486 (mifepristone; Murphy, B.E.P. et al. J. Psychiat. Neurosc. 18, 209-213, 1993). A double-blind, 4-week, paroxetine-controlled study of PT150 (ORG 34517) was conducted in patients with depression. Paroxetine, a selective serotonin reuptake inhibitor, is considered an effective antidepressant in the treatment of major depressive disorder. Select patients with major depressive disorder who meet diagnostic criteria for MDD with recurrent (296.3) episodes as defined by DSM-IV and whose depression is severe enough to result in a HAMD total score of at least 22 -21 (Hamilton Depression Rating Scale; see Hamilton, M. “Rating Scale for Depression.” J. Neurol. Neurosurg. Psychiat. 1960, 23, 56-62) Basic scale. Patients had a depressive episode lasting at least 2 weeks before the start of the study. In this study, patients were randomly assigned to one of three treatment groups. Group I patients (50 patients) received two capsules of PT150 of 75 mg and one placebo (total daily dose of 150 mg), two capsules of PT150 of 75 mg and one capsule of 150 mg (total daily dose of 300 mg) the following 2 weeks ; Group II patients (46 patients) took 3 capsules of 150 mg PT150 in the first 2 weeks (total daily dose 450 mg) and 4 capsules PT150 in the next 2 weeks (total daily dose 600 mg); Group III patients (44 patients) received 2 capsules of paroxetine of 10 mg and 1 capsule of placebo for the first 2 weeks (total daily dose of 20 mg), then 2 capsules of 10 mg capsules and 1 capsule of paroxetine of 20 mg (total daily dose of 40 mg ) within the next 2 weeks. Take the medicine orally in the morning. Efficacy was assessed on days 4, 7, 10, 14, 21, 28 and 35 using the 21-item HAMD scale.
Therefore, GCR antagonist or agonist therapy may prove a useful mechanism for the treatment of selected individuals unresponsive to current antidepressant therapies such as SSRIs, providing a means of enhancing response or as a means of achieving maintenance of emotional equanimity, an alternative method.
Psychotic depression.
This invention relates to the use of GCR antagonists, such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, in the prevention or treatment of psychotic depression. Psychotic major depressive disorder has long been recognized as a separate psychiatric disorder with a psychotic and depressive component in the differential diagnosis. Psychotic major depressive disorder is common. An estimated 25% of depressed patients admitted to hospital have major psychotic depressive disorder (Coryell (1984) J. Nerv. Ment. Dis. 172:521). Like major depressive disorder, psychotic depression is often the result of high circulating cortisol levels. Various lines of evidence support this claim. Psychosis is associated with Cushing's syndrome (Gerson (1985) Can. J. Psychiatry 30:223-224; Saad (1984) Am. J. Med. 76:759-766). GR antagonists have been used to treat acute psychiatric disorders caused by Cushing's syndrome. One study has shown that relatively high doses of this GR antagonist (400 to 800 mg daily) can be used to rapidly reverse acute psychosis in patients with severe Cushing's syndrome caused by ectopic secretion of ACTH from adrenal and lung carcinomas (Van der Lely (1991) .) ) Ann. Intern. Med. 114:143; Van der Lely (1993) Pharmacy World & Science 15:89-90; Sartor (1996) above). Relatively high doses of mifepristone, ranging from 8-12 mg/kg/day, have also been shown to be effective in the treatment of psychosis associated with psychotic major depressive disorder over a relatively short period of time (4 days) (International Patent Application WO 99/17779; Schatzberg and Belanoff).
Immunosuppression in the elderly associated with surgery.
There is a physiological balance between pro-inflammatory and anti-inflammatory mediators in healthy, young and middle-aged individuals exposed to stress. In the elderly, due to the decline of several components of the immune system (immunosenescence) and the transition to a chronic pro-inflammatory state (the so-called "inflammatory" effect (Butcher and Lord, (2004) Aging Cells, pp. 151-160).
Because cortisol production remains fairly constant with age, while total DHEA and DHEAS levels gradually decline from the third decade onwards, reaching 10-20% of their peak by the eighth decade, Butcher and Lord (2004, supra) proposed an age-stress model in which showed that an age-related increase in the ratio of cortisol to DHEAS, together with increased cortisol release during stress, resulted in a significant decrease in immunity in aging subjects. This is the explanation that elderly subjects are more susceptible to infections under stressful conditions. (Butcher and Lord (2004, supra); Butcher et al. (2005, Aging Cell 5, pp. 319-324).
The subject invention relates to the use of GCR antagonists, such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts, in the prevention or treatment of infections or infectious conditions, in elderly patients, such as human subjects. The beneficial effects of GCR antagonists can be explained on the basis of their corrected effect on the cortisol/DHEA(S) ratio. It is believed that the performance of selected subjects found to have high circulating cortisol by the saliva test of the present invention may be explained by the imbalanced immunosuppressive effect of an increased cortisol/DHEAS ratio compared to the age group. Balanced effects of cortisol and DHEAS on the immune system in normal subjects.
The meaning of the term "elderly subject" or "elderly subject" will be well understood in the context of use according to the invention. Although not tied to an exact lower age limit, this general concept in the human case usually refers to a person who is at least 55 years old, but it is more specific to set a minimum age limit of 60, 65, 70, and 75 years, respectively.
In the context of the present invention, an infection or infectious condition may be caused by any of a variety of pathogens, for example bacteria, viruses or fungi. Also in the context of the present invention, the term "infectious disorder" refers to asymptomatic or subclinical infection and a disorder that does not lead to an overt infectious disease, but in which at least one parameter is associated with an infectious disease, eg, leukemia. (such as neutrophils, basophils or eosinophils) the number of cells or levels of certain antibodies or certain cytokines are higher than normal. Normal values are known to those skilled in the art and can be found in standard medical manuals.
A particular use according to the invention relates to elderly subjects suffering from an infection or an infectious condition accompanied by stress caused by trauma. This invention particularly relates to the use in which the subject is suffering from bone fractures and/or the effects of bone surgery, for such injury or for joint replacement for osteoarthritis or rheumatoid arthritis. The invention also relates to a use in which the subject suffers from an infection or an infectious condition accompanied by psychological stress, especially acute emotional stress.
Post-traumatic stress disorder (PTSD).
PTSD is a severe anxiety disorder that can develop after exposure to any traumatic event. The event may involve a threat of death to self or others, or a threat to the physical, sexual, or psychological integrity of self or others, exceeding the individual's ability to cope. As a consequence of psychological trauma, PTSD occurs less frequently but lasts longer than the usual response to acute stress. Diagnostic symptoms of PTSD include reliving the original trauma through flashbacks or nightmares, avoidance of trauma-related stimuli, and increased arousal such as difficulty falling or sleeping, anger, and hypervigilance. Formal diagnostic criteria (DSM-IV-TR and ICD-9) require that symptoms persist for more than a month with severe impairment in social, occupational, or other important areas of functioning. (Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatric Association. 1994. Washington, DC: American Psychiatric Association.) PTSD shows biochemical differences in the brain and body from other psychiatric disorders such as major depressive disorder. There is considerable evidence that individuals diagnosed with PTSD have a disruption of HPA axis physiology, although the nature of the disruption varies: some have low cortisol levels, some have normal levels, others have high cortisol levels, some may have normal cortisol levels, but the circadian rhythm is lost. Presumably these reflect different underlying mechanisms, but when cortisol levels are elevated, either persistently during the day or with loss of circadian rhythm due to elevated levels at night, this may be an important component of clinical symptomatology. Lindley SE, et al. Basal and dexamethasone suppressed salivary cortisol concentrations in a community sample of PTSD patients. Biol. Psychiatry 2004; 55: 940-5). the antagonist is expected to have a therapeutic or beneficial effect on PTSD symptoms. Use antipsychotics and antidepressants to prevent weight gain in patients. Antipsychotics and some antidepressants (such as SSRIs) are among the most important tools in the treatment of various mental illnesses. However, treating patients taking many of these drugs for chronic, long-term conditions is difficult because of their significant side effect profile. One of the most important factors is weight gain and the resulting metabolic syndrome. For example, it has been estimated that 40-80% of patients receiving long-term antipsychotics experience significant weight gain, often 20% or more above their ideal body weight (Umbricht et al., J. Clin. Psychiatry 1994; 55: 157-160; Khan A Y, et al. J Psychiatr Pract. 2010; 16: 289-96; Pramyothin P, Khaodhiar L. Curr Opin Endocrinol Diabetes Obes. 2010; 17: 460-6; . 2010; 123:225-33). This weight gain is one of the most common causes of poor adherence to antipsychotics and antidepressants, and thus one of the most common causes of long-term treatment failure. In addition, antipsychotics are often associated with the development of insulin resistance and metabolic syndrome (along with the development of type 2 diabetes and hyper/dyslipidemia) and a potentially significantly increased risk of cardiovascular disease; these conditions have enormous medical consequences, patients thus fall into a "can't live with them, can't live without them" treatment situation. Although all antipsychotics can cause weight gain, it is particularly common and tends to worsen with newer or "atypical" AP medications (Allison et al. Am J Psychiatry 1999; 156:1686-1696; Rummel-Kluge C et al., Schizophr Res. 2010;123:225-33).
Elevated cortisol is associated with changes in body fat and insulin resistance. Several years ago, in a proof-of-principle clinical trial, a GCR antagonist (mifepristone) was reported to be highly effective against multiple medical complications in patients with Cushing's disease, whose disease was refractory to surgery and radiotherapy No response, including reversal of dependent diabetes on insulin: patients were able to discontinue insulin administration within a month (Chu et al., J. Clin. Endocrinol. Metab. 2001; 86, 3568-3573.). These data suggest that GCR antagonists could be used to block and reverse insulin resistance and weight changes in some patients treated with atypical antipsychotics. To this end, the compound was tested in rats with olanzapine-induced weight gain and increased abdominal fat; weight gain was reversed and abdominal fat was reduced (Beebe et al., Behav. Brain Res. 2006; 171, 225-229). This benefit in humans was confirmed in a 2-week study of mifepristone 600 mg/day in which the compound reduced olanzapine-induced weight gain in 57 healthy, non-overweight men with a body mass index below 25 (Gross et al., 2018). , Adv Ther. 2009; 26: 959-69.). Therefore, GCR antagonist or agonist therapy could prove to be a useful mechanism for targeted therapy in psychotic patients treated with atypical antipsychotics. The present invention relates to the use of GCR antagonists, such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, in the prevention or treatment of PTSD.
Cushing's syndrome
Cushing's syndrome is a group of conditions in which high levels of circulating cortisol or other GCR agonists cause a variety of severely debilitating and sometimes life-threatening signs and symptoms, including but not limited to psychiatric disorders (eg, anxiety, depression, psychosis), immunosuppression, insulin resistance and metabolic syndrome, skin conditions, hypertension and osteoporosis. Endogenous cortisol can be produced by benign or malignant tumors of the ACTH-secreting pituitary gland ("Cushing's disease") or adrenal cortex. These are rare conditions, so Cushing's syndrome is considered an "orphan disease".
A proof-of-concept trial of RU486 in patients with tumor-associated Cushing's syndrome demonstrated efficacy in alleviating symptoms of abnormal glucose metabolism (ie, glucose intolerance; (group 1) and hypertension (group 2)). Both patient groups achieved statistically significant improvement: 60% in the glucose intolerance group responded and 43% in the hypertension group (Corcept Therapeutics press release, December 22, 2010). Therefore, GCR antagonist or active drug therapy is expected to provide clinical benefit to patients with Cushing's syndrome when administered before tumor surgery to improve surgical outcome and/or postoperatively to relieve symptoms in patients who cannot be cured by surgery.
Furthermore, treatment with GCR antagonists or agonists is expected to provide clinical benefit to patients, for example, in hospitals, nursing homes, nurseries, daycare centers, schools, work environments, public transportation, medical facilities, psychiatric facilities, and long-term care facilities.
The present invention relates to the use of GCR antagonists, such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, in the prevention or treatment of Cushing's syndrome.
Diagnostic systems and sets
The diagnostic kit may contain some or all of the following components: 1) one or more standards containing one or more biomarkers of the present invention, such as cortisol; 2) ligands, such as antibodies or multiple antibodies, that are specific for the biomarker are determined using the kit; 3) Written instructions; 4) Diluents for samples and standards; 5) Washing buffer; 6) Chromogenic reagent; 7) Stop solution; 8) a ligand carrier, such as an antibody carrier, such as a lateral flow device, or a microwell plate with bound antibodies, or polystyrene beads. An example of such an accessory is a quantitative ELISA (enzyme-linked immunosorbent assay), which determines the concentration of one or more biomarkers according to the methods covered by the invention. The principle of the test is the use of a quantitative sandwich enzyme immunoassay technique in which monoclonal or polyclonal antibodies selective for a biomarker are pre-coated in the wells of a carrier such as a microplate. Standards and samples are then pipetted into the wells, and any biomarkers present bind to the immobilized antibody. The wells are then washed with wash buffer, and enzyme-linked monoclonal or polyclonal biomarker-specific antibodies are added to the wells.
The washing is done again, and then the substrate solution is added to the wells. The color then develops in proportion to the amount of polypeptide of the invention bound in the first step. Color development was stopped with stop solution, and color intensity was measured with a microplate reader.
The method of the invention can be performed using, for example, lateral flow analysis. This lateral flow assay has the potential to be a cost-effective, rapid, simple and sensitive method, eg for in situ screening tests. Lateral flow assays involve a support that allows lateral flow, where the sample or detection reagent is transferred from one location on the support to another. There are many lateral flow test formats suitable for use with the methods embodied in the present invention, and one skilled in the art will readily know how to select and optimize a particular format. An exemplary lateral flow test strip of the present invention includes, for example, the following components:
Sample pad - an absorbent pad with a coated test sample.
Reagent Conjugates or Pads – Contains antibodies specific for analytes of interest bound to colored particles, usually colloidal gold particles or latex microspheres.
Reactive membrane – usually a hydrophobic nitrocellulose or cellulose acetate membrane to which the anti-target analyte antibody is immobilized as a line across the membrane, serving as a capture zone or test line (control zones containing pairs of conjugated antibodies to specific antibodies may also be present).
Wick or Waste Container - A further absorbent pad designed to draw the sample through the reaction membrane by capillary action and collect it.
Double Sandwich Antibody Test——
In this format, the sample migrates from the sample pad to the conjugate pad, where any analyte of interest present binds to the conjugate. The sample then continues to migrate through the membrane until it reaches the capture zone, where the target/conjugate complex will bind to the immobilized antibody, creating a visible line on the membrane. The sample then migrates further along the strip until it reaches the control zone where the excess conjugate will bind and produce a second visible line on the membrane. This control line indicates that the sample migrated through the membrane as expected. Two clear lines on the membrane are a positive result.
One line in the control area is a negative result. The double antibody sandwich method works best for larger analytes with multiple antigenic sites, such as bacterial pathogens and viruses. Competitive assays are primarily used to test small molecules and differ from the double antibody sandwich format in that the conjugate pad contains antibodies already bound to the target analyte or its analog. If the analyte of interest is present in the sample, it will not bind to the conjugate and remain unlabeled.
As the sample migrates along the membrane and reaches the capture zone, excess unlabeled analyte will bind to the immobilized antibody and prevent capture of the conjugate, so no visible line will form.
The unbound conjugate will then bind to the antibody in the control zone, creating a visible control line. One control line on the membrane is a positive result. Two visible lines in the capture zone and the control zone are negative results. However, in the absence of excess unlabeled target analyte, the capture zone may produce a faint line indicating inconclusive results. Competitive assays are best for detecting small molecules that cannot be bound by multiple antibodies simultaneously, such as mycotoxins. There are many variations of lateral flow techniques. The capture zone on the membrane may contain immobilized antigen or enzyme - depending on the analyte of interest - instead of antibody. Multiple recording regions can also be applied to create multiple tests. For example, commercial strips have been developed that can separately detect enterohemorrhagic E. coli Shiga toxins ST1 and ST2 in the same sample. The lateral flow immunoassay is easy to use by untrained operators and usually provides results within 15 minutes. They are very stable and strong, have a long life and usually do not require cooling. They are also relatively cheap to manufacture. These properties make them ideal for use at the point of care and for field and laboratory sample testing. However, their sensitivity is limited without additional enrichment or incubation procedures.
