TWI619494B - Compositions and methods of use of phorbol esters - Google Patents

Abstract

A composition comprising a derivative of crotonate or crotonate and methods of use thereof are provided for the treatment of chronic and acute symptoms. These symptoms may be caused by the disease, may be symptoms of the disease or sequelae. Chronic and acute symptoms can be caused by viral infections such as human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), neoplastic disease, stroke, kidney disease, urinary incontinence, autoimmune disease, Parkinson's disease, prostatic hypertrophy, Caused by aging, or treatment of such diseases. Additional compositions and methods for applying crotonate or a derivative compound in combination with at least one additive are provided to provide a more effective therapeutic tool against acute and chronic symptoms in a mammalian individual.

Description

Crotonyl ester composition and method of use

Cross-references to related applications

This application is a continuation of the U.S. Patent Application Serial No. 12/023,753, filed on Jan. 31, 2008, which is incorporated herein by reference. The entire contents of this are incorporated herein by reference.

The invention generally relates to the pharmaceutical use of phorbol esters.

Plants have historically been used for many medical purposes. The World Health Organization (WHO) estimates that 4 billion people, 80% of the world's population are using herbal medicines for general health care (World Health Organization's December 2008 briefing). However, it is difficult to separate a specific compound having a medical effect therefrom and remanufacture it in commercial specifications. In addition, although the active compound can be isolated from plants, other components of the plant, such as minerals, vitamins, volatile oils, glycosides, alkaloids, raw Isoflavones, and other substances may also be involved in the functioning of the active ingredients, or the medicinal effects of such plants, and thus the purification and commercialization of plants into pharmaceutical systems is a challenge.

Crotonol is a plant-derived organic compound of the natural, biguanide family of the tilliane. It is the first hydrolyzed product isolated from croton oil extracted from the seeds of Croton tiglium , which was native to the Euphorbiaceae family leaf shrubs of Southeast Asia in 1934. Various esters of croton have important biological properties, including the ability to mimic the function of diacylglycerol and activate protein kinase C (PKC), regulate downstream cell signaling pathways, and include mitogen-activated protein kinases (mitogen- Activated protein kinase, MAPK) pathway. The phorbol esters are additionally thought to bind to chimaerins, Ras activator (RasGRP), and vesicle-priming protein Munc-13 (Brose N, Rosenmund C. , JCell Sci; 115: 4399-411 (2002)). Certain crotonides also contain nuclear factor-kappa B (NF-κB). The most striking physiological property of croton is known as tumor promoters (Blumberg, 1988; Goel, G et al., Int, Journal of Toxicology 26, 279-288 (2007)).

12-O-tetradecanoylphorbol-13-acetate (TPA), also known as crotyl-12-myristate-13-acetate ( Phorbol-12-myristate-13-acetate (PMA) is an inducer of differentiation and apoptosis of multiplex cells and primary cells used in models of carcinogenesis. 12-O-tetradecyldecylcrotonol-13-acetate is also known to enhance the blood leukocytes and neutrophils in patients with bone marrow dysfunction due to chemotherapy (Han ZT et al. Proc .Natl.Acad.Sci.95,5363-5365 (1998)), and inhibition of the effects of human immunodeficiency virus (HIV) cytopathic effects in MT-4 cells (Mekkawy S. et al., Phytochemistry 53, 47-464 (2000)). However, for various reasons, including the corrosion reaction when exposed to skin and its potential toxicity, 12-O-tetradecyldecylcrotonol-13-acetate has not been used to treat, manage, or prevent human immunodeficiency. Virus or acquired immunodeficiency syndrome, or as an adjuvant for chemotherapy. In fact, crotonyl ester plays an important role in the activation of protein kinase C (PKC), which catalyzes various cellular responses resulting from immune responses and tumor development (Goel et al., Int, Journal of Toxicology 26, 279-288 (2007)). Crotonyl esters are generally excluded from cancer or immune diseases such as rheumatoid arthritis, or therapeutic candidates for symptoms involving an immune response such as stroke, autoimmune disease, and prostatic hypertrophy.

With the development of modern medicine, the survival rate of both chronic and acute diseases has increased, creating new challenges in dealing with chronic symptoms, acute disease syndromes, and treatment side effects. There is a continuing need for certified pharmaceuticals, including plant-based agents that can be used to treat diseases, prevent injuries from acute attacks, treat symptoms of disease, and treat side effects of disease treatment. When a molecular target has produced many successful agents, it often contains many message delivery paths, and blocking a path can be easily compensated. The treatment of side effects in individuals who are novel and more effective in treating and suffering from various symptoms are explicitly required, especially chronic or potentially occurring symptoms such as cancer, immune diseases, autoimmune diseases, stroke, rheumatoid arthritis, inflammation. , uterine fibroids, prostatic hypertrophy, urinary incontinence, Parkinson's disease, and kidney disease.

The present invention relates to a composition comprising crotonate and a method of using same. Such compositions and methods are useful in treating chronic or potential symptoms, or repairing an acute attack of a particular condition.

In one embodiment, crotonyl esters and croton ester derivatives are used to treat diseases such as human immunodeficiency virus (HIV) and related symptoms, such as acquired immunodeficiency syndrome (AIDS). The compositions and methods of the present invention can be used to treat human immunodeficiency virus and its associated symptoms, such as acquired immunodeficiency syndrome, by any means. In some embodiments, the compositions and methods modify the activity of a human immunodeficiency virus receptor in a mammalian individual. In other embodiments, the compositions and methods described herein reduce the amount of virus in human immunodeficiency virus-infected individuals' latent HIV reservoirs. In another embodiment, the compositions and methods described herein enhance the activation of human immunodeficiency virus in latent pro-viral cells. In another embodiment, it inhibits the HIV-cytopathic effect of human immunodeficiency virus.

In another embodiment, a composition comprising a derivative of crotonate and crotonate is useful for treating or treating a mammalian subject suffering from symptoms of human immunodeficiency virus and acquired immunodeficiency syndrome. Symptoms treated and treated using the compositions and methods described herein include oral lesions, fatigue, skin thrush, fever, loss of appetite, diarrhea, aphthous ulcers, malabsorption, thrombocytopenia, wasting, anemia, lymph nodes Secondary diseases of swelling, susceptibility and severity, such as mycobacterium avium complex, salmonellosis, syphilis, neurosyphilis, tuberculosis (TB), bacillary angioma (bacillary) Angiomatosis), Aspergillosis, candidiasis, coccidioidomycosis, listeriosis, pelvic inflammatory disease, Burkitt's lymphoma, cryptococcal Meningitis), histoplasmosis, Kaposi's sarcoma, lymphoma, systemic non-Hodgkin's lymphoma (NHL), primary central nervous system lymphoma, hidden Sporozoites, isospores coccidiosis, microsporosis, pneumocystis carinii pneumonia (PCP), toxoplasmosis, cytomegalovirus (CMV), hepatitis, herpes simplex , herpes zoster, human papillomavirus (HPV, genital warts, cervical cancer), infectious soft palate, oral hairy leukoplakia (OHL), and progressive multiple local white matter Progressive multifocal leukoencephalopathy (PML), but not limited to this.

In another embodiment, a composition comprising a derivative of crotonate and crotonate is useful for treating a neoplastic disease. These tumors can be malignant or benign. In certain embodiments, the tumor can be a solid cancer or a non-solid cancer. In other embodiments, the tumor can be a recurrent tumor. In other embodiments, the tumor can be refractory. Examples of tumors include, but are not limited to, hematological malignancies/bone marrow diseases including, but not limited to, leukemia, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), Chronic myeloid leukemia blast crisis, myelodysplasia, myeloproliferative syndrome; lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma; subcutaneous adenocarcinoma Subcutaneous adenocarcinoma); ovarian teratocarcinoma; liver cancer: breast cancer: bone cancer; lung cancer: pancreatic cancer; non-small cell lung cancer and prostate cancer. Other tumor symptoms suitable for treatment by the methods and compositions described herein include other cancer diseases and conditions, including various types of solid tumors. Successful treatment and/or remission will be assessed according to traditional methods, such as assessing the reduction in size of the body tumor and/or assessing the growth, stage, metastatic status, or potential, extinction or performance of the pathological tumor marker by histopathological studies. Degree and so on.

The compositions and methods herein may additionally be used to treat symptoms of a neoplastic disease, including, but not limited to, anemia; chronic fatigue: excessive or prone to bleeding, such as nasal, gum, subcutaneous bleeding: prone to bruising, In particular, there are no obvious reasons for indigo; shortness of breath; ecchymosis; repeated fever; swollen gums; slow wound healing; bone and joint discomfort; recurrent infections; weight loss; itching; night sweats; swollen lymph nodes; fever; Pain and discomfort; visual impairment; cough; loss of appetite; chest pain; difficulty swallowing; swelling of the face, neck and upper limbs; frequent urination, especially at night; difficulty in urinating or punishing; weak or easily interrupted urination; Cautery; erectile difficulty; ejaculation pain; blood urine or blood essence; lower back, buttocks and thighs often pain or stiffness; weakness.

The compositions and methods herein are more useful for treating the side effects of chemotherapy and radiation therapy commonly used in the treatment of neoplastic diseases. These side effects include, but are not limited to, hair loss, nausea, vomiting, loss of appetite, soreness, neutropenia, anemia, thrombocytopenia, dizziness, fatigue, constipation, mouth ulcers, itchy skin, peeling, nerve and muscle damage. Hearing changes, weight loss, diarrhea, immunosuppression, indocyanine, heart damage, hemorrhage, liver damage, kidney damage, edema, mouth and sore throat, infertility, fibrosis, hair removal, wet desquamation, mucous membrane dryness, dizziness And brain lesions.

In another embodiment, the derivatives of crotonyl esters and crotonides described herein can be used to modulate cellular signaling pathways. This adjustment can have a variety of results, for example, In certain embodiments, the use of a composition comprising a derivative of crotonate and crotonate increases the increase in white blood cell content in a mammalian individual. In other embodiments, a composition comprising a derivative of crotonate and crotonate alters the release of Th1 cytokines in a mammalian individual. In another embodiment, a composition comprising a derivative of crotonate and/or crotonate alters the release of interleukin-2 (IL-2) from a mammalian individual. In another embodiment, a composition comprising a derivative of crotonate and/or crotonate can alter the release of interferon in a mammalian individual. In another embodiment, a composition comprising a derivative of crotonate and/or crotonate can alter the rate of ERK phosphorylation.

In another embodiment, the croton esters and croton ester derivatives described herein are useful for the prevention and treatment of stroke and damage from stroke. Symptoms of prevention and treatment of stroke by using the derivatives of crotonides and crotonides described herein include, but are not limited to, sputum, dysfunction, decreased judgment, left neglect, memory loss, aphasia, coordination, and Balance problems, nausea, vomiting, cognitive dysfunction, sensory impairment, disorientation, ipsilateral hemianopia, or impulsivity.

In another embodiment, the derivatives of crotonyl esters and crotonides described herein are useful for the treatment of rheumatoid arthritis. Symptoms of rheumatoid arthritis that can be prevented and treated by the use of the crotonic esters and croton ester derivatives described herein include, but are not limited to, joint pain, morning stiffness, uneven tissue under the skin of the arm, fatigue , energy loss, loss of appetite, low fever, muscle and joint pain.

In further embodiments, the croton esters and croton ester derivatives described herein can be used to treat prostatic hypertrophy. The compositions and methods described herein can be used to prevent or treat symptoms of prostatic hypertrophy, including, but not limited to, dripping at the end of urination, retention of urine, incomplete bladder emptying, urinary incontinence, frequent urination, painful urination Hematuria Slow or delayed urine, urinary flow suddenly stop, urinary need to be strong, weak urine flow, sudden urgency.

In another embodiment, the crotonic esters and croton ester derivatives described herein can be used in the treatment of kidney diseases.

In another embodiment, the croton esters and croton ester derivatives described herein can be used in the treatment of urinary incontinence.

In other embodiments, the croton esters and croton ester derivatives described herein can be used in the treatment of uterine fibroids.

In other embodiments, the croton esters and croton ester derivatives described herein can be used in the treatment of dementia.

In other embodiments, the croton esters and croton ester derivatives described herein can be used in the treatment of diabetes.

In one embodiment, the crotonic esters and croton ester derivatives described herein can be used to reduce the apparent signs of aging in an individual.

In other embodiments, the croton esters and croton ester derivatives described herein can be used to reduce swelling around the eye.

In other embodiments, the crotonic esters and croton ester derivatives described herein can be used in the treatment of autoimmune diseases, including, but not limited to, myasthenia gravis. Symptoms of myasthenia gravis that can be prevented or treated by using the compositions and methods described herein, including, but not limited to, drooping eyelids, diplopia, speech disorders, fatigue, muscle weakness, difficulty swallowing, dysphonia .

In further embodiments, the croton esters and croton ester derivatives described herein can be used to treat and prevent, for example, Parkinson's disease central nervous system disorders. can Symptoms of Parkinson's disease treated or prevented by using the compositions and methods described herein include, but are not limited to, restless tremors, stiffness, bradykinesia, stiffness, speech disorders, cognitive dysfunction, dementia, mood Disorders, lethargy, insomnia, and unstable posture.

In another embodiment, the croton esters and croton ester derivatives described herein can be used to treat and prevent carpal tunnel syndrome.

The present invention provides crotonyl esters by providing novel and surprisingly effective methods and compositions for modulating cellular signaling pathways and/or treating disease and disease-related symptoms for the above purposes and for other purposes and advantages. Or a derivative composition of the following formula I:

Wherein R ₁ and R ₂ may be hydrogen; Wherein the alkyl group contains from 1 to 15 carbon atoms; , , And substituted derivatives thereof and R ₃ may be hydrogen or And its substituted derivatives.

In some embodiments, at least one of R ₁ and R _{2 is} not hydrogen and R ₃ is hydrogen or And its substituted derivatives. In other embodiments, one of R ₁ or R ₂ is , the remaining R ₁ or R ₂ is And R ₃ is hydrogen.

The alkyl, alkenyl, phenyl, and benzyl groups herein may be unsubstituted or hydrogenated, preferably chloro, fluoro, or bromo; nitro; amine; and/or the like. Substituted by the base.

In other embodiments, the present invention provides a novel and surprisingly effective method and composition for modulating cellular signaling pathways and/or treating disease and disease related symptoms for the above purposes and for other purposes and advantages. Some of the compositions comprise a crotonate composition, such as 12-O-tetradecanoylphorbol-13-acetate (TPA) of the following formula II:

Useful croton esters and related compounds and derivatives and methods of the invention include, but are not limited to, other pharmaceutically acceptable salts, active isomers, mirror image isomers, polymorphs of the compounds ( Polymorphs), glycosylated derivatives, solvates, hydrates, and/or precursors of the compound drug. Illustrative forms of crotonides for use in the compositions and methods of the present invention include, but are not limited to, phorbol 13-butyrate, phorbol 12-decanoate ), phorbol 13-decanoate, phorbol 12,13-diacetate, crotonol-13,20-diacetate (phorbol) 13,20-diacetate), phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, crotyl alcohol -12,13-didecanoate, phorbol 12,13-dihexanoate, crotyl-12,13-dipropionate Phorbol 12,13-dipropionate), phorbol 12-myristate, phorbol 13-myristate, crotyl-12-myristate- Phorbol 12-myristate-13-acetate (also known as TPA or PMA), crotonol-12,13,20-triacetate, 12- 12-deoxyphorbol 13-angelate, 12-deoxycrotonol-13-angelate 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxycrotonol-13-isobutyric acid 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxycrotonol-13-benzene 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, crotyl-12-cis acid Ester-13-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate ), and phorbol 13-acetate.

Crotonyl ester of formula I according to the process of the invention, in particular TPA, The treated mammalian subjects include, but are not limited to, individuals infected with HIV and AIDS, and also include HIV and AIDS-related symptoms, or second or opportunistic diseases such as oral lesions, fatigue, skin ulceration, fever, Loss of appetite, diarrhea, aphthous, malabsorption, thrombocytopenia, weight loss, anemia, lymphadenopathy, avian mycobacteria, salmonellosis, syphilis, neurosyphilis, tuberculosis (TB), bacillary hemangioma, sputum , candidiasis, coccidioidomycosis, listeriosis, pelvic inflammatory disease, Burkitt's lymphoma, cryptococcal meningitis, histoplasmosis, Kaposi's sarcoma, lymphoma, systemic non Hodgkin's lymphoma (NHL), primary central nervous system lymphoma, cryptosporidiosis, isospores coccidiosis, microsporosis, Pneumocystis carinii pneumonia (PCP), toxoplasmosis, giant cells Virus (CMV), hepatitis, herpes simplex, herpes zoster, human papillomavirus (HPV, condyloma acuminata, cervical cancer), infectious soft palate, oral leukoplakia (OHL), and progressive multiple Local leukoencephalopathy (PML).

The croton ester of formula I according to the method of the present invention, particularly TPA, and other mammalian subjects treated, including, but not limited to, individuals suffering from neoplastic diseases, including malignant tumors such as solid cancers and non-solid cancers . Non-solid cancers may include hematological malignancies/bone marrow diseases including, but not limited to, leukemia, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic myelogenous leukemia, acute spinal cord hyperplasia, myeloproliferation Sexual syndrome. Solid cancers may include, but are not limited to, lymphomas, including Hodgkin's lymphoma and non-Hodgkin's lymphoma; subcutaneous adenocarcinoma; ovarian teratoma; liver cancer: pancreatic cancer: non-small cell lung cancer and prostate cancer .

The croton ester of formula I according to the method of the invention, in particular TPA, may also comprise a subject having symptoms of a neoplastic disease, such as anemia, chronic fatigue, excessive or prone to bleeding, such as nose, gums, and subcutaneous bleeding, Blood stasis, especially indigo, shortness of breath, freckle, frequent fever, swollen gums, no obvious cause Slow wound healing, bone and joint discomfort, repeated infection, weight loss, itchy skin, night sweats, swollen lymph nodes, fever, abdominal pain and discomfort, visual disturbance, cough, loss of appetite, chest pain, difficulty swallowing, face, neck and upper limbs Swelling, frequent urination, especially at night, difficulty urinating, difficulty urinating, weak or interrupted urine, painful or burning urinating, erectile dysfunction, ejaculation pain, hematuria or blood, lower back, buttocks, upper thigh often painful or Stiff or weak, but not limited to this. In certain embodiments, certain cancers may be relapsed or difficult to treat.

The croton ester of the formula I according to the method of the present invention, particularly TPA, may further comprise a side effect caused by chemotherapy or radiation therapy for treating a tumor disease, the tumor disease comprising a malignant tumor disease such as a solid cancer. And non-physical cancer. Side effects include, but are not limited to, hair loss, nausea, vomiting, loss of appetite, soreness, neutropenia, anemia, thrombocytopenia, dizziness, fatigue, constipation, mouth ulcers, itchy skin, peeling, nerve and muscle damage, Auditory changes, weight loss, diarrhea, immunosuppression, indocyanine, hemorrhage, heart damage, liver damage, kidney damage, edema, mouth and throat ulcers, infertility, wet desquamation, hair loss, mucous membrane dryness, dizziness and brain Lesion.

According to the method and composition of the present invention, a croton ester of the formula I, in particular TPA, and a treated mammalian human-containing individual comprises an individual suffering from a stroke. Individuals treated with crotonyl esters of formula I, particularly TPA, include individuals with symptoms of stroke. Symptoms of stroke include, but are not limited to, delirium, spatial disorders, decreased judgment, left neglect, memory loss, aphasia, coordination, and Balance problems, nausea, vomiting, cognitive dysfunction, sensory disturbances, disorientation, ipsilateral hemianopia, and impulsivity.

Crotonyl ester of formula I according to the process and composition of the present invention, especially TPA, while a treated mammalian human-containing individual comprises an individual suffering from rheumatoid arthritis. Symptoms of rheumatoid arthritis that can be prevented or treated by crotonyl esters of formula I, particularly TPA, include, but are not limited to, joint pain, morning stiffness, unevenness of the underlying skin of the arm, fatigue, energy loss Loss of appetite, low fever, sore muscles and joints.

The croton ester of formula I according to the method of the invention, in particular TPA, and other mammalian subjects comprising humans treated comprise an individual suffering from prostatic hypertrophy. The compositions and methods described herein can be used to prevent or treat symptoms of prostatic hypertrophy, including, but not limited to, dripping at the end of urination, retention of urine, incomplete bladder emptying, urinary incontinence, frequent urination, urination Pain, hematuria, slow or delayed urination, urinary flow, sudden urination, urination, weak urine flow, and sudden urgency.

The croton ester of formula I according to the method of the invention, in particular TPA, and other mammalian subjects comprising humans, comprise an individual suffering from a kidney disease.

The croton ester of formula I according to the method of the invention, in particular TPA, and other mammalian individuals comprising humans treated comprise individuals suffering from urinary incontinence.

The croton ester of formula I according to the method of the invention, in particular TPA, and other mammalian individuals comprising humans treated comprise individuals having significant signs of aging.

The croton ester of formula I according to the method of the invention, in particular TPA, and other mammalian subjects comprising humans treated comprise individuals having periocular swelling.

The croton ester of formula I according to the method of the invention, in particular TPA, and other mammalian subjects comprising humans treated comprise individuals having uterine fibroids.

Crotonyl ester of formula I according to the process of the invention, especially TPA, and Other mammalian individuals treated including humans include individuals with dementia.

The croton ester of formula I according to the method of the invention, in particular TPA, and other mammalian individuals comprising humans treated comprise an individual having diabetes.

The croton ester of formula I according to the method of the invention, particularly TPA, and other mammalian subjects comprising humans comprising an individual suffering from an autoimmune disease, including, but not limited to, myasthenia gravis. Symptoms of myasthenia gravis that can be prevented or treated using the compositions and methods described herein include, but are not limited to, drooping eyelids, diplopia, speech disorders, fatigue, muscle weakness, difficulty swallowing, or dysphonia.

The croton ester of formula I according to the method of the invention, in particular TPA, and other mammalian individuals comprising humans treated comprise individuals suffering from Parkinson's disease. Symptoms of Parkinson's disease that can be prevented or treated using the compositions and methods described herein include, but are not limited to, restless tremors, stiffness, bradykinesia, stiffness, speech disorders, cognitive dysfunction, dementia, mood disorders , lethargy, insomnia, and unstable posture.

In another embodiment, a mammalian subject having a carpal tunnel syndrome can be treated according to the croton of Formula I of the method of the invention, particularly TPA.

By administering an effective amount of a crotonyl ester of formula I, these and other systems are effectively treated prophylactically and/or therapeutically, sufficient to prevent or reduce viral load and reduce latent HIV reservoirs. Increase viral load, increase immune response, increase Th1 cytokine release, prevent or reduce HIV or AIDS-related symptoms or conditions, reduce and/or reduce tumor cells, increase white blood cell content, trigger remission, maintain remission, prevent or reduce malignant tumors Symptoms or conditions, increase ERK phosphorylation, reduce or reduce radiation damage, enhance the immune system, reduce nausea, reduce or avoid hair loss, Increase appetite, reduce soreness, replenish energy, reduce gastrointestinal discomfort, reduce bruising, reduce mouth ulcers, reduce or reduce skin damage caused by radiation, increase or maintain neutrophils, increase or maintain platelet content, reduce edema, Reduce or reduce wet desquamation, avoid or treat delirium, increase spatial awareness, reduce memory loss, reduce aphasia, promote coordination and balance, improve perception, reduce or reduce tremor, reduce or reduce stiffness, improve sleep quality, increase stability, Improves mobility, improves bladder control, improves appetite, relieves muscle or joint pain, improves vision, and/or improves muscle control.

Therapeuticly useful methods and formulations of the present invention will effectively utilize various forms of crotonyl esters of formula I, as described above, including any active pharmaceutically acceptable salts of the compounds, as well as having active isoforms. Constructs, mirror image isomers, polymorphs, solvates, hydrates, prodrugs, and/or combinations thereof. The TPA of Formula II is applied hereinafter as an example of an illustrative embodiment of the invention.

In other aspects of the invention, there is provided a combination formulation and method for applying an effective amount of a crotonyl ester of formula I in combination with one or more secondary or adjunctive therapeutic agents, a secondary or adjunctive therapeutic agent Combinatorially formulated or coordinated administration of formula I has produced an effective response to an individual.

In the treatment of viral cytopathic diseases, such as exemplary combinations and synergistic treatments of HIV and AIDS, the use of crotonyl ester of formula I with one or more added retroviruses, HIV or AIDS treatment or other Secondary or adjuvant therapy. The combination preparation and the synergistic treatment method can, for example, follow or be extended by a highly active retroviral treatment regimen (HAART protocols) Stretching and comprising, for example, two nucleoside analogue reverse transcriptase inhibitors plus one or more protease inhibitors or non-nucleoside analog reverse transcriptase inhibitors in other combinations. Other combination preparations and synergistic treatment methods can, for example, include treatments for opportunistic infections as well as compounds for retroviral treatment regimens. In these embodiments, secondary or adjunctive therapeutic agents for binding crotonyl esters, such as TPA, may have antiviral efficacy, either directly or indirectly, which may have other effective adjunctive therapeutic activities either alone or in combination with crotonyl esters, such as TPA. (e.g., preventing HIV, treating HIV, activation of the HIV virus pool, increasing the activity of Th1 cytokines), or may be present alone or in combination with croton, such as TPA, for the treatment of HIV-associated opportunistic infections.

Adjuvant therapeutics that are effective in combination and synergistic therapeutic methods include, for example, protease inhibitors including, but not limited to, saquinavir, indinavir, ritonavir ), nelfinavir, atazanavir, darunavir, fosamprenavir, tipranavir, and amprenavir; Nucleoside reverse transcriptase inhibitors, including, but not limited to, zidovudine, didanosine, stavudine, lamivudine, zalcitabine (zalcitabine), emtricitabine, tenofovir disoproxil fumarate, AVX754 and abacavir; non-nucleoside reverse transcriptase inhibitors, including, but not limited to, Wei Zi ( Nevaripine), delavaridine, calanolide A, TMC125, and efavirenz; combination drugs include, but are not limited to, Xining/emtricitabine/tenofovir (efavirenz/emtricitabine/tenofovir disoproxil fumarate), lamivudine/zidovudine (la Mivudine/zidovudine), abacavir/lamivudine, Abacavir/lamivudine/zidovudine, emtricitabine/tenofovir disoproxil fumarate, sulfamethoxazole/trimethoprim ( Sulfamethoxazole/trimethoprim), and lopinavir/ritonavir; entry and fusion inhibitors include, but are not limited to, enfuvirtide, AMD070, BMS-488043, fuzivudine Foster (fozivudine tidoxil), GSK-873, 140, PRO 140, PRO 542, peptide T (Peptide T), SCH-D, TNX-355, and UK-427,857; treatment of AIDS-related opportunistic infections and other symptoms associated with HIV Including, but not limited to, ritonavir, Adefovir Dipivoxil, aldesleukin, amphotericin B, azithromycin, hydroxyapatite Calcium (hydroxyquinapatite), clarithromycin, doxorubicin, dronabinol, Entecavir, epoetin alfa, etoposide, fluconazole Fluconazole, ganciclovir, immunoglobulin Protein, interferon alpha-2, isoniazid, itraconazole, megestrol, paclitaxel, peginterferon alfa-2, Pentamidine, poly-1-lactic acid, ribavirin, rifabutin, rifampin, somatotropin, anthracycline (testosterone), trimetrexate, and valganciclovir; Integrase Inhibitors include, but are not limited to, GS 9137, MK-0518; microbicides, but not Limited to, BMS-378806, C31G, carbopol 974P, carrageenan, cellulose sulfate, Cyanovirin-N, dextransulfate, hydroxyethyl Hydroxyethyl cellulose, PRO 2000, P SPL7013, tenofovir (tenofovir), UC-781, and interleukin-2.

In an exemplary combination formulation and synergistic treatment for treating neoplastic disease, a crotonate compound of formula I is used in combination with one or more additional neoplastic disease treatments or other secondary or adjunctive therapeutic agents. Secondary or adjunctive therapeutic agents for binding crotonyl esters, such as TPA, in such embodiments may have direct or indirect chemotherapeutic effects, alone or in combination with, for example, TPA; or may have other effective adjuvants in combination with crotonyl esters, such as TPA. Therapeutic activity (eg cytotoxicity, anti-inflammatory, inhibition of transcription factor (NF-κB), induction of apoptosis, increase of Th1 cytokine activity); or use alone or in combination with, for example, TPA may be effective for the treatment of tumors or related symptoms Auxiliary therapeutic activity.

In a combination preparation and synergistic treatment method for treating tumor diseases, an effective auxiliary or secondary therapeutic agent comprises doxorubicin, vitamin D3, cytarabine, cytosine arabinoside , daunorubicin, cyclophosphamide, gemtuzumab ozogamicin, ozogamicin, idarubicin, mercaptopurine, Mitoxantrone, thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, Fludarabine, methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate. In addition, adjuvant or secondary therapy can be used, but is not limited to, radiation therapy, hormone therapy, or surgery.

In an exemplary combination preparation and synergistic treatment method for preventing or treating the side effects of chemotherapy, a crotonate compound of the formula I is used in combination with one or more additional Chemoprotective or other secondary or adjunctive therapeutic agents. In such embodiments, a secondary or adjunctive therapeutic agent for a croton ester, such as TPA, may have a direct or indirect chemical protection effect either alone or in combination with, for example, TPA; or may be otherwise effective in combination with a croton ester, such as TPA. Auxiliary therapeutic activity (eg anti-inflammatory, neutrophil stimulating, stimulating erythropoiesis, inhibition of osteopathy, strengthening bone, antiemetic, analgesic); or use alone or in combination with crotonate, such as TPA for chemotherapy or its related The treatment and prevention of symptoms have an effective adjuvant therapeutic activity.

In these combination preparations and synergistic treatment methods for preventing or treating the side effects of chemotherapy in mammalian individuals, effective auxiliary or secondary therapeutic agents include, but are not limited to, pegfilgrastim, erythropoietin (epoeitn alfa) , long-acting erythropoietin (darbepoetin alfa), alendronate sodium (alendronate sodium), risedronate, ibandronate, G-CSF, 5-HT ₃ receptor antagonism Agents, NK ₁ antagonists, olanzapine, corticosteroids, dopamine antagonists, serotonin antagonists, benzodiazepines, aprepitant, and cannabinoids (cannabinoids).

In an exemplary combination preparation and synergistic treatment method for preventing or treating side effects of radiation therapy, the croton ester compound of formula I is used in combination with one or more additional radiation protective or other secondary or auxiliary therapeutic agents. . In such embodiments, the secondary or adjunctive therapeutic agent to be combined with the croton ester, such as TPA, may have a direct or indirect radiation protection effect either alone or in combination with, for example, TPA; or may have other combinations with crotonyl esters, such as TPA. Effective adjuvant therapeutic activity (eg, anti-swelling, cytoprotective, anti-mucosal, epithelial irritant, anti-fibrotic, platelet irritant); or use alone or in combination with crotonate, such as TPA, may be a side effect of radiation therapy or its related The treatment and prevention of symptoms have an effective adjuvant therapeutic activity.

In these combination preparations and synergistic treatment methods for preventing or treating radiation treatment side effects of mammalian individuals, effective auxiliary or secondary therapeutic agents include, but are not limited to, steroids, amifostine, and chlorhexidine Chlorhexidine, benzydamine, sucralfate, keratinocyte growth factor (KGF), palifermin, Cu/Zn superoxide dismutase, interleukin 11 Or prostaglandin.

In exemplary combined and synergistic methods of preventing or treating stroke, the crotonate compound of Formula I is used in combination with one or more additional prophylactic or therapeutic stroke or other secondary or adjunctive therapeutic agents. In such embodiments, the secondary or adjunctive therapeutic agent to be combined with the crotonyl ester, such as TPA, may have a direct or indirect effect of preventing or recovering from a stroke, either alone or in combination with, for example, TPA; or may be combined with, for example, TPA. Having other effective adjunctive therapeutic activities (e.g., anticoagulation, hypolipidemic, vasodilating, hypotensive); or alone or in combination, e.g., TPA may have an effective adjuvant therapeutic activity for the treatment and prevention of stroke or its associated symptoms.

In these combination preparations and synergistic treatment methods for preventing or treating stroke in a mammalian individual, effective auxiliary or secondary therapeutic agents include, but are not limited to, tissue plasminogen activator, anticoagulation Anticoagulant, statin, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitor, beta-blocker (beta-blocker), calcium channel blocker or diuretic. In addition, adjuvant or secondary treatment can be used, for example, but not limited to, carotid endarterectomy, angioplasty, stent placement, craniotomy, Endovascular embolization Endovascular coil emobilization, patent foramen ovale closure.

In an exemplary combination formulation and synergistic treatment for treating Parkinson's disease, a crotonate compound of Formula I is used in combination with one or more additional treatments for Parkinson's disease or other secondary or adjunctive therapeutic agents. In such embodiments, the secondary or adjunctive therapeutic agent to be combined with the croton ester, such as TPA, may have a direct or indirect anti-Parkinson's effect alone or in combination with, for example, TPA; or may have, for example, TPA binding Other effective adjunctive therapeutic activities (eg, increase of dopamine, inhibition of catechol-O-methyl transferase, inhibition of aromatic L-amino acid decarboxylase, Dopamine antagonism, neuroprotection, anticholinergic); or alone or in combination, such as TPA, may have an effective adjuvant therapeutic activity for the treatment and prevention of Parkinson's disease.

In these combination preparations and synergistic treatment methods for preventing or treating Parkinson's disease in mammalian individuals, effective auxiliary or secondary therapeutic agents include, but are not limited to, levodopa, tolcapone , carbidopa, dopamine agonist, MAO-B inhibitor, pyridoxine, amantidine, seleyiline, rasagiline ( Rasagiline), or anticholinergic drugs. In addition, adjuvant or secondary treatment can be used, for example, but not limited to, deep brain stimulation and lesion formation.

In an exemplary combination formulation and synergistic treatment for the treatment of prostatic hypertrophy, the crotonate compound of Formula I is used in combination with one or more additional therapeutic or prophylactic or other secondary or adjunctive therapeutic agents. In these embodiments, used with croton The ester, such as a TPA-binding secondary or adjunctive therapeutic agent, may have a direct or indirect effect, alone or in combination with, for example, TPA; or may have other effective adjunctive therapeutic activities in combination with, for example, TPA (type II 5-alpha reductase inhibitor) , muscle relaxant); or alone or in combination, for example, TPA can have an effective adjuvant therapeutic activity for the treatment and prevention of prostatic hypertrophy.

In these combination preparations and synergistic treatment methods for preventing or treating prostatic hypertrophy in a mammalian body, effective auxiliary or secondary therapeutic agents include, but are not limited to, finasteride, dutasteride, hydrochloric acid Terazosin, doxazosin, tamsulosin or alpha receptor blockers. In addition, adjuvant or secondary treatment can be used, for example, but not limited to, transurethral resection of the prostate, transurethral incision of the prostate, laser surgery, or prostatectomy. (prostatectomy).

In an exemplary combination formulation and synergistic treatment for the treatment of rheumatoid arthritis, a crotonate compound of formula I is used in combination with one or more additional therapeutic rheumatoid arthritis or other secondary or adjunctive therapeutic agents. In such embodiments, the secondary or adjunctive therapeutic agent used in combination with the croton ester, such as TPA, may have a direct or indirect effect, either alone or in combination with, for example, TPA; or may be otherwise effective in combination with a croton ester, such as TPA. Adjuvant therapeutic activity (eg anti-inflammatory, immunosuppressive, TNF inhibition, anti-inflammatory, calcineurin inhibitor, pyrimidine synthesis inhibitor, 5-LO inhibitor, antifolate, IL-1 receptor antagonist, T cell co-stimulation inhibition; or alone or in combination, for example, TPA can have an effective adjuvant therapeutic activity for the treatment and prevention of rheumatoid arthritis.

In these combination preparations and synergistic treatment methods for preventing or treating rheumatoid arthritis in mammalian individuals, effective auxiliary or secondary therapeutic agents include, but are not limited to, non-steroidal anti-inflammatory drugs, steroids, disease-modifying antirheumatic agents. Disease-modifying anti-rheumatic drug, immunosuppressive agent, TNF-α inhibitor, anakinra, abatacept, adalimumab, azathioprine ), chloroquine, hydroxychloroquine, cyclosporin, D-penicillamine, etanercept, golimumab, gold Gold salts, infliximab, leflunomide, methotrexate, minocycline, sulfasalazine, rituximab Resistant (rituximab), or tocilizumab.

In exemplary combined and synergistic methods of treating autoimmune diseases, the crotonate compound of Formula I is used in combination with one or more additional therapeutic autoimmune diseases or other secondary or adjunctive therapeutic agents. In such embodiments, the secondary or adjunctive therapeutic agent used in combination with the croton ester, such as TPA, may have a direct or indirect effect, either alone or in combination with, for example, TPA; or may be otherwise effective in combination with a croton ester, such as TPA. Adjuvant therapeutic activity (eg, immunosuppression, antibody inhibition, anticholinesterase); or use alone or in combination with crotonyl esters, such as TPA, for the treatment and prevention of autoimmune diseases, including myasthenia gravis or related symptoms Effectively aids in therapeutic activity.

In these combination preparations and synergistic treatment methods for preventing or treating autoimmune diseases in mammalian individuals, effective auxiliary or secondary therapeutic agents include, but are not limited to, anti-cholinesterase, corticosteroid, or immunosuppressive agent. .

In exemplary combination and synergistic treatments for the treatment of kidney disease, the crotonate compound of Formula I is used in combination with one or more additional therapeutic kidney diseases or other secondary or adjunctive therapeutic agents. In such embodiments, the secondary or adjunctive therapeutic agent to be combined with, for example, TPA may have a direct or indirect effect, alone or in combination with, for example, TPA; or may have other effective adjunctive therapeutic activities in combination with, for example, TPA ( For example, anticholinergic, antidepressant; or alone or in combination, for example, TPA may have an effective adjuvant therapeutic activity for the treatment and prevention of kidney disease or related symptoms.

In these combination preparations and synergistic treatment methods for preventing or treating kidney diseases in mammalian individuals, effective auxiliary or secondary therapeutic agents include, but are not limited to, anticholinergic drugs, topical estrogen, and imiamine ( Imipramine) or duloxetine.

In an exemplary combination formulation and synergistic treatment for treating urinary incontinence, a crotonate compound of Formula I is used in combination with one or more additional therapeutic urinary incontinence or other secondary or adjunctive therapeutic agents. In such embodiments, the secondary or adjunctive therapeutic agent to be combined with, for example, TPA may have a direct or indirect effect, alone or in combination with, for example, TPA; or may have other effective adjunctive therapeutic activities in combination with, for example, TPA ( For example, anticholinergic, antidepressant; or alone or in combination, for example, TPA may have an effective adjuvant therapeutic activity for the treatment and prevention of kidney disease or related symptoms.

In these combination preparations and synergistic treatment methods for preventing or treating rheumatoid arthritis in mammalian individuals, effective auxiliary or secondary therapeutic agents include, but are not limited to, anticholinergic drugs, topical estrogen, Mamine (imipramine) or duloxetine (duloxetine).

The above and other objects, features, aspects and advantages of the present invention will become more apparent from the Detailed Description.

Novel methods and compositions have been defined for the treatment of chronic or recurrent symptoms, or for repairing the damage left by the onset of the disease or treating a disease involving a mammalian human.

In various embodiments, the methods and compositions are effective for preventing or treating human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), associated symptoms, diseases caused by HIV or AIDS, HIV or AIDS sequelae And/or diseases caused by HIV or AIDS infection. In other embodiments, the methods and compositions are effective for preventing or treating neoplastic diseases and their symptoms. The neoplastic disease may or may not be malignant. In some embodiments the neoplastic disease can be a solid cancer or a non-solid cancer. In other embodiments, the tumor can be recurrent or difficult to treat. In other embodiments, the methods and compositions are effective to prevent or ameliorate the side effects of chemotherapeutic agents. In other embodiments, the methods and compositions described herein are effective to prevent or ameliorate the side effects of radiation therapy. In other embodiments, the methods and compositions described herein are effective for preventing or treating injury caused by a stroke. In other embodiments, the methods and compositions described herein are effective for treating rheumatoid arthritis. In other embodiments, the methods and compositions described herein are effective to reduce signs of aging. In other embodiments, the methods and compositions described herein are effective for treating prostatic hypertrophy. In other embodiments, the methods and compositions described herein are effective for treating autoimmune diseases. In other embodiments, the methods and compositions described herein are effective for treating urinary incontinence. In other embodiments, the methods and compositions described herein are effective in treating Treat kidney disease. In other embodiments, the methods and compositions described herein are effective for treating Parkinson's disease.

The methods and compositions described herein prevent or reduce viral load, reduce human immunodeficiency virus-infected individuals, latent HIV reservoirs, increase immune response, increase Th1 cytokine release, prevent or reduce HIV and AIDS Related symptoms and conditions, reduce and / or reduce tumor cells, increase white blood cell volume, trigger remission, maintain remission, prevent or reduce the symptoms or conditions associated with malignant tumors, increase ERK phosphorylation, reduce or reduce radiation damage, enhance immunity System, reduce nausea, reduce or avoid hair loss, increase appetite, reduce soreness, replenish energy, reduce gastrointestinal discomfort, reduce bruising, reduce mouth ulcers, reduce or reduce skin damage caused by radiation, increase or maintain neutrophils Increase or maintain platelet content, reduce edema, reduce or reduce wet desquamation, avoid or treat delirium, increase spatial awareness, reduce memory loss, reduce aphasia, promote coordination and balance, improve perception, reduce or reduce tremor, reduce or decrease Stiffness, improve sleep quality, increase stability, improve living Motility, improve bladder control, increase control, improve appetite, relieve muscle or joint pain, improve vision, and/or improve muscle control, and strengthen the immune system.

The formulations and methods provided herein are the use of a crotonate or a derivative compound of the formula I, which is described in more detail in U.S. Patent Application Serial No. 12/023,753, filed on Jan. 31, 2008, which is incorporated herein. Priority benefit of U.S. Provisional Patent Application Serial No. 60/8,098, 810, filed on Jan. 31, the entire disclosure of which is incorporated herein by reference. Formula I

Wherein R ₁ and R ₂ may be hydrogen; Wherein the alkyl group contains from 1 to 15 carbon atoms; , , And substituted derivatives thereof and R ₃ may be hydrogen or Containing all active pharmaceutically acceptable compounds of the present disclosure, as well as known and known compounds, salts, solvates, isomers, mirror image isomers, polymorphs, and These compounds are precursor drugs and combinations thereof as novel therapeutic compounds for HIV and AIDS.

The present invention provides a crotonate or a derivative compound of the formula I as described above, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes, Salts, solvates, isomers, mirror image isomers, polymorphs, and precursor compounds of these compounds, and combinations thereof, serve as novel viral reduction agents.

The present invention provides a croton ester or a derivative compound of the above formula I, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes, Salts, solvates, isomers, mirror image isomers, polymorphs, and precursors of these compounds and It is combined as an immunostimulatory compound.

The Th1 cytokine-increasing agent and method for use herein comprises the use of a crotonate or a derivative compound of the above formula I, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, and also includes various known and known complexes. Salts, solvates, isomers, mirror image isomers, polymorphs, and precursor compounds of these compounds, and combinations thereof, are useful as novel Th1 cytokine enhancing agents.

The formulations and methods provided herein additionally employ a croton or a derivative compound of the above formula I, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes, salts, and salts. Classes, solvates, isomers, mirror image isomers, polymorphs, and prodrugs of such compounds and combinations thereof for use in the treatment of neoplastic diseases.

Formulations and Methods for Inducing Apoptosis Thereof Use the crotonate or derivative compound of Formula I above, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes. Salts, solvates, isomers, mirror image isomers, polymorphs, and precursor compounds of these compounds, and combinations thereof, are used as chemotherapeutic agents for inducing apoptosis of tumor cells.

Formulations and Methods for Promoting Relief Thereof The use of a croton or a derivative compound of Formula I as described above, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, also includes various known and known complexes, Salts, solvates, isomers, mirror image isomers, polymorphs, and precursor compounds of these compounds, and combinations thereof, are useful as antitumor agents.

The formulations and methods provided herein further employ a crotonate or derivative compound of formula I as described above, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, Also included are various known and known compounds, salts, solvates, isomers, mirror image isomers, polymorphs, and precursors of such compounds and combinations thereof for use in the treatment of side effects Prevention or treatment.

The formulations and methods provided herein further employ a croton or a derivative compound of the above formula I, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes and salts. , solvates, isomers, mirror image isomers, polymorphs, and prodrugs of such compounds and combinations thereof for the prevention or treatment of side effects of radiation therapy.

Formulations and methods for treating stroke therefor use a croton or a derivative compound of formula I as described above, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes, Salts, solvates, isomers, mirror image isomers, polymorphs, and precursor compounds of these compounds, and combinations thereof, are useful as anti-stroke agents.

Formulations and Methods for Treating Rheumatoid Arthritis Provided Therewith, a croton or a derivative compound of Formula I as described above, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, also includes various known and known Complexes, salts, solvates, isomers, mirror image isomers, polymorphs, and prodrugs of such compounds, and combinations thereof, are useful as agents against rheumatoid arthritis.

Formulations and methods for providing anti-Parkinson's disease thereto The use of a croton or a derivative compound of the above formula I, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, also includes various known and known Complexes, salts, solvates, isomers, mirror image isomers, polymorphs, and precursor compounds of these compounds, and combinations thereof, are useful as anti-Parkinson's agents.

The formulations and methods provided herein also employ a croton or a derivative compound of the above formula I, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes and salts. , solvates, isomers, mirror image isomers, polymorphs, and precursor compounds of these compounds, and combinations thereof, for the treatment of prostatic hypertrophy.