Quantitative test—
While most lateral flow immunoassays can only provide qualitative results, some degree of quantification can be obtained by measuring the amount of conjugate bound to the capture zone. This can be done using a special reader to measure the intensity of the colored test leads. For example, Neogen Corporation developed the Accuscan™ lateral flow reader for use in its Reveal® line of test kits, while Charm Sciences also offers readers for its Rosa® line of mycotoxin test strips. More sophisticated techniques, such as fluorescent dye-labeled conjugates, have also been developed to increase the quantitative potential of lateral flow assays. In the 20 years since the first lateral flow test was introduced, applications have expanded to include a large number of different tests developed based on the same technology. The first commercial sets were aimed at clinical diagnostics, but today the products are available in almost all branches of microbiology. Clinical Microbiology - Lateral flow tests have been developed for bacterial pathogens, respiratory and intestinal viruses, intestinal parasites and bacterial toxins. Many lateral flow immunoassay products designed for the clinical sector are intended for point-of-care use for direct testing of stool, blood, and urine samples, as well as nasal and throat swabs, where ease of handling and speed of testing are critical for their use outside the laboratory. However, the same test strip can also be used as a rapid confirmatory test after laboratory culture of clinical specimens. Food and Agricultural Microbiology - Test strips are available for bacterial pathogens, bacteria and food-borne mycotoxins. In the field of food microbiology, although on-site mycotoxin detection kits are available in grain samples, the main application is more likely to be carried out in the laboratory. Detection of foodborne bacterial pathogens usually involves at least one enrichment phase followed by confirmation of the presence or absence of the pathogen using test strips. Some manufacturers, such as Dupont®, have developed enrichment media and methods specifically designed for use with lateral flow test strips. Dip strips can also be used to quickly confirm the identity of bacterial isolates from routine microbiological testing.
A kit diagnostic system of the present invention includes, for example, a polypeptide, an antibody preparation, or a monoclonal antibody preparation of the present invention in an amount sufficient to perform at least one test as a packaged reagent. Instructions for use of packaged reagents are usually included.
A diagnostic system in the form of a kit of the invention may include, for example, a device for detecting the presence of biological material in a test sample, including, for example, a lollipop-shaped device consisting of a handle integrated with a base and a head integrated with a stem, with For collecting test samples, for example, saliva or body fluid samples of subjects. The tip may contain a transfer sponge reservoir to provide a large volume of voids to absorb a sufficient sample of saliva or body fluid. See U.S. Pat. LOUSE. Patent no. 7,993,283, which is incorporated herein by reference in its entirety.
The kit diagnostic system of the present invention may include, for example, means for combining a test sample and a buffer system (reagent 1) containing a viscosity control agent and a stabilizer into a reaction vessel and mixing the solutions. The diagnostic system in the form of a kit according to the invention may include, for example, means for reading the parameters of a reaction vessel with a sample and a buffer, and means for binding the test sample and buffer mixture to a fluorescently labeled ligand (reagent 2) A biological substance is placed in a reaction vessel, and the solution was stirred to obtain the measuring solution. also,
Reagent 2 can be delivered to the reaction vessel without further diluting the volume of the test solution.
As used herein, the term "package" refers to a solid matrix or material, such as glass, plastic, paper, foil, etc., which may contain a polypeptide, antibody preparation, or monoclonal antibody composition of the invention within fixed limits. Thus, for example, the package can be a glass vial containing milligram amounts of the desired polypeptide or it can be a well of a microtiter plate to which microgram amounts of the desired polypeptide are operatively immobilized, i.e. attached so as to enable immunization with antibodies.combined.
"Directions for use" usually include a tangible term describing the concentration of the reagent or at least one parameter of the test method, such as the relative amounts of reagent and sample to be mixed, the time period the reagent/sample mixture is maintained, temperature, buffer conditions, etc.
In preferred embodiments, the diagnostic system of the invention further comprises a label or indicator that can signal the formation of a complex containing the polypeptide or antibody molecule of the invention.
As used herein, the term "complex" refers to the product of a specific binding reaction, such as an antibody-antigen or receptor-ligand reaction. An exemplary complex is a product of an immune reaction.
As used herein, the terms "label" and "indicator" in their various grammatical forms refer to individual atoms and molecules that participate, directly or indirectly, in producing a detectable signal indicating the presence of a complex. Any labeling or indication agent may be attached to or incorporated into an expressed protein, polypeptide, or antibody molecule as part of an antibody or monoclonal antibody preparation of the invention, or may be used alone, and such atoms or molecules may be used alone or in combination with other reagents Where used, such markers are well known per se in clinical diagnostic chemistry and form part of this invention only to the extent that they are used in combination with other novel protein methods and/or systems.
The labeling agent may be a fluorescent labeling agent, which chemically binds antibodies or antigens without denaturing them to form fluorescent dye(s), which are useful immunofluorescent tracers. Suitable fluorescent labeling agents are fluorescent dyes such as fluorescein isocyanate (FIC), fluorescein isocyanate (FITC), 5-dimethylamine-1-naphthalenesulfonyl chloride (DANSC), rhodamine-based tetramethylisothiocyanate (TRITC), lissamine, rhodamine 8200 sulfonyl chloride ( RB 200 SC) and the like. DeLuca, "Immunofluorescence Analysis," in Antibody As a Tool, Marchalonis, et al., eds., John Wiley & Sons, Ltd., p. 189-231 (1982), which is incorporated by reference and incorporated into this article.
In preferred embodiments, the indicator group is an enzyme, such as horseradish peroxidase (HRP), glucose oxidase, and the like. In cases where the primary indicator group is an enzyme such as HRP or glucose oxidase, additional reagents are required to demonstrate the fact that a receptor-ligand complex (immunoreactant) has been formed. Such additional reagents for HRP include hydrogen peroxide and oxidizing dye precursors such as diaminobenzidine. Another reagent that can be used with glucose oxidase is 2,2'-azido-bis-(3-ethyl-benzothiazoline-G-sulfonic acid) (ABTS).
Radioactive elements are also useful labeling agents and are used here as examples. Examples of radiolabeling agents are radioactive elements that produce gamma rays. Elements that emit gamma rays themselves, such as .sup. 1241, .sup. 1251, .sup. 1281, .sup. 1321 and ,sup.51Cr represent a class of indicator groups for radioactive elements that produce gamma ray emission. Especially desirable is .sup. 1251. Another group of useful labeling methods are elements such as 11C, 18F, 150 and 13N, which themselves emit positrons. The positrons thus emitted produce gamma rays when they encounter electrons present in the animal's body. Beta emitters are also useful, such as 11lindium or 3H.
Linking tags, ie. labeling of polypeptides and proteins is well known in the art. For example, antibody molecules produced by hybridomas can be labeled by metabolic incorporation of amino acids containing radioactive isotopes provided as components of the medium. See, e.g. Galfire et al., Meth. Enzymology, 73:3-46 (1981). Techniques for conjugation or joining of proteins via activated functional groups are particularly suitable. See e.g. Aurameas et al., Scand. J. Immunology, Vol. 8 Appendix. 7:7-23 (1978), Rodwell et al., Biotech., 3:889-894 (1984), and US Pat. U.S. Patent no. 4,493,795, which is incorporated herein by reference in its entirety.
The diagnostic system may also include, preferably as a separate package, a specific binding agent. A "specific binding agent" is a molecular entity capable of selectively binding a reagent species of the invention or a complex containing such species, but which is not itself a polypeptide or antibody molecular composition of the invention. Examples of specific binding agents are secondary antibody molecules, complement proteins or their fragments,Staphylococcus aureusprotein A etc. Preferably, the specific binding agent binds the reagent species when the reagent species is present as part of the complex.
In preferred embodiments, the specific binding agent is labeled. However, when the diagnostic system includes an unlabeled specific binding agent, this reagent is generally used as an amplification agent or reagent. In these embodiments, the labeled specific binding agent is capable of specifically binding the enhancing agent when the enhancing agent is bound to a complex containing a reagent substance.
The diagnostic kit of the present invention can be used in an "ELISA" format to detect the presence or amount of cortisol in, for example, samples of body fluids such as serum, plasma or urine. "ELISA" refers to an enzyme immunoassay that uses an antibody or antigen bound to a solid phase and an enzyme-antigen or enzyme-antibody conjugate to detect and quantify the amount of antigen or antibody present in a sample. ELISA techniques are described in D. P. Sites et al., 4th ed., Basic and Clinical Immunology, Chapter 22, published by Lange Medical Publications, Los Altos, CA, 1982, and US Pat. 3,654,090; 3,850,752; and 4,016,043, all issued by Herein incorporated by reference.
Thus, for example, a polypeptide, antibody molecule composition, or monoclonal antibody molecule composition of the invention can be immobilized on a solid substrate to form a solid support containing a package in the subject diagnostic system. Reagents are typically immobilized onto solid substrates by adsorption from an aqueous medium, although other immobilization methods well known to those skilled in the art may be used.
Useful solid matrices are also well known in the art. Such materials are water insoluble and include cross-linked dextran; agarose; polystyrene beads from about 1 micron to about 5 mm in diameter; polyvinyl chloride, polystyrene, cross-linked polyacrylamide, nitrocellulose or nylon supports, such as sheets, strips or paddles or wells of test tubes, plates or microtiter plates, such as those made of polystyrene or polyvinyl chloride.
Reagent species, labeled specific binding agents, or amplification reagents for any of the diagnostic systems described herein may be provided in solution, liquid dispersion, or substantially dry powder form, for example in lyophilized form. When the indicator is an enzyme, the substrate for the enzyme can also be supplied in a separate kit for the system. A solid support such as the aforementioned microtiter plate and one or more buffers may also be included in the diagnostic test system as individually packaged items.
The packaging materials discussed herein in connection with diagnostic systems are those commonly used for diagnostic systems. These materials include glass and plastic (such as polyethylene, polypropylene, and polycarbonate) bottles, vials, plastic and plastic wrap envelopes, and more. In one embodiment, the diagnostic system of the present invention can be used to determine the presence of cortisol, for example. Such systems include a package in the form of a kit containing antibodies to, eg, cortisol.
"Sample" refers to, for example, essentially any source from which the material of interest (eg, ligands and anti-ligands, such as antibodies and antigens, and nucleic acids and their complements) to be analyzed can be obtained. Samples can be obtained from virtually any organism, including animals and plants, as well as cell cultures, recombinant cells, and cell components. Samples can be from biological tissue, body fluids or samples, and can be taken from diseased or healthy organisms. Samples may include, but are not limited to, saliva, sputum, amniotic fluid, blood, blood cells (eg, white blood cells), urine, semen, peritoneal fluid, pleural fluid, tissue or fine needle biopsy samples, and tissue homogenates. Samples may also include tissue sections, such as frozen sections for histological purposes. Usually, samples are taken from people. However, samples can also be obtained from other mammals including, for example, but not limited to dogs, cats, sheep, cows and pigs. Samples can be pretreated if necessary by diluting or concentrating in an appropriate buffer solution. Any of a number of standard aqueous buffer solutions can be used, using one of a variety of buffering agents such as phosphate, Tris, etc., preferably at physiological pH.
Biological samples can be obtained from patients using well-known techniques such as venipuncture, lumbar puncture, fluid samples such as saliva or urine, or tissue biopsies, among others. When the biological material is of non-human origin, such as commercial livestock, blood and tissue samples are conveniently obtained from livestock processing plants. Alternatively, the biological sample can be obtained from a cell or blood bank that stores tissue and/or blood, or from an in vitro source, such as cell culture.
Techniques for establishing cell cultures for use as a source of biological material are well known to those skilled in the art.
In one embodiment, the sample is selected from or derived from, for example, a microbial product or a biological product.
While the above examples relate to antigens associated with disease, immunoassay devices can be used, for example, as allergy test kits, drug abuse tests, or to analyze samples of non-human origin, such as bovine, porcine and veterinary tests. The particular reagents used in the assay device will be selected to ensure the detection of the particular analyte of interest, as is well known in the art. The analyte of interest can be any analyte, for example it can be an organic or inorganic chemical reagent and optionally includes a hapten, protein, polypeptide, microorganism or nucleic acid sequence.
In particular, the analyte is a hormone, for example a fertility hormone such as progesterone or a stress hormone such as cortisol. However, these types of tests are widely used in diagnostic and analytical fields. The detection of marker proteins or hormones enables the diagnosis of certain disease states in humans or animals, and may also require the detection of the presence of drugs or drug residues, for example in animal husbandry, forensic science or interdiction or detection. illegal drugs.
Alternatively, the analyte is a chemical reagent, such as a small molecule, which conveniently contains a hapten. Small molecules usually contain a single identifiable binding site. Typically, their molecular weight is less than 1 kDa.
When a labeled analyte binding partner is used in an assay and the analyte is a chemical reagent, the binding partner may include any other reagent that reacts with or otherwise associates with the chemical reagent by forming a covalent bond with the reagent or ionic bonds, or through creating other interactions such as hydrogen bonds or van der Waals interactions. For example, when the chemical reagent is an acid, binding partners may include alcohols or amines that form esters or amides with the acid under the various conditions found in the analysis. Alternatively, the binding partner may comprise a base that forms a salt with the acid. Conversely, the binding partner may comprise the acidic portion of the reactive pair.
When the analyte is or contains a hapten or protein antigen, the binding partner may comprise an antibody or a binding fragment thereof, which may be monoclonal, polyclonal or recombinant, but preferably monoclonal. When the analyte is a hormone or enzyme, the labeled binding partner may comprise a labeled receptor for the analyte. However, when the analyte itself is an immunoglobulin, particularly an antibody, labeled binding partners may also include, for example, antigens or recombinant antigens and anti-antibody immunoglobulins such as antisera.
Antibodies or conjugated fragments to small molecules such as haptens are produced by linking the molecule to an immunogenic agent and administering it to an animal such as a mouse or rabbit. Antibodies are then collected from the animals in the usual manner. Monoclonal antibodies are obtained by fusing splenocytes with hybridoma cells and selecting cells that bind the hapten using conventional procedures.
For example, when the analyte is a bioactive substance, such as the active agrochemicals discussed above, the specific reagents used in the assay device will be selected to ensure detection of the specific bioactive substance of interest, as is well known in the art. The substance can be any active chemical, such as an agrochemical, e.g. a chemical agent that can be organic or inorganic, and optionally contains a hapten, protein, polypeptide, microorganism or nucleic acid sequence. Most preferably, the biologically active material is a chemical agent, such as a small molecule suitable for containing a hapten. Small molecules usually have only one antibody binding site. Typically, their molecular weight is less than 1 kDa.
Antibodies or conjugated fragments to small molecules such as haptens are produced by linking the molecule to an immunogenic agent and administering it to an animal such as a mouse or rabbit. Antibodies are then collected from the animals in the usual manner. Monoclonal antibodies are obtained by fusing splenocytes with hybridoma cells and selecting cells that bind the hapten using conventional procedures.
microgrid
The method of the invention is particularly suitable for use in combination with the analysis of gene expression profiles. In some embodiments, a gene expression profile, e.g., a collection of transcription rates for a number of genes, is converted into a predicted gene expression profile. A predicted gene expression profile is a set of expression values. In some embodiments, conversion is achieved by averaging the rate of gene transcription. In some other embodiments, other linear projection methods may be used.
Microarrays can be prepared and analyzed using methods known in the art. Oligonucleotides can be used as probes or targets in microarrays. Microarrays can be used to simultaneously monitor the expression levels of a large number of genes and identify genetic variations, mutations and single nucleotide polymorphisms. Such information can be used to determine gene function; to understand the genetic basis of a condition, disease or disorder; to diagnose a condition, disease or disorder; for the development and monitoring of the activity of therapeutic drugs. (See, e.g., Brennan et al. (1995) U.S. Patent No. 5,474,796; Schena et al. (1996) Proc. Natd. Acad. Sci. 93:10614-10619; Baldeschweiler et al. (1995) PCT Application WO 95 /251116; Shalon et al (1995) PCT Application WO 95/35505; Heller et al (1997) Proc. Natl. Acad. Sci. 94:2150-2155; and Heller et al (1997); US Pat. 5,605,662.) Hybridization Probes Needles can also be used to map naturally occurring genome sequences. Sequences can be mapped to specific chromosomes, specific chromosome regions, or artificial chromosome constructs such as human artificial chromosomes (HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial PI constructs, or single-chromosomal DNA libraries.
Using the methods of the present invention, one skilled in the art can readily select and prepare microarray probes that contain specific individual probes for less than all genes in the genome and less than all genes in the genome. In such embodiments, the microarray contains one or two or more individual probes, each probe hybridizing to the expression products (eg, mRNA, or cDNA or cRNA derived therefrom) of a desired number of genes. Thus, for example, changes in the expression of all or most genes in the entire genome of a cell or organism can be monitored by using surrogates and measuring the expression of a representative genome on a single microarray for all or most of the genome. genes in the genome. Such microarrays can be prepared using selected probes and are therefore part of the present invention.
stroke
Stroke (herein also referred to as acute stroke, ischemic stroke, and/or cerebrovascular ischemia) is often considered the third leading cause of death in the industry, after ischemic heart disease and cancer. Stroke kills about 300,000 people in the United States each year and is the leading cause of hospitalization and long-term disability. Therefore, the socioeconomic impact of stroke and its accompanying social burden is almost immeasurable.
The World Health Organization defines "stroke" as rapidly developing clinical signs of a focal or global disorder of brain function, with symptoms lasting at least 24 hours. Stroke is also associated with death with no apparent cause other than effects of vascular origin. A stroke is usually caused by a blockage or occlusion of a blood vessel in or within the brain.