The formulations and methods provided herein additionally employ a croton or a derivative compound of the above formula I, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes, salts, and salts. Classes, solvates, isomers, mirror image isomers, polymorphs, and prodrugs of such compounds and combinations thereof for use in the treatment of autoimmune diseases.

The formulations and methods provided herein further employ a croton or a derivative compound of the above formula I, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes and salts. , solvates, isomers, mirror image isomers, polymorphs, and precursor compounds of these compounds, and combinations thereof, for use in the treatment of carpal tunnel syndrome.

The formulations and methods provided herein additionally employ a croton or a derivative compound of the above formula I, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known complexes, salts, and salts. Classes, solvates, isomers, mirror image isomers, polymorphs, and prodrugs of such compounds and combinations thereof for use in the treatment of kidney diseases.

Formulations and methods for promoting urinary continence herein employ a crotonate or derivative compound of formula I as described above, which comprises all of the active pharmaceutically acceptable compounds of the present disclosure, as well as various known and known Provided with a composite, Salts, solvates, isomers, mirror image isomers, polymorphs, and prodrugs of these compounds, and combinations thereof, are useful as agents for promoting urine control.

A wide range of mammalian individuals, including humans, can be treated using the formulations and methods of the invention. Such individuals include, but are not limited to, individuals suffering from a disease, or individuals having symptoms of a tumor disease and a viral disease such as HIV and AIDS, and also suffering from side effects of Parkinson's disease, stroke, rheumatoid arthritis, and chemotherapy. Individuals with side effects of radiation therapy, prostatic hypertrophy, urinary incontinence, myasthenia gravis and kidney disease.

Individuals who can be treated include HIV-positive humans or other mammalian individuals who exhibit oral pathology, fatigue, skin ulceration, fever, loss of appetite, diarrhea, mouth sores, malabsorption, thrombocytopenia, weight loss, anemia, swollen lymph nodes, and susceptibility ( Susceptibility) and severe secondary conditions, such as mycobacterium avium complex, salmonellosis, syphilis, neurosyphilis, tuberculosis (TB), bacillary angioma Angiomatosis), aspergillosis, candidiasis, coccidioidomycosis, listeriosis, pelvic inflammatory disease, Burkitt's lymphoma , cryptococcal meningitis, histoplasmosis, Kaposi's sarcoma (lymphoma), systemic non-Hodgkin's lymphoma (NHL) Primary central nervous system lymphoma, cryptosporidiosis, isosceles Disease (isosporiasis), microsporidiosis, pneumocystis carinii pneumonia (PCP), toxoplasmosis, cytomegalovirus (CMV), hepatitis, herpes simplex (herpes) Simplex), Herpes zoster, human papiloma virus (HPV, genital warts, cervical cancer), infectious soft palate (molluscum contagiosum), oral hairy leukoplakia (OHL) ), and progressive multiple leukoencephalopathy (PML) and other symptoms.

By the method and composition of the present invention, one or more of the crotonyl ester compounds of Formula I disclosed herein are formulated or administered as effective agents for the treatment of HIV/AIDS and/or related diseases. In an exemplary embodiment, 12-O-tetradecanoylphorbol-13-acetate (TPA) is used for illustrative purposes and is considered to be a pharmaceutical preparation and A therapeutically effective agent for use alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, and more The crystalline form, and the prodrugs disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the treatment of HIV/AIDS and related conditions with the methods and compositions of the present invention.

Acquired immune deficiency syndrome (AIDS) or acquired immunodeficiency syndrome (Aids) is a general term for symptoms and infections caused by damage to the immune system caused by infection with human immunodeficiency virus (HIV). . Damage to the immune system makes individuals susceptible to opportunistic infections and tumors. Although existing treatments for AIDS and HIV delay the progression of the virus and the severity of the symptoms, there are no known cases of recovery.

HIV is a retrovirus that first infects the human immune system. Compositions such as CD4+ T cells, macrophages, and dendritic cells. When CD4+ T cells are destroyed and their total blood content is reduced to 200 CD4+ T cells/μl, or the percentage of CD4+ T cells is less than 14% of total lymphocytes, the immune function of the cells is deleted, resulting in AIDS. .

It has recently been suggested that the balance of T _h 1 and _Th 2 cytokines may contribute to the immune disorder associated with HIV infection. _Th1 cells produce cytokines that stimulate the proliferation of killer T cells. T _h 2 cells produce cytokines for activating human immune responses in healthy humans. HIV infection to progress the development of AIDS-based by IL-2, IL-12 reduced IFN-γ and a concomitant Th ₁ cytokines IL-4, IL-5 and IL-10 increased cytokine Th ₂ is defined. (Clerci, Immunology Today, v. 14, No. 3, p. 107-110, 1993; Becker, Virus Genes 28: 1, 5-18 (2004)). Thus, regulation according to T _h 1>T _h 2 is resistant to HIV infection and/or progression to AIDS.

CD4+ memory T cells have intact HIV transcritpionally inactive proviruses. These latent virus libraries can be activated by specific antigens or cytokines to produce infectious virus. The half-life of these CD4 memory T cells is at least 44 months, making it extremely difficult to eliminate HIV, and it is necessary to extend the continuation of antiviral therapy even when the amount of HIV in the peripheral blood is undetectable.

Prostratin, 12-deoxyphorbol 13-acetate, a non-tumor-promoting crotonyl ester, has been shown to have an effective inhibitory effect on the cytotoxicity of HIV-induced cell death and disease. Prostratin is thought to activate viral expression in latently infected cell lines, but has little or no effect on chronically infected cell lines. (Gulakowski, et al., Antiviral Research v. 33, 87-97 (1997); Williams, et al., JBC v. 279, No. 40, P. 42008-42017 (2004)). Prostratin is a uniquely distinguished protein kinase C activator that has a unique biological activity unlike non-tumor-promoting crotonides such as TPA.

A mammalian subject which can be treated with a crotonyl ester of the formula I according to the method of the invention, in particular TPA, comprises, but is not limited to, a lactating individual suffering from a neoplastic disease, a tumor and comprising a solid or non-solid cancer comprising blood Systemic malignancies/bone marrow diseases, such as leukemia, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic myeloid leukemia blast crisis, spinal cord abnormalities Myelodysplasia, myeloproliferative syndrome; lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma; subcutaneous adenocarcinoma; ovarian teratocarcinoma; and prostate cancer. In some embodiments, the tumor can be recurrent or difficult to treat.

By the methods and compositions of the present invention, one or more of the crotonyl ester compounds of Formula I described herein are effectively formulated or administered as a medicament to effectively treat neoplastic disease. In an exemplary embodiment, TPA is used to illustrate the utility as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, and more The crystalline form, and the prodrugs disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the treatment of neoplastic diseases and symptoms associated with the disease with the methods and compositions of the present invention.

Tumor disease is any abnormal cell that is uncontrollable The resulting cells grow or tumor; they spread through the lymphatic system or bloodstream to other parts of the body. Such growth can be malignant or benign, physical or non-physical.

In some embodiments, the tumor and may be a hematological malignancy/myeloid disease, such as acute myeloid leukemia (AML). AML (also known as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia, and acute nonlymphocytic leukemia) is the most common type of leukemia in adults. In AML, stem cells produced by bone marrow often develop into immature white blood cells called myeloblasts (or myeloid blasts). In individuals with AML, these myeloid mother cells cannot mature into healthy white blood cells. In addition, stem cells of individuals suffering from AML may develop into abnormal red blood cells or platelets. Lack of normal white blood cells increases the chances of infection, anemia, and bleeding. In addition, leukemia cells can be spread outside the blood to other parts of the body, including the central nervous system (brain and spinal cord), skin and gums.

The average age of patients with AML is greater than 64 years. Patients treated with AML over 64 years of age with standard chemotherapy have a survival rate of less than 20%. In addition, patients who develop AML after suffering from a blood disease or who develop AML before chemotherapy/radiotherapy for leukemia have a poor prognosis.

Chemotherapy is a cancer treatment that utilizes anti-tumor drugs or a combination of such drugs. Chemotherapy works by attenuating the regeneration of rapidly dividing cells. However, it is unable to actively distinguish between healthy and rapidly dividing healthy cells and cancerous cells, and has many side effects such as, but not limited to, hair loss, nausea, vomiting, loss of appetite, soreness, neutropenia, anemia, Thrombocytopenia, dizziness, fatigue, constipation, mouth ulcers, itchy skin, peeling, nerve and muscle leprosy, auditory changes Change, white blood cell lesions, weight loss, diarrhea, immunosuppression, indigo, prone to bleeding, heart damage, liver damage, kidney damage, dizziness or brain lesions.

Mammalian individuals which may be treated with crotonyl esters of formula I according to the methods of the invention, particularly TPA, include, but are not limited to, mammalian individuals undergoing chemotherapy.

By the methods and compositions of the present invention, one or more of the crotonyl ester compounds of Formula I described herein are effectively formulated or administered as a medicament to effectively treat side effects due to chemotherapy. In an exemplary embodiment, TPA is used to illustrate the utility as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, and more The crystalline form, and the prodrugs disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the prevention or treatment of side effects of chemotherapy with the methods and compositions of the present invention.

Radiation therapy uses high-energy radiation to shrink tumors and kill cancer cells. It can be applied externally, internally or systemically. It can cause acute or chronic side effects. Acute side effects occur during treatment and chronic side effects occur months or even years after the end of treatment. The side effects develop depending on the area of the body being treated, the daily dose administered, the total dose administered, the general medical condition of the patient, and the concurrently administered treatment. (National Cancer Institute, 2011). Common side effects of radiation therapy are wet peeling, pain, diarrhea, nausea, vomiting, loss of appetite, constipation, itching of the skin, peeling, ulceration of the mouth and throat, edema, infertility, fibrosis, depilation, or mucous membrane dryness.

Crotonyl ester of formula I according to the process of the invention, in particular TPA The mammalian body to be treated includes, but is not limited to, a mammalian individual undergoing radiation therapy.

By the method and composition of the present invention, one or more of the crotonyl ester compounds of the formula I described herein are effectively formulated or administered as an agent to effectively prevent or treat side effects caused by radiation therapy. In an exemplary embodiment, TPA is used to illustrate the utility as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, and more The crystalline form, and the prodrugs disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the prevention or treatment of side effects of radiation therapy with the methods and compositions of the present invention.

Rheumatoid arthritis affects approximately 1% of the population in the United States. However, the reason is unknown, and it is believed recently that it is caused by gene recombination and environmental factors. It is a chronic form of arthritis that typically occurs on joints on both sides of the body and is also considered an immune disease. In rheumatoid arthritis, the immune system is attached to synovium, causing fluid to accumulate in the joints, causing pain and frequent systemic inflammation. Different symptoms in different people usually lead to joint pain and stiffness, especially in the morning or after sedentary, joint swelling, fever, muscle aches, joint inflammation, and rheumatoid nodules.

Mammalian individuals which may be treated with crotonyl esters of formula I according to the methods of the invention, particularly TPA, include, but are not limited to, mammalian individuals suffering from rheumatoid arthritis.

By the method and composition of the present invention, one or more of the crotonyl ester compounds of formula I described herein are effectively formulated or administered as an agent to effectively prevent or treat the symptoms of rheumatoid arthritis. In an exemplary embodiment, TPA is used to illustrate the utility as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer. Polymorphic forms, and prodrugs of the compounds disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the prevention or treatment of rheumatoid arthritis and its symptoms with the methods and compositions of the present invention.

An estimated 4 to 6 million people suffer from Parkin's disease, a chronic and progressive neurodegenerative brain disease. It is currently believed to be triggered by both genes and the environment, but the actual reasons are unknown. Many of the symptoms of Parkinson's disease are caused by a lack of dopamine and low norepinephrine. It is also thought to be caused by the presence of Lewy bodies, although its exact function is still unknown. Parkinson's disease is identified by tremors, bradykinesia, speech disorders, postural instability, and dementia.

Mammalian individuals which may be treated with crotonyl esters of formula I according to the methods of the invention, particularly TPA, include, but are not limited to, mammalian individuals suffering from Parkinson's disease.

By the method and composition of the present invention, one or more of the crotonyl ester compounds of formula I described herein are effectively formulated or administered as an agent to effectively prevent or treat Parkinson's disease. In an exemplary embodiment, TPA is used to illustrate the use as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more Auxiliary therapeutic agents are used in combination. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, and more The crystalline form, and the prodrugs disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the prevention or treatment of Parkinson's disease and its symptoms with the methods and compositions of the present invention.

Stroke is the second leading cause of death worldwide, accounting for 4.4 million (9%) of the total 55,000 deaths per year. (http://www.theuniversityhospital.com/stroke/stats.htm University Hospital, Newark New Jersey, 2011) In the United States, 19% of stroke patients suffer from certain types of injuries and cause disability in adults. A stroke occurs when a blood vessel in the brain is blocked or ruptured. In the absence of oxygen, brain cells begin to die, causing sudden numbness, tingling, weakness, or loss of exercise in the face, arms, or legs. It can also cause sudden visual changes, difficulty speaking, confusion, difficulty walking or balancing, and sudden, severe headaches. After a stroke, the individual may have delirium, space disorders, decreased judgment, left neglect, memory loss, aphasia, coordination and balance problems, nausea, vomiting, cognitive dysfunction, sensory disturbance, disorientation, ipsilateral hemianopia, or impulsivity.

Mammalian individuals which may be treated with crotonyl esters of formula I according to the methods of the invention, particularly TPA, include, but are not limited to, mammalian individuals suffering from a stroke or at risk of stroke.

By the method and composition of the present invention, one or more of the crotonyl ester compounds of formula I described herein are effectively formulated or administered as a medicament to effectively prevent or treat the effects of stroke. In an exemplary embodiment, TPA is used to illustrate the use as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more Auxiliary therapeutic agents are used in combination. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, and more The crystalline form, and the prodrugs disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the prevention or treatment of stroke and its symptoms with the methods and compositions of the present invention.

Prostatic hypertrophy occurs in more than half of men over the age of 60, up to 90% of men aged 70 and 80. As the prostate grows, the tissue layer surrounding it prevents the prostate from expanding, causing the glands to compress the urethra. The bladder wall thickens and is susceptible to irritation, and begins to contract even when it contains a small amount of urine, causing more frequent urination. Finally, it leads to bladder weakness and loss of self-emptying capacity (NIH Publication No. 07-3012, 2006). The most common symptoms of prostatic hypertrophy are intermittent, interrupted, weak urine flow; leakage of urine or urine; and frequent urination, especially at night. Other symptoms include dripping at the end of urination, retention of urine, incomplete bladder emptying, urinary incontinence, frequent urination, painful urination, hematuria, slow or delayed urination, or urination.

Mammalian individuals which may be treated with crotonyl esters of formula I according to the methods of the invention, particularly TPA, include, but are not limited to, mammalian individuals suffering from prostatic hypertrophy or at risk of prostatic hypertrophy.

By the method and composition of the present invention, one or more of the crotonyl ester compounds of formula I described herein are effectively formulated or administered as a medicament to effectively prevent or treat prostatic hypertrophy. In an exemplary embodiment, TPA is used to illustrate the utility as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex and a derivative. , salts, solvates, isomers, mirror image isomers, polymorphs, and compounds disclosed herein, and combinations thereof, and methods and compositions of the invention for preventing or treating prostate Hypertrophy and its symptoms act as an effective therapeutic.

Autoimmune diseases occur when the immune system mistakenly attacks or destroys healthy body tissues. In individuals with autoimmune diseases, the immune system cannot distinguish healthy body tissues from antigens. The result is an immune response that destroys healthy body tissue. In myasthenia gravis, the anti-system directly counteracts the body's own proteins. Most of its own antibodies are generally resistant to the nicotinic acetylcholine receptor (nAChR), which is the neurotransmitter acetylcholine used to stimulate muscle contraction in motor end plates ( Receptor for neurotransmitter acetylcholine) (Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor. Science (1973) 180: 871-2.). Symptoms of myasthenia gravis include drooping eyelids, diplopia, speech disorders, fatigue, muscle weakness, difficulty swallowing, and dysphonia.

Mammalian individuals which may be treated with crotonyl esters of formula I according to the methods of the invention, particularly TPA, include, but are not limited to, mammalian individuals suffering from autoimmune diseases or at risk of autoimmune diseases.

By the method and composition of the present invention, one or more of the crotonyl ester compounds of formula I described herein are effectively formulated or administered as an agent to effectively prevent or treat an autoimmune disease comprising myasthenia gravis. In an exemplary embodiment, TPA is used to illustrate the utility as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound. It comprises a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, a polymorph, and a compound precursor drug disclosed therein, and combinations thereof, and the method and composition of the present invention It is an effective therapeutic agent for preventing or treating autoimmune diseases including myasthenia gravis and its symptoms.

Carpal tunnel syndrome occurs when the median nerve, which extends from the forearm to the palm of the hand, is compressed or squeezed at the wrist. Sometimes thickened inflammatory tendons or other swelling narrows the tunnel, causing the median nerve to be compressed. As a result, the hand or wrist is painful, weak or numb and passed to the hand. Although the painful sensation may be other symptoms, carpal tunnel syndrome is the most common and well-known chronic entrapment neuropathies in which the peripheral nerves of the body are compressed and traumatized (NIH Publication No. 03-4898, 2002).

Mammalian individuals which may be treated with crotonyl esters of formula I according to the methods of the invention, particularly TPA, include, but are not limited to, mammalian individuals suffering from carpal tunnel syndrome or at risk of carpal tunnel syndrome.

By the method and composition of the present invention, one or more of the crotonyl ester compounds of formula I described herein are effectively formulated or administered as a medicament to effectively prevent or treat carpal tunnel syndrome. In an exemplary embodiment, TPA is used to illustrate the utility as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, and more The crystalline form, and the prodrugs disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the prevention or treatment of carpal tunnel syndrome with the methods and compositions of the present invention.

Chronic kidney disease is the ability of the kidney to be damaged and to reduce the regulation of water and electrolytes, the discharge of metabolites and the secretion of essential hormones. Symptoms of kidney disease include urinary incontinence, increased urine output, uremia, or oliguria.

Mammalian individuals which may be treated with crotonyl esters of formula I according to the methods of the invention, particularly TPA, include, but are not limited to, mammalian individuals suffering from or at risk of kidney disease.

By the method and composition of the present invention, one or more of the crotonyl ester compounds of formula I described herein are effectively formulated or administered as an agent to effectively prevent or treat kidney disease. In an exemplary embodiment, TPA is used to illustrate the utility as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, and more The crystalline form, and the prodrugs disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the prevention or treatment of kidney disease and its symptoms with the methods and compositions of the present invention.

Urinary incontinence is a common and embarrassing problem. Its severity ranges from occasional leakage of urine during coughing or sneezing to complete loss of control. Urinary incontinence can be caused by a variety of conditions, including infection, pregnancy, aging, bladder stones, prostate cancer, bladder cancer, obstruction, prostatitis, hysterectomy and medication. It can be temporary or permanent.

Mammalian individuals which may be treated with crotonyl esters of formula I according to the methods of the invention, particularly TPA, include, but are not limited to, mammalian individuals suffering from urinary incontinence or at risk of urinary incontinence.

By the method and composition of the invention, one or more of the formulas described herein The crotonyl compound of I is effectively formulated or administered as an agent to effectively prevent or treat urinary incontinence. In an exemplary embodiment, TPA is used to illustrate the utility as an agent effective in pharmaceutical formulations and methods of treatment, either alone or in combination with one or more adjunctive therapeutic agents. The present disclosure further provides a pharmaceutically acceptable crotonate compound which is a natural or synthetic compound comprising a complex, a derivative, a salt, a solvate, an isomer, a mirror image isomer, and more The crystalline form, and the prodrugs disclosed herein, and combinations thereof, are useful as an effective therapeutic agent in the prevention or treatment of urinary incontinence and its symptoms with the methods and compositions of the present invention.

Crotonol is a plant-derived organic compound of the natural, biguanide crotonoid family. It is the first hydrolyzed product isolated from croton oil extracted from the seeds of Croton tiglium in 1934. It is soluble in most polar organic solvents and water. Crotonyl ester has the general structure of formula I below:

Wherein R ₁ and R ₂ may be optionally hydrogen; Wherein the alkyl group contains from 1 to 15 carbon atoms; , , And a group of substituted derivatives thereof, and R ₃ may be hydrogen or And its substituted derivatives.

The term "lower alkyl" or "lower alkenyl" as used herein means a moiety containing from 1 to 7 carbon atoms. In the compounds of formula I, the alkyl or alkenyl group may be straight or branched. In certain embodiments, one or both of R ₁ and R ₂ are long chain carbon moieties (ie, Formula I is decanoat or myristate).

The alkyl, alkenyl, phenyl and benzyl groups of the formula herein may be unsubstituted or substituted with a halogen such as chlorine, fluorine or bromine; nitrogen; an amine group and a similar free radical.

Organic and synthetic forms of croton, containing any extract or extract from herbal sources such as Croton tiglium , which are considered to contain crotonides (or croton ester analogs, related compounds and/or derivatives) The composition is effective for the embodiments described herein. The croton esters and/or related compounds which are effective in the examples described herein generally have the structure depicted in Formula I, and functional equivalent analogs, complexes, conjugates and derivatives of the compounds will also be utilized by the present invention. It is obvious to those who have a general knowledge of the field to which they belong.

In a more detailed embodiment, an illustrative structural modification according to Formula I above will be selected to provide an effective candidate compound for the treatment and/or prevention of HIV and AIDS and/or neoplastic disease, wherein: at least one of R ₁ and R ₂ is Hydrogen and R ₃ is selected from hydrogen, And a group of substituted derivatives thereof. In other embodiments, one of R ₁ and R ₂ is , another R ₁ and R ₂ are And R ₃ is hydrogen.

An exemplary embodiment of a crotonate compound of formula I effective for treating cytopathic diseases, such as HIV and AIDS and/or neoplastic diseases, particularly AML, is crotyl alcohol-12-myristate-13-acetate ( Phorbol 12-myristate-13-acetate) (also known as PMA or 12-O-tetradecanoylphorbol-13-acetate (TPA)), such as the following formula II shows.

Other effective crotonides and related compounds and derivatives of the methods and formulations of the present invention include, but are not limited to, other pharmaceutically acceptable salts, active isomers, mirror image isomers, polymorphs of the compounds ( Polymorphs), glycosylated derivatives, solvates, hydrates, and/or prodrugs of the compounds. Another exemplary form of the crotonate of the method and composition of the present invention includes, but is not limited to, phorbol 13-butyrate, phorbol 12-decanoate , phorbol 13-decanoate, phorbol 12,13-diacetate, crotonol-13,20-diacetate (phorbol 13 ,20-diacetate), crotonol-12,13-dibenzoate (phorbol) 12,13-dibenzoate), crotonol-12,13-dibutyrate, phorbol 12,13-didecanoate, crotyl alcohol Phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, crotonol-12-myristate (phorbol 12- Myristate), phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxycrotonol-13 - 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxycrotonol-13- 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxycrotonol- 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxycrotonol -13-tetradecanoate, crotonol-12-cis acid -13- phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate And phorbol 13-acetate.

The crotonate comprises HIV and AIDS therapeutic agents comprising an anti-AIDS effective amount of a crotonate compound of formula I effective to prevent and/or treat HIV, AIDS, and/or HIV related symptoms of a mammalian subject, including opportunities Sexual infection. The effective dose of the active compound for "anti-HIV", "anti-AIDS" or "treatment of AIDS" is in the form of a single or multiple unit dose, which can be used to measure the relief of AIDS symptoms and/or infection in an individual during the specific period of intervention. An effective treatment for the relief of one or more symptoms or conditions associated with an individual with HIV. In an exemplary embodiment, the composition of the invention is A treatment that is effective in relieving AIDS symptoms or other HIV-related symptoms in HIV-infected humans or other mammalian individuals.

The crotonate composition herein may additionally comprise a chemotherapeutic composition comprising an antitumor effective amount of a crotonyl ester or derivative of formula I effective for repairing or treating a malignant tumor of a mammalian individual or a symptom due to cancer . "Chemotherapeutic", "anti-tumor", "cancer treatment", "apoptosis inducing", "remission inducing", and "remission inducing" of active compounds The effective dose of "remission maintaining" is in the form of a single or multiple unit dose, which can measure the relief of one or more malignant tumor symptoms and/or the individual with malignant tumor during a specific period of intervention therapy. Effective treatment for the relief of one or more symptoms or conditions. In an exemplary embodiment, the compositions of the present invention are effective in ameliorating a symptom associated with a neoplastic disease in a human or other mammalian subject having a malignancy.

The compositions described herein comprise a chemically protective composition comprising an effective amount of a crotonate compound of formula I for preventing or ameliorating the side effects of chemotherapy. "Chemoprotective", "anti-inflammatory", "neutrophil stimulating", "erythropoiesis stimulating", "inhibition of bone erosion" The effective dose of "resorbtion inhibiting", "bone strengthening", "antiemetic", "pain relieving" is in the form of single or multiple unit doses, during the specific period of intervention. An effective treatment for the relief of one or more of the side effects of chemotherapy in an individual. In an exemplary embodiment, the compositions of the present invention are effective in ameliorating a therapeutic method having side effects of chemotherapy in a human or other mammalian subject undergoing chemotherapy.

The compositions described herein comprise a radiotherapeutic protective composition comprising an effective amount of a crotonate compound of formula I for preventing or ameliorating the side effects of radiation therapy. "radiation protection", "anti-swelling", "cytoprotective", "anti-mucositis", "epithelial stimulating" of active compounds The effective amount of "anti-fibrotic" or "platelet stimulating" is in the form of a single or multiple unit dose, and one or more radiotherapy treatments can be measured during a specific period of intervention. Effective treatment for the relief of side effects. In an exemplary embodiment, the compositions of the present invention are effective in ameliorating treatments for side effects of radiation therapy in human or other mammalian individuals undergoing radiation therapy.

The compositions described herein comprise a composition for treating stroke comprising an effective amount of a crotonate compound of formula I for use in preventing and/or preventing stroke injury, which is effective for preventing and/or treating a stroke or stroke associated with a mammalian individual. Symptoms or sequelae. "Stroke treatment", "anti-clotting", "anticholesterolemic", "vasodilating", "antihypertensive", "neural" A neuroprotective effective amount is an effective treatment for the relief of one or more stroke symptoms or sequelae of an individual during a particular period of intervention therapy in the form of a single or multiple unit dose. In an exemplary embodiment, the compositions of the present invention are effective in the treatment of stroke symptoms or sequelae in humans or other mammalian individuals who have a stroke.

The composition described herein further comprises a composition for treating Parkinson's disease, comprising an effective amount of a crotonyl ester compound of the formula I, which is effective for preventing and/or treating a Parkinson's disease or a Pajin good governance related to a mammalian individual. Symptoms. "Parkinson's disease treatment" and "addition of dopamine" to active compounds "increased", "inhibition of catechol-O-methyl transferase inhibiting, "aromatic L-amino acid decarboxylase", "dopamine" Effective dose of "dopamine agonist", "neuroprotective" or "anticholinergic" in single or multiple unit doses, one or more of the individual may be measured during the specific period of intervention Effective treatment for symptom relief in Parkinson's disease. In an exemplary embodiment, the compositions of the present invention are effective for preventing or alleviating the symptoms of a human or other mammalian individual suffering from Parkinson's disease or at risk of Parkinson's disease.

The compositions described herein further comprise a composition for treating prostatic hypertrophy comprising an effective amount of a crotonate compound of formula I effective for preventing and/or treating symptoms or sequelae associated with prostatic hypertrophy in a mammalian subject. The effective amount of the active compound "prostate hypertrophy treatment", "type II 5-alpha reductase inhibitor", or "muscle relaxant" is a single Or multiple unit dosage forms that measure the effective treatment of prostatic hypertrophy or sequelae relief in one or more individuals during a particular period of intervention therapy. In an exemplary embodiment, the compositions of the invention are effective in preventing or ameliorating Symptoms or sequelae of human or other mammalian individuals with enlarged prostate or risk of prostatic hypertrophy.

The composition described herein further comprises a composition for treating rheumatoid arthritis, comprising an effective amount of a crotonate compound of formula I against rheumatoid arthritis, which is effective for preventing and/or treating a mammalian individual or the like. Rheumatoid arthritis or related symptoms. "Anti-rheumatoid", "anti-inflammatory", "TNF inhibiting", "antibiotic", calcineurin inhibitor, active compound Pyrimidine synthesis inhibitor (pyrimidine synthesis inhibitor), 5-LO inhibitor (5-LO inhibitor), anti-folate (antifolate), IL-1 receptor antagonist (IL-1 receptor antagonist) or T cell costimulation inhibitor An effective amount is an effective treatment for the symptoms of rheumatoid arthritis in one or more individuals during a particular period of intervention therapy in the form of a single or multiple unit dose. In an exemplary embodiment, the compositions of the present invention are effective for preventing or ameliorating the symptoms of a human or other mammalian subject suffering from rheumatoid arthritis or having a risk of rheumatoid arthritis.

The composition described herein further comprises a composition for treating an autoimmune disease comprising an effective amount of a crotonate compound of formula I for treating an autoimmune disease, which is effective for preventing and/or treating a mammalian individual such as myasthenia gravis Inability to autoimmune disease or related symptoms or sequelae. "Autoimmune disorder treatment", "myasthemia gravis treating", "immunosuppressive", "antibody suppressing", or "anticholinergic" of the active compound The effective dose of anticholinesterase is in the form of a single or multiple unit dose, and the effective symptoms of autoimmune disease symptoms or sequelae, particularly myasthenia gravis, can be measured during the specific period of intervention. In an exemplary embodiment, the compositions of the present invention are effective in preventing or ameliorating the symptoms of a human or other mammalian subject suffering from myasthenia gravis or having a risk of myasthenia gravis.

The compositions described herein further comprise a composition for treating kidney disease comprising an effective amount of a crotonyl ester compound of formula I effective for preventing and/or treating a kidney disease or related symptoms or sequelae of a mammalian subject. The "antichollinesterase" or "antidepressant" effective amount of the active compound is in the form of a single or multiple unit dose, which can be measured in one or more periods during the specific period of intervention. A kidney disease symptom or sequelae of an individual, including an incontinent individual. In an exemplary embodiment, the compositions of the present invention are effective for preventing or alleviating the symptoms of a human or other mammalian subject suffering from or at risk of kidney disease.

The compositions described herein further comprise a composition for treating urinary incontinence comprising an effective amount of a crotonyl ester compound of formula I effective for preventing and/or treating urinary incontinence in a mammalian subject. The "continuous increase", "anticholinesterase", "antibiotic" or "antidepressant" effective amount of the active compound is in the form of a single or multiple unit dose. The symptoms of urinary incontinence in one or more individuals can be measured during a specific period of intervention therapy. In an exemplary embodiment, the compositions of the present invention are effective for preventing or alleviating the symptoms of a human or other mammalian subject suffering from urinary incontinence or at risk of urinary incontinence.

Crotonyl ester treatment, including chemotherapy, chemical protection, radiation protection, palliative stroke, Parkinson's disease treatment, prostatic hypertrophy treatment, rheumatoid arthritis treatment, anti-aging, kidney disease treatment, incontinence control, autoimmune disease treatment, And HIV treatment, the compositions of the present invention generally comprise an effective or unit dose of a crotonyl ester compound of Formula I, which may be associated with enhanced stability, release rate, absorption rate, half-life, pharmacokinetics, and/or pharmacodynamics. To reduce adverse side effects; or to provide one or more medically acceptable carriers, excipients, carriers, stabilizers, preservatives, buffers, and/or other additive co-formulations. An effective amount of a crotonate compound or derivative of formula I (eg, comprising an effective concentration/dosage of TPA or a selected TPA in a pharmaceutically acceptable salt, isomer, mirror image isomer, solvate, The unit dosage of the crystalline form and/or prodrug is readily identifiable by those of ordinary skill in the art based on clinical and patient specific factors. The active compound for administration to a mammalian subject comprising a human can be from about 10 to about 1500 μg, from about 20 to about 1000 μg, from about 25 to about 750 μg, from about 50 to about 500 μg, from about 150 to about 500 μg. From about 125 to about 500 μg, from about 180 to about 500 μg, from about 190 to about 500 μg, from about 220 to about 500 μg, from about 240 to about 500 μg, from about 260 to about 500 μg, from about 290 to about 500 μg. In certain embodiments, a therapeutically effective dose of a crotonyl ester compound of Formula I or a derivative or related compound can be selected from a narrower range, such as 10 to 25 μg, 30 to 50 μg, 75 to 100 μg, 100 to 300 μg, or 1500 to 500 μg. These or other effective doses may be administered in a single dose, or may be administered in daily, weekly, or monthly multiple doses, for example, daily, weekly, or monthly from 1 to 5 or 2 to 3 The dose is administered in a dosage regimen. In an exemplary embodiment, doses of 10 to 30 μg, 30 to 50 μg, 50 to 100 μg, 100 to 300 μg, or 300 to 500 μg are administered in 1, 2, 3, 4, or 5 times per day. In a more detailed embodiment, doses of 50 to 100 μg, 100 to 300 μg, 300 to 400 μg, or 400 to 600 μg are administered in a dose of 1 or 2 times per day. In another embodiment, doses of 50 to 100 μg, 100 to 300 μg, 300 to 400 μg, or 400 to 600 μg are administered every other day. In alternative embodiments, the dosage is calculated based on body weight and may, for example, range from about 0.5 μg/m ² to about 300 μg/m ² per day, from about 1 μg/m ² per day to about 200 μg/m ² per day, about 1 μg/ m ² to about 187.5 μg/m ² per day, about 1 μg/m ² per day to about 175 μg/m ² per day, about 1 μg/m ² per day to about 157 μg/m ² per day, about 1 μg/m ² per day to about 125 μg/ m ² per day, about [mu] g / m ² and about 75μg per day / m ² per day, about [mu] g / m ² per day to about 50 ug / m ² per day, about [mu] g / m ² per day to about 50 ug / m ² per day, about 2μg / m ² is administered daily to a dose of about 30 μg/m ² per day, or about 3 μg/m ² per day to about 30 μg/m ² per day.

In other embodiments, the dosage can be administered at a lesser frequency, such as from about 0.5 μg/m ² to about 300 μg/m ² every other day, from about 1 μg/m ² to about 200 μg/m ² every other day, about 1 μg/ m ² to about 187.5 μg/m ² every other day, about 1 μg/m ² to about 175 μg/m ² every other day, about 1 μg/m ² to about 157 μg/m ² every other day, about 1 μg/m ² to about 125 μg/m ² every other day, about 1 μg/m ² to about 75 μg/m ² every other day, about 1 μg/m ² to about 50 μg/m ² every other day, about 2 μg/m ² to about 50 μg/m ² per Every other day, from about 2 μg/m ² to about 30 μg/m ² every other day, or from about 3 μg/m ² to about 30 μg/m ² every other day. In other embodiments, the dose may be 3 times/week, 4 times/week, 5 times/week, only Monday to Friday, only with other treatment regimens, administered for two consecutive days, or according to clinical Or the specific factors of the patient are administered in the manner of administering the appropriate dose.

A therapeutically effective amount of a crotonate compound of formula I comprising a cytopathic disease (treatment of AIDS, prevention of HIV, treatment of HIV, activation of HIV virus pool, increase of Th1 cytokines, induction of ERK phosphorylation, chemotherapy, anti-tumor, treatment of cancer, The amount of administration, the administration time, and the mode of administration of the composition of the present invention which induces amelioration, maintenance, and induction of apoptosis are periodically adjusted on an individual basis, depending, for example, on the weight, age, and The course of gender, as well as the condition, cytopathic disease, and/or associated symptoms, whether prophylactic or therapeutic, and affects drug delivery, absorption, pharmacokinetics, such as half-life, and efficacy, according to other conventions.

The preparation of the present invention is used for immediate disease treatment (or, AIDS treatment, HIV treatment, HIV prevention, HIV virus library activation, or increase of Th1 cytokines, induction of ERK phosphorylation, chemotherapy, anti-tumor, cancer treatment, induced cells) Apoptosis, triggering remission, maintenance remission, chemical protection, anti-inflammatory, stimulating neutrophils, stimulating erythropoiesis, inhibiting bone erosion, strengthening bones, antiemetic, analgesic, radiation protection, anti-swelling, cytoprotective, anti- Mucositis, epithelial irritability, anti-fibrosis, stimulation of platelets, stroke therapy, anticoagulation, hypolipidemicemia, vasodilation, lowering blood pressure, treatment of Parkinson's disease, increase of dopamine, inhibition of catechol-O-methyltransferase Suppressing fragrance Family L-amino acid decarboxylase, dopamine antagonism, neuroprotection, anticholinergic, prostatic hypertrophy treatment, type II 5-alpha reductase inhibitor, muscle relaxant, anti-rheumatic, anti-inflammatory, immunosuppressive, TNF inhibition , anti-inflammatory, calcineurin inhibitor, pyrimidine synthesis inhibitor, 5-LO inhibitor, anti-folate, IL-1 receptor antagonist, T cell co-stimulating inhibitor, autoimmune disease treatment, myasthenia gravis treatment, An effective amount or multiple dose treatment of immunosuppression, antibody inhibition, anti-cholinesterase, renal disease treatment, incontinence control, anti-depression, will generally be selected from a minimally minimal dosing regimen that is necessary and sufficient to substantially prevent or Relieving an individual's AIDS- or neoplastic disease such as cancer and related opportunistic diseases, stroke, autoimmune disease, kidney disease, urinary incontinence, Parkinson's disease, carpal tunnel syndrome or prostatic hypertrophy, and/or substantial prevention or Alleviate AIDS in individuals, such as cancer diseases of cancer, stroke, autoimmune diseases, aging, urinary incontinence, kidney disease, Parkinson's disease, carpal tunnel syndrome, prostatic fertilizer , Chemotherapy, radiation therapy, or one or more symptoms. Dosage and dosing schedules will typically include repeated dosing treatments over several days or even one or more weeks or years. An effective treatment regimen can also be included in a one-day prophylactic dose administration or multiple doses per day depending on the previous day, week, month or even year.

Various detection and pattern systems can be easily used to determine the therapeutic effect of treatment for cytopathic diseases. For example, the therapeutic effect of HIV or AIDS can be caused by a decrease in the amount of virus, an increase in the amount of CD4 cells, an increase in the amount of CD3 cells, an increase in the production of IL-2 and IFN, a decrease in the production of IL-4 and IL-10, and It is confirmed by the reduction or slowing of the symptoms of AIDS, which is a method known to those skilled in the art to confirm the therapeutic effect.

The therapeutic effect of the method and composition of the present invention can be determined, for example, by detecting the amount of HIV antibody, virus, CD4, CD8, and CD3 in the blood. Broken. The standard value for CD4 is typically between 600 and 1200/μl, or 32 to 68% of lymphocytes. Individuals with a CD4 content below 350 have a weakened immune system. Individuals with a CD4 content of less than 200 are considered to have AIDS. The CD8 content of healthy individuals is generally between 150 and 1000/μl. The CD3 content of healthy individuals is generally between 885 and 2270/μl. CD3, CD4, and CD8 cells can be used, for example, by flow cytometry. An effective amount of a composition of the invention will increase the amount of CD3, CD4, and CD8 cells by at least about 10%, 20%, 30%, 50%, or an increase in replication rate of about 75 to 90% or 95% or more. An effective amount also directs the individual's CD3, CD4, and CD8 cells toward the best species of each glycoprotein.

Individuals can also be assessed using the beta ₂ -microglobulin (beta ₂ -M) assay. Beta ₂ -microglobulin is a protein that is released into the blood when the cell dies. The rising beta ₂ -M value in the blood can be used to measure the course of AIDS. An effective amount of the composition of the present invention will increase the amount of beta ₂ -M decreased or stopped.

The treatment effect can be more complete blood count (CBC). The blood measurement method includes a white blood cell count (WBC), a red blood cell count (RBC), a red cell distribution width, a hematocrit, and a hematocrit. The amount of hemoglobin. AIDS-specific related signs in routine blood testing include a low hematocrit ratio, a sharp decrease in the number of platelets, and a low neutrophil value. An effective dose of the composition of the present invention will increase 10%, 20%, 30%, 50%, or substantially increase to about 75 to 90% or 95% or more of the measured value in the routine blood test. An effective amount also directs the individual's blood protein to the best species of each prion protein.

The therapeutic effects of the methods and compositions of the invention may also be by HIV or Symptoms of AIDS, including, but not limited to, lesions, burnout, itchy skin, fever, loss of appetite, diarrhea, mouth ulcers, malabsorption, thrombocytopenia, weight loss, anemia, and lymphadenopathy, are measured.

The therapeutic effects of the compositions and methods of the present invention can also be manifested by a reduction in susceptibility and severity of secondary and opportunistic conditions, such as mycobacterium avium complex, salmonellosis, syphilis , neurosyhyphilis, tuberculosis (TB), bacillary angiomatosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, pelvic inflammatory disease ( Pelvic inflammatory disease), Burkitt's lymphoma, cryptococcal meningitis, histoplasmosis, Kaposi's sarcoma, lymphoma, systemic non-Hodgkin Systemic non-Hodgkin's lymphoma (NHL), primary central nervous system lymphoma, cryptosporidiosis, isospores, microsporosis, pneumocystis carinii pneumonia (PCP) , toxoplasmosis, cytomegalovirus (CMV), hepatitis, herpes simplex, herpes zoster, human papillomavirus (HPV, sharp wet Gen (genital warts), cervical cancer, infectious soft palate, oral hairy leukoplakia (OHL), and progressive multifocal leukoencephalopathy (PML).

The effectiveness can be further confirmed by a decrease in the amount of HIV detectable in an HIV-infected individual, maintenance of a normal T cell amount, or maintenance of a normal p24 antigen value.

The effectiveness of treating a neoplastic disease can also be confirmed by a number of methods, such as, but not limited to, ECOG Performance Assessment (ECOG Performance Scale), Karnofsky Daily Karenofsky Performance Scale, microscopic examination of white blood cells, aspiration and biopsy, cytogenetic analysis, sectioning, immunophenotyping, blood chemistry Blood chemistry studies, routine blood tests, lymph node sections, peripheral blood smear, visual interpretation of tumors or lesions, or assessments of common knowledge in the field of surgery and/or diagnosis of malignant tumors and tumors Any other method of the course of the disease.

For example, the therapeutic effects of the methods and compositions of the invention for treating hematological malignancies/bone marrow disorders can be assessed using an absolute neutrophil count (ANC). The normal absolute neutrophil count is between 1500 and 8000/mm ³ . Individuals suffering from a malignant blood disease/bone marrow disease typically have an absolute neutrophil count of less than 1500/mm ³ and may even be less than 500/mm ³ . The effective amount of the method and composition herein will increase the individual's absolute neutrophil count by 10%, 20%, 30%, 50%, or substantially increased to about 75 to 90% or 95% or more. An effective dose can increase the absolute neutrophil value by more than 1500/mm ³ .

The therapeutic effects of the methods and compositions of the present invention for treating hematological malignancies/bone marrow diseases can be further evaluated, for example, by the number of platelets. The platelet count is usually between 150,000 and 450,000/μl (x10~6/liter). Individuals suffering from a malignant blood disease/bone marrow disease typically have platelet values below 100,000/μl. The effective amount of the method and composition herein will increase the number of platelets in the individual by 10%, 20%, 30%, 50%, or substantially increased to about 75 to 90% or 95% or more. An effective dose increases the platelet value by more than 100,000/μl.

Method of the invention for treating malignant blood diseases/bone marrow diseases The effectiveness of the composition can be further evaluated, for example, by measuring the number of myeloid mother cells. Bone marrow mother cells usually account for 5% of the cells in the bone marrow, but should not be present in circulating blood. The effective amount of the methods and compositions herein will reduce the number of myeloid mother cells by 10%, 20%, 30%, 50%, or substantially reduce to about 75 to 90% or 95% or more. An effective dose reduces the number of myeloid mother cells to less than 5%.

The therapeutic effects of the methods and compositions of the present invention for treating hematological malignancies/bone marrow diseases can be further evaluated by detecting the presence of Auer rods in bone marrow mother cells. An effective amount of the composition of the present invention will reduce the number of visible Auer's bodies by 10%, 20%, 30%, 50%, or substantially reduce to about 75 to 90% or 95% or more to Auer's body. Completely eliminated.

The effectiveness of the methods and compositions of the present invention can also be achieved by reducing the symptoms of an individual suffering from a neoplastic disease, such as, but not limited to, anemia; chronic burnout; excessive or prone to bleeding, such as nasal, gum, subcutaneous bleeding; Injury, especially indigo without obvious cause; shortness of breath; freckle; repeated fever; swollen gums; slow wound healing; bone and joint discomfort; frequent infection; weight loss; itching; night sweats; swollen lymph nodes; Abdominal pain and discomfort; visual impairment; cough; loss of appetite; chest pain; difficulty swallowing; swelling of the face, neck and upper limbs; frequent urination, especially at night; difficulty in urinating or punishing; weak or easily interrupted urine; Pain or burning; erectile dysfunction; ejaculation pain; blood urine or blood; common pain or stiffness in the lower back, buttocks and thighs;

The effectiveness of the methods and compositions of the present invention can also be achieved by reducing the symptoms of chemical treatment such as, but not limited to, hair loss, nausea, vomiting, loss of appetite, soreness, neutropenia, anemia, thrombocytopenia. , dizziness, fatigue, constipation, Oral ulcers, itchy skin, peeling, nerve and muscle leprosy, hearing changes, blood problems, weight loss, diarrhea, immunosuppression, indocyanine, tendency to easily bleed, heart damage, liver damage, kidney damage, dizziness and brain lesions Confirmed.