In the case of complete occlusion, the cessation of cerebral circulation causes the electrical activity of neurons to cease within a few seconds. Depletion of high-energy phosphate, failure of membrane ion pumps, cellular efflux of potassium, influx of sodium chloride and water, and membrane depolarization occur within minutes after deterioration of energy status and ion homeostasis. If the blockage lasts longer than 5 to 10 minutes, it can cause irreparable damage. However, with incomplete ischemia, outcome is difficult to assess and is highly dependent on residual perfusion and oxygen availability. Complete ischemia after thrombotic occlusion of a cerebral vessel is rare. Some residual perfusion usually exists in the ischemic region, depending on collateral flow and regional perfusion pressure.
Subjects suffering from stroke were diagnosed as such based on experienced symptoms and/or physical examination including invasive and non-invasive diagnostic tools such as CT and MR imaging. The methods of the invention are useful for treating various clinical manifestations in individuals with stroke. People who have had a stroke may experience one or more of the following symptoms: paralysis, weakness, reduced sensation and/or vision, numbness, tingling, aphasia (eg, inability to speak or slurred speech, difficulty reading or writing), agnosia (i.e. inability to recognize or recognize sensory stimuli), memory loss, difficulty with coordination, drowsiness, sleepiness or confusion, incontinence, and cognitive decline (eg, dementia, limited attention, inability to concentrate). By using medical imaging techniques, a subject suffering from a stroke can be identified as having a heart attack or cerebral hemorrhage.
The present invention relates to the use of GCR antagonists, such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, in the prevention or treatment of stroke.
Treatment and/or prevention of infection after stroke may be directed at patients who have experienced a stroke or may be prophylactic treatment. Short-term prophylactic therapy is indicated for subjects undergoing surgery or diagnostic procedures in which there is a risk of releasing emboli, lowering blood pressure, or reducing blood flow to the brain to reduce injury from any ischemic event that occurs as a consequence of the procedure. Long-term or chronic prophylactic treatment is indicated for people with heart disease or diseases that directly affect the vasculature of the brain, which can lead to reduced blood flow in the brain. If prophylactic, the treatment is for subjects at abnormally increased risk of ischemic stroke, as described above. If the subject has suffered a stroke, treatment may include acute treatment. Acute treatment for the prevention of infection after stroke in patients refers to the administration of the drug of this invention within 48 hours, preferably within 24 hours, more preferably within 12 hours, more preferably within 6 hours, when symptoms of the disease appear or after the onset, even more preferably within 3 hours from the onset of symptoms.
An important embodiment of the invention is the treatment of subjects with an abnormally increased risk of ischemic stroke. As used herein, subjects at abnormally elevated risk of ischemic stroke are categories determined in accordance with conventional medical practice; these subjects may also be identified in conventional medical practice as those with known risk factors for stroke or at increased risk for cerebrovascular events. Subjects at unusually increased risk of ischemic stroke include, for example, individuals undergoing surgical procedures or diagnostic procedures that risk releasing emboli, lowering blood pressure, or reducing blood flow to the brain, such as carotid artery endarterectomy, cerebral angiography, neurosurgery in in which a blood vessel is compressed or blocked, cardiac catheterization, angioplasty, including balloon angioplasty, coronary artery bypass surgery or similar procedures.
central nervous system injury
Conditions suitable for treatment in accordance with the present invention include, for example, epilepsy, pain syndromes, neurodegenerative diseases (including motor neuron disease, myelopathy, radiculopathy and sympathetic nervous system disease), dementia, cerebrovascular disorders, movement disorders, cerebral trauma, cranial nerve disease nerve, neuropsychiatric disease and other disorders Neuropathy (including viral neuropathy, diabetes-related neuropathy, Guillian-Barre syndrome, dysproteinemia, transthyretin-induced neuropathy, and carpal tunnel syndrome). The present invention relates to the use of GCR antagonists, such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, in the prevention or treatment of CNS damage.
As used herein, seizure disorders include complex partial seizures, simple partial seizures, secondary generalized partial seizures, generalized seizures (including absence, grand mal seizures (tonic-clonic), status epilepticus, tonic, atonic, myoclonus), neonatal and infantile spasms , drug-induced seizures, trauma-induced seizures and febrile seizures and other specific epilepsy syndromes such as juvenile myoclonic epilepsy, Lennox-Gastaut, medial temporal lobe epilepsy, frontal lobe nocturnal epilepsy, progressive epilepsy with mental retardation and progressive myoclonic epilepsy such as seizures associated with mass lesions of the central nervous system.
Pain syndromes include, for example, headache (eg, migraine, tension and cluster headaches), acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain and inflammatory pain, drug-induced neuropathic pain, causalgia, pain, complex pain, regional pain type I and II syndrome and reflex sympathetic dystrophy (RSDS).
Neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, ALS, spinal muscular atrophy, muscular dystrophy, prion-related diseases, cerebellar ataxia, Friedrich's ataxia, SCA, Wilson's disease, RP, Gullian Bane syndrome, adrenoleukodystrophy, Menke's Sx , Cerebral autosomal dominant arteriopathy with subcortical infarction (CADASIL), Charcot Marie Tooth disease, neurofibromatosis, von-Hippel Lindau, fragile X, spastic paraplegia, tuberous sclerosis, Wardenburg syndrome, spinal motor atrophy, Tay-Sachs disease, Sandoff disease, familial spastic paraplegia, myelopathy, radiculopathy, encephalopathy associated with trauma, radiation, drugs and infections, and disorders of the sympathetic nervous system (eg, Shy Drager (familial autonomic disorder), diabetic neuropathy, drug-induced neuropathy, and alcoholic neuropathy).
Dementias include Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, Huntington's disease and MCI.
Cerebrovascular disorders suitable for treatment in accordance with the present invention include cerebrovascular disease and stroke (eg, thrombotic, embolic, thromboembolic, hemorrhagic [including AVM and berry aneurysm], venoconstrictive and venous).
Movement disorders include Parkinson's disease, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, and Tourette syndrome.
Brain trauma as used herein includes traumatic brain and spinal cord injury as well as radiation brain injury.
Cranial nerve disorders include trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, and Bell's palsy. Neuropsychiatric disorders including panic syndrome, generalized anxiety disorder, all types of phobias, mania, manic depression, hypomania, unipolar depression, depression, stress disorder, post-traumatic stress disorder, somatoform disorders, personality disorders, psychoses and schizophrenia) and substance dependence/addiction ( eg alcohol, psychostimulants (eg crack, cocaine, speed, methamphetamine), opioids and nicotine) and drug-induced mental illness.
Other diseased neuropathies that can be treated with the compositions and methods described herein include Guillian-Barre neuropathy associated with diabetes, dysproteinemia, transthyretin-induced neuropathy, neuropathy associated with HIV, herpes viruses (including herpes zoster), or neuropathy associated with other viral infections, Lyme disease, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid neuropathy, leprosy neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis neuropathy, cranial polyp neuropathy, heavy metal neuropathy, transition metal neuropathy, drug-induced neuropathy, post-meningitis syndrome, post- polio syndrome, prion disease and radiation-related neurological syndrome. Other diseases amenable to treatment by the present invention include fatigue syndromes (eg, chronic fatigue syndrome and fibromyalgia), ataxia syndromes, olivopontocerebellar degeneration, striatonigral degeneration, and brain axonal damage.
The invention is particularly useful in the treatment of neuropsychiatric disorders such as depression, agitation, anxiety, epilepsy such as grand mal seizures, status epilepticus, treatment and prevention of migraine, Alzheimer's disease, Parkinson's disease and traumatic brain and spinal cord injuries.
Furthermore, the higher doses achieved by this invention are expected to be particularly important for dementias including Alzheimer's disease, Parkinson's disease and vascular dementia, pain syndromes including headache and migraine, epilepsy, movement disorders and traumatic brain injury.
In addition, the ease of use and convenience of the dosage forms offered have been developed to be administered once daily or administered less frequently in therapeutically effective amounts from the start of treatment, which is important in the treatment of diseases including Alzheimer's disease and Parkinson's disease. It has value in dementia, epilepsy, pain syndrome and cerebrovascular diseases.
Alternatives to certain routes of administration
Pharmaceutical preparations can be optimized for a specific type of delivery. For example, pharmaceutical compositions for oral administration are formulated using pharmaceutically acceptable carriers well known in the art. The carrier allows the agents in the composition to be formulated as, for example, tablets, pills, capsules, solutions, suspensions, sustained release formulations; powders, liquids or gels for oral administration by the subject.
GCR antagonists can also be delivered as an aerosol spray formulation from a pressurized pack, nebulizer, or dry powder inhaler. Suitable propellants that can be used in the nebulizer include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, and carbon dioxide. In the case of pressurized aerosols, the dosage can be determined by fitting a valve to deliver a prescribed amount of compound.
Preparations for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid preparations may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered orally, intranasally, or by the respiratory route for local or systemic effect. Preparations in preferably sterile pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulized solutions can be inhaled directly from a nebulizer, or the nebulizer can be attached to a mask, tent, or intermittent positive pressure breathing apparatus. Solution, suspension or powder preparations can be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
regenerative therapy
The activity of GR agonists and their changes in cellular function are variable and depend on complex intracellular molecular signals specific to cells and tissues. Among the cells with receptors for glucocorticoids are stem and progenitor cells of all tissues and organs in the body. Therefore, the binding of these molecules to normal "intra-tissue" stem cells and to the progeny of these stem cells (so-called "transit-amplified" progenitors) results in various cell- and tissue-specific effects, inhibiting or enhancing stem cell and progenitor cell function. it includes activation, proliferation, migration and differentiation, all depending on the tissue/organ in question.
The present invention relates to the use of GCR antagonists or active agents (such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, their combinations and their pharmaceutically acceptable salts) for the prevention or treatment of the following diseases. the action of GR agonists in a tissue-specific manner enhances the function of some stem/progenitor cells and inhibits the function of others. GR antagonists will have beneficial effects in certain clinical settings where regenerative medicine approaches can be used to treat disease and heal wounds, including: improving post-transplant function of autologous stem cell transplantation (depending on the source tissue and/or target tissue). Reducing the perioperative effects of catabolic stress hormones associated with surgery or other physical trauma such as combat trauma.
Systemic GR blockade is not suitable, but direct application of the present invention includes the use of GCR antagonists, such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, for prophylaxis or treatment at the site of injury/injury , topically (eg to prevent wound dehiscence) or by direct injection or intravascular infusion (for internal organ injuries) would be useful.
The present invention relates to the use of cortisol blockers (glucocorticoid receptor [GR] antagonists) for the treatment of stem cells for regenerative therapy.
stem cell
The term "stem cells" generally refers to cells that face two developmental choices when they divide: the daughter cells can be identical to the original cell (self-renewal) or they can be progenitors of more specialized cell types (differentiation). Thus, stem cells can go one way or the other (there is another way where one of each type of cell can be formed). Therefore, stem cells are cells that are not terminally differentiated and are capable of giving rise to other types of cells.
Embryonic stem (ESC) cells can be isolated from the inner cell mass (ICM) of the blastocyst, the developmental stage of the embryo at the time of implantation.
Pluripotent stem cells are true stem cells that have the potential to give rise to any differentiated cell in the body. However, they do not contribute to the production of trophoblast-derived extraembryonic membranes.
Several types of pluripotent stem cells have been discovered.
Pluripotent stem cells are true stem cells, but they can differentiate into only a limited number of types. For example, bone marrow contains pluripotent stem cells from which all blood cells arise, but not other types of cells. Pluripotent stem cells are found in adult animals. Every organ in the body is thought to contain them, and they replace dead or damaged cells. Methods for characterizing stem cells are known in the art and include the use of standard assays such as clonogenic assays, flow cytometry, long-term culture, and molecular biology techniques such as PCR, RT-PCR, and Southern blotting.
Adult stem cells include several types, including neural, skin, and hematopoietic stem cells, which are active ingredients in bone marrow transplantation.
These latter types of stem cells are also the main features of cord-derived stem cells. Adult stem cells can mature into functional, more specialized cell types in the laboratory and in vivo, although the exact number of cell types is limited by the type of stem cells selected.
Induced pluripotent stem cells, often abbreviated iPS cells or iPSCs, are a type of pluripotent stem cells that are artificially derived from non-pluripotent cells (usually adult somatic cells) by inserting certain genes. iPS cells are reviewed and discussed in Takahashi, K. & Yamanaka (2006), Yamanaka S, et. Al. (2007), Wemig M et al. Al. (2007), Maherali N, et al. Al. (2007), Yu J et al (2007) and Takahashi et al (2007), all of which are incorporated herein by reference.
iPS cells are usually obtained by transfection of certain stem cell-related genes into non-pluripotent cells such as adult fibroblasts. Transfection is usually achieved by viral vectors, for example by retroviral reprogramming. Transfected genes included the master transcriptional regulators Oct-3/4 (Pouf51) and Sox2, although other genes were thought to increase induction efficiency. After 3-4 weeks, a small number of transfected cells begin to resemble pluripotent stem cells in morphology and biochemistry and are usually isolated by morphological selection, doubling time, or infection with reporter genes and antibiotics. IPSCs can be induced from somatic cells such as fibroblasts by transfection with one or more transcription factors. In some cases, cells were transformed with Oct3/4, Sox2, c-Myc and Klf4. Cells can additionally be transfected with other genes, including transcription factors and/or marker genes. Genes can be introduced using a transposon system such as the Cre/loxP recombination system or using a non-integrating vector to generate iPSCs without exogenous reprogramming genes. Transfection can be achieved using viral vectors, such as retroviruses. The virus can be an amphotropic virus. Once the cells are transfected, they can be grown on feeder cells and then transferred to ESC medium.
iPS cells can be derived from any suitable cell type, including lung, foreskin fibroblasts, skin fibroblasts, keratinocytes, blood progenitor cells, bone marrow cells, hepatocytes, gastric epithelial cells, pancreatic cells, neural stem cells, B lymphocytes, somatic cells derived from ES cells and embryonic fibroblasts. In some cases the cells are not human dermal fibroblasts. IPSCs can exhibit similar gene expression and phenotypic patterns to ESCs.
A source of induced pluripotent stem cells
Several methods have been proposed for the isolation of pluripotent stem cells that do not lead to the destruction of the embryo, for example by transforming (inducing) adult somatic or germ cells. These methods include:
1. Reprogramming nuclear transmission. The technique involves the transfer of a nucleus from a somatic cell to an oocyte or fertilized egg. In some cases, this could lead to the creation of animal-human hybrid cells. For example, a cell can be produced by the fusion of a human cell with an animal oocyte or zygote or by the fusion of a human oocyte or zygote with an animal somatic cell. 2. Reprogramming by fusion with embryonic stem cells. The technique involves fusing somatic cells with embryonic stem cells. This technique can also lead to the creation of animal-human hybrid cells, as shown above 1. 3. Spontaneous reprogramming of the culture.
This technique involves the generation of pluripotent cells from non-pluripotent cells after long-term culture. For example, pluripotent embryonic germ cells (EGs) have been generated by long-term culture of primordial germ cells (PGCs) (Matsui et al., Extraction of pluripotent embryonic stem cells from cultured mouse primordial germ cells. Cell 70, 841-847 , 1992, incorporated herein by reference ). The development of pluripotent stem cells after long-term culture of cells derived from bone marrow has also been reported (Jiang et al., Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41-49, 2002, herein incorporated by reference). They called these cells multipotent adult progenitor cells (MAPCs). Shinohara et al. also showed that pluripotent stem cells, which they termed multipotent germline stem cells (mGS), can be generated during germline stem cell (GS) culture of neonatal mouse testes (Kanatsu-Shinohara et al.,
Generation of pluripotent stem cells from neonatal mouse testes. Cells 119, 1001-1012, 2004). 4. Reprogramming with defined factors. For example, the introduction of transcription factors (such as Oct-3/4, Sox2, c-Myc and KLF4) into mouse embryonic or adult fibroblasts by retrovirus-mediated introduction (as described above. Kaji et al. (virus-free) induction of pluripotency and subsequent excision of reprogramming factors. Nature. Online publication March 1, 2009) also described non-viral transfection of a single polyprotein expression vector containing the coding sequences for c-Myc, Klf4, Oct4 and Sox2 with a 2A peptide linked , can reprogram mouse and human fibroblasts . iPS cells generated with this non-viral vector show strong expression of pluripotency markers, indicating that the reprogramming state is determined by in vitro differentiation assays and that the chimeric formation of adult mice is functionally confirmed. They successfully established reprogrammed human cell lines from embryonic fibroblasts with strong expression of pluripotency markers.