The effectiveness of the methods and compositions of the present invention may also be accompanied by symptoms of radiation therapy, such as, but not limited to, wet peeling, soreness, diarrhea, nausea, vomiting, as compared to individuals receiving the same radiation therapy. Deficiency of appetite, constipation, itchy skin, peeling, mouth and throat ulcers, edema, infertility, fibrosis, hair loss, or mucosal dryness.

The effectiveness of treating rheumatoid arthritis can be demonstrated, for example, by using various animal models, including collagen-induced arthritis, as described in Example 30 below, pristane induced arthritis (pristane induced) Arthritis), adjuvant induced arthritis, streptococcal cell wall induced arthritis, ovalbumin induced arthritis, ovalbumin induced arthritis, or Airbag model.

The effectiveness of the methods and compositions of the present invention in treating rheumatoid arthritis can also be achieved by reducing the symptoms of rheumatoid arthritis, including, but not limited to, joint pain, stiffness, especially in the morning or after sedentary , joint swelling, fever, muscle aches, joint inflammation, rheumatoid nodules (rheumatoid nodules) confirmed.

The effectiveness of the methods and compositions of the present invention in the treatment of rheumatoid arthritis can also be confirmed by the erythrocyte sedimentation rate. Individuals with rheumatoid arthritis typically have elevated red blood cell sedimentation rates. An effective amount of the composition of the present invention will reduce the erythrocyte sedimentation rate by 10%, 20%, 30%, 50%, or reduced to about 75 to 90% or 95% or substantially reduced to the initial diagnostic level of erythrocyte sedimentation rate. The therapeutic effect can also be confirmed by a change in the values of rheumatoid factor and anti-cyclic citrullinated antibodies.

The effectiveness of the methods and compositions of the present invention in treating Parkinson's disease may be due to symptoms of Parkinson's disease, including, but not limited to, tremor, bradykinesia, stiffness, speech disorders, cognitive dysfunction, and dementia. Confirmed. The therapeutic effect of the crotonyl ester compound of the present invention in the treatment of Parkinson's disease can be confirmed by an increase in dopamine and/or norepinephrine. These values can be increased by 10%, 20%, 30%, 50%, or substantially increased to about 75 to 90% or 95% or increased to normal values.

The effectiveness of the methods and compositions of the present invention in treating Parkinson's disease can be confirmed by a reduction in the presence of Lewy bodies. Therapeutic effects can also be achieved by using animal models such as MPTP-induced Parkinson's disease model, retenone induced Parkinson's, surgically induced Parkinson's, and Bara's induction The mice were confirmed by paraquat induced Parkinson's, 6-OHDA-induced Parkinson's disease pattern, or α-synuclein overexpressing mice. The methods and compositions of the present invention will reduce the symptoms of Parkinson's disease in mice exhibiting these patterns by about 0%, 20%, 30%, 50% or more, up to about 75 to 90%, 96% or more. The animals were more reduced than the control group.

The therapeutic effects of the methods and compositions of the present invention in the treatment of stroke can be achieved by using a variety of animal models including a temporary middle cerebral artery occlusion as shown in Example 22, as shown in Example 21 for permanent Middle cerebral artery embolization pattern (permanent middle cerebral artery) Occlusion, endovascular filament middle cerebral artery occlusion, embolic middle cerebral artery occlusion, endothelin-1 induced arteries and veins as shown in Example 20. Endothelin-1-induced constriction of arteries and veins, or cerebrocortical photothrombosis. The use of the croton esters of the invention will reduce the symptoms produced by these modes by about 0%, 20%, 30%, 50% or more, by up to about 75 to 90%, 96% or as compared to the control group of animals. Reduce more.

The therapeutic effect of the method and composition of the present invention in the treatment of stroke can be confirmed by a decrease in symptoms exhibited by an individual suffering from a stroke. These symptoms include, but are not limited to, paralysis, space disorders, decreased judgment, left neglect, memory loss, aphasia, coordination and balance problems, nausea, vomiting, cognitive dysfunction, sensory disturbances, disorientation, ipsilateral hemianopia, and impulse. The use of the crotonate composition of the present invention will reduce the symptoms exhibited by the individual by about 0%, 20%, 30%, 50% or more, to about 75 to 90%, 96% or as compared to The initial state is reduced more.

The effectiveness of the method and composition of the present invention in treating prostate hypertrophy may be related to symptoms associated with prostatic hypertrophy, including, but not limited to, sputum, interference, weak urine flow; urination drip; frequent urination; drip at the end of urination; urine Fluid retention; incomplete bladder emptying; urinary incontinence; painful urination; hematuria; slow or delayed urination; or sudden reduction in urgency. The use of the crotonate composition of the present invention will reduce the symptoms exhibited by the individual by about 0%, 20%, 30%, 50% or more, to about 75 to 90% or 96%, or The initial state is reduced more.

The effectiveness of the method and composition of the present invention in treating prostatic hypertrophy It may additionally be confirmed by various tests such as post-void residual urine, pressure flow studies, or cystometry. The use of the crotonate composition of the present invention will reduce residual urine volume or increase the pressure urine flow rate by about 0%, 20%, 30%, 50% or more, to about 75 to 90% or 96% or more than Croton The results before the ester compound treatment.

The effectiveness of the methods and compositions of the present invention in treating myasthenia gravis can be manifested by symptoms associated with myasthenia gravis, including, but not limited to, drooping eyelids, diplopia, speech disorders, fatigue, muscle weakness, difficulty swallowing, Or confirmed by a decrease in dysphonia. The use of the crotonate composition of the present invention will reduce the symptoms exhibited by the individual by about 0%, 20%, 30%, 50% or more, to about 75 to 90%, 96%, or as compared to The initial state is reduced more.

The effectiveness of the methods and compositions of the present invention in treating myasthenia gravis can also be achieved by using the Tensilon test or the ice test, the nerve conduction studies, the single fiber EMG, or the serum. Confirmation of the detection of the amount of choline receptor antigen. The therapeutic effect may additionally be achieved by using an animal with a myasthenia gravis pattern, for example, an animal co-inoculated with torso californica acetylcholine receptors (AChR) and Freund's adjuvant. The use of the crotonate composition of the present invention will reduce the symptoms exhibited by the individual by about 0%, 20%, 30%, 50% or more, to about 75 to 90%, 96%, or as compared to The initial state and/or control group is reduced more.

The effectiveness of the methods and compositions of the present invention in treating carpal tunnel syndrome can be confirmed by the symptoms associated with carpal tunnel syndrome, including, but not limited to, pain, weakness, or hand and wrist paralysis, transmitted to the entire arm, etc. . Crotonyl ester of the invention The use of the composition will reduce the symptoms exhibited by the individual by about 0%, 20%, 30%, 50% or more, to about 75 to 90%, 96%, or to decrease more than the initial state. .

The effectiveness of the methods and compositions of the present invention in treating kidney disease can be demonstrated by kidney disease related symptoms including, but not limited to, urinary incontinence, increased urine output, uremia, or reduced oliguria. The use of the crotonate composition of the present invention will reduce the symptoms exhibited by the individual by about 0%, 20%, 30%, 50% or more, to about 75 to 90%, 96%, or as compared to The initial state is reduced more.

The effectiveness of the methods and compositions of the present invention in treating urinary incontinence can be demonstrated by a reduction in symptoms associated with urinary incontinence. The use of the crotonate composition of the present invention will reduce the symptoms exhibited by the individual by about 0%, 20%, 30%, 50% or more, to about 75 to 90%, 96%, or as compared to The initial state is reduced more.

Each of the symptoms described herein, in one or more individuals associated with the disease, or a related disease or condition, compared to the group administered with the placebo or other suitable control group individual, the individual being tested Symptoms showing 10%, 20%, 30%, 50% or more will be alleviated, and as many as 75 to 90% or 96% or more of the symptoms are alleviated.

In another aspect of the invention, combined disease treatment (HIV prevention, HIV treatment, HIV prevention, HIV virus library activation, increased Th1 cytokines, induction of ERK phosphorylation, induction of apoptosis, chemotherapy, resistance Tumor, cancer treatment, triggering remission, maintenance remission, chemical protection, anti-inflammatory, stimulating neutrophils, stimulating erythropoiesis, inhibiting bone erosion, strengthening bones, antiemetic, analgesic, radiation protection, anti-swelling, cytoprotective , anti-mucositis, epithelial irritancy, anti-fibrosis, stimulation of platelets, stroke treatment, anticoagulation, hypolipidemic, vasodilation, blood pressure lowering, pa Treatment of Jinsen's disease, increase of dopamine, inhibition of catechol-O-methyltransferase, inhibition of aromatic L-amino acid decarboxylase, dopamine antagonism, protection of nerves, anticholinergic, treatment of prostatic hypertrophy, type II 5-还原Reductase inhibitor, muscle relaxant, anti-rheumatic, anti-inflammatory, immunosuppressive, TNF inhibition, anti-inflammatory, calcineurin inhibitor, pyrimidine synthesis inhibitor, 5-LO inhibitor, anti-folate, IL-1 receptor Preparations and synergistic effects of body antagonists, T cell co-stimulatory inhibitors, autoimmune disease treatment, myasthenia gravis treatment, immunosuppression, antibody inhibition, anti-cholinesterase, renal disease treatment, incontinence control, anti-depression The method is provided by using an effective amount of a crotonyl ester compound of the formula I with one or more second or auxiliary agents, a second or auxiliary agent in combination with a crotonyl ester compound of the formula I or a synergistic administration of a plurality of combinations which have been obtained Disease treatment composition or synergistic treatment method.

An exemplary combination formulation and a synergistic treatment method herein employs a crotonate compound of Formula I in combination with one or more secondary anti-AIDS agents or one or more adjunctive therapeutic agents that are effective in a selected combination formulation or synergistic treatment regimen Treat or prevent the target (or related) disease, condition, and/or condition. In most of the combination and synergistic treatment methods of the invention, the crotonate compound of formula I or a related or derivative compound is co-administered or synergistically administered with one or more secondary or adjunctive therapeutic agents to obtain a combined preparation or synergistic treatment. The methods are effective in combination or synergistically effective in treating the symptoms of HIV/AIDS and/or one or more opportunistic or secondary diseases in an individual. An exemplary combination formulation and a synergistic treatment method herein employs a crotonate compound of Formula I in combination with one or more secondary anti-AIDS agents or one or more secondary or adjunctive therapeutic agents selected from, for example, protease inhibitors, which comprise , but not limited to, saquinavir, indinavir, ritonavir, nelfinavir, atazanavir, darunavir ( Darunavir), fosamprenavir, tipranavir and amprenavir; nucleotide reverse transcriptase inhibitors, including, but not limited to, Zidovudine, didanosine, stavudine, lamivudine, zalcitabine, emtricitabine, Tylenol Tenofovir disoproxil fumarate, AVX754 and abacavir; non-nucleotide reverse transcriptase inhibitors, including, but not limited to, nevaripine, delavaridine, kalan Calanolide A, TMC125, and efavirenz; combination drugs include, but are not limited to, efavirenz/emtricitabine/tenofovir disoproxil fumarate, Ramiv Lamivudine/zidovudine, abacavir/lamivudine, abacavir/lamivudine/zidovudine, 恩Etpicitabine/tenofovir disoproxil fumarate, sulfamethoxazole/trimethoprim, and lopinavir/ritonavir; entry and Fusion inhibitors include, but are not limited to, enfuvirtide, AMD070, BMS-488043, fozivudine tidoxil, GSK-873, 140, PRO 140, PRO 542, Peptide T, SCH-D, TNX-355, and UK-427,857; AIDS associated with HIV Treatment of opportunistic infections and other symptoms includes, but is not limited to, ritonavir, adefovir Dipivoxil, aldesleukin, amphotericin B, azithromycin (azithromycin), calcium hydroxyapatite, clarithromycin, doxorubicin, dronabinol, entecavir, epoetin alfa, etto Etoposide, fluconazole, ganciclovir, immunoglobulin, interferon alpha-2, isoniazid, itraconazole, megestrol (megestrol), paclitaxel, 珮格西施 α-2 (peginterferon alfa-2), pentamidine, poly-1-lactic acid, ribavirin, rifabutin, rifampin, growth Somatropin, testosterone, trimetrexate, and valganciclovir; Integrase Inhibitor, but not limited to, GS 9137, MK-0518; fungicide (microbicides) include, but are not limited to, BMS-378806, C31G, carbopol 974P, carrageenan, cellulose sulfate, cyanobacterial antiviral protein-N (Cyanovirin-N), dextran sulfate a group consisting of (dextransulfate), hydroxyethyl cellulose, PRO 2000, P SPL7013, tenofovir, UC-781, and interleukin-2.

Other exemplary combination preparations and synergistic treatment methods may additionally employ one or more secondary anticancer agents of Formula I, or one or more accessory therapeutic agents, which are effective in the selected combination formulation or synergistic treatment regimen. For treating or preventing a subject (or related) disease, condition, and/or condition. In a combination formulation and synergistic treatment method of the majority of the invention, the crotonate compound of Formula I or a related or derivative compound is formulated or synergistically administered in combination with one or more secondary or adjunctive therapeutic agents to obtain a combined formulation. Or a synergistic therapeutic method having a combined therapeutic or synergistic effect on a tumor disease of an individual and a symptom of one or more secondary diseases or conditions. Exemplary combination preparations and synergistic treatment methods herein employ a crotonate compound of Formula I in combination with one or more secondary or adjunctive therapeutic agents selected from, for example, chemotherapeutic agents, anti-inflammatory agents, doxorubicin, vitamin D3, Cytosine arabinoside, cytarabine, rhodococcus streptomycin, cyclophosphamide, gemtuzumab, oxazolidine, idarubicin, thiol oxime, mitoxantrone, thioguanine, ar Interleukin, aspartate, carboplatin, estoproxyl phosphate, fludarabine, amine folic acid, estoproxil, dexamethasone, and choline magnesium salicylate. In addition, Auxiliary or secondary treatments can be used, such as, but not limited to, radiation therapy, hormone therapy, and surgery.

Exemplary combination preparations and synergistic treatment methods for preventing or treating side effects of chemotherapy include the use of a crotonate compound of formula I in combination with one or more additional, chemically protective or other functional secondary or adjunctive therapeutic agents effective for treatment Or prevent the underlying disease, condition and/or symptoms. In a combination formulation and synergistic treatment method of the majority of the invention, the crotonate compound of Formula I or a related or derivative compound is formulated or synergistically administered in combination with one or more secondary or adjunctive therapeutic agents to obtain a combined formulation. Or a synergistic treatment method which has a combined therapeutic effect or synergistic effect on the prevention or treatment of side effects of chemotherapy in an individual. Exemplary combination formulations and synergistic treatments herein employ a crotonate compound of Formula I in combination with one or more secondary or adjunctive therapeutic agents selected from the group consisting of pegfilgrastim, erythropoietin (epoeitn alfa), long acting Darbepoetin alfa, alendronate sodium, risedronate, ibandronate, G-CSF, 5-HT ₃ receptor antagonist, NK ₁ antagonists, olanzapine, corticosteroids, dopamine antagonists, serotonin antagonists, benzodiazepines, aprepitant, and cannabinoids .

Exemplary combination preparations and synergistic treatment methods for preventing or treating side effects of radiation therapy using a crotonate compound of formula I in combination with one or more additional secondary or adjuvant therapeutic agents, radiation protective or other functions, which are effective for treatment Or prevent the underlying disease, condition and/or symptoms. In a combination formulation and synergistic treatment method of the majority of the invention, the crotonate compound of Formula I or a related or derivative compound is formulated or synergistically administered in combination with one or more secondary or adjunctive therapeutic agents to obtain a combined formulation. Or a synergistic treatment method for preventing or treating side effects of radiation therapy in an individual Therapy has a combined effect or synergistic effect. Exemplary combination preparations and synergistic treatment methods herein employ a crotonate compound of Formula I in combination with one or more secondary or adjunctive therapeutic agents selected from the group consisting of steroids, amifostine, chlorhexidine. Benzydamine, sucralfate, keratinocyte growth factor (KGF), palifermin, Cu/Zn superoxide dismutase, interleukin 11 or prostaglandin.

Exemplary combination preparations and synergistic treatments for preventing or treating stroke using a crotonate compound of Formula I in combination with one or more additional, neuroprotective or other functional secondary or adjunctive therapeutic agents effective for treating or preventing the subject matter Disease, condition and/or symptom. In a combination formulation and synergistic treatment method of the majority of the invention, the crotonate compound of Formula I or a related or derivative compound is formulated or synergistically administered in combination with one or more secondary or adjunctive therapeutic agents to obtain a combined formulation. Or synergistic treatment methods, which have a combined therapeutic effect or synergistic effect on preventing or treating the effects of stroke or stroke. Exemplary combination preparations and synergistic treatment methods herein employ a crotonate compound of Formula I in combination with one or more secondary or adjunctive therapeutic agents selected from the group consisting of tissue plasminogen activators, anticoagulants ( Anticoagulant), statins, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, beta-blockers (beta) -blocker), calcium channel blocker or diuretic.

Exemplary combination preparations and synergistic treatments for preventing or treating Parkinson's disease using a crotonate compound of Formula I in combination with one or more additional, neuroprotective or other functional secondary or adjunctive therapeutic agents, which are effective for treatment Or prevent the underlying disease, condition and/or symptoms. Combination preparation and synergistic treatment method in most of the present invention Wherein a crotonyl compound of formula I or a related or derived compound is formulated or synergistically administered in combination with one or more secondary or adjunctive therapeutic agents to obtain a combined or synergistic treatment for preventing or treating Parkinson's disease The disease has a combined therapeutic effect or synergistic effect. Exemplary combination preparations and synergistic treatment methods herein employ a crotonate compound of Formula I in combination with one or more secondary or adjunctive therapeutic agents selected from the group consisting of MAO-B inhibitors, pyridoxine, amantadine ), seleyiline, rasagiline, or anticholinergic drugs.

Exemplary combination preparations and synergistic treatments for preventing or treating prostatic hypertrophy use a crotonyl ester compound of formula I in combination with one or more secondary or adjunctive therapeutic agents effective to treat or prevent the underlying disease, condition and/or condition. In a combination formulation and synergistic treatment method of the majority of the invention, the crotonate compound of Formula I or a related or derivative compound is formulated or synergistically administered in combination with one or more secondary or adjunctive therapeutic agents to obtain a combined formulation. Or a synergistic treatment method, which has a combined therapeutic effect or synergistic effect for preventing or treating prostatic hypertrophy. Exemplary combination preparations and synergistic treatment methods herein employ a crotonate compound of Formula I in combination with one or more secondary or adjunctive therapeutic agents selected from the group consisting of finasteride, dutasteride, and tetrazosin hydrochloride. (terazosin), doxazosin, tamsulosin or alpha receptor blockers.

Exemplary combination preparations and synergistic treatments for preventing or treating rheumatoid arthritis using a crotonate compound of formula I in combination with one or more additional secondary or anti-rheumatic or other functional secondary or adjunctive therapeutic agents Effective for treating or preventing the underlying disease, condition and/or condition. In a combination formulation and synergistic treatment method of the majority of the invention, the crotonate compound of Formula I or a related or derivative compound is formulated or synergistically administered in combination with one or more secondary or adjunctive therapeutic agents to obtain a combined formulation. Coordination The same treatment method has a combined therapeutic effect or synergistic effect for preventing or treating rheumatoid arthritis. Exemplary combination preparations and synergistic treatment methods herein employ a crotonate compound of Formula I in combination with one or more secondary or adjunctive therapeutic agents selected from the group consisting of non-steroidal anti-inflammatory drugs, steroids, disease modifying antirheumatic drugs, immunosuppressive agents, TNF-α inhibitor, anakinra, abatacept, adalimumab, azathioprine, chloroquine, hydroxychloroquine, ring Cyclosporin, D-penicillamine, etanercept, golimumab, gold salts, infliximab, come Leflunomide, methotrexate, minocycline, sulfasalazine, rituximab, or tocilizumab.

Exemplary combination preparations and synergistic treatments for preventing or treating myasthenia gravis use a crotonate compound of formula I in combination with one or more secondary or adjunctive therapeutic agents effective to treat or prevent the underlying disease, condition and/or condition. In a combination formulation and synergistic treatment method of the majority of the invention, the crotonate compound of Formula I or a related or derivative compound is formulated or synergistically administered in combination with one or more secondary or adjunctive therapeutic agents to obtain a combined formulation. Or a synergistic treatment method which has a combined therapeutic effect or synergistic effect for preventing or treating myasthenia gravis. Exemplary combination preparations and synergistic treatment methods herein employ a crotonate compound of Formula I in combination with one or more secondary or adjunctive therapeutic agents selected from the group consisting of anticholinesterase, corticosteroids, or immunosuppressive agents. .

Exemplary combination preparations and synergistic treatment methods for preventing or treating kidney diseases using a crotonyl ester compound of formula I in combination with one or more secondary or adjunctive therapeutic agents for incontinence or other functions, which are effective for treating or preventing a target disease or condition And/or disease shape. In a combination formulation and synergistic treatment method of the majority of the invention, the crotonate compound of Formula I or a related or derivative compound is formulated or synergistically administered in combination with one or more secondary or adjunctive therapeutic agents to obtain a combined formulation. Or a synergistic treatment method which has a combined therapeutic effect or synergistic effect for preventing or treating kidney diseases. Exemplary combination preparations and synergistic treatment methods herein use anticholinergic drugs, topical estrogen, imipramine or duloxetine.

Some embodiments of the present invention provide combination disease treatment (AIDS treatment, HIV prevention, HIV treatment, HIV virus library activation, increase of Th1 cytokines, induction of ERK phosphorylation, induction of apoptosis, chemotherapy, anti-tumor, cancer treatment) , triggering relief, maintaining relief, chemical protection, anti-inflammatory, stimulating neutrophils, stimulating erythropoiesis, inhibiting bone erosion, strengthening bones, antiemetic, analgesic, radiation protection, anti-swelling, cytoprotective, anti-mucositis , epithelial irritant, anti-fibrosis, stimulating platelet, stroke treatment, anticoagulation, hypolipidemic, vasodilatation, lowering blood pressure, treatment of Parkinson's disease, increasing dopamine, inhibiting catechol-O-methyltransferase, inhibiting Aromatic L-amino acid decarboxylase, dopamine antagonism, neuroprotection, anticholinergic, prostatic hypertrophy treatment, type II 5-alpha reductase inhibitor, muscle relaxant, anti-rheumatic, anti-inflammatory, immunosuppressive, TNF Inhibition, anti-inflammatory, calcineurin inhibitor, pyrimidine synthesis inhibitor, 5-LO inhibitor, anti-folate, IL-1 receptor antagonism, T cell co-stimulation inhibition, The autoimmune disease treatment, myasthenia gravis treatment, immunosuppression, antibody inhibition, anti-cholinesterase, kidney disease treatment, incontinence control, anti-depression) preparation comprises crotonate and one or more adjuvants having therapeutic activity for the disease. With these combination preparations, the crotonyl ester of the formula I and the adjuvant having therapeutic activity for the disease will be used for the treatment of diseases (AIDS treatment, HIV prevention, HIV treatment, HIV virus library activation, increase of Th1 cytokines, induction of ERK phosphorylation). Role, induce apoptosis, chemotherapy, anti-tumor, cancer treatment, trigger Relief, maintain remission, chemical protection, anti-inflammatory, stimulate neutrophils, stimulate red blood cell production, inhibit bone erosion, strengthen bones, antiemetic, analgesic, radiation protection, anti-swell, cytoprotective, anti-mucositis, epithelium Irritant, anti-fibrosis, platelet stimulation, stroke therapy, anticoagulation, hypolipidemicemia, vasodilation, blood pressure lowering, treatment of Parkinson's disease, increase of dopamine, inhibition of catechol-O-methyltransferase, inhibition of aromatics L-amino acid decarboxylase, dopamine antagonism, neuroprotection, anticholinergic, prostatic hypertrophy treatment, type II 5-alpha reductase inhibitor, muscle relaxant, anti-rheumatic, anti-inflammatory, immunosuppressive, TNF inhibition, Anti-inflammatory, calcineurin inhibitor, pyrimidine synthesis inhibitor, 5-LO inhibitor, anti-folate, IL-1 receptor antagonism, T cell co-stimulation inhibition, autoimmune disease treatment, myasthenia gravis treatment, immunosuppression, Combination formulations of effective doses of antibody inhibition, anti-cholinesterase, renal disease treatment, incontinence control, anti-depression, presented separately or in combination. In an exemplary embodiment, the crotonyl ester and non-crotonide of Formula I will each be presented as a disease treatment/preventive dose (ie, a single dose that can be detected by the palliative condition of the individual's symptoms alone). Alternatively, the combination preparation may comprise one or both of a crotonic ester of the formula I and a non-crotonide of a sub-therapeutic singular dosage, wherein the combined preparation comprising the two has a combined dose of the two, The alleviation of cytopathic disease or the alleviation of symptoms has a combined therapeutic effect. Thus, one or both of the crotonic esters and non-crotonic esters of Formula I can be presented as a formulation using a low single dose, or administered in a synergistic administration regimen, with a common formulation or method of treatment slowing the individual Symptoms of cytopathic diseases. For example, in certain embodiments, a combination formulation can comprise one or more compounds from a highly active retroviral treatment regimen (HAART protocols) in combination with crotonate. Other combination preparations, for example, may include crotonyl esters and/or compounds effective to treat opportunistic infections of AIDS as well as compounds from HAART treatment regimens. In other embodiments, the combined preparation may One or more additional chemotherapeutic agents are included. In other embodiments, the combination formulation can include one or more additional chemical protectants. In other embodiments, the combination formulation can include one or more radiation protectants. In other embodiments, the combination formulation can include one or more neuroprotective agents. In other embodiments, the combination formulation may comprise one or more anti-inflammatory agents or other minor or additional therapeutic agents described herein.

To practice the synergistic administration of the present invention, the crotonyl ester compound of Formula I can be administered concurrently or sequentially with one or more of the secondary or adjunctive therapeutic agents described herein in a synergistic therapeutic regimen. Thus, in certain embodiments, the compound is administered in combination with a non-crotonide, or any other secondary or adjunctive therapeutic agent described herein, using an individual formulation or a combination of the above (ie, comprising Administration of the crotonate compound of Formula I or a related or derivative compound and a non-crotonide therapeutic agent). This synergistic administration can be accomplished simultaneously or sequentially, and when one or both (or all) of the active therapeutic agents exert their biological activity individually and/or synergistically, it takes a period of time.

In one embodiment, the synergistic therapeutic methods can, for example, follow or be extended by various HAART treatment regimens, and include, for example, but are not limited to, two nucleoside analogue reverse transcriptase inhibitors plus one Or a plurality of protease inhibitors or non-nucleotide reverse transcriptase inhibitors and a crotonyl ester of formula I in other combinations. Other synergistic treatments can, for example, include crotonyl esters and/or treatments for opportunistic infections and treatments for retroviral treatment regimens. A distinguishing aspect of these synergistic treatments is that the crotonyl ester of Formula I exerts at least some activity which has a good clinical response in combination with a reduction in AIDS symptoms or a different clinical response provided by a secondary or adjunctive therapeutic agent. . In general, a synergistic administration of a crotonate compound of Formula I with a secondary or adjunctive therapeutic agent will result in a therapeutic effect compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Improved treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more secondary HIV therapeutics, or other ancillary therapeutic agents, for example, selected from protease inhibitors, including, but not limited to, saquinavir. (saquinavir), indinavir, ritonavir, nelfinavir, atazanavir, darunavir, fosamprenavir ), tilanavir and amprenavir; nucleotide reverse transcriptase inhibitors, including, but not limited to, zidovudine, didanosine, s Stavudine, lamivudine, zalcitabine, emtricitabine, tenofovir disoproxil fumarate, AVX754 and abacavir a non-nucleotide reverse transcriptase inhibitor, including, but not limited to, nevaripine, delavaridine, calanolide A, TMC125, and efavirenz; Drugs include, but are not limited to, Xining/emtricitabine/tenofovir (efavirenz/emtricitabine/ Tenofovir disoproxil fumarate), lamivudine/zidovudine, abacavir/lamivudine, abacavir/lamivudine/zidovudine Abacavir/lamivudine/zidovudine), emtricitabine/tenofovir disoproxil fumarate, sulfamethoxazole/trimethoprim, and lopinavir/ritonavir (lopinavir/ritonavir); entry and fusion inhibitors include, but are not limited to, enfuvirtide, AMD070, BMS-488043, fozivudine tidoxil, GSK-873, 140, PRO 140, PRO 542, Peptide T, SCH-D, TNX-355, and UK-427,857; treatment of AIDS-related opportunistic infections and other symptoms including, but not limited to, ritonavir, ar Defovir (Adefovir Dipivoxil), aldesleukin, amphotericin B, azithromycin, calcium hydroxyapatite, clarithromycin, doxorubicin , dronabinol, entecavir, epoetin alfa, etoposide, fluconazole, ganciclovir, immunoglobulin, interferon -2-2, isoniazid, itraconazole, megestrol, paclitaxel, peginterferon alfa-2, sputum Pentamidine), poly-1-lactic acid, ribavirin, rifabutin, rifampin, somatropin, testosterone, Trimetrexate and valganciclovir; Integrase Inhibitors include, but are not limited to, GS 9137, MK-0518; microbicides include, but are not limited to, BMS- 378806, C31G, carbopol 974P, carrageenan (ca Rrageenan), cellulose sulfate, Cyanovirin-N, dextransulfate, hydroxyethyl cellulose, PRO 2000, P SPL7013, Tylenol Tenofovir, UC-781, and interleukin-2 are administered in a synergistic manner (administered simultaneously or sequentially in a combined or separate formulation).

In other embodiments, this synergistic treatment can be, for example, followed or extended by various chemotherapeutic regimens. Other synergistic treatments can, for example, include treatment with crotonyl esters and/or other symptoms of neoplastic disease. In contrast to these synergistic treatments, the croton of Formula I exerts at least some activity, which has a good clinical balance in coping with the symptoms of the tumor disease, or the different clinical responses provided by the secondary or adjuvant therapeutic agents. reaction. Generally speaking, compared to the use of the crotonate compound of formula I alone, or secondary Or the therapeutic effect of the adjunctive therapeutic agent, the synergistic administration of the crotonyl ester compound of formula I with a secondary or adjunctive therapeutic agent will result in improved therapeutic or prophylactic results. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more secondary cancer therapeutics, or other ancillary therapeutic agents, such as doxorubicin, vitamin D3, cytosine arabinoside, cytarabine, Streptavidin, cyclophosphamide, gemtuzumab, oxazolidine, idarubicin, thiol oxime, mitoxantrone, thioguanine, adiponectin, aspartate, carboplatin , estoproxyl phosphate, fludarabine, amine folic acid, estoproxil, dexamethasone, and choline magnesium salicylate in combination (in combination or sequential preparation of combined or separate preparations) Cast).

In other embodiments, such synergistic treatment can be, for example, followed or extended by various palliative protocols for chemotherapeutic patients. Synergistic treatment methods can, for example, include crotonyl esters and/or other treatments for side effects of chemotherapy. In contrast to these synergistic treatments, the croton of Formula I exerts at least some activity, which is beneficial in the reduction of side effects associated with chemotherapy, or the different clinical responses provided by secondary or adjuvant therapeutic agents. Clinical response. In general, the synergistic administration of a crotonyl compound of Formula I with a secondary or adjunctive therapeutic will result in improved therapeutic effects compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more minor chemotherapeutic side effects compounds, or other ancillary therapeutic agents, such as pegfilgrastim, erythropoietin (epoeitn alfa), Long-acting erythropoietin (darbepoetin alfa), alendronate sodium, risedronate, ibandronate, G-CSF, 5-HT ₃ receptor antagonist , NK ₁ antagonists, olanzapine, corticosteroids, dopamine antagonists, serotonin antagonists, benzodiazepines, aprepitant, and cannabinoids Cannabinoids) are administered synergistically (administered simultaneously or sequentially in a combined or separate formulation).

In other embodiments, this synergistic treatment can be extended, for example, by or according to various mitigation protocols for radiation therapy patients. Synergistic treatment methods can, for example, include croton esters and/or other treatments for side effects of radiation therapy. In contrast to these synergistic treatments, the croton of Formula I exerts at least some activity, which is beneficial in reducing the side effects of radiation therapy or the different clinical responses provided by secondary or adjuvant therapeutic agents. Clinical response. In general, the synergistic administration of a crotonyl compound of Formula I with a secondary or adjunctive therapeutic will result in improved therapeutic effects compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more secondary radiation therapy side effects, or other ancillary therapeutic agents, such as steroids, amifostine, chlorhexidine ( Chlorhexidine), benzidamine, sucralfate, keratinocyte growth factor (KGF), palifermin, Cu/Zn superoxide dismutase, interleukin 11 or prostate Synergistic administration (administered simultaneously or sequentially in combination or separate formulations).

In other embodiments, this synergistic treatment can be, for example, followed or extended by various protocols for stroke treatment. Synergistic treatment methods can, for example, include Croton Esters and/or other treatments used to prevent or treat injuries caused by stroke. In contrast to these synergistic treatments, the croton of Formula I exerts at least some activity, which is good in combination with a stroke prevention or therapeutic agent, or a different clinical response provided by a secondary or adjuvant therapeutic agent. Clinical response. In general, the synergistic administration of a crotonyl compound of Formula I with a secondary or adjunctive therapeutic will result in improved therapeutic effects compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more secondary stroke therapeutic compounds, or other ancillary therapeutic agents, such as tissue plasminogen activators, anticoagulants ( Anticoagulant), statins, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, beta-blockers (beta) -blocker), calcium channel blocker or diuretic are administered synergistically (administered simultaneously or sequentially in a combined or separate formulation). In addition, adjuvant or secondary therapeutic agents may be used in the treatment of stroke or stroke sequelae such as, but not limited to, carotid endarterectomy, angioplasty, stent placement. , craniotomy, endovascular coil emobilization, patent foramen ovale closure.

In other embodiments, such synergistic treatment can be, for example, followed or extended by various protocols for Parkinson's disease treatment. Synergistic treatment methods can, for example, include crotonyl esters and/or other treatments for the prevention or treatment of Parkinson's disease. In contrast to these synergistic treatments, the croton of Formula I only exerts at least some activity, Good clinical response to different clinical responses provided by Parkinson's disease prevention or treatment agents, or by secondary or adjunctive therapeutic agents. In general, the synergistic administration of a crotonyl compound of Formula I with a secondary or adjunctive therapeutic will result in improved therapeutic effects compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more secondary Parkinson's disease treatment compounds, or other ancillary therapeutic agents, such as levodopa, tolcapone, card Carbidopa, dopamine agonist, MAO-B inhibitor, pyridoxine, amantidine, seleyiline, rasagiline Or synergistic administration of anticholinergic drugs (administered simultaneously or sequentially in combination or separate formulations). In addition, adjuvant or secondary treatment may be used for the treatment of Parkinson's disease, such as, but not limited to, deep brain stimulation and lesion formation.

In other embodiments, such synergistic treatment can be, for example, followed or extended by various protocols for the treatment of prostatic hypertrophy. Synergistic treatment methods can, for example, include crotonyl esters and/or other treatments for preventing or treating prostatic hypertrophy. In contrast to these synergistic treatments, the croton of Formula I exerts at least some activity, which is good in the combination of prostatic hypertrophy prophylaxis or therapeutic agents, or different clinical responses provided by secondary or adjunctive therapeutic agents. Clinical response. In general, the synergistic administration of a crotonyl compound of Formula I with a secondary or adjunctive therapeutic will result in improved therapeutic effects compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more minor prostatic hypertrophy therapeutic compounds, or other ancillary therapeutic agents, such as finasteride, dutasteride, tetrazolium hydrochloride. Terazosin, doxazosin, tamsulosin or alpha receptor blockers are administered synergistically (administered simultaneously or sequentially in a combined or separate formulation). In addition, adjuvant or secondary treatment may be used for the treatment of prostatic hypertrophy, such as, but not limited to, transurethral resection of the prostate, transurethral incision of the prostate, laser surgery, Or prostatectomy (prostatectomy).

In other embodiments, such synergistic treatment can be, for example, followed or extended by various protocols for the treatment of rheumatoid arthritis. Synergistic treatment methods can, for example, include crotonides and/or other treatments for the prevention or treatment of rheumatoid arthritis. In contrast to these synergistic treatments, the croton of Formula I exerts at least some activity in combination with rheumatoid arthritis prophylaxis or therapeutic agents, or different clinical settings provided by secondary or adjunctive therapeutic agents. The response has a good clinical response. In general, the synergistic administration of a crotonyl compound of Formula I with a secondary or adjunctive therapeutic will result in improved therapeutic effects compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more minor rheumatoid arthritis therapeutic compounds, or other ancillary therapeutic agents, such as non-steroidal anti-inflammatory drugs, steroids, disease modifying antirheumatic drugs ( Disease-modifying anti-rheumatic drug), immunosuppressant, TNF-α inhibitor, anakinra, abatacept, adalimumab, azathioprine, Chloroquine, hydroxychloroquine, Cyclosporin, D-penicillamine, etanercept, golimumab, gold salts, infliximab, Leflunomide, methotrexate, minocycline, sulfasalazine, rituximab, or tocilizumab (administered simultaneously or sequentially in a combined or separate formulation).

In other embodiments, such synergistic treatment can be, for example, followed or extended by various protocols for the treatment of autoimmune diseases. Synergistic treatment methods can, for example, include crotonyl esters and/or other treatments for preventing or treating myasthenia gravis. In contrast to these synergistic treatments, the croton of Formula I exerts at least some activity, which has a different clinical response to the myasthenia gravis prevention or treatment agent, or the secondary or adjuvant therapeutic agent. Good clinical response. In general, the synergistic administration of a crotonyl compound of Formula I with a secondary or adjunctive therapeutic will result in improved therapeutic effects compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more minor myasthenia gravis treatment compounds, or other ancillary therapeutic agents, such as anticholinesterase, corticosteroids, or immunization. Inhibitors are administered synergistically (administered simultaneously or sequentially in a combined or separate formulation).

In other embodiments, such synergistic treatment can be, for example, followed or extended by various protocols for the treatment of kidney disease. Synergistic treatment methods can, for example, include crotonyl esters and/or other treatments for preventing or treating the symptoms of kidney disease and kidney disease. Different from these synergistic treatment methods, the croton of formula I only plays at least Some activities have a good clinical response in combination with a renal disease prophylaxis or therapeutic agent, or a different clinical response provided by a secondary or adjunctive therapeutic agent. In general, the synergistic administration of a crotonyl compound of Formula I with a secondary or adjunctive therapeutic will result in improved therapeutic effects compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more minor renal disease treatment compounds, or other ancillary therapeutic agents, such as anticholinergics, topical estrogen, imipramine. Or duloxetine is administered synergistically (administered simultaneously or sequentially in a combined or separate formulation).

In other embodiments, such synergistic treatment can be, for example, followed or extended by various protocols for urinary incontinence treatment. Synergistic treatment methods can, for example, include crotonyl esters and/or other treatments for preventing or treating urinary incontinence. In contrast to these synergistic treatments, the croton of Formula I exerts at least some activity, which is good in combination with urinary incontinence prevention or therapeutic agents, or different clinical responses provided by secondary or adjuvant therapeutic agents. Clinical response. In general, the synergistic administration of a crotonyl compound of Formula I with a secondary or adjunctive therapeutic will result in improved therapeutic effects compared to the use of a crotonate compound of Formula I alone, or a secondary or adjunctive therapeutic agent. Treatment or prevention outcomes. This condition considers direct and indirect effects.

In an exemplary embodiment, the crotonate compound of Formula I will be combined with one or more minor urinary incontinence treatment compounds, or other ancillary therapeutic agents, such as anticholinergics, topical estrogen, imipramine. Or duloxetine is administered synergistically (administered simultaneously or sequentially in a combined or separate formulation).

As recited above, in all of the various embodiments of the invention herein, The method and formulation for the treatment may use various forms of the crotonate compound of the formula I, including pharmaceutically acceptable salts, isomers, mirror image isomers, polymorphs, solvates, hydrates, and/or Any or combination of prodrugs. In an exemplary embodiment of the invention, TPA is used in therapeutic formulations and methods for illustrative purposes.

The pharmaceutical compositions of the present invention can be administered by any method which achieves the therapeutic or prophylactic objectives contemplated by them. Suitable routes of administration for the compositions of the present invention include, but are not limited to, conventional routes of administration, machines, and means for injecting methods, such as, but not limited to, intravenous, intramuscular, peritoneal Intraperitoneal, intraspinal, intrathecal, intraracerebroventricular, intraarterial, subcutaneous, and intranasal routes.

The compositions of the present invention may further comprise a pharmaceutically acceptable carrier for use in a particular mode of administration method employed. The pharmaceutical forms of the compositions of the present invention comprise excipients that are recognized in the art of pharmaceutical formulation as suitable for use in the dosage units discussed above. Such excipients include, but are not limited to, binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrating agents, foaming agents And other traditional excipients and additives.

If desired, the compositions of the present invention can be administered in a controlled release form by the use of a slow release carrier, such as a hydrophilic, slow release polymer. Exemplary controlled release agents herein include, but are not limited to, hydroxypropylmethyl cellulose having a viscosity of from about 100 cps to 100,000 cps, or other biocompatible matrix.

Certain crotonyl ester compositions of the formula I of the invention are designed for parenteral administration Parental administration, for example, intravenous, intravenous, subcutaneous or intraperitoneal, comprising aqueous and non-aqueous sterile injectable solutions, for example other compositions of the invention may optionally comprise antioxidants, buffers, bacteriostatic And solute which can penetrate the blood of the mammalian individual with the preparation; and an aqueous and non-aqueous sterile suspension which may contain a suspending agent and/or a thickening agent. The formulations may be presented in single or multiple dose containers. Other compositions and formulations of the invention may comprise a polymer for extended release following parenteral administration. The parenteral preparation can be a solution, dispersion or emulsion suitable for the administration mode. The preparation may also be prepared as a polymer for sustained release after parenteral administration. Pharmaceutically acceptable formulations and ingredients will generally be sterilized or sterilized, biologically inert, and easy to manage. Such polymeric materials are well known to those of ordinary skill in the art of pharmaceutical formulation. Parenteral formulations typically comprise a buffer and a preservative, and a pharmaceutically and physiologically acceptable injection, such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or analog. Extemporaneous injection solutions, emulsions and suspensions can be prepared from sterile powders, granules and tablets of the type previously described. Preferred unit dosage formulations comprise a daily dose or unit of the active ingredient, a daily dose, as described above, or a suitable fraction thereof.

In a more detailed embodiment, the compositions of the present invention may comprise a crotonate compound of Formula I encapsulated in microcapsules, microparticles, or microsomes, such as, for example, coacervation techniques or interfacial polymerization (interfacial) Prepared by, for example, hydroxypropyl methylcellulose or gelatin microcapsules and poly(methylmethacylate) microcapsules; in a colloidal drug delivery system (eg Liposomes, albumin microparticles, Microemulsion, nanoparticle and nanocapsules); or as a crude emulsion.

As set forth above, in some embodiments of the compositions and methods of the present invention, pharmaceutically acceptable salts such as the crotonyl ester compounds of Formula I above and/or acid addition salts of related or derived compounds may be used ( Acid addition salt) or base salt. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts. Suitable acid addition salts are formed from acids formed from non-toxic salts such as hydrochloride, hydrobromide, hydroiodide, sulphate, sulfuric acid Hydrogen sulphate, nitrate, phosphate, and hydrogen phosphate salt. Other pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salts, potassium salts, barium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts and the like; and organic amine salts, For example, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt , N,N'-dibenzylethylenediamine salt and its analogues; organic acid salts such as acetate, citrate, lactate , succinate, tartrate, maleate, fumarate, mandelate, dichloroacetate, trifluoroacetate Trifluoroacetate), oxalate, formate salt; sulfonate (ulfonates), such as methanesulfonate, benzenesulfonate, and p-toluenesulfonate (p- Toluenesulfonate); and an amine salt such as arginine (Arginate), aspartate salts (asparginate), salts of glutamic acid (glutamate), tartrate (tartrate), as well as gluconate (gluconate salt). Suitable basic salts are formed from bases formed from non-toxic salts such as aluminum, calcium, lithium, Magnesium, potassium, sodium, zinc and diethanolamine salts.

In other detailed embodiments, the compositions and methods of the present invention utilize a croton ester prodrug of Formula I. The pro-drug is a covalently bonded carrier that releases an active parent drug in vivo . Examples of effective prodrugs of the present invention include a hydroxyalkyl group or an aminoalkyl group as a substituent ester or an amine, and which can be obtained by, for example, succinic anhydride (succinic) The anhydrides are prepared by reacting anhydrides.

The invention disclosed herein is also to be understood to encompass a crotonyl ester of formula I comprising an in vivo metabolite (using a precursor compound administered in vivo, or administered directly in the form of its metabolite). These products may be produced, for example, by an oxidation reaction, a reduction reaction, a hydrolysis reaction, an amidation reaction, an esterification reaction or the like of a compound to be administered, mainly due to an enzyme hydrolysis reaction. Accordingly, the present invention encompasses the use of the compounds and methods of the present invention produced by the process comprising contacting a crotonyl ester of Formula I with a mammalian for a period of time to produce a metabolic product thereof. The products are typically identified by the radiolabeled compound of the present invention and administered parenterally to the animal at a detectable dose, such as a rat, mouse, guinea pig, monkey or human, through a sufficient Time metabolism to produce and separate transformed products from urine, blood or other biological samples.