Methods 1-4 are described and discussed by Shinya Yamanaka in Strategies and New Developments in the Generation of Patient-Specific Pluripotent Stem Cells (Cell Stem Cell 1, July 2007 Elsevier Inc), which is incorporated herein by reference. 5. Derivation of hESC lines from individual blastomeres or biopsied blastomeres. See Klimanskaya I, Chung Y, Becker S, Lu S J, Lanza R. Human embryonic stem cell lines derived from a single blastomere. Nature 2006;444:512, Xeno-free derivation and culture of human embryonic stem cells by Lei et al: Status, issues and challenges. Cell Research (2007) 17:682-688, Chung Y, Klimanskaya I, Becker S, et al. Embryonic and extraembryonic stem cell lines from single mouse blastomeres. nature. 2006;439:216-219. Klimanskaya I, Chung Y, Becker S, et al. A human embryonic stem cell line derived from a single blastomere. nature. 2006;444:481-485. Chung Y, Klimanskaya I, Becker S, et al. The resulting human embryonic stem cell lines did not destroy the embryos. Cell stem cells. 2008; 2:113-117 and Duško Ilić et al. (Derivation of Human Three Embryonic Stem Cell Lines from Biopsied Blastomas on Human Feeders with Minimal Exposure to Xenomaterials. Stem Cells and Development-Pre-Publication Paper), incorporated by reference in its entirety into this article. 6. hESC lines derived from arrested embryos that have arrested cleavage and cannot develop into morula and blastocysts in vitro. See Zhang X, Stojkovic P, Przyborski S, et al. Extraction of human embryonic stem cells from developing and arrested embryos. Stem cells 2006;24:2669-2676 and Lei et al. Derivation and culture of human embryonic stem cells without xenon: status, problems and challenges. Cell Research (2007) 17:682-688, all of which are incorporated herein by reference. 7. Parthenogenesis (or parthenogenesis). The technique involves chemically or electrically stimulating unfertilized eggs to develop into blastomeres from which embryonic stem cells can be produced. See, for example, Lin et al. Multipotency of homozygous stem cells from metaphase II oocytes. mother station. 2003;21(2):152-61, They use chemical activation of unfertilized metaphase II oocytes to generate stem cells. 8. Stem cells of fetal origin. These cells are interpotent between embryonic stem cells and adult stem cells and can be used to obtain pluripotent or multipotent cells. Human umbilical cord-derived fetal mesenchymal stem cells (UC fMSCs) -1-81, minimal evidence of senescence using β-galactosidase staining and consistent expression of telomerase activity) were successfully performed by Chris H. Jo et al. Mesenchymal stem cells maintain naive state) characteristics during extensive expansion (Cell Tissue Res (2008) 334:423-433, incorporated herein by reference). Pure mesenchymal stem cells were isolated by Winston Costa Pereira et al. (Reproducible methodology for the isolation of human umbilical cord mesenchymal stem cells and their cardiomyocyte-generating potential J Tissue Eng Regen Med 2008; 2: 394-399, herein incorporated by reference ).Stem cell population derived from human umbilical cord Wharton's jelly cells. Troyer & Weiss also reviewed Wharton's jelly-derived mesenchymal stem cells (Summary review: Jelly-derived Wharton's cells are a primitive population of stromal cells. Stem Cells 2008:26:591-599) Kim et al. (Ex vivo characterization of human amniotic membrane Cloning Stem Cells 2007 Winter; 9(4):581-94, herein incorporated by reference) successfully isolated human amniotic membrane mesenchymal cells from human amniotic membrane. Stem cells derived from the umbilical cord, a tissue that is usually discarded, often do not raise moral or ethical objections.
The advantage of induced pluripotent stem cells is that they can be obtained by methods that do not cause the destruction of embryos, specifically human or mammalian embryos. Thus, aspects of the invention may be practiced or put into practice using cells that are not exclusively prepared by methods that necessarily involve the destruction of the human or animal embryo from which the cells are derived. This optional limitation is designed to take into account decision G 0002/06 of 25 November 2008 of the Enlarged Board of Appeal of the European Patent Office.
mesenchymal stem cells
Mesenchymal stem cells are known to be pluripotent and have the potential to differentiate into various cell/tissue lineages, including cartilage, bone, adipose tissue, tendons and ligaments. These multipotent mesenchymal progenitor cells are called stromal or mesenchymal stem cells. Bone marrow contains two main types of cells: hematopoietic cells and stromal cells. Stem cells of non-hematopoietic tissues are called mesenchymal cells because of their ability to differentiate into mesenchymal or stromal cells.
Therefore, in this specification, mesenchymal stem cells (MSCs) refer to pluripotent stem cells capable of differentiation into osteoblasts, chondrocytes, muscle cells, adipocytes and endothelial cells. In this specification, MSCs specifically refer to pluripotent stem cells capable of differentiating into osteoblasts as part of the bone formation process.
Mesenchymal cells are easily obtained from bone marrow using minimally invasive techniques and can be expanded in culture and allowed to differentiate into desired lineages. Differentiation can be induced by the application of specific growth factors. Transforming growth factor β (TGF-β) superfamily proteins such as bone morphogenetic proteins (BMPs) are important factors in the chondrogenic and osteogenic differentiation of mesenchymal stem cells.
Suitable MSCs can be obtained from bone marrow aspirates (eg, Wexler et al. Adult bone marrow is a rich source of human mesenchymal "stem" cells, but adult umbilical cord and mobilized blood are not. HAEMOPOESIS AND LEUKOCYTES British Journal of Hematology 121(2) . ) :368-374, April 2003) or Wharton's Jelly of the umbilical cord (eg Ta et al. Long-term Expansion and Pluripotent Marker Array Analysis of Wharton's Jelly-Derived Mesenchymal Stem Cells. Stem Cells Dev. July 20 2009 (e-edition).
Differentiation of MSCs towards the osteogenic lineage can be achieved by cultivation in osteogenic media. For example, MSCs were plated at a density of 3000/cm2 in maintenance medium (DMEM, 1 g/l glucose, 10% FCS, 2 mM L-glutamine, 50 U/ml penicillin and 50 U/ml chain 6-12 wells and chamber slides in 1000 g/ml ascorbic acid and 10 mM β-glycerophosphate) for 24 hours before changing to bone medium. Cells were then maintained for up to 28 days with media changes every 3-4 days. After 14 days, the cells in the slides can be fixed in 4% PFA and stored at 4 °C. C. Immunohistochemistry in PBS. After 14 and 28 days, cells were stained with Alizarin Red S for calcium and von Kossa for calcium phosphate. RNA can also be extracted for analysis using the Nucleospin RNA extraction kit according to the manufacturer's instructions (Macherey Nagel), and protein samples can be extracted for analysis.
Differentiation of MSCs to the adipogenic lineage can be achieved by cultivation in adipogenic media. For example, MSCs were seeded in maintenance medium at a density of 18,000/cm 2 and incubated for 2 days as described above.
Remove the medium and add adipogenic maintenance medium (DMEM, 4.5 g/l glucose, 10% FCS, L-glutamine and penicillin and streptomycin) or adipogenic medium (adipogenic maintenance medium, containing 10 µg/ml insulin, 115 µg / ml methylisobutylxanthine, 1 µM dexamethasone and 20 µM indomethacin). Cells were then maintained for up to 28 days with media changes every 3-4 days. After 14 and 28 days, cells can be stained with Oil Red O to stain lipid droplets. RNA and protein can also be extracted for analysis.
Differentiation of MSCs towards the chondrocyte lineage can be achieved by cultivation in osteoblast medium. For example, MSCs were counted and resuspended 5 times. 10.sup.5 cells/ml in chondrogenic medium (DMEM and Cambrex Chondrogenic Monoaliquot) with or without 10 ng/ml TGF.quadrature.3 (Cambrex), then a 500 ml aliquot. Samples were placed in 15 ml tubes and centrifuged at 150° C. times.g Incubate for 10 min at room temperature and 2 days at 37°C. After two days, the tube will contain loose round beads. Medium was changed every 3–4 days before RNA was isolated using Trizol (Invitrogen) or cell pellets were fixed in 4% PFA and embedded for cryosectioning, pellets were maintained for 21 days and then mounted on glass slides. Make serial sections before storing at -80° C. For immunohistochemistry.
When studying osteogenic and adipogenic differentiation in confluent conditions, cells can be seeded at 30,000/cm2and allowed to reach confluency before being transferred to the relevant differentiation medium and cultured as above.
stem cell cultures
Any suitable method of culturing stem cells can be used, and any suitable container can be used to propagate the stem cells. Suitable containers include those described in US Patent Publication US2007/0264713 (Terstegge).
For example, vessels may include bioreactors and centrifuges. A "bioreactor" is a vessel suitable for the large-scale cultivation of eukaryotic cells, such as animal cells or mammalian cells. Typical culture volumes for conditioning bioreactors are between 20 mL and 500 mL. Bioreactors can include controlled bioreactors, where one or more conditions, such as oxygen partial pressure, can be controlled or monitored. Devices for measuring and adjusting these conditions are known in the art. For example, an oxygen electrode can be used for the partial pressure of oxygen. The partial pressure of oxygen can be adjusted by the amount and composition of the selected gas mixture (eg air or a mixture of air and/or oxygen and/or nitrogen and/or carbon dioxide). Bailey, J E. (Bailey, J E., Fundamentals of Biochemical Engineering, Second Edition, McGraw-Hill, Inc. ISBN O-07-003212-2 Higher Education, (1986)) or Jackson A T. Jackson A T . , Verfahrenstechnik in der Biotechnologie, Springer, ISBN 3540561900 (1993)).
Other suitable containers include spinners. Rotators are regulated or unregulated bioreactors that can be mixed using various mixing mechanisms such as glass ball mixers, impeller mixers and other suitable mixers. Rotary culture volumes are usually between 20 mL and 500 mL. Roller bottles are round bottles for cell cultures made of plastic or glass with a culture surface between 400 and 2000 cm2. The cells are grown along the entire inner surface of these flasks, the cells are covered with a substrate, and this is done with a "rolling" movement, that is, by rotating the flasks around their own axis.
Alternatively, cultivation can be static, i.e. without active culture/media mixing. By reducing the agitation of the culture, the formation of cell clusters can be allowed. Such mixing can be applied so as not to substantially disrupt aggregate formation, although some mixing can be used to facilitate the distribution and flow of media over the cultured cells. For example, low speed mixing, such as less than 30 revolutions per minute or less than 20 revolutions per minute, may be used.
It reproduces through channels. Cell culture methods may involve passage or splitting during culture. The method may involve batch or serial passes. Cells in culture can be isolated from matrices or flasks and "dissociated", subcultured or transferred by diluting into tissue culture medium and replating/reculturing. The term "passaging" can generally refer to the process by which an aliquot of a cell culture is taken, the cells are completely or partially separated, diluted, and inoculated into the culture medium. The pass can be repeated one or more times. An aliquot may contain all or part of the cell culture. Aliquots of cells can be fully, partially or non-confluent. The passage may include at least some of the following steps: aspiration, washing, trypsinization, incubation, removal, quenching, reseeding, and aliquoting. The protocol published by the UC San Diego Hedrick Lab can be used.
Cells can be separated by any suitable means, such as mechanical or enzymatic methods known in the art. Cells can be disrupted by mechanical dissociation, for example using cell scrapers or pipettes. Cells can be sieved through a mesh of appropriate size, such as 100 micron or 500 micron mesh. Cells can be dissociated by enzymatic dissociation, for example by treatment with collagenase, or harvested with trypLE. Dissociation can be complete or partial. The dilution can be any suitable dilution. Cells in cell culture can be divided in any suitable ratio. For example, cells can be divided at a ratio of 1:2 or more, 1:3 or more, 1:4 or more, or 1:5 or more. Therefore, stem cells can be passaged 1 or more times. For example, stem cells can be passaged 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, more than 25 articles. Passage can be expressed as the number of generations of cell growth. Stem cells can reproduce 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 , 24, 25 generations or more. Stem cells can reproduce 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 , 24 , 25 cell doubling or multiple co-cultivation and feeding methods may involve culturing stem cells with or without co-cultivation. The term "co-culture" refers to a mixture of two or more different types of cells grown together. Two or more different types of cells can be grown on the same surface, such as the surface of a container of particles or cells, or on different surfaces. Different types of cells can grow on different particles. Feeder cells can refer to cells that are used or needed to grow different types of cells. In the context of stem cell culture, feeder cells have the function of ensuring cell pluripotency, i.e. survival, proliferation and maintenance of pluripotency. Pluripotency/pluripotency of cells can be ensured by direct cocultivation of feeder cells. For example, the inner surface of a container such as a Petri dish can be coated with a layer of feeder cells. Nutrient cells release nutrients into the medium. Alternatively, or additionally, feeder cells can be grown in culture medium to regulate them. Conditioned media can be used to grow stem cells. Therefore, layouts where power cells are missing or not needed are also possible.
The invention provides for the treatment of stem cells with a GR antagonist for the production of stem cells treated with a GR antagonist.
Osteoporosis and bone-related injuries
Glucocorticoids (GK) are crucial in the treatment of inflammatory and immune diseases. However, these steroids can have profound effects on the bones, especially if taken for a long time. In fact, high-dose GC therapy is almost universally associated with bone loss, resulting in one of the most severe forms of osteoporosis. Despite the frequency and severity of GC-induced osteoporosis, treatment outcomes are unsatisfactory, suggesting that its pathogenesis is not fully understood. The present invention provides a method and treatment of these diseases and rapid site-specific bone growth achieved by a combination of cortisol blockers, i.e. the present invention relates to the use of GCR antagonists such as ORG34517, PT150, PT155, PT156, PT157, PT158, TCY1 and their combinations and pharmaceutically acceptable salts thereof for prophylaxis or treatment and optionally using bone marrow lavage, osteocompatible bone cement and PTH therapy.
The present invention relates to the use of GR antagonists or stem cells treated with GR antagonists for the prevention or treatment of stress osteoporosis and the rapid healing of bone-related injuries
The present invention relates to the therapeutic use (human and veterinary) of GR antagonists or stem cells treated with GR antagonists in the treatment of bone fractures. GR antagonists and GR antagonist-treated stem cells are reported herein to promote bone wound healing. GR antagonists promote bone regeneration after injury and contribute to better bone wound healing. GR antagonists and stem cells treated with GR antagonists increased the rate of fracture repair, allowing for a shorter recovery time after injury.
A fracture is a medical condition. As used herein, "fracture" includes an injury to a bone or an injury in which a bone breaks, breaks, or crumbles. A fracture refers to a discontinuity in a bone. Fractures can be caused by physical shock, mechanical stress, or medical conditions such as osteoporosis or osteoarthritis.
Orthopedic classification of fractures includes closed and open and simple or multifragmentary fractures. In closed fractures, the skin remains intact, while in open fractures, the bone may be exposed through the wound site, which poses a greater risk of infection. Simple fractures occur along a line that tends to split the bone in two. A multifragmentary fracture breaks a bone into several parts.
Other fracture types include compression fractures, compact fractures, spiral fractures, complete and incomplete fractures, transverse, linear and oblique fractures, and comminuted fractures. Bone healing (fracture healing) occurs naturally and begins after injury in most subjects. Bleeding usually causes clotting and the attraction of white blood cells and fibroblasts, which then produce collagen fibers. This is followed by the deposition (mineralization) of the bone matrix (calcium hydroxyapatite), which transforms the collagen matrix into bone. Immature regenerated bone is generally weaker than mature bone, and over time the immature bone undergoes a remodeling process to produce mature "lamellar" bone. The complete bone healing process takes a long time, usually months.
Fractured bones that may benefit from treatment with GR antagonists include all bone types, particularly all mammalian bones, including but not limited to long bones (eg, femur, humerus, phalanges), short bones (eg, carpus, tarsus), flat bones bones, Bones (eg skull, ribs, scapula, sternum, pelvic girdle), irregular bones (eg vertebrae), sesamoids (eg patella). Fractures also involve pathological porosity, such as that exhibited by patients with osteoporosis. GR antagonists and GR antagonist-treated stem cells and pharmaceutical compositions and medicaments comprising GR antagonists and GR antagonist-treated stem cells are provided for procedures for treating bone fractures in a mammalian subject.
Treatment may include bone wound healing. Treatment can include bone repair, regeneration and growth. GR antagonist and stem cells treated with GR antagonist promote fracture repair by promoting new bone growth. GR antagonists are used to increase the rate of fracture healing, allowing the bone to heal faster, thus shortening recovery time after injury.
Treatment can improve bone strength. Treatment may also include treating osteoporosis or osteoarthritis. Application of GR antagonists and GR antagonist treated stem cells can be, for example, tissue surrounding bone fractures. This may involve administering medication directly into the bone tissue where the fracture occurred. Application can be to the connective tissue surrounding the bone or fracture, or to the vasculature (eg blood vessels) close to and supplying the bone. Application can be directly to the site of injury and can be to the blister formed by the initial healing of the wound.
The drugs and pharmaceutical preparations according to the invention can be formulated for administration by different routes. GR antagonists and GR antagonist-treated stem cells can be formulated in a liquid or liquid form for injection, or as part of a gel suitable for application to bone or other tissue surrounding a fracture.