The invention disclosed herein will also be understood to encompass diseases for the diagnosis of mammalian individuals, including, but not limited to, neoplastic diseases including leukemia diseases such as leukemia, stroke, Parkinson's disease, myasthenia gravis, rheumatoid joints. Inflammation, kidney disease, enlarged prostate, and the risk value, presence, severity, treatment index, or other diagnostic component of AIDS or related diseases or symptoms, including cancer, stroke, Parkinson's disease, myasthenia gravis, and Rheological arthritis, kidney disease, prostatic hypertrophy, and/or the risk or presence of one or more symptoms of AIDS, such that it can be detected (eg, by isotope calibration, fluorescing, or other conventional methods) The calibration compound calibrates the crotonate compound of Formula I to contact a mammalian individual (eg, a cell, tissue, organ, or individual) and then detects the calibrated compound using any conventional reagent assay and calibration/detection method. Presence, location, metabolism, and/or binding status (eg, detection of binding to HIV receptor physiology/metabolism, or malignant tumor cell receptors) Physiology/metabolism is the calibration part). In an exemplary embodiment, the crotonate compound of Formula I is isotopically labeled with one or more atoms substituted with atoms having different atomic mass or mass trees. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ^{31, respectively.} P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl. Compounds that are isotopically labeled are then administered to an individual or other individual and, as described above, are detected as described above, producing useful diagnostic and/or therapeutic collation data according to conventional techniques.

Instance

The examples described below show novel and potent uses of crotonides and derivative compounds as HIV therapeutic agents which are effective in slowing the symptoms of AIDS. Individuals who do not respond to traditional treatments for HIV and AIDS in exemplary clinical trials It is responsive to the treatment of TPA. TPA treatment is permitted as a humanitarian treatment, and according to the attending physician, the recovery of some patients is considered to be life-saving. The examples described below additionally demonstrate the treatment of croton and derivative compounds for the treatment of neoplastic diseases, as a chemoprotective agent, radiation protectant, treatment of stroke, Parkinson's disease, prostatic hypertrophy, rheumatoid arthritis, kidney disease, The effects of urinary incontinence and treatment of myasthenia gravis. Crotonate additionally provides unexpected cosmetic effects to reduce the production of dark circles and increase the youthfulness of the skin. These and other findings are detailed and clarified by the following examples.

Example I Effect of TPA on Peripheral White Blood Cells (WBC) and Hemoglobin (Hb) in S180 Cell-Injected Mice

Sarcoma cells (Sarcoma 180, S18) were injected into Kwen-Ming mice. On day 3, mice were administered 50, 100 or 200 μg/kg/day of TPA for 7 consecutive days by intraperitoneal injection. After the completion of the treatment on the second day, blood was collected from the tail for analysis of white blood cells and hemoglobin. The white blood cell volume of the treated group (continuous injection of TPA at 50, 100 or 200 μg/kg/day for 7 days) was 16.1±7.4, 18.7±.3.0 and 20.7±.3.4 x10 ⁹ /L, respectively; the white blood cell volume of the control group It is 13.6 ± 1.8 x 10 ⁹ /L. The hemoglobin levels of the treated groups were 136 ± 11, 149 ± 12, and 149 ± 10 g / L, respectively, while the hemoglobin amount in the control group was 136 ± -15 g / L. This result shows that intraperitoneal injection with TPA will increase the amount of white blood cells around the mouse in a proportional manner to the dose, whereas the amount of hemoglobin in the mice administered with TPA has no significant effect compared to the control group.

Example II Dose range study

Due to the strong local irritation caused by the application of TPA, TPA is administered to the patient by intravenous injection. The TPA solution of the sterile syringe was added to 200 ml of sterile saline and uniformly mixed for intravenous injection.

Toxicity and side effects of clinical administration of different doses of TPA:

(1) Inject 1 mg TPA/patient/week:

A 1 mg TPA solution was mixed with 200 ml of sterile saline for intravenous injection, which was completed in 1 hour at a rate of 16 μg/min. One hour after the administration of TPA, the patient felt cold for 3 to 5 hours, followed by a fever (the patient's temperature reached 37.5 to 39.5 ° C for 3 to 5 hours, and then returned to normal) and sweated in large amounts. These symptoms can be alleviated by administering glucocorticoids to the patient. This dose of TPA causes a small number of patients to bleed, many patients are difficult to breathe in a short period of time, and hemoglobin is detected in the urine. However, these side effects are transient and reverting. The patient's heart, liver, kidney and lung function are normal.

(2) 0.5 mg TPA/patient x 2/week: (twice a week)

A 0.5 mg TPA solution was mixed with 200 ml of sterile saline for intravenous injection, which was completed in 1 hour at a rate of 8 μg/min. The response after administration was the same as the dose of 1 mg TPA, but was lighter than the dose of 1 mg. Patients are more likely to tolerate lower doses. Occasionally, hemoglobin can be detected in the patient's urine. There is no difficulty in breathing. The patient's heart, liver, kidney and lung function are normal.

(3) 0.25 mg TPA/patient x 4/week:

A 0.25 mg TPA solution was mixed with 200 ml of sterile saline for intravenous injection, which was completed in 1 hour at a rate of 4 μg/min. After administration, Symptoms such as chills and fever also occur, but the higher doses are mild. No hemoglobin was detected in the patient's urine, and no patient felt difficulty breathing. The patient's heart, liver, kidney and lung function are normal.

Example III The first clinical trial of TPA treatment in HIV+ patients

Twelve patients with symptoms ranging from 35 to 52 years old who were infected with HIV by transfusion in 1995 and who were refractory to HIV criteria (5 males and 7 females) were treated with TPA. Each patient was administered TPA in a body weight adjusted dose (75 μg/sq m) dissolved in 200 ml of sterile saline by intravenous injection for more than 1 hour. This dose was administered daily for the first 3 days of treatment. On days 4 to 18, each patient was then dosed every other day, followed by a 6-month rest period prior to the second course of treatment according to the same treatment.

Blood samples were collected prior to the first dose of TPA, and on days 4 and 40 of the treatment cycle. The values of CD3, CD4, and CD8 in peripheral blood were measured using monoclonal antibodies (Becton Dickson Scientific Co., Franklin Lakes, NJ) and flow cytometry (B. D. Bioscience, San Diego, CA).

As shown in Table 1, the values of CD3, CD4, and CD8 are not consistently changed or correlated.

As shown in Table 2 below, there was no consistent change in the amount of virus in five patients with an increased amount of HIV, while the amount of virus in the other seven patients did not change or decrease.

Although the amount of virus was not associated with the values of CD3, CD4, and CD8, 11 patients showed significant improvement after treatment. Symptoms disappeared in 8 patients and 5 of them resolved for up to 6 to 12 months. Three patients had a slowing of symptoms.

Example IV Second clinical trial of TPA treatment in HIV+ patients

A second course of TPA was given to 9 patients in Example III. Of the 9 patients, 7 were asymptomatic at the beginning of the second course of treatment. The 10th patient (patient number 2a) with symptoms and previous treatment without TPA was also added to the trial. Each patient was administered TPA in a body weight adjusted dose (75 μg/sq m) dissolved in 200 ml of sterile saline by intravenous injection for more than 1 hour. This dose was administered to each patient once daily for 10 consecutive days, followed by a 10-day rest period, three cycles of the above course, and a total of 30 doses of TPA. Patient numbers 5a, 6a, and 8a discontinued the use of anti-AIDS drugs prior to initiation of TPA therapy and started taking the drug again one month after three cycles. Patient numbers 1~4a, 7a, and 9a-10a continued to take anti-AIDS drugs throughout the treatment period.

Blood samples were collected 3 days before the start of treatment, after the first 10 days of circulating TPA administration, and after the last TPA administration, and the values of CD3, CD4, CD8, white blood cells, red blood cells, heme, and platelets were measured.

As shown in Table 3, after the first and third TPA administrations, all patients had increased CD3 values and reached the highest value after three cycles, with the exception of two patients (5a & 10a). There is an increasing trend for CD8 and CD4. These results show that TPA treatment has an enhanced effect on the immune system. The variability results were obtained from HIV values (Table 4). The measurement of HIV in some patients is below the detection limit of these methods (less than 200), and some are increased. The amount of white blood cells, red blood cells, hemoglobin, and platelets were measured as normal changes (Table 5).

Of the 9 patients who had been treated with TPA during the first course of treatment, only one of them (label 9a) presented some AIDS symptoms before the second course of treatment. After three TPA cycles of treatment in the second course of treatment, the patient and another patient who did not receive TPA (label 2a) showed signs of AIDS symptoms disappearing, and both recovered and returned to normal daily life. The other 8 patients had no symptoms of AIDS at the start of the trial and were asymptomatic at the end of the trial. All patients are still under observation. Anti-AIDS drug treatment continues uninterrupted.

As can be seen in Table 4, the levels of CD3, CD4 and CD8 increased in all patients, and the increase in CD3 levels was the most striking and consistent. The viral load of HIV has changed. Undetectable (<200) in three patients; I don't know why it increased in the other six patients and decreased in one patient.

Example V The third clinical trial of TPA treatment for HIV+ patients

Six patients aged between 37 and 52 years, two males and four females (patient number 13-18) were given TPA. Four of these patients have previously received treatment with two prior clinical trials of TPA in combination with anti-HIV drugs. Two of the patients did not receive TPA, but have received anti-HIV medication. All treatments were stopped three days before the start of the third clinical trial until 60 days after the completion of TPA treatment. The standard HIV treatment response is due to local health authorities.

Each patient in the test was intravenously injected into 150 μg of TPA dissolved in 200 ml of sterile saline for a period of 1.5 to 2 hours for a total of 60 days to administer a total dose of 9.0 mg. After 60 days of TPA treatment, these patients did not receive treatment for the next 60 days and continued to observe.

The CD3, CD4, and CD8 values in the peripheral blood were quantified using flow cytometry and appropriate antibodies obtained by B.D. Bioscience, San Diego, CA before starting treatment and at 30 and 60 days of treatment. The amount of virus was measured using the conventional method of Kuang Ann Men Hospital, Beijing, China. The patient's red blood cells, white blood cells, platelets, and hemoglobin values were also measured.

As shown in Table 6, despite the discontinuation of traditional retroviral therapy, the 6 patients had low or difficult viral levels at the start of the trial and remained low throughout the clinical trial. In addition, the virus values did not rise as in the previously described patients with plasma virus values below 50 HIV copies/ml 6 to 15 days after stopping the retroviral treatment. (Harrigan et al., AIDS 13, F59-F62 (1999)). The CD3, CD4, and CD8 values are changed and uncertain.

White blood cells (WBC), red blood cells (RBC), heme (Rb), and platelets (PLt) were measured before TPA treatment, 15 days, 30, 45, 60 days after initiation of TPA treatment, and 30 days after discontinuation of TPA treatment. As shown in Table 7, all numbers are directly in the normal range.

Patients who participated in the third clinical trial showed no common viral recovery after antiretroviral therapy was stopped. These patients did not show symptoms of AIDS on the 120th day of observation and during the treatment period, and they felt normal and could perform their normal Daily life.

Instance VI case study

The results of treatment of patients with initial AIDS symptoms with TPA were based on the treatments of Examples III, IV, and V. Patients participating in multiple trials are identified in more cases by more than one patient number. All patient identification numbers correspond to patient numbers in Tables 1 through 7.

Patient numbers 1 and 15: HLY, female, 35 years old, diagnosed with AIDS in 2003 and have a definite condition and participated in three clinical trials. At the beginning of the first trial, it had frequent fever, diarrhea, oral ulceration, poor appetite, weight loss, left eye vision loss (syncytia production, and cough (tuberculosis). In 2004, he began receiving antiviral drugs, stavudine (D ₄ T), lamivudine (NVP) and zidovudine (AZT). Despite taking anti-AIDS drugs, the patient The CD4 value is 3 and no manual work can be done.

During the first trial of the method of treatment according to Example III as described above, the patient experienced 4 episodes of body temperature rise to 38-39 ° C for 2 to 4 hours. After treatment with TPA, the symptoms have a gradual improvement. The patient's appetite improved, and diarrhea, oral ulceration, and signs of burnout disappeared, but his vision was still affected. The The patient added a little weight and claimed to be able to return to homework. The patient continues to receive antiviral therapy. The patient's improvement in symptoms was not associated with changes in CD3, CD4, CD8 values and viral load.

H.L.Y participated in the second test of Example IV above. In the second trial, the patient did not have the symptoms of AIDS. The patient did not have an adverse effect during the subsequent TPA treatment. After the first and third cycles of TPA, the patient's CD3, CD4, and CD8 values increased as the number of white blood cells. The patient had a higher amount of HIV, but the patient continued to work and continued to have no AIDS symptoms.

H.L.Y participated in the third test of Example V above. At the beginning of the third trial, the patient's eyes were still problematic. During the third trial, the patient developed a fever to 38 to 38.5 °C on the 3rd and 4th day of TPA administration. There was no recurrence of AIDS symptoms during the test period or during the 60-day observation period. Except for vision, the patient did not develop symptoms, felt normal, and was able to perform normal daily life. The patient resumed antiviral therapy 60 days after the observation period and remained in medical care.

Patient No. 2: C.X, female, 49 years old, diagnosed with AIDS in 2004 and has a definite condition and participated in the first clinical trial. The patient had mild oral lesions, burnout, itchy skin, fever and poor appetite. Some of these symptoms are due to herpes virus. The patient has been treated with AZT, DDI, and NVP, but drug treatment is terminated due to side effects. The patient did not receive medical treatment 3 months before TPA treatment. The patient was hospitalized frequently and was unable to work. The CD4 value of this patient was 26 before treatment.

During the TPA treatment according to the treatment method of Example III, the patient experienced three episodes of body temperature rise to 37 to 38 ° C for 1 to 2 hours. In TPA After the treatment, the patient's oral lesions, itchy skin and fever disappeared. The appetite is fully improved, thus increasing the patient's weight and getting enough energy to return to homework. During this period, the patient was asymptomatic for five months and did not take any anti-AIDS drugs. The patient's improvement in symptoms was not associated with changes in CD3, CD4, CD8 values and viral load.

Patient No. 2a: M.S., male, 48 years old, participated only in the second clinical trial with frequent fever, diarrhea, weight loss, weakened immune system, severe depression and inability to work.

During the TPA treatment according to the treatment method of Example IV, the patient experienced 5 episodes of body temperature rise to 38.5 to 39 ° C for 2 to 4 hours.

After three cycles of TPA treatment, there was no problem with fever and diarrhea. The patient's CD3, CD4, and CD8 values increased as the number of white blood cells and the amount of HIC virus. The patient's physical and mental condition recovered and worked.

Patient No. 3: Y.P., male, 51 years old, was diagnosed with AIDS in 2004 and had a definite condition and participated in the first clinical trial. The main symptoms of the patient were diarrhea, burnout, weight loss, anemia, and purpura on the skin of the legs; and the patient was unable to work. The patient received AZT, DDI, and NVP treatment 4 months prior to TPA treatment, but the treatment was terminated due to severe anemia. The patient had an initial CD4 value of 32.

During the TPA treatment according to the treatment method of Example III, the patient experienced three episodes of body temperature rise to 38-39 ° C for 1 to 2 hours. After TPA treatment, the symptoms improved significantly, and the patient was able to recover from heavy labor and live a normal life. The patient developed no symptoms within 5 months after TPA treatment. And did not take antiviral drugs during this period. The patient's improvement in symptoms was not associated with changes in CD3, CD4, and CD8 values, but a slight increase in viral load was observed.

Patient No. 4: L.W., male, 34 years old, diagnosed HIV positive in 2004 with a definite condition and participated in the first clinical trial. The main symptoms of the patient were diarrhea, fever, weight loss, cough (tuberculosis), swollen lymph nodes in the right neck, and the patient was unable to work. It does not respond well to the initial stage of treatment. The course of treatment for 3TC, DDI, and NVP antiviral therapy is irregular and stops at the time of TPA treatment. The patient had an initial CD4 value of 173.

During the TPA treatment according to the treatment method of Example III, the patient developed 5 times of body temperature rise to 38-39 ° C for 0.5 to 1 hour. After treatment with TPA, the treatment of sporadic diarrhea was successfully treated with anti-diarrheal drugs. The improved appetite island to weight and energy increased the patient's ability to return to regular work. The lymph nodes return to their normal size. The patient continued to be treated with antiviral drugs. The patient's improvement in symptoms was not associated with changes in CD3, CD4, CD8 values and viral load.

Patient Nos. 5 and 3a: HS, female, 37 years old, diagnosed HIV positive in 2004 with a definite condition and participated in the first and second clinical trials. At the beginning of the first trial, the main symptoms of the patient were itchy skin, hair loss, oral infection, weight loss and burnout. The patient has received D ₄ T, DDI, and NVP antiviral therapy but stopped due to loss of renal function. The patient had an initial CD4 value of 106 and was able to perform regular labor work.

During the TPA treatment according to the treatment method of Example III, the patient developed 5 times of body temperature rise to 37.5 to 38 ° C for 0.5 to 1 hour. There is no symptomatic improvement after TPA treatment. No treatment after returning antiviral drugs The previous side effects were produced and their symptoms improved or improved after one month. The treatment continues and the patient has returned to work. The patient's improvement in symptoms was not associated with changes in CD3, CD4, CD8 values or HIV virus levels.

During the second trial, the patient developed no symptoms of AIDS and also had no adverse effects during the treatment as described in Example IV. After the second trial, the patient's CD3, CD4, and CD8 values increased as their white blood globular and platelet values. The patient's HIV virus amount was not detected initially, but increased after three cycles of treatment. The patient is currently working.

Patient Nos. 6, 4a, and 17: H.S.C, male, 36 years old, diagnosed HIV positive in 2004 with a definite condition and participated in three clinical trials. At the beginning of the first trial, the patient had dizziness, headache, poor appetite, and increased sensitivity to upper respiratory tract infections, but the patient was able to work routinely. The patient received antiviral therapy for AZT, DDT, and NVP, but was terminated due to adverse reactions. The patient had an initial CD4 value of 232.

During the TPA treatment according to the treatment of Example III, the patient had no increase in body temperature or any other side effects. After TPA treatment, the patient's symptoms did not change and thrombocytopenia was not associated with TPA treatment. The patient continued to be treated with antiviral drugs and was able to work as before. The patient's improvement in symptoms was not associated with changes in CD3, CD4, CD8 values or viral load.

During the second trial, the patient was asymptomatic and his immune system was functioning normally. During the second trial according to Example IV, the patient also had no side effects for TPA treatment. The patient's CD3, CD4, and CD8 values were as high as their white blood cells. The initial viral dose could not be detected, but increased after three cycles of treatment. However, the patient did not have any symptoms of AIDS and could return to work.

At the beginning of the third trial, the patient was asymptomatic. During TPA treatment according to the treatment of Example V, the patient developed local irritation on the 32nd day due to a missed needle, but returned to treatment within three days. The patient still has no symptoms, feels normal, and is able to work hard. The patient started antiviral therapy after the completion of the 60-day observation period and continued in medical care.

Patient numbers 7, 5a, and 16: HCL, male, 49 years old, were diagnosed HIV-positive and have a definite condition in 2004 and participated in three clinical trials. At the beginning of the first trial, the main symptoms of the patient were weight loss, itchy skin, burnout, poor appetite and cough (tuberculosis), but the patient was able to work in low labor. The patient received both D ₄ T, DDT, and NVP as well as anti-tuberculosis medication. The patient had an initial CD4 value of 10.

During the TPA treatment according to the treatment method of Example III, the patient developed 2 episodes of body temperature rise to 38 ° C with a slight dizziness and headache. After treatment, the patient's symptoms remained unimproved and returned to antiviral treatment one month later. The patient's cough, appetite and energy values were then improved and worked. The patient was treated with antiviral and antituberculosis drugs at the same time. The patient's improvement in symptoms was not associated with changes in CD3, CD4, CD8 values or viral load.

During the second clinical trial, the patient had no symptoms of AIDS and his immune system appeared to function normally. The patient had no adverse reactions during the TPA treatment in the second clinical trial. After treatment, the patient's CD4 value did not change, but his CD3 and CD8 values increased with white blood cell volume. The patient's viral amount could not be detected. The patient also did not have any AIDS symptoms and returned to work.

At the beginning of the third clinical trial, the patient did not show symptoms of AIDS. In the treatment according to the treatment method of Example V, the patient had a fever once. It is still asymptomatic, feels normal, and can perform heavy work. The patient resumed antiviral therapy after the completion of the 60-day observation period and continued in medical care.

Patient numbers 8, 6a, and 18: Y.X.O, female, 36 years old, were diagnosed HIV positive in 2004 and participated in three clinical trials. At the beginning of the first trial, the patient's main symptoms of upper respiratory tract infection were also increased. The patient was treated with AZT, DDI and NVP. At the start of the trial, the patient had a CD4 value of 524 and was able to perform regular labor work.

During the TPA treatment according to the treatment method of Example III, the patient developed a condition in which the body temperature rose to 38.5 ° C for 4 hours. After treatment, the frequency of the cold is reduced and there are no other symptoms. The patient continues to receive antiviral drugs and can work. The patient's improvement in symptoms was not associated with changes in CD3, CD4, CD8 values or viral load.

During the second clinical trial, the patient had no symptoms of AIDS and his immune system appeared to function normally. During the second trial, according to Example IV, the patient's body temperature rose again to 38.5 ° C for 2 hours. After treatment, their CD3 and CD8 values increased while their CD4 values and white blood cell values remained unchanged. The viral amount of the patient could not be detected. The patient is normal and can perform work that requires a lot of physical strength.

The patient developed no symptoms during the third clinical trial. The only side effect of the treatment according to Example V was skin irritation caused by a needle leak that occurred on the second day of treatment to 38 to 39 ° C for 2 hours and on the 36th day resolved within two days. The patient is still asymptomatic, feels normal, and can perform heavy work. The patient started antiviral therapy after the completion of the 60-day observation period and continued in medical care.

Patient Nos. 9 and 7a: C.T.F, male, 44 years old, was diagnosed HIV positive in 2004 with a definite condition and participated in the first two clinical trials. The initial symptoms of the patient included repeated diarrhea, headache, loss of appetite, weight loss and burnout. It showed a positive response in AZT, DDI and NVP treatment and the amount of HIV in the blood was close to the minimum limit. Despite the positive reaction, the patient's symptoms persisted and he was hospitalized for 20 days of persistent diarrhea. The patient was very depressed and could not do any work.

During the TPA treatment according to the treatment method of Example III, the patient developed 6 times of body temperature rise to 37.5 ° C for 2 to 4 hours. Severe skin irritation caused by missing needles occurred during TPA administration, but it has been properly treated. After 8 TPA treatments, there was a faint dizziness and headache, but the chance of diarrhea began to decline and its appetite improved. One week later, the patient's diarrhea completely healed and had a normal appetite. The patient was able to return to work and receive antiviral treatment. Its CD3, CD4 and CD8 are on the rise, and the amount of HIV virus cannot be detected.

During the second trial, the patient had no symptoms of AIDS and his immune system showed normal functioning. The patient had no adverse reactions during the TPA treatment according to the treatment method of Example IV. After treatment, their CD3, CD4, and CD8 values increased while their white blood cell values remained unchanged. The amount of HIV in this patient is still undetectable. The patient was able to work hard.