Administration is preferably a "therapeutically effective amount" sufficient to improve fracture healing compared to a corresponding untreated fracture or a fracture treated with GR antagonist-treated stem cells obtained from cultures under control conditions. The actual amount applied, rate and time course of application will depend on the nature and severity of the fracture. Prescribing treatment, eg decisions on dosage, etc., are the responsibility of general practitioners and other doctors, usually taking into account the nature of the fracture, the condition of the individual patient, the place of delivery, the method of administration and other factors known to practitioners. Single or multiple doses of GR antagonists or stem cells treated with GR antagonists can be administered according to the instructions of the prescribing physician. Examples of the above techniques and protocols can be found in Remington's Pharmaceutical Sciences, 20th ed., 2000, Lippincott, Williams and Wilkins ed.
GR antagonists or stem cells treated with GR antagonists can be used to treat fractures with other treatments, such as the administration of pain-relieving or anti-inflammatory drugs, immobilization and bone immobilization such as immobilizing the injured limb with a cast, surgical intervention such as bone reset, or of moving bones to correct misalignments, angles, or misalignments. If surgery is required, the GR antagonist or GR antagonist-treated stem cells can be applied (eg, administered) directly to the bone fracture during surgery.
The pharmaceutical compositions and drugs of the present invention may be in the form of biological materials coated and/or impregnated with stem cells treated with GR antagonists or GR antagonists. Implants or prostheses can be formed from biological materials. Such implants or prostheses may be placed surgically to assist in bone growth, regeneration, reconstruction and/or remodeling.
GR antagonists or stem cells treated with GR antagonists can be applied to implants or prostheses to accelerate new bone formation at desired sites. Biomaterials can be coated or impregnated with GR antagonists or stem cells treated with GR antagonists. Impregnation may involve bringing the GR antagonists into contact with the biological material such that they are adsorbed and/or absorbed onto and/or into the biological material. The coating may involve adsorption of the GR antagonist or GR antagonist treated stem cells on the surface of the biomaterial. Coating or impregnating the biomaterial may include implanting a GR antagonist or GR antagonist-treated stem cells onto or into the biomaterial.
The biomaterial should allow the coated or impregnated GR antagonist or GR antagonist-treated stem cells to be released from the biomaterial when administered or implanted into a subject. The release kinetics of biomaterials can be altered by changing the structure, such as the porosity of the biomaterial.
By coating or impregnating a biomaterial with a GR antagonist or a stem cell treated with a GR antagonist, one or more bioactive molecules can be impregnated or coated onto the biomaterial. For example, at least one selected from: BMP-2, BMP-4, OP-1, FGF-1, FGF-2, TGF-β1, TGF-β2, TGF-β3; vascular endothelial growth factor; collagen; laminin: fibronectin; vitronectin. In addition to or instead of the bioactive molecules described above, one or more bisphosphonates can be impregnated or coated onto the biomaterial together with the GR antagonist. Examples of useful bisphosphonates may include at least one selected from the group consisting of etidronate; clodronate; alendronate; pamidronate; risedronate; phosphonates. Optionally, the GR antagonist or stem cells treated with the GR antagonist are not impregnated or coated on the biomaterial.
Biomaterials coated or impregnated with stem cells treated with GR antagonists or GR antagonists can be used for medical and veterinary purposes. It will be appreciated that the invention may improve the quality of life of a patient or potentially extend the lifespan of an animal, such as a valuable breeding racehorse.
Biomaterials provide a scaffold or matrix support. Biomaterials may be suitable for implantation into tissues or may be suitable for drug delivery (for example, as microcapsules in solution). Implants or prostheses should be biocompatible, eg non-toxic and low immunogenic (preferably non-immunogenic). The biomaterial may be biodegradable such that the biomaterial breaks down as wound healing occurs, eventually leaving only regenerated bone in situ within the subject. Alternatively, non-biodegradable biomaterials can be used, for example, to direct bone regeneration at large discontinuities and/or to act as structural support during bone healing, the surgical removal of which is an optional requirement after successful wound healing.
Biomaterials can be soft and/or elastic, such as hydrogels, fibrin meshes or meshes, or collagen sponges. A "hydrogel" is a substance which, when an organic polymer (which may be natural or synthetic) solidifies or hardens to form a three-dimensional open lattice structure, the structure traps molecules of water or other solutes to form a gel. Coagulation can occur via aggregation, coagulation, hydrophobic interactions, or cross-linking.
Alternatively, the biomaterial may be a relatively rigid structure, for example made of a solid material such as plastic or a biologically inert metal such as titanium. Biomaterials can have a porous matrix structure that can be provided by cross-linked polymers. Preferably, the matrix is permeable to the nutrients and growth factors required for bone growth.
The matrix structure can be formed by cross-linking fibers such as fibrin or collagen, or liquid films of sodium alginate, chitosan or other polysaccharides with suitable cross-linking agents such as calcium salts, polyacrylic acid, heparin. Alternatively, the scaffold may be formed as a gel, made of collagen or alginate, cross-linked using well-established methods known to those skilled in the art.
Suitable polymeric matrix forming materials include, but are not limited to, biodegradable/bioresorbable polymers that can be selected from the group consisting of agarose, collagen, fibrin, chitosan, polycaprolactone, poly(DL-lactide-co-caprolactone), poly( L-lactide-co-caprolactone-co-glycolide), polyglycolide, polylactide, polyhydroxyalkanoate, its copolymers or non-biodegradable polymers, which can be chosen from: cellulose acetate; cellulose butyrate, alginate, polysulfone, polyurethane, polyacrylonitrile, sulfonated polysulfone, polyamide, polyacrylonitrile, polymethyl methacrylate, their copolymers.
Collagen is a promising matrix building material because of its biocompatibility and favorable properties that support cell attachment and function (US Patent No. 5,019,087; Tanaka, S.; Takigawa, T.; Ichihara, S. and Nakamura, T. Mechanical properties of bioabsorbable polyglycolic acid- collagen nerve conduits Polymer Engineering & Science 2006, 46, 1461-1467) Clinically acceptable collagen sponges are exemplary matrices and are well known in the art (eg from Integra Life Sciences).
Fibrin scaffolds such as fibrin glue offer an alternative matrix material. Fibrin glue is widely used clinically as a wound sealant, as a growth factor delivery container, and as an aid in the placement and fixation of biological implants (Rajesh Vasita, Dhirendra S. Katti. Growth Factor Delivery Systems for Tissue Engineering: A Materials Perspective .Expert Medical Device Review. 2006;3(1):29-47; Wong C, Inman E, Spaethe R, Helgerson S. Thromb. Haemost. 2003 89(3):573-582; D S. Fibrin scaffolds as effective delivery vehicles. acidic growth factor (FGF-1). J. Biomaterials Applications. 2000; 14(3); 229-242; DeBlois Cote M F. Doillon C J. Heparin-Fibroblasts Growth factor fibrin complexes: in vitro and in vivo applications of materials on based on collagen Biomaterials 1994;15(9):665-672.).
Luong-Van et al (In Vitro Biocompatibility and Bioactivity of Microencapsulated Heparan Sulfate Biomaterials 28 (2007) 2127-2136), incorporated herein by reference, describe sustained local delivery of HS from polycaprolactone microcapsules. Another example of a biomaterial is a polymer containing hydroxyapatite or hyaluronic acid.
Biomaterials can be supplemented with additional cells. For example, biomaterials can be 'seeded' (or co-synthesized) with fibroblast-derived feeder cells, which can help support the growth and maintenance of GR antagonists.
The subject to be treated can be any animal or human. The subject is preferably a mammal. In some embodiments, the subject is a human. In other embodiments, the subject is an animal, more preferably a non-human mammal. A non-human mammal can be a pet or an animal kept for commercial purposes, such as a pet. A racehorse or farmed livestock such as pigs, sheep or cattle. Therefore, this invention can be used in veterinary medicine. Non-human mammals include rabbits, guinea pigs, rats, mice or other rodents (including all animals of the order Rodentia), cats, dogs, pigs, sheep, goats, cattle (including all animals of the order Bos), horses (including ungulates), donkeys and non-human primates. Subjects can be male or female. The subject can be a patient.
Wound treatment and transplantation
Although elevated cortisol plays an important role in physiological homeostasis under conditions of extreme physical and emotional stress, it can inhibit cells important for wound healing, including stem cells, by binding to the glucocorticoid receptor (GR), thereby negatively affecting wound healing.
Administration of GR antagonists or active agents, such as ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof, may improve wound healing in such conditions. However, blocking the systemic binding of cortisol to GR must be avoided. Therefore, the present invention provides that topical application of PT155, PT156, or PT157 to wounds (by topical application to skin wounds or by direct injection or local vascular infusion) will aid wounds in the event of acute physical trauma such as war. wound repair) while maintaining systemic homeostasis promoted by cortisol. Also provided are uses in stem cell therapy by pretreatment of transplantable stem cells with ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof, and pharmaceutically acceptable salts thereof. Additionally, the present invention provides for the pretreatment of implantable organs prior to implantation in the recipient. The subject invention provides treatment of the organ for implantation during implantation in the recipient.
Perfusion system
Cell perfusion systems can be used to expose tissues or organs to GR antagonists in liquid or semi-solid form. Perfusion refers to the continuous flow of a solution through or through a population of cells. This means that the cells are retained within the culture unit, rather than a continuous flow culture, which flushes the cells with withdrawn media (eg, a chemostat). Perfusion allows better control of the culture environment (pH, pO2, nutrient levels, GR antagonist levels, etc.) and is a method to significantly increase surface utilization for cell-attached cultures.
Perfusion techniques have been developed to mimic the cellular environment in vivo in which cells are constantly supplied with blood, lymph, or other body fluids. In the absence of physiological perfusion of nutrients, cultured cells undergo alternating phases of feeding and starvation, limiting the full expression of their growth and metabolic potential. In the context of the present invention, the perfusion system can also be used to perfuse cells with GR antagonists to induce arrest.
Those skilled in the art are familiar with perfusion systems, and a variety of perfusion systems are available on the market. Any of these perfusion systems can be used in the present invention. An example of a perfusion system is a perfused bed reactor using a nonwoven layer matrix (CelliGen®, New Brunswick Scientific, Edison, NJ; Wang et al., 1992; Wang et al., 1993; Wang et al., 1994). Briefly, the reactor includes improved anchorage-dependent and -independent cell culture reactors. The reactor is designed with a packed bed that ensures internal recirculation. Preferably, the fiber matrix carrier is located in a basket inside the reactor vessel. The basket has holes at the top and bottom that allow the medium to flow through the basket. A specially designed rotor allows media to be recirculated through the space occupied by the fiber matrix to ensure an even supply of nutrients and waste removal. This also ensures that a small amount of the total cell mass is suspended in the medium. The basket and recirculation combination also allows oxygenated media to flow through the fibrous matrix without bubbles. The fibrous matrix is a nonwoven fabric with "pores" ranging from 10 microns to 100 microns in diameter, providing a large internal volume, with a pore volume corresponding to 1 to 20 times the volume of individual cells.
There are several advantages of a perfused bed reactor. With the support of the fibrous matrix, the cells are protected from mechanical stress caused by agitation and foam. The free medium flowing through the basket provides the cells with an optimally regulated level of oxygen, pH and nutrients. The product can be continuously removed from the culture, and the collected product is cell-free and can be produced in a low-protein medium, facilitating subsequent purification steps. This technique is described in detail in WO 94/17178 (Aug. 4, 1994, Freedman et al.), the entire contents of which are incorporated herein by reference.
Cellcube® (Corning-Costar) modules provide a large surface area of styrene for substrate-bound cell fixation and growth. It is a monolithically encapsulated sterile single-use device with a series of parallel culture plates joined together to create a thin, hermetically sealed laminar flow space between adjacent plates.
Cellcube® modules have inlet and outlet openings diagonally opposite each other to facilitate media flow regulation. During the first few days of growth, the medium contained in the system after the initial seeding will usually meet the needs of the culture. The amount of time between the initial seeding and the start of medium perfusion depends on the cell density and growth rate of the cells in the seeded inoculum. Measuring the concentration of nutrients in the circulating medium is a good indicator of culture status. When establishing a program, it may be necessary to monitor nutrients at different perfusion rates to determine the most economical and efficient operating parameters.
Other commercially available perfusion systems include, for example, CellPerf® (Laboratories MABIO International, Tourcoing, France) and Stovall Flow Cell (Stovall Life Science, Inc., Greensboro, NC). The time and parameters of the production phase of the culture depend on the type and use of the particular cell line. The production of many cultures requires a different medium than that required for the growing phase of the culture. The transition from one stage to another may require multiple washing steps in traditional cultures. However, one of the advantages of perfusion systems is the ability to provide smooth transitions between different working phases. The perfusion system may also facilitate the transition from anagen to quiescence induced by GR antagonists. Likewise, the perfusion system can facilitate the transition from quiescent to anagen phase by replacing the solution containing the GR antagonist with, for example, physiological nutrient medium.
formula
The compounds of the invention can be administered enterally or parenterally. A mixture with pharmaceutically suitable adjuvants, for example, as described in the standard reference Gennaro et al., Remington's Pharmaceutical Sciences. The compounds can be compressed into solid dosage units such as pills, tablets, or processed into capsules or suppositories. The compounds may also be administered in the form of solutions, suspensions, emulsions, eg as injections or eye drops, or as sprays, eg as nasal sprays, via pharmaceutically acceptable liquids.
For the preparation of dosage units, e.g. tablets, common additives such as fillers, dyes, polymer binders and the like come into play. In general, any pharmaceutically acceptable additive that does not interfere with the function of the active compounds can be used. Suitable carriers with which the composition may be administered include lactose, starch, cellulose derivatives and the like or mixtures thereof used in appropriate amounts.
dosage form
The composition of the subject invention can be processed by agglomeration, air suspension cooling, air suspension drying, spheroidization, agglomeration, coating, crushing, compression, freezing granulation, encapsulation, extrusion, wet granulation, dry granulation, homogenization, wrapping, lyophilization, melting processing, microencapsulation, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray cooling, spray coagulation, spray drying, or other methods known in the art. The composition can be provided in the form of microcapsules, capsules, smart capsules, tablets, implants, pastilles, lozenges (mini-tablets), temporary or permanent suspensions, ovules, suppositories, wafers, tablets, chewable tablets, fast-dissolving or fast-dissolving tablets. dissolution, effervescent tablets, buccal or sublingual solids, granules, films, sprays, pills, balls, pellets, powders, milled plates, tablets, strips or sachets. The formulation may also be administered as a "dry syrup", whereby the finished dosage form is placed directly on the tongue and swallowed or followed by a drink or drink.
These forms are well known in the art and are conveniently packaged. The preparations can be formulated for oral, nasal, buccal, ophthalmic, urethral, transmucosal, vaginal, topical or rectal administration.
The pharmaceutical composition may be coated with one or more enteric coatings, impermeable coatings, film coatings, protective coatings, compression coatings, disintegrating coatings, or enzymatically degradable coatings. It is possible to apply multiple layers to achieve the desired properties. Additionally, dosage forms may be designed for immediate release, pulsed release, controlled release, sustained release, delayed release, targeted release, synchronized release, or targeted delayed release. To control release/absorption, solid carriers can be made of different types of components and number of layers or coating thicknesses, with or without an active ingredient. These different solid carriers can be mixed in a dosage form to obtain the desired properties. Definitions of these terms are known to those skilled in the art. In addition, the release profile of the dosage form can be influenced by the composition of the polymer matrix, coated matrix composition, multiparticulate composition, multiparticulate composition, ion exchange resin-based composition, osmotic-based composition, or biodegradable polymer composition. work. Without wishing to be bound by theory, it is believed that release can be achieved by favorable diffusion, dissolution, erosion, ion exchange, osmosis, or combinations thereof.
When formulated as a capsule, the capsule may be a hard or soft gelatin capsule, a starch capsule, or a cellulose capsule. Although not limited to capsules, such dosage forms may also be coated with, for example, seal coatings, enteric coatings, sustained release coatings, or targeted delayed release coatings. These various coatings are known in the art, but for the sake of clarity the following brief description is given: Sealant or barrier coating: for various reasons, including particle porosity, can be applied in thicknesses up to 20 microns, thin film reduction, dust reduction, chemical protection, taste masking, odor reduction, minimizing gastrointestinal irritation and more. The insulating effect is directly proportional to the thickness of the coating. Water soluble cellulose ethers are preferred for this application. A combination of HPMC and ethylcellulose or Eudragit E100 may be particularly suitable for masking taste. Traditional enteric coating materials listed elsewhere may also be used to form the protective layer.
Sustained-release coatings are designed to achieve delivery over a longer period of time. The sustained release coating is a pH-independent coating formed from, for example, ethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, acrylate or sodium carboxymethylcellulose. Depending on the choice of coating material and/or coating thickness, those skilled in the art can readily design various sustained release dosage forms to achieve delivery to the small intestine and colon, only to the small intestine, or only to the colon.
Enteric coatings are mixtures of pharmaceutically acceptable excipients that are applied, combined, mixed or otherwise added to a carrier or preparation. The coating may be applied to compressed or shaped or extruded tablets, gelatin capsules and/or carriers or pellets, beads, granules or granules of the composition. Coatings can be applied by aqueous dispersion or after dissolution in a suitable solvent. Additional additives and their quantities and the choice of one or more primary coating materials will depend on the following properties: 1. Solubility and disintegration in the stomach; 2. Responsiveness to gastric juices and impermeability of drug/carrier/enzyme; 3. The ability to quickly dissolve or disintegrate at the target site in the intestines 4. Physico-chemical stability during storage 5. Non-toxic 6. Ease of application as a coating (friendly to the substrate) 7. Economic practicality.
Dosage forms of the compositions of the invention may also be formulated as enteric-coated delayed-release oral dosage forms, i.e., as oral dosage forms of the pharmaceutical compositions described herein, which use an enteric coating to effect release in the lower gastrointestinal tract. Enteric coated dosage forms can be compressed or shaped or extruded tablets/moulds (coated or uncoated), containing granules, pellets, spheres or granules of the active ingredient and/or other components of the preparation, which are themselves coated or uncoated. Enteric-coated oral dosage forms can also be capsules (coated or uncoated) containing solid carriers or pellets, balls or granules of the preparation, which are themselves coated or uncoated.
Sustained release generally refers to delivery such that release can be achieved at some generally predictable location in the lower digestive tract that is further away than it would be in the absence of the sustained release modification. The preferred method of delaying release is coating. Each coating should be applied in a sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but does dissolve at a pH of about 5 or higher. It is contemplated that any anionic polymer exhibiting a pH-dependent solubility profile may be used as an enteric coating in the practice of the invention to achieve delivery to the lower GI tract. Polymers useful in this invention are anionic carboxylic acid polymers.
Shellac, also known as pure varnish, is a refined product obtained from the resinous secretions of insects. The coating dissolves in a medium with a pH >7.
In addition to plasticizers, colorants, detackifiers, surfactants, antifoams, lubricants, stabilizers such as hydroxypropyl cellulose, acids/alkalis, etc. can be added to paint to dissolve or disperse the paint, improve the performance of coatings and painted products .
In practicing the methods of the present invention, the combinations of the present invention may be administered to mammalian species such as dogs, cats, humans, etc. and thus may be incorporated into conventional systemic dosage forms such as tablets, capsules, elixirs or injections. The above dosage forms also include the necessary carrier materials, excipients, lubricants, buffers, antibacterial agents, fillers (such as mannitol), antioxidants (ascorbic acid or sodium bisulfite) and the like.
The subject invention provides a smart pill or smart capsule which, in an exemplary embodiment, is an ingestible drug delivery device configured to wirelessly communicate with other ingestible drug delivery devices, said drug delivery device comprising: a capsule comprising: a sensor for detecting at least one biological condition in the patient and providing a first representative signal thereof; a bioactive substance module containing the volume and/or quantity of a bioactive substance container and a microactivator for dispersing said bioactive substance from said container to a location outside said capsule; an electronic module connected to said sensor and said bioactive substance module, said electronic module includes a processor, a transponder and a memory (eg flash memory, OTP, etc.) that includes data selected from the group consisting of: (a) data relating on patients who are allowed to swallow a medical device for drugs (b) data related to the specified bioactive substance; (c) data relating to the healthcare provider enabling said electronic module; (d) data relating to said sensor; (e) data relating to said camera; (f) their combination, a power supply connected to said sensor, said bioactive substance module and said electronic module; and wherein said processor controls said transponder with at least one other. An edible medical device transmits at least one wireless signal and receives at least one wireless signal, and wherein said processor receives said first signal and analyzes said first signal and all of said data receiving at least one wireless signal for the Microactivator is controlled to disperse the bioactive substance .
In an exemplary embodiment, ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof are variable in capsules/tablets/smart pills resulting in intermittent dosing instead of continuous pill dosing, tablets can be coded (e.g. . color or shape) to indicate which pills to take in which order (part of the day, or daily, weekly or monthly pill protocol) to achieve the correct dose. Balance or GCR blockade (like birth control pills with varying levels of hormones every day for a month). In other words, some capsules/tablets/smart pills will contain only opiates, some will contain opiates and one or more different doses of PT150 in the same capsule/tablet/smart pill, etc. In an exemplary embodiment, the patient will not know the contents of any capsule /tablets/smart pills, but will know when to take a specific coded version in their dosing regimen.
In an example embodiment, the smart capsule may identify the number of pills taken and the type of pills taken (with or without ORG 34517, PT150, PT155, PT156, PT157, PT158, TCY1, combinations thereof and pharmaceutically acceptable salts thereof) to provide records to treating personnel about the medications taken and also prevented the smart tablet from being opened in case the wrong pill is taken.
The applied dosage must be carefully adapted to the age, weight and condition of the patient, as well as the method of administration, dosage form and regimen, and the desired result. The pharmaceutical composition of the present invention can be administered in single or divided doses from one to four times a day. Patients are advised to start with a low-dose combination and gradually increase to a high-dose combination.
Tablets of various sizes can be prepared, for example, with a total weight of about 1 to 2000 mg, containing one or two active pharmaceutical ingredients, the remainder being a physiologically acceptable carrier of other substances in accordance with accepted pharmaceutical practice.
These tablets can be split to obtain fractional doses. Gelatin capsules can be formulated in a similar way.
Liquid formulations may also be prepared by dissolving or suspending the active ingredient(s) in combination in a conventional pharmaceutically acceptable liquid carrier to give the desired dosage of one to four teaspoonfuls.
The dosage form can be administered to the patient according to a regimen of, for example, one, two, three, four, five, six or other doses per day
For a more precise adjustment of the dosage regimen, the active substances can be administered simultaneously or separately at carefully coordinated times in separate dosage units. Since blood levels are established and maintained according to the prescribed dosing schedule, the same result can be achieved by the simultaneous presence of both substances. The individual substances may be formulated separately into separate unit dosage forms in a manner similar to that described above. In formulating preparations, the above-mentioned amounts of active substances may be present in a certain type of unit in accordance with accepted pharmaceutical practice together with physiologically acceptable carriers, carriers, excipients, binders, preservatives, stabilizers, aromas, etc. mixed dosage form.
Examples of adjuvants that can be incorporated into tablets are the following: binders such as tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate or cellulose; disintegrants such as corn starch, potato starch, alginic acid, etc. Lubricants such as stearic acid or magnesium stearate; Sweeteners such as sucrose, aspartame, lactose or saccharin; Flavor enhancers such as orange, peppermint, wintergreen or cherry oil. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or otherwise modify the physical form of the dosage unit. For example, tablets or capsules may be coated with shellac, sugar, or both. The elixir syrup may contain the active compound, water, alcohol, etc. as a carrier, glycerin as a solubilizer, sucrose as a sweetener, methyl and propylparabens as preservatives, colors and flavors such as cherry or orange.
One embodiment of the invention includes methods of treating, preventing, or diagnosing a particular disease or condition by administering the disclosed nanoparticles, composite nanoparticles, nanosuspensions, or nanocapsules to a subject. In many cases, nanoparticles, composite nanoparticles, or nanocapsules are administered alone or may be included in pharmaceutical compositions. An effective amount of a pharmaceutical composition is generally defined as an amount sufficient to ameliorate, reduce, minimize, or limit the extent of a disease or condition. Stricter definitions may apply, including the removal, eradication or cure of a disease or condition.
"Nanoparticles" are solid particles having an average particle size, eg, less than about 1 micron (micrometer). A micron is equal to 1000 nanometers (nm). A "stabilized" nanoparticle is one that is coated with a stabilizing material and has a reduced tendency to aggregate and disperse losses compared to nanoparticles of the compound of the invention without a stabilizing coating. A nanospray is a spray that contains or produces nanoparticles. A nanodispersion is a dispersion that contains nanoparticles. A nanosuspension is a suspension containing nanoparticles. The liquid formulations useful herein may contain solvents, solutions, suspensions, microsuspensions, nanosuspensions, emulsions, microemulsions, gels or even melts containing the active ingredient or ingredients.
In some embodiments, the nanoparticles, nanofibers, or nanofibers may be in, or within or above, particles, powders, suspensions, solutions, soluble films, pads, meshes, tablets, or releasable forms, particularly releasable dosage forms. Other particularly useful forms are concentrates which are added to the diluent before use. It is also possible to spray the product on the inner surface of the container, add the liquid to the container later before use, and release the nanoparticles, nanofibers, or nanofibers into the liquid.
The pharmaceutical preparation of the invention may contain nanoparticles, composite nanoparticles, nanosuspension or nanocapsules of the invention. In certain non-limiting embodiments, the pharmaceutical composition may contain, for example, at least about 0.1% of the active ingredient or nanoparticles, composite nanoparticles, or nanocapsules. In other embodiments, the active ingredient or nanoparticles, composite nanoparticles or nanocapsules may comprise from about 2% to about 75% by weight of the unit, or for example from about 25% to about 60%, and any range derived therefrom. In non-limiting examples of the ranges that can be derived for the numbers herein, ranges from about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 micrograms/kg/body weight to about 500 mg/kg/body weight weight, etc., may be given.
The composition may also include various antioxidants to delay the oxidation of one or more active ingredients or nanoparticles, composite nanoparticles, nanosuspensions or nanocapsules. The action of microorganisms can be prevented by preservatives such as various antibacterial and antifungal agents, including but not limited to parabens (eg, methylparaben, propylparaben), chlorobutanol, phenol, sorbic acid, thimerosal, or combinations thereof.
In order to improve the therapeutic effect of the use of nanoparticles, nanogels, composite nanoparticles, nanosuspensions or nanocapsules of the present invention, it may be necessary to combine these nanoparticles, nanogels, composite nanoparticles or nanocapsules with other therapies effective in the treatment of certain specific diseases or conditions.
Formulations as described above can be administered chronically, i.e. as long as the disease or disorder is likely to exist or symptoms persist.
Packing/handling kits
The present invention relates to a kit for convenient and efficient execution of the method according to the invention. Such devices may be suitable for delivery of solid oral forms such as tablets or capsules. Such kits may contain multiple unit doses. Such kits may include means for keeping the doses oriented in order for their intended use. An example of a method of including doses according to the order of intended use is a card. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, the blister can be in the form of a child-safe blister, i.e. a blister that is difficult for children to open, but can be easily opened by an adult. If desired, memory aids can be provided, e.g. in the form of numbers, letters or other markings or with calendar features and/or calendar inserts, indicating the days in the treatment plan and the part of the day in which doses can be administered, e.g. morning doses packaged with a "noon" dose and an afternoon dose. Or the AM dose is packed with the PM dose. Alternatively, a placebo dose or a vitamin or dietary supplement, in a form similar to or different from the pharmaceutically active dose, may be included.
In one aspect, the package, kit, or container comprises a "blister pack" (also known as a blister pack or a blister pack). In one aspect, the blister pack comprises two or more separate compartments: an Am dose of the invention, and a PM dose of the invention, or mid-day dose of the invention. Blister packaging consists of two separate material elements: a transparent plastic cavity that conforms to the shape of the product and its blister sheet base. The two elements are then joined by a heat welding process, allowing the products to be hung or displayed. Examples of blister pack types include: Face Seal Blister Pack, Interactive Blister Pack, Simulated Blister Pack, Interactive Blister Pack, Slide Blister Pack.
Blister packs, folding packs or trays are forms of packaging for goods; therefore, the invention provides blister packs, shells, formats or trays. Blister packs, clamshell packs or trays can be designed to be non-resealable so that consumers can tell if the pack has been opened. They are used for packaging goods for sale where tampering with the product must be considered, such as the pharmaceutical products of this invention. In one aspect, a blister pack of the invention comprises a molded PVC base with raised areas ("blisters") to accommodate the tablets, pills, etc. comprising the combination of the invention, covered with a foil laminate. Tablets, pills, etc. can be removed from the packaging by peeling off the foil or by pushing the blister, forcing the tablet to break through the foil. On the one hand, a special form of blister packaging is the stick pack.
In one aspect, blister packaging also includes a packaging method where a composition containing a combination of ingredients of the present invention is sandwiched between a card and clear PVC. PVC can be transparent so that the object (pills, tablets, gel sheets, etc.) can be seen and easily inspected; on the one hand, it can be vacuum formed around the mold so that it fits tightly against the object and has room to open up when purchased. On the one hand, the cards are brightly colored and designed according to what's inside (pills, tablets, gel patches, etc.), and the PVC is attached to the card using pre-shaped stickers, which are then applied with glue. The glue can be strong enough to hang the package on a hook, but weak enough that a person can tear the joint and get at the item. Sometimes for bulky items or multiple attached pills, tablets, gel sheets, etc. the card has a perforated window for easy access. On the one hand, use safer blister packs, for example, for items such as pills, tablets, gel sheets, etc. of this invention, which may consist of two vacuum-formed PVC sheets, edged together, with an information card inside.
In one aspect, a blister pack contains at least two components (e.g., a multi-ingredient drug combination of the invention): a thermoformed "blister" containing the product (e.g., a drug combination of the invention), followed by a "blister card" is a printed card with an adhesive layer on the front side. During assembly, the blister components, usually made of PVC, are attached to the blister cards using a blister machine. The machine applies heat to the blister flange area, activating the adhesive in specific areas on the card and finally attaching the PVG blister to the printed blister card. Thermoformed PVG blister and printed blister cards are available from small to large. Conventional blister packs can also be sealed using conventional heat sealing tools (eg, using AERGO 8 DUO.RTM., SCA Consumer Packaging, Inc., DeKalb, 111.). This alternative aspect, using a heat sealing tool, can seal conventional types of thermoformed packaging.
As explained herein, the article of manufacture of the invention may contain single or combined packages of the therapeutic drug combinations of the invention, as a "blister pack" or as multiple packages, including blister packs with lids, blister packs with lids, a lid or blister card or wrapper, or shrink wrap.
In one aspect, laminated aluminum foil blister packs are used, for example, in the manufacture of drugs designed to melt immediately in the patient's mouth. This exemplary method involves preparing a pharmaceutical combination of the invention as an aqueous solution that is sprayed (eg, by metered doses) into an aluminum (eg, aluminum foil) laminated portion of a blister pack tray. The container is then freeze-dried to form blister pack tablets. The aluminum foil laminate of the tray and lid adequately protects all highly hygroscopic and/or sensitive individual doses. On the one hand, the package includes a child-resistant safety laminate. On the one hand, the system provides identification marks for the pills by imprinting the design into the foil pouch, which is occupied by the pill as it transitions from an aqueous to a solid state. On the one hand, individual "push-fit" blister packs/pouches are used, for example, with a rigid aluminum (eg aluminum foil) closure material. On the one hand, hermetically sealed high-barrier aluminum laminates (e.g. aluminum foil) are used. In one aspect, any manufactured product of the present invention, including kits or blister packs, is used for high barrier packaging.
Other means of holding unit doses may include bottles and vials containing memory aids such as printed unit dose administration labels. The sticker may also include a removable reminder sticker to place in a calendar or diary to further help the patient remember when and when to take the medication.
local preparations
The term "topical" as used herein refers to the use of the compounds, derivatives or analogs described herein, incorporated into a suitable pharmaceutical carrier and applied to the site of topical action. Accordingly, such topical preparations include those forms in which the compound is applied topically, by direct contact with the skin surface to be treated. Common forms used for this purpose include ointments, liniments, creams, shampoos, lotions, pastes, jellies, sprays, aerosols, soaps, etc., and may be presented as plasters depending on the part of the body being treated. or in the form of an impregnated bandage. The term "ointment" includes formulations (including creams) with oil, absorbent, water-soluble and emulsion bases, such as petrolatum, lanolin, polyethylene glycols and mixtures thereof.
For topical use, the medicaments of the invention may conveniently be formulated using an ointment, cream, liniment or patch as a carrier for the active ingredient. Additionally, these formulations may or may not contain preservatives, depending on the dispenser and nature of use. Such preservatives include those mentioned above, as well as methyl-, propyl- or butyl-paraben, betaine, chlorhexidine, benzalkonium chloride and the like. Various sustained release matrices can also be used. Typically, the dose to be administered ranges from about 0.1 ng to about 100 mg per day, or from about 1 ng to about 10 mg per day, or from about 10 ng to about 1 mg per day, depending on the formulation. Non-limiting examples of topical products may include, but are not limited to, applicator sticks, mascara, eyebrow tinting products, eye shadows or other lid tinting products, eyeliners, makeup removers, anti-aging products, face or body powders , nail polishes, foams, sprays, styling gels, nail polishes, body washes, shampoos, conditioners, conditioners, hair coloring and coloring products, hair conditioners, suntan lotions and face creams and sprays, tanning and sun creams, lotions for skin regeneration, cold creams, moisturizing creams, hair sprays, soaps, body scrubs, scrubs, astringents, depilatory and permanent lotions, anti-dandruff preparations, antiperspirants and antiperspirants, shaving products , pre-shave and after-shave, moisturizers, deodorants, cold creams, cleansers, skin gels and rinses.
Additionally, topical products can be administered topically using patches or other delivery devices. Delivery devices may include, but are not limited to, those that can be heated or cooled, and those that use iontophoresis or ultrasound.
For example, topical products can be formulated, for example, by applying the composition in the form of a body lotion, clear lotion, lotion, cream, gel, foam, ointment, paste, cream, spray, conditioner, toner, cosmetic applicators, stain sticks, pencils , powders, nail polishes, aftershaves, etc. are intended to be left on the skin or other keratinous tissue (ie "leave-on" compositions). After the composition is applied to keratinous tissue (eg, skin), in one embodiment, it is left on for at least about 15 minutes, or at least about 30 minutes, or at least about 1 hour, or at least about 1 hour. a watch. At least a few hours, for example up to around 12 o'clock. In one embodiment, the topical product is left overnight. In another embodiment, the topical product is left on throughout the day. Any external part of the face, hair and/or nails can be treated (e.g. face, lips, under eye area, eyelids, scalp, neck, torso, arms, legs, chest, arms, legs, feet, nails, toenails , hair, eyelashes, eyebrows, etc.)
Topical products may be applied by any convenient method, including, but not limited to, for example, the use of palms and/or fingers or devices or accessories (eg, cotton balls, cotton swabs, pads, applicators, sprays), eyebrow brushes , eyebrow brushes, pencils, pencils, mascara brushes, etc.) Another way to ensure continuous exposure of keratinous tissue to at least a minimal level of topical product is to use a patch to apply the compound, for example, to the face. Patches can be occlusive, semi-occlusive or non-occlusive, and can be adhesive or non-adhesive. Topical products can be included in the patch or applied to the skin before applying the patch. The patch may also contain additional active substances, such as chemical initiators for exothermic reactions, such as PCT application WO 9701313 and U.S. Pat. patents no. 5,821,250, 5,981,547 and 5,972,957 to Wu et al. The patch can be left on for any convenient time. For example, a period of at least about 5 minutes, or at least about 15 minutes, or at least about 30 minutes, or at least about 1 hour, or at night as a form of night treatment, or in another embodiment during the day.
administrative
Pharmaceutical preparations can be optimized for a specific type of delivery. For example, pharmaceutical compositions for oral administration are formulated using pharmaceutically acceptable carriers well known in the art. The carrier allows the agents in the composition to be formulated as, for example, tablets, pills, capsules, solutions, suspensions, sustained release formulations; powders, liquids or gels for oral administration by the subject.
Pharmaceutical preparations can also be delivered from pressurized packs, nebulizers, or from dry powder inhalers in the form of aerosol spray formulations. Suitable propellants that can be used in the nebulizer include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, and carbon dioxide. In the case of pressurized aerosols, the dosage can be determined by fitting a valve to deliver a prescribed amount of compound. Preparations for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid preparations may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered orally, intranasally, or by the respiratory route for local or systemic effect. Preparations in preferably sterile pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulized solutions can be inhaled directly from a nebulizer, or the nebulizer can be attached to a mask, tent, or intermittent positive pressure breathing apparatus. Solution, suspension or powder preparations can be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
Typically, the composition can be topically applied multiple times over an extended period of time to the part of the body being treated, such as the eyelids, eyebrows, skin or scalp. A dosing regimen typically includes regular dosing, eg, daily dosing, over a treatment period of at least one month, or at least three months, or at least six months.
Alternatively, the preparation can be administered intermittently or in pulses. Accordingly, an alternative embodiment of the present invention is to administer the composition in an intermittent or pulsatile dosing regimen. For example, the preparation of this invention may be used for two or more days, discontinued, then resumed after 2 weeks to 3 months, and in the case of the scalp at even longer intervals.
The route of administration of the compounds of the invention will naturally vary with the site and nature of the condition being treated and includes, for example, inhalation, intradermal, transdermal, parenteral, intravenous, intramuscular, intranasal, subcutaneous, transdermal, intratracheal, intraperitoneal, intratumoral, perfusion, lavage, direct injection, oral administration and formulation. As detailed below, GR antagonists can be administered by inhalation or intubation as a medical gas, intravascular, intravenous, intraarterial, intracerebroventricular, intraperitoneal, subcutaneous administration as an injectable liquid, as a topical liquid or gel, or as an oral solid form. dosage form.
Furthermore, the amount may vary depending on the type of biological material (cell type, tissue type, genus and species, etc.) and/or its size (weight, surface area, etc.). Typically, the larger the organism, the higher the dose. Therefore, the effective amount for mice is usually lower than that for rats, the effective amount for rats is usually lower than that for dogs, and the effective amount for dogs is usually lower than that for humans. For example, the effective concentration of a compound of the invention to achieve cessation in humans depends on the dosage form and route of administration. For inhalation, in some embodiments, the effective concentration is in the range of 50 ppm to 500 ppm, delivered continuously. For intravenous administration, in some embodiments, effective concentrations are in the range of 0.5 to 50 milligrams per kilogram of body weight administered continuously.
Likewise, the length of administration may vary depending on the type of biological material (cell type, tissue type, biological genus and species, etc.) and/or its size (weight, surface area, etc.) and will partially depend on the dosage form and method of drug administration. In particular embodiments, compounds of the invention can provide about or at least 30 seconds, 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, four hours hours, five hours , six hours, eight hours, twelve hours, twenty-four hours or more than twenty-four hours. The compounds of the invention may be administered in single or multiple doses with varying time intervals between doses.
Treatment can consist of different "unit doses". A unit dose is defined as containing a predetermined amount of therapeutic preparation. The amounts to be administered, as well as the specific routes and formulations, are within the knowledge of those skilled in the clinical art. A unit dose need not be administered as a single injection, but may consist of a continuous infusion over a period of time. Alternatively, said amount may be an amount given as an average daily dose, an average weekly dose or an average monthly dose.
In the case of transplantation, the present invention can be used to immobilize the host or transplanted material before and/or after surgery. In a specific embodiment, the 30° surgical site can be injected or perfused with a formulation containing a GR antagonist. Perfusion can be continued after surgery, for example, by leaving an indwelling catheter at the surgical site.
Further devices or instruments for delivery
In some embodiments, it is contemplated that the method or composition will include a specific delivery device or devices. Any of the methods discussed herein may be practiced with any delivery or administration device, including but not limited to those discussed herein.
For topical administration, the GR antagonists of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations may include those designed for administration by injection or infusion, such as subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, and those designed for transdermal, transmucosal, oral, or pulmonary administration.
The present invention provides a topical pharmaceutical formulation for the treatment of a subject comprising a composition according to the present invention and at least one pharmaceutically acceptable excipient.
The present invention provides a method of treating a patient in need of such treatment, which consists of administering a topical pharmaceutical preparation according to the present invention.
The present invention provides a topical pharmaceutical formulation for the treatment of a subject comprising a composition according to the present invention and at least one pharmaceutically acceptable excipient. The subject invention also provides a topical formulation according to the invention, wherein said formulation is in a form selected from the group consisting of: cream, lotion, gel, oil, ointment, suppositories, spray, foam, liniment, aerosol, buccal and lingual tablets or transdermal devices or patches for absorption through the skin or mucosa. The present invention also provides a topical formulation according to the invention, wherein said pharmaceutical formulation is a transdermal patch. The present invention also provides a topical formulation of the invention, wherein said pharmaceutical formulation is an oral formulation.
For oral administration, the GR antagonists of the present invention are formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral administration by patients being treated or oral liquid preparations such as, on for example, suspensions, elixirs and solutions.
For buccal administration, the preparations may be in the form of tablets, pastilles and the like formulated in a conventional manner. Other intramucosal delivery can be via suppository or intranasal delivery.
For direct administration to the lungs by inhalation, the compounds of the invention may be conveniently delivered to the lungs by a variety of devices.
Another drug delivery system includes one or more spherical semiconductor aggregates and facilitates the release of the drug stored in the container. The first polymer is used for sensors and memory, and the second for control aspects such as pumping and drug delivery. The system can communicate with a remote control system or operate independently on a local power source to deliver drug over an extended period of time on patient demand, system-controlled time release, or delivery based on measured markers. Infusion Pumps and Devices: Infusion pumps or infusion devices inject fluids, drugs, or nutrients into a patient's circulatory system. Infusion pumps provide a very reliable and inexpensive way to inject fluids. For example, they may inject 0.1 mL every hour (too little for a dropper), every minute, repeat bolus injections as requested by the patient, up to hourly injections (such as patient-controlled analgesia), or a fluid whose volume changes over time .
Implantable drug delivery system: Another drug delivery system includes one or more spherical semiconductor aggregates and facilitates the release of the drug stored in the container. The first polymer is used for sensors and memory, and the second for control aspects such as pumping and drug delivery. The system can communicate with a remote control system or operate independently on a local power source to deliver drug over an extended period of time on patient demand, system-controlled time release, or delivery based on measured markers.
Diagnostic systems and sets
The diagnostic kit may contain some or all of the following components: 1) one or more standards containing one or more biomarkers of the present invention, such as cortisol; 2) ligands, such as antibodies or multiple antibodies, which are specific for the biomarker are determined using the kit; 3) Written instructions; 4) Diluents for samples and standards; 5) Washing buffer; 6) Chromogenic reagent; 7) Stop solution; 8) a ligand carrier, such as an antibody carrier, such as a lateral flow device, or a microwell plate with bound antibodies, or polystyrene beads. An example of such a kit is shown in US patent application no. 20120201747 (Altschul et al.), which is incorporated herein in its entirety.
While the present invention has been described in detail with reference to specific examples thereof, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from its spirit and scope.
The present invention will be described in more detail with reference to the following examples, but it should be understood that the present invention is not limited thereto.
example Example 1 Antiretroviral activity of ORG34517 and PT155: increased activity and reduced toxicity of PT155 compared to ORG34517
Preliminary results indicate that modification of ORG34517 with a thiosemicarbazone form of PT155 is beneficial for overall antiretroviral activity and host cytotoxicity:
Test method: HIV-1 reverse transcriptase (RT) replication assay.
HIV-1let(=HIV-1BRU=LAV-1) in primary [freshly donated from healthy (tested HIV-1 negative, HBV negative and HCV negative)_
blood donors, and isolated by single-phase Ficoll-Hypaque centrifugation] human peripheral blood mononuclear cells (PBM) in the presence of the drug under evaluation. A parameter of antiviral activity was the reduction of RT activity in the cell supernatant after Triton X-100-mediated lysis of released virions, by incorporation of [5fN-3H]dTTP (5fN-tritium thymidine 5'-triphosphate) (rA) into measure)⋅poly(dT)-guided with the initial RNA template poly(rA)⋅oligo(dT). It should be noted that this assay does not detect inhibition of RT by the potential RT inhibitors themselves, but rather indirectly quantifies the amount of HIV-1 released in the supernatant. A detailed test method was published by Schinazi et al., based on the old test system of Spiro et al. (Ref. 38). Experiments were performed in triplicate and statistically processed by regression curve analysis (r2 coefficient of determination). The RT inhibitor AZT (zidovudine, 3'-azido-3'-deoxythymidine; RETROVIR™) was used as a positive control. Cytotoxicity of the tested compounds on PBL cells was determined using CellTiter 96® AQ as described by Stuyver et al.LiquidOne Solution Cell Proliferation Assay (Promega Corp., Madison, WI). Briefly, phenazine ethosulfate (PES) coupled reduction of the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) Purple, water-soluble formazan was measured in live, undamaged cells. _
Example 2 .(11β,17β)-17-Hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-dien-3-one (ORG34517)× (2EZ)-2-{(11β,17β)-17-hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-diene-3 -podjedinica} hydrazine methylsulfonamide [71.8% (E), 28.2% (Z)] hemihydrate × ¾ acetone ×. Ethanol (PT155)_
Material:
,,h ORG34517 [Pop Test Oncology LLC, Cliffside Park, N.J., USA; manufactured by Sai Life Sciences Ltd., Pune, India, lot number: SPO-MA1401-07; w (n/n)=99.72% (HPLC, UV detection at 210 nm)]
,,h Thiosemicarbazide Prius. Annually [Sigma-Aldrich Corp., St. Louis, MO, USA, Batch Number: 1167177V (Fluka); w (m/m)=100.1% (iodometric method), m.t. 181°C (decomposition), residue on ignition <0.05 %, trace metal analysis (inductively coupled plasma mass spectrometry) = 50-5 mg/kg]
,,h Glacial acetic acid (acetic acid 100% p.a.) [AppliChem GmbH, Darmstadt, Germany; serial number: 8Y002937; w (m/m) = 100.0% (titration), water 0.0% (Karl Fischer titration), acetic anhydride = 0.05%, formic acid = 0.01%, non-volatile matter = 0.001%]
Description: ORG34517 (M=430.54 g/mol, 2.000 g, 4.6453 mmol) and thiosemicarbazide puriss. Annual (M=91.14 g/mol, 435 mg, 4.7729 mmol) was suspended in 90% (v/v) ethanol in water (100 ml). Glacial acetic acid (1000 μl, 17.4854 mmol) was added. The suspension was gently refluxed for 1 h. All solids went into solution and turned pale yellow during reflux.
Then the yellow solution was left to stand at room temperature (RT, f°=18.0°C) for 12 minutes. The still warm yellow solution was then filtered through a layer of filter paper. Transfer the precipitate and wash with 90% (v/v) ethanol in water (40 ml) followed by water (40 ml). The yellow filtrate was cooled to +0-2°C for 30 minutes. After adding water (40 ml), the precipitated suspension was frozen at -25°C for 2 hours. The first milky yellow crude PT155 that precipitated was filtered and dried over CaCl2 in vacuo. The filtrate was mixed with water (40 ml) and frozen at -25°C for 4 hours. The precipitated creamy yellow crude PT155 was filtered and dried under vacuum over CaCl2. Combine the two yields.
The crude product was dissolved in acetone (80 ml). Water (2 x 40 ml) was then added in portions with stirring to give a pale yellow emulsion. The precipitated emulsion with clumps of sticky yellow material was frozen at -25°C for 4 hours. The first product (1.677 g) of yellow PT155 was filtered and dried with CaCl22) in vacuum. The filtrate was mixed with water (20 ml) and frozen at -25°C for 1 hour. Water (20 ml) was then added and the precipitated suspension was frozen at -25°C for 1 hour. A second crop (139 mg) of yellow PT155 was filtered and dried over CaCl2) in vacuum. Combine the two yields (1.816 g).
Connection: PT155
Molecular formula: ⅓C28H30Europa4×C29H33Yes3Europa3S×¾C3H6O×⅛C2H5OH×½H2Europa
Molecular weight: 705.49 g/mol
Prinos: 1.816 g (74%)
Elemental analysis: Calculated: C 69.52 %; H 7.04%; N 5.96%; With 4.55%; About 12.95%; Found: C 69.81 %; 4.25%; About 12.90%; C 69.40%; for H 7.13%, N 5.91%, S 4.48%, O 12.70%;
1'H-NMR: 0,41 (3H, s; 18-CH3, (E)-TSC*), 0,42 (1,18 H, s; 18-CH3, (Z)-TSC**),
(DMSO-d6, ppm) 0,44 (1,393 H, s; 18-CH3, ORG34517), 1,06 (0,523 H, t;3J(H,H)=7,1 Hz, etanol CH3), 1,23-2,77 (m; steroidi CH i CH2), 1,83 (5,58 H, br s; R—C=C—CH3methyl, all three), 2.09 (6.27 H, s; acetone CH3), 3,44 (0,348 H, m; etanol CH2), 4,28 (0,393 H, m; 11a-CH, (Z)-TSC), 4,30 (IH, d;3J(H,H)=7,7 Hz, 11a-CH, (E)-TSC), 4,35 (0,174 H, t;3J(H,H) = 5,1 Hz; etanol OH), 4,38 (0,464 H, d;3J(H,H)=7,1°C； 11α-CH, ORG34517), 5,11 (1H, s; 17β-OH, (E)-TSC), 5,12 (0,393 H, s; 17β-OH, (Z)- TSC), 5,14 (0,464 H, s; 17p-OH, ORG34517), 5,66 (0,464 H, s; 4-CH, ORG34517), 5,86 (1 H, s; 4-CH, (E)-TSC), 5,97 (3,716 H, br s; O-CH2-O benzobisoxazole, all three species), 5.97 (0.393 H, s; 4-CH, (Z)-TSC), 6.60 (1.858 H, d;3J(H,H) = 8.3 Hz; 5'-CH benzobisoxazole, sve tri vrste), 6.67 (0.393 H, s; 2'-CH benzobisoxazole, (Z)-TSC), 6.77 (1.464 H, s; 2'-CH benzobisoxazole, (E )-TSC i ORG34517), 6.78 (0.393 H, d;3J(H,H) = 8,0 Hz, 6'-CH benzobisoksazol, (Z)-TSC), 6,79 (1,464 H, d;3J(H,H)=8,0 Hz; 6'-CH benzobisoksazol, (E)-TSC i ORG34517), 7,51 (0,393 H, br s; NH2, HA(Z)-TSC), 7,57 (1 broj s; NH2, HA(E)-TSC), 7,97 (0,393 H, br s; NH2, HOther(Z)-TSC), 8,08 (IH, br s; NH2, HOther, (E)-TSC), 10,05 (1H, br s; N-H, (E)-TSC), 10,42 (0,393 H, br s; N-H, (Z)-TSC). *,** (E ili Z )-TSC=(E ili Z)-thiosemicarbazone.
Example 3 1/17(11β,17β)-17-Hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-dien-3-one (ORG34517 )×(2EZ)-2-{(11β,17β)-17-hydroxy-11-[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-diene -3-ylidene}-N-phenylhydrazine methylsulfamide [74.1% (E), 25.9% (Z)] 11/17 hydrate (PT156)
Material: org34517
4-Phenylthiosemicarbazide 99% [Sigma-Aldrich Corp., St. Louis, Mo., SAD, Lot: BCBL2527V (Aldrich); w(m/m)=99,7% (klorovodična kiselina4acidity titration), w (n/n) = 99.3% (HPLC, area %), mp 138-140°C.]
Glacial acetic acid (acetic acid 100% p.a.) [AppliChem GmbH, Darmstadt, Germany; serial number: 8Y002937; w(m/m)=100.0% (titration), water 0.0% (Karl Fischer titration), acetic anhydride≤ 0.05%, formic acid≤0.01%, non-volatile matter≤0.001%]
instructions:
Suspend ORG34517 (M=430.54 g/mol, 4.000 g, 9.2907 mmol) and 99% 4-phenylthiosemicarbazide (M=167.23 g/mol, 1.600 g, 9.5677 mmol) in 90% (v/v) v) an aqueous solution of ethanol (100 ml). Glacial acetic acid (1000 μl, 17.4854 mmol) was added. The suspension was gently refluxed for 1 h. All solids went into solution and turned dark yellow during reflux.
The yellow solution was then allowed to stand at room temperature (RT, θ = 15.6 °C) for 4 minutes. Then filter the still hot, cloudy, dirty yellow solution through a layer of filter paper. Transfer the residue and wash with 90% (v/v) ethanol in water (35 ml). The clear yellow filtrate is cooled to +0-2°C for 4 hours. The pellet suspension was then frozen at -25°C for 3 hours. The precipitated light yellow crude PT156 was filtered and dried over CaCl22) in a vacuum. The filtrate contained a large amount of impure ORG34517 and was discarded.
The crude product (3.463 g) was dissolved in acetone (30 ml). Water (10 ml) was then added in portions with stirring to give an oily yellow emulsion. The viscous emulsion was redissolved by adding acetone (15 ml). The mixture was then frozen at -25°C for 2 hours. Water (5 ml) was then added, causing a sticky mass of material to settle. The mixture was vigorously shaken for 30 s and frozen at -25 °C for 70 min. Finally, water (20 ml) was added, vigorously shaken for 30 seconds, and the precipitated emulsion was frozen at -25°C for 75 minutes. Light yellow crystalline PT156 of the first product (3.285 g) was filtered and dried over CaCl22) in vacuum. The filtrate was frozen at -25°C for 12 hours. A second crop (29 mg) of light yellow crystalline PT156 was filtered off and dried over CaCl2) in a vacuum. The filtrate contained a small amount of pure ORG34517 and was discarded. Combine the two yields.
Connection: PT156
Molecular formula:
Molecular weight: 616.73 g/mol
Yield: 3.314 grams (61%)
Elemental Analysis: Calculated: C 71.37%, H 6.55%, N 6.81% S, 5.20% O, 10.07%;
Discovery: C 71.47%; H 6.83%; N 6.83%; With 5.58%; About 10.05%; %;
1'H-NMR: 0,42 (3H, s; 18-CH3, (E)-PTSC*), 0.43 (1.05 H, s; 18-ONLY3, (Z)-PTSC**),
(DMSO-d6, ppm) 0,44 (0,238 H, s; 18-CH3, ORG34517), 1,24-2,80 (m; steroidi CH i CH2), 1,83 (4,288 H, br s; R—C=C—CH3methyl, all three types), 2.09 (6H, s; acetone CH3), 4.31 (0.35 H, m; 11a-CH, (Z)-PTSC), 4.33 (IH, d;3J(H,H)=7.6 Hz, 11a-CH, (E)-PTSC), 4.37 (0.079 H, d;3J(H,H)=7,2°C； 11α-CH, ORG34517), 5,12 (1H, s; 17β-OH, (E)-PTSC), 5,13 (0,35 H, s; 17β-OH, (Z)- PTSC), 5,14 (0,079 H, s; 17p-OH, ORG34517), 5,66 (0,079 H, s; 4-CH, ORG34517), 5,97 (2,859 H, br s; O-CH2-O benzobisoxazole, all three species), 6.00 (1.35 H, s; 4-CH, (E)-PTSC and (Z)-PTSC), 6.62 (1.429 H, d;3J(H,H) = 8.0 Hz; 5'-CH benzobisoxazole, all three species), 6.73 (0.35 H, s; 2'-CH benzobisoxazole, (Z)-PTSC), 6.78 (1.079 H, s; 2'-CH benzobisoxazole, (E)-PTSC i ORG34517), 6.80 (0.35 H, d;3J(H,H) = 8,0 Hz, 6'-CH benzobisoksazol, (Z)-PTSC), 6,80 (1,079 H, d;3J(H,H)=8,0 Hz; 6'-CH benzobisoksazol, (E)-PTSC i ORG34517), 7,14 (0,35 H, m; 4″-H fenil, (Z)-PTSC), 7,15 (1 H, t;3J(H,H)=7.4 Hz; 4″-H phenyl, (E)-PTSC), 7.31 (0.7 H, m; 3″,5″-H phenyl, (Z)-PTSC), 7.33 (2 H , t;3J(H,H)=8,0 Hz; 3",5"-Hfenil, (E)-PTSC), 7.60 (0.7 H, d;3J(H,H)=8.0Hz; 2",6"-Hphenyl, (Z)-PTSC), 7.62 (2H, d;3J(H,H)=7,6 Hz; 2″,6″-Hfenil, (E)-PTSC), 9,83 (0,35 H, br s; C6H5-N-H, (Z)-PTSC), 9.89 (IH, br s; C6H5—N—H, (E)-PTSC), 10.48 (1H, br s; =N—N—H, (E)-PTSC), 10.83 (0.35 H, br s; =N— N—H, ( Z)-PTSC). *,** (E ili Z)-PTSC=(E ili Z)-4-feniltiosemikarbazon.
PT150 Purification of crude ORG34517 (PT150): (11β,17β)-17-hydroxy-11[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-dien-3 - one
Material: ORG34517 [Palisades Therapeutics, a division of Pop Test Oncology LLC, Cliffside Park, NJ, USA; manufactured by Wilmington PharmaTech Company LLC, Newark, DE, USA; TD2 Translational Drug Development, Scottsdale, Ariz., USA, Lot: 1930 -120-23], CAS Registry Number: [189035-07-2] Double Distilled Water, Purified and Sterile, Ethyl Acetate Pro Analysis [PanReac AppliChem LLC, batch number: 0000518022; w(n/n) = 99.9% (gas) chromatography), w (H2O) (m/m) = 0.01% (Karl Fischer titration), ethanol <0.1%, methanol <0.02% , methyl acetate <0.02%, trace elements (Cr, Fe, Ni, Pb, Zn, P, S, K, Mg) <0.00001%, Si <0.00002%, Na <0.0002% , non-volatile matter<0.001%, pH<0.0005 meq/g] specification: ORG34517 (M=430.54 g/mol, 4.000 g , 9.2907 mmol)
Suspend in distilled water (200 mL) in a 1000 mL round bottom flask. Then ethyl acetate (EtOAc, 100 mL)
Added as supernatant. Close the flask carefully and shake the mixture vigorously for a full 1 minute. After standing for 1 minute at room temperature (RT, 16.4 °C), the biphasic mixture was shaken vigorously for exactly 1 minute. Initially yellow EtOAc phase
Lighten the color by shaking the program. After standing at room temperature for 1 minute, transfer the mixture to a 500 mL separatory funnel and separate the phases (~10 minutes). The EtOAc phase was separated. The separated aqueous phase was re-extracted with EtOAc (100 ml) by shaking for exactly 10 s. Separate the phases (~10 min). The first and second EtOAc phases were combined. The separated residual aqueous phase was re-extracted with EtOAc (50 ml) by shaking for exactly 5 s. Separate the phases (~20 min). Combine all EtOAc phases [cool the remaining aqueous phase to +0-2°C for 1 h, separate the precipitated EtOAc phase (~20 min) and mix with the cooled EtOAc phase] and freeze at -25°C for 1.5 h. The ice-cold EtOAc phase containing ice was decanted from the frozen aqueous residue adhering to the glass surface into a 500 mL round bottom flask. The volume of the EtOAc solution was reduced to near volume under vacuum at low temperature (30-40 °C). 20 ml, when crystal lumps appear (stop evaporation before evaporating to dryness!). Wash the crystalline material adhered to the glass surface with 90% (v/v) ethanol in water (10 mL). The mixture was then frozen at -25°C for 80 minutes. Water (30 ml) was then added and the crystal suspension was frozen at -25°C for 15 minutes. The first crop (2.076 g) of beautifully crystalline ORG34517 (approx. white crystalline portion) was filtered and dried over CaCl2 in vacuo. Sticky residue in flask. The volume of the EtOAc solution was reduced to near volume under vacuum at low temperature (30-40 °C). 20 ml, when crystal lumps appear (stop evaporation before evaporating to dryness!). Wash the crystalline material adhered to the glass surface with 90% (v/v) ethanol in water (10 mL). The mixture was then frozen at -25°C for 80 minutes. Water (30 ml) was then added and the crystal suspension was frozen at -25°C for 15 minutes. The first crop (2.076 g) of beautifully crystalline ORG34517 (approx. white crystalline portion) was filtered and dried over CaCl2 in vacuo. The sticky residue in the flask was washed with 90% (v/v) ethanol in water (5 ml) and mixed with the first filtrate. Phase separation occurs. Evaporate the separated EtOAc phase to complete filtrate under as low a vacuum as possible (~30 min). The crystallized suspension was frozen at -25°C for 15 minutes. The precipitated second product (1.573 g) ORG34517 was filtered and dried over CaCl2 under vacuum. The residue in the flask (and vacuum bottle) was washed with 90% (v/v) ethanol in water (4 ml) and mixed with the second filtrate. The crystal suspension was frozen at -25°C for 1.5 hours. The liberated third yield (210 mg) of ORG34517 was filtered and dried over CaCl2 under vacuum. If desired, an additional small amount of material (100% difference: 141 mg) was collected from the third filtrate by freezing for 1 hour and processing as before.
Link: ORG34517 (PT150)
Molecular formula: C28H30Europa4
Molecular weight: 430.54 g/mol
Prinos: 3.859 g (96%)
Elemental analysis: Calculated: C, 78.11%; H, 7.02%; Oh, 14.86%
Found: C 78.26%; H 7.04%; About 14.71%; C 78.44%; H 7.04%; About 14.71%;
1'H-NMR: 0,44 (3H, s; 18-CH3), 1,24-2,76 (m; steroidi CH i CH2), 1.82 (3H, s;
(DMSO-d6, ppm) R—C≡C—CH3methyl), 4.37 (1H, d;3J(H,H)=7,7 Hz; 11□-CH), 5,14 (1H, s; 17□-OH), 5,66 (1H, s; 4-CH), 5,97 (2H, s; O- CH2-obenzodioksan), 6,60 (IH, d;3J(H,H)=7,7 Hz; 5'-CH benzodioksan), 6,78 (1H, s; 2'-CH benzodioksan), 6,79 (1H, d;3J(H,H)=8,3 Hz; 6′-CH benzodioksan)
second step (11β,17β)-17-Hydroperoxy-11[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-dien-3-one—(11β,17β) -17-hydroxy-11[3,4-(methylenedioxy)phenyl]-17-(1-propyn-1-yl)estra-4,9-dien-3-one (1:1) (PT157)
Material:
Crystalline ORG34517, purified as previously described (amorphous material extracted from capsules or tablets may also be used), CAS Registry Number: [189035-07-2]
Potassium ferricyanide K3[irontri(depth)6] [Potassium Red Cyanide, Potassium Hexacyanoferrate(III)] BioChemica≥99% [AppliChem GmbH, Batch: 6Y000987; w (m/m)=99.9% (titration), pH (1 M in H2O)6.1, klorid≤0,05%, sulfat≤0,005%, Pb≤0,002%]
Sodium bicarbonate (sodium bicarbonate) pro analysis NaHCO3[AppliChem GmbH, batch number: 4W000829; w (m/m)=100.42% (titration), pH (5% in H2O) 8.04 (20°C), chloride ≤ 0.001%, sulfate ≤ 0.005%, phosphate ≤ 0.005%, cation (K, Mg, Ca) ≤ 0.005%, As ≤ 0.0001%, heavy metal (Cu, Fe, Pb ) ≤0.0005%]
instructions:
Crystalline (amorphous material can also be used) ORG34517 (M = 430.54 g/mol, 3.136 g, 7.2839 mmol) was suspended in 90% (v/v) aqueous ethanol (110 ml) in a round-bottom flask of 500 ml. Heat the suspension and finally reflux until all solids have dissolved (~10 min). Independently, potassium ferricyanide solution K3[irontri(depth)6] (M = 329.26 g/mol, 5.795 g, 17.6001 mmol = 2.42 x molar amount of ORG34517) was prepared in water (65 ml). Pour the last solution all at once into the hot ORG34517 solution. Discard the residue and rinse with water (15 ml). The dark yellow solution was mixed with 90% (v/v) aqueous ethanol (60 mL) and refluxed for 8 min. After that, NaHCO was analyzed with sodium bicarbonate solution (NaHCO3).3(M = 84.01 g/mol, 1.497 g, 17.8193 mmol) in water (15 ml) was added via a reflux condenser. Discard the residue and rinse with water (8 ml). The solution first brightened, then darkened and was refluxed for another 12 minutes. The dark yellow solution was then cooled to room temperature (RT, θ = 17.1 °C) for 30 minutes. Kristali K3sodium [irontwo(depth)6]×(tall2back)nHe appeared. The crystal suspension is cooled to +0-2°C for 2.5 hours. Then the suspension was filtered through two layers of filter paper. Transfer the residue and wash with 90% (v/v) ethanol in water (50 ml). Finally, wet K3sodium [irontwo(depth)6]×(tall2back)nPress the filter cake with a spoon to obtain a dark yellow filtrate (V ≈ 320 ml). The filtrate was precipitated by adding water (65 ml). The pellet suspension was frozen at -25°C for 1 hour. Additional water (35 ml) was then added. The pellet suspension was frozen at -25°C for 4.5 hours. Filter the first product (2.464 g) of beige PT157 on a sintered glass filter. The material was dried by filtration with suction on the filter for 30 minutes. Then the material without pyrite was washed with water (200 ml) on the filter and dried over CaCl22) in vacuum. The filtrate was transferred, washed with water (100 ml) and frozen at -25°C for 3.5 hours. Filter a second yield (304 mg) of beige PT157 on a sintered glass filter. The material was dried by filtration with suction on the filter for 30 minutes. Then the material without pyrite was washed with water (200 ml) on the filter and dried over CaCl22) in vacuum. Combine the two returns. Discard the dark green filtrate.
Connection: PT157
Molecular formula: C56H60Europa9
Molecular weight: 877.07 g/mol
Yield: 2.768 grams (87%)
Elemental analysis: Calculated: C 76.69%; H 6.90%; N 0.00 %; About 16.42%; Found: C 76.85%; H 7.04%; N 0.30%; About 15.09%; 76.98%; H 7.12%, N 0.31%, O 15.27%;
Purity: caused by nitrogen content (0.30%), caused by incorporation of K3sodium [irontwo(depth)6] (nitrogen content is N 23.86%), the purity of PT157 can be calculated as 98.74% (m/m) [or 96.93% (n/n)]
1'H-NMR: 0,44 (3H, s; 18-CH3), 1,24-2,76 (m; steroidi CH i CH2), 1.83 (3H, s;
(DMSO-d6, ppm) R—C≡C—CH3methyl), 4.38 (1H, d;3J(H,H)=7,1 Hz; 11□-CH), 5,14 (1H, s; 17□-OH), 5,66 (1H, s; 4-CH), 5,97 (2H, s; O- CH2-obenzodioksan), 6,61 (IH, d;3J(H,H)=8,3 Hz; 5'-CH benzodioksan), 6,78 (1H, s; 2'-CH benzodioksan), 6,79 (1H, d;3J(H,H)=8,3 Hz; 6′-CH benzodioksan)
Example 4
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Example 5
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Example 6
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Example 7
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Example 8
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Example 9
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Example 10
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Example 11
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While the present invention has been described in detail with reference to specific examples thereof, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from its spirit and scope.