Patient Nos. 10 and 8a: W.F.W, female, 47 years old, diagnosed HIV positive in 2003 with a definite condition and participated in the first two clinical trials. The patient's symptoms at the beginning of the first trial included hypothermia, diarrhea, low platelet count, hemoptysis, bloody stool, dizziness, headache, loss of appetite, weight loss, burnout accompanied by mild itching and deep depression. The patient was hospitalized for two months due to bloody stools. The patient is very depressed and unable to work. It has no positive response to AZT, DDI, and NVP treatment and its symptoms are not controlled.

During the first treatment of TPA according to Example III, the patient developed a condition in which the body temperature rose to 38.5 ° C for 4 hours. After TPA treatment, dizziness, headache, and diarrhea gradually diminished. Finally, the appetite of the patient increased his weight and improved his physical strength. The platelet value increased to 30,000 to 110000/μL, and skin itching and diarrhea were also alleviated. The patient was able to return to work and receive antiviral medication. The patient will have occasional fever and diarrhea, but it can be controlled by drugs.

The patient sustained mild headache and dizziness for 6 months in the second trial of TPA. In the second trial with TPA, the patient experienced 5 episodes of body temperature rise to 37.5 to 38 ° C for 2 to 4 hours. At 20 hours after the 13th injection of TPA, the patient's body temperature reached 40.5 ° C for several hours. It can be inferred that the rise in body temperature is not associated with TPA therapy.

After the second treatment of TPA, the patient's symptoms disappeared, his appetite improved, and his weight gained, he was able to recover his strength and return to work and normal life. The patient developed asymptomatic within one year after the second TPA treatment and had several colds in the first six months. Its CD3, CD4 and CD8 values have an increasing trend with the amount of HIV virus.

During the second bed test of the treatment according to Example IV, the patient continued to have no symptoms of AIDS and his immune system appeared to function normally. The patient had no side effects during the treatment period. After treatment, the CD3, CD4 and CD8 values follow Increase in the number of white blood cells. The amount of HIV virus has also increased. As a result of these tests, the patient became healthy and able to work in labor.

Patient Nos. 11 and 9a: C.T.L, female, 40 years old, was diagnosed with AIDS in 2003 and had a definite condition and participated in the first two clinical trials. At the beginning of the first trial, the patient had repeated diarrhea, hypothermia, mouth sores, severe itchy skin, itching, purple spots on the face and lips, dizziness, headache, loss of appetite, and burnout and depression. It does not respond well to AZT, 3TC, and NVP treatments. The patient's symptoms were not controlled and could not work. Its initial CD4 amount is 40.

During the first treatment of TPA, the patient experienced 4 changes in body temperature to 38-39 ° C for 2 to 4 hours. It occurs twice shortly for 20 to 30 minutes.

After the sixth dose of TPA, the patient's skin itching began to disappear and until the end of TPA treatment, dizziness, headache, fever, and itchy skin improved and gradually disappeared. The apparent appetite, physical condition, and melancholia in the patient improved her ability to return to work.

The patient due to the mild skin itching, diarrhea, dizziness and ^other symptoms of relapse and a second TPA treatment for 18 months. In the second treatment, the patient experienced three changes in body temperature to 37.5 to 38 ° C for 2 to 4 hours. There are no other adverse reactions. After treatment with TPA, the patient's symptoms completely disappeared and his physical condition improved sufficiently to allow him to return to work. The patient had no recurrence of symptoms within a year and was not susceptible to a cold. The CD3, CD4 and CD8 values have an increasing trend, but their HIV values have not changed.

During the second clinical trial according to Example IV, the patient presented symptoms of AIDS, including headache, dizziness, loss of appetite, and weakened immune system. The patient had no adverse reactions during the treatment period. After treatment, the CD3 and CD8 values increased while the CD4 values did not change. Its HIV value increased dramatically but other changes were not found. The patient's mental and physical condition improved and he was able to perform intense labor.

Patient Nos. 12 and 10a: C.C.L, female, 39 years old, was diagnosed with AIDS in 2003 and had a definite condition and participated in the first two clinical trials. The patient had repeated hypothermia, itchy skin, dizziness, headache, loss of appetite, mouth sores, burnout and deep depression at the beginning of the first trial. The patient did not respond well to AZT, 3TC, and NVP treatments and was unable to work. Its initial CD4 value is 84.

The patient received TPA twice from March 2005 to March 2006. During the first TPA treatment, the patient experienced an increase in body temperature to 38 to 38.5 ° C for 2 to 4 hours. The patient had a shortness of breath that lasted 15 minutes and skin irritation caused by a needle leak.

After 7 injections, the patient's mouth sores disappeared. After all injections are completed, all symptoms disappear and their physiological condition is adequately improved to allow them to return to work.

After 6 months, the patient was re-treated with TPA due to mild diarrhea and dizziness recurrence. The patient had a 6-fold increase in body temperature to 37.5 to 38 ° C for 2 to 6 hours. At the start of the 8th injection, the dose was increased to about 150 μg to 250 μg of TPA. No adverse reactions occurred. After completing the TPA treatment, all symptoms disappeared. The physiological condition returns to normal and will go to work and lead to normal production. There was no symptom in the following year and there was very little cold. The patient's CD3, CD4 or CD8 The value did not change, but the amount of HIV increased.

During the second clinical trial, the patient had no symptoms of AIDS because it had no weak immune system. The patient received treatment according to the treatment of Example IV and had no adverse reactions. After treatment, the CD3, CD4 or CD8 values increased slightly, white blood cells, red blood cells and hemoglobin increased moderately, and platelets decreased. The amount of HIV has decreased. The patient became healthy and able to work hard because of treatment.

Patient No. 13: L.F.L, female, 53 years old, was diagnosed with AIDS in 2004 and was only involved in the third clinical trial. The patient had mild symptoms such as poor appetite and weight loss. Long-term antiviral drugs are effective and the viral dose is reduced below the detection value and CD3, CD4 or CD8 values are elevated. The patient was asymptomatic before TPA treatment and had no side effects on the administration. The patient is still asymptomatic, feels normal, and can perform normal daily life. The patient was re-treated with antiviral medication after completing the 60-day observation period.

Patient No. 14: K.S.M, female, 45 years old, was diagnosed with AIDS in 2004 and was only involved in the third clinical trial. The patient had mild and persistent symptoms such as poor appetite and frequent flu. The patient has been treated with antiviral drugs but has been terminated due to severe liver toxicity. The patient was asymptomatic before TPA treatment and only had side effects on the 43rd day due to the stimulation caused by the leaking needle, which was easily treated. No AIDS symptoms occurred during the entire treatment period and during the observation period. The patient feels normal and is able to perform his or her daily activities. The patient stopped the trial after completing the 60-day observation period and did not restart antiviral therapy.

Example VII TPA for the treatment of recurrent/refractory malignant tumors

Patients with pathologically determined relapsed/refractory hematological malignancies/bone marrow disease were treated with TPA (Xichuan Pharmaceuticals, Nan Yang, Henan, China) in combination with dexamethasone and magnesium choline trisalicylate. A comparative method for confirming the efficacy of TPA in the treatment of acute myeloid leukemia (AML) will be applied to confirm the use of TPA for the treatment of other tumor symptoms and malignancies. Other tumor symptoms and malignant tumor diseases that are treated using the methods and compositions of the present invention include various forms of cancer, including malignant tumors of blood and bone, and various types of solid cancer. In other specific methods, successful treatments and/or mitigation methods will be used to detect different tumors and malignant conditions detected by any conventional cancer detection and assessment method, such as by detecting solid cancer. Size reduction, pathological section studies to assess tumor growth, stage, metastatic potential, presence or performance values of tissue cancer markers, and the like.

AML is a malignant disease that usually requires urgent and powerful treatment. The mean age of patients diagnosed with AML was 64-68 years, and the survival rate of patients over 60 years of age with AML treated with standard chemotherapy was less than 20%. In addition, patients who develop AML after suffering from a blood disease or who develop AML prior to chemotherapy/radiotherapy for leukemia have a poor prognosis associated with specific adverse cytogenetic and clinical features. Therefore, most patients diagnosed with AML have very poor post-patient and/or disease-related characteristics. For patients with recurrent disease, there is no standard non-transplant therapy that has proven to be curable. For these patients, AML is a terminal illness. A new approach to the treatment of AML is needed.

Using the method and composition of the present invention, the TPA system is developed as a therapeutic agent for the treatment of AML, which can reduce the differentiation and/or apoptosis of the cell line due to the novel role of TPA in regulating the intracellular signaling pathway, and clinical Data show that TPA is treating swelling Tumors and malignant diseases, including the effectiveness of myeloid malignancies.

Clinical evaluation of TPA has been shown to have direct cytotoxic therapeutic effects in at least one AML case, and the period is measured by cell viability and apoptosis analysis. In the primary culture analyzed by the Western blotting method, TPA strongly induced ERK phosphorylation in one hour of culture. After 24 hours of in vivo exposure, the cytotoxicity of TPA in primary AML cells is associated with a phospho-ERK pro-survival signal. This finding is consistent with other studies that suggest that MEK inhibitors, such as PD98059, U0126, and PD 184352, pharmacologically interfere with ERK messages, and reduce the survival of primary AML. In this study, loss of ERK messages was associated with ERK phosphatase induction.

In addition to the activation of protein kinase C and ERK, TPA is a well-known elicitor of NF-κB, a pro-survival transcription factor that is frequently activated in AML mother cells or leukemia stem cells. Recent studies in our laboratory have confirmed that NF-κB is inhibited after 48 hours of treatment of AML cells with dexamethasone + choline magnesium succinate (CMT). In addition, we also show that dexamethasone can induce MKP-1 ERK phosphatase expression and enhance the cytotoxicity of TPA on primary AML samples. Herein, we chose to use dexamethasone and CMT as adjuvants in the following exemplary embodiments, using 24 hours before and 24 hours after TPA treatment. These drugs are well tolerated and are expected to be used to reduce the inflammatory side effects of the treatment and to enhance the cytotoxicity of TPA by increasing the potentiation of ERK phosphatase expression and inhibition of NF-κB. In addition, dexamethasone and CMT will be used as an auxiliary drug system because it has anti-inflammatory properties, can improve adverse reactions, and can inhibit the anti-apoptotic effect and induce the decrease by inhibiting the sustained expression of NF-κB. The message transmits the activity of phosphatase activation to enhance the anti-leukemia effect.

The initial TPA Phase I trial enrolled 35 patients (23 with recurrent/refractory AML, 2 with other bone marrow malignancies (CML-blast crisis, excessive mother cells) Myeloid hyperplasia syndrome, 3 patients with Hodgkin's disease, 3 patients with non-Hodgkin's lymphoma and 4 patients with parenchymal tumors. The subject's patient suffers from recurrent/refractory AML. The clinical outcome included an AML patient receiving 8 TPA injections with a stable course of greater than 5 months. In the second AML patient, the number of circulating blasts decreased significantly (5 times) after TPA administration. The decline in leukemia mother cells lasted for 4 weeks, and the patient eventually died of a mold infection. Finally, after receiving TPA, patients receiving high-dose chemotherapy and autologous stem cell rescue had partial relief of the chest wall mass of patients with recurrent Hegelin's disease, which is extremely difficult to treat. The dose of TPA has been increased to present grade III non-hematologic dose limiting toxicities (DLT) in patients treated with TPA at doses of 0.188 mg/m2 d1-5, 8-12. The maximum tolerated dose of TPA was 0.125 mg/m2/d for single agents of d1-5 and 8-12.

In the case of AML and other hematological malignancies, the patient was given a 1 mg/week initial dose of TPA for 3 weeks (days 1, 8, and 15), with continuous/intermittent control of pulse oximetry for 6 hours. . At 24 hours prior to initiation of TPA treatment, the patient was continuously administered 10 mg of dexamethasone per 6 hours and 1500 mg of choline magnesium succinate (CMT) per 8 hours until 24 hours after TPA administration. After the initial dose of TPA is administered, it can have a 2-week rest period after the patient is reassessed. Patients who have a disease response or are stabilized by the initial dose of TPA will be treated for 6 cycles of 28 days according to the following treatment.

After a 2-week rest period, 650 mg of Tylenol and 25-50 mg of Benadry (depending on the patient's size and age) were administered to the patient 30 minutes prior to TPA administration. The intravenous injection of TPA was then administered through a central venous catheter for 5 days a week for 2 weeks and followed by a 2 week rest period. TPA was dissolved in normal saline for 1 hour at a dose of 1 mg. At 24 hours prior to TPA treatment, patients were administered 10 mg of dexamethasone per 6 hours and 1500 mg of choline magnesium succinate (CMT) per 8 hours until 24 hours after TPA administration.

The content of TPA in the blood is measured before and after the injection, and the biochemical reagent for extracting the differentiation activity is extracted using an organic solvent. 1 ml of the blood line was extracted twice with 5 ml of ethyl acetate, and the extracted residue was re-dissolved into 50 g of ethanol to aliquot the HL60 cells. At 48 hours, measure the attached cells.

Blood samples collected before and after TPA injection were also tested for white blood cells, platelets, and neutrophils. The specimen was additionally analyzed for the presence of myeloid cells and Auer's bodies. These and ongoing experiments will further clarify the therapeutic effects and other effects of TPA on cytotoxicity. TPA can resist tumor cells and other tumors and malignant conditions in AML.

Example VIII Measurement of the regulation of ERK activation

The amount of phosphorylated ERK in the circulating malignant cells of patients with leukemia and peripheral blood mononuclear cells in patients with leukemia/parenchymal cancer is measured. The blood test system was collected before and after treatment with TPA according to the treatment method of Example VII.

In having In a 1000/μL leukocyte-derived leukemia patient, the fluorescent group ((BD Biosciences, San Jose, CA) was directly measured by flow cytometry using cell surface antigen-specific and phosphorylated ERK-specific antibodies. The test system was collected on days 1, 2, and 11 of the initial treatment according to the treatment method of Example VII, before the TPA administration and 1 hour after the TPA injection, and on the first and eleventh days of the cycle. Number of leukemia mother cells In 2500/μL leukemia patients, as well as other non-leukemia patients, peripheral blood test systems were collected on days 1, 8, and 15 of the initial treatment cycle according to the treatment of Example VII, and at 1 and 4 hours prior to injection. The samples were also analyzed by Western blotting to analyze the phosphorylated ERK and total ERK1/2 expression to confirm the results obtained by flow cytometry and related clinical responses.

The foregoing analysis will further illustrate the role of TPA in the treatment of tumors and malignant conditions, including the cytotoxic effects of TPA on malignant cells, explained by primary AML cells, and the reduction in phosphorylation-ERK survival-promoting messages associated with TPA.

Example IX Measurement of NF-κB regulation

In previous studies, it was shown that the activity of NF-κB can be adjusted after the patient receives the administration of TPA and dexamethasone. In addition, dexamethasone was shown to induce the expression of MKP-1 ERK phosphatase and potentiate the cytotoxicity of TPA. The next study was designed to clarify how the activity of NF-κB is therapeutically modulated by treatment with TPA and dexamethasone.

NF-κB was measured on peripheral blood samples from patients. The system was taken from patients who were treated with TPA according to Example VII, collected before and after injection, and using ELISA-based assays (BD Bioscience, San Jose, USA). )Measure. NF-κB was quantified using luminescence intensity and detected using a limit value of a cell extract of a 96-well plate. In addition, the number of mother cells with absolute leukemia was measured by electrophoretic mobility shift assay NF-κB in peripheral blood samples collected from 2500/μL leukemia patients and non-leukemia patients with normal white blood cell counts.

The foregoing study will further elucidate that TPA is an inducer of NF-κB, however, these experiments confirmed that NF-κB in AML cells can be inhibited by dexamethasone and magnesium choline trisalicylate.

Example X Determination of changes in leukemia gene expression

TPA induces RNA expression of many dual-specific phosphatases, thereby terminating the pro-survival ERK message pathway. A blood test system collected from AML patients treated with TPA according to the method of Example VII was used to study the expression of AML signaling members, such as MAPK-specific dual specific phosphatase RNA, using real-time quantitative RT-PCR and Oligonucleotide microarray analysis.

Although the present invention has been described in detail with reference to the embodiments of the present invention, it will be apparent to those of ordinary skill in the art that a part of the changes and modifications may be practiced in the scope of the appended claims. Presented in a manner that illustrates nature rather than nature. In this document, various publications and other references are included in the previous disclosure to save the description. Each of these references is hereby incorporated by reference in its entirety. It is to be understood that the disclosures of the various publications disclosed herein are incorporated in The right to retain these disclosures is reserved.

Example XI Lymphoma treatment

Patient MJ, 60 years old, male, was diagnosed with recurrent lymphoma and had a lump diameter of 3.5 cm. The patient was administered 0.19 mg of TPA (0.125 mg/m ² ) with 15 injections every other day for 30 days and the mass disappeared. As of 2011, the patient has been relieved for 3 years.

Example XII Breast cancer treatment

Patient ML, 50 years old, female, was diagnosed with the end of breast cancer. The patient did not respond to radiation or chemotherapy, and the cancer had metastasized to the bone and required a wheelchair. The patient received 35 injections of a progressive dose of 0.18 mg of TPA (1 x 0.125 mg/m ² ) to 0.26 mg of TPA (1.5 x 0.125 mg/m ² ), three to four times a week, the current name The patient's symptoms are relieved and they are able to walk normally.

Example XIII Treatment of lung cancer

Patient JL, 56 years old, male, was diagnosed with terminal lung cancer that was difficult to cure with chemotherapy. The cancer was transferred to the patient's bones making it impossible to walk. 35 injections of a progressive dose from 0.19 mg of TPA (1 x 0.125 mg/m ² ) to 0.26 mg of TPA (1.5 x 0.125 mg/m ² ), three to four times a week, the patient is currently symptomatic And can walk normally.

Example XIV Treatment of liver cancer

Patient X, male,? Aged, diagnosed with metastatic liver cancer. Its initial alpha fetoprotein value is 48813. After chemotherapy and radiation therapy, the alpha fetal protein value still rose to 50000+. The patient received three injections of 0.19 mg of TPA (0.125 mg/m ² ), and the alpha fetal protein value began to decrease and returned to normal after four months.

Example XV TPA as an adjuvant to traditional cancer treatment

Patient NK, female, 54 years old, was diagnosed with pancreatic cancer with terminal metastases. The patient received five injections per week of 0.18 mg of TPA (0.125 mg/m ² ) per week for 12 weeks in addition to chemotherapy. These treatments reduced the pancreatic tumor of the patient from 6.3 cm to 2.4 cm. The patient maintained appetite and had no hair loss and had significantly reduced symptoms of vomiting and nausea compared to previous chemotherapy without TPA treatment.

Patient PT, male, 42 years old, was diagnosed with non-small cell lung cancer. Cancer has been transferred and ^{Tarceva® (erlotinib) and Iressa TM (} gefitinib) is difficult to cure. The patient received gemcitabine and cisplatin combination therapy according to standard treatment with injection of 0.19 mg of TPA (0.125 mg/m ² ) per week for 8 weeks. During the combination of chemotherapy and TPA, the patient had no hair loss and had a significantly reduced nausea compared to previous chemotherapy. The patient has been relieved on June 30, 2010.

Patient BL, male, 59 years old, was diagnosed with nasopharyngeal carcinoma and received both chemotherapy and radiation therapy. The patient received 0.19 mg of TPA (0.125 mg/m ² ) injection/day for 5 days prior to initiation of radiation therapy, and then received 0.19 mg of TPA (0.125 mg/m ² ) for injection per One day, a total of 20 injections. The patient has been relieved for 2 and a half years without any significant skin damage from radiation therapy.

Example XVI Chemical protection of TPA

A colony forming assay was used, which contained Semi-Solid Medium containing DMEM and 0.5% acacia gum. In these cultures, the monocyte line was cultured at a density of ^2.5 x 10 ⁵ cells/ml, and GM-CSF and G-CSF at a concentration of about 100 U/ml were added. The cells were cultured in a 5% CO ₂ incubator at 100% humidity for 37 days at 37 °C. At the end of the incubation, 50 or more cell populations were calculated by two independent observers using an inverted microscope. (Hamburger, 1977)

Peripheral stem cells were randomly added to 4 groups of cells of ⁵ x 10 ⁵ cells/ml in DMEM supplemented with 10% fetal bovine serum. The first and fourth groups were treated with the control group, while the second and third groups were cultured with 0.05 μg/mL of TPA for 24 hours. After 24 hours, the cells were washed with DMEM supplemented with 10% fetal bovine serum. Groups 3 and 4 were then incubated with 25 μg/mL of 5-fluorodeoxyuridine monophosphate for 20 hours, which is a metabolite of Fluorouracil. Next, all groups were washed twice and the cells were placed in semi-solid medium. Cell populations were calculated on day 14.

Example XVII TPA is used for radiation damage

Three cell lines were used to detect the effectiveness of TPA against radiation damage: IL-3-dependent murine hematopoietic progenitor cell line, human bone marrow stromal cell Line, KM101), and bronchial epithelial cells (IB3). The 32D cl 3 IL-3 dependent murine hematopoietic progenitor cell line was differentiated by long-term bone marrow culture of C3H/HeJ mice as described by Epiply, 2008. Cell lines were subcultured to 15% WEHI-3 cell conditioned medium (as a source of IL-3), 10% fetal bovine serum (Hyclone Laboratories, Logan, UT) and McCoy's medium. Human bone marrow stromal cell lines were subcultured weekly to 24 cm ³ of Falcon plastic culture flasks, among which were McCoy's 5A conditioning medium (GIBCO BRL, Gaithersburg, MD) and 10% fetal bovine serum (Hyclone Laboratories, Logan, UT). The IB3 cell line was subcultured twice a week in standard DMEM (Lonza, Allendale, NJ) with 10% fetal bovine serum (Hyclone Laboratories, Logan, UT), 1% L-glutamine (GIBCO BRL, Gaithersburg). , MD), and 1% penicillin/streptomycin (GIBCO BRL, Gaithersburg, MD), in a 75 cm ³ tissue cultured Falcon bottle, and cultured in a 5% CO ₂ incubator at 37 ° C 48~ 72 hours to reach 80% full, as described by Rwigema, 2011.

The cell line of each cell strain was suspended at 1 × 10 ⁵ cells/mL and irradiated with 0 to 8 Gy. TPA was administered to the irradiated cells after 10 minutes of irradiation. The cells were then divided into four sections and cultured in a high-humidity incubator, cultured at 37 ° C, 95% air, 5% CO _{2 for} 7 days, and the cell lines were stained with crystal violet and cell populations larger than 50 cells were counted. Each experimental department was performed at three different times in three days. The data was analyzed using linear quadratic and single-hit (multi-target models) (see Epperley, 2001). The dose-reduction factor (DRF) of TPA is calculated as the ratio of the dose of 50% of the cells surviving, divided by the 50% surviving dose in the control group, according to the group administered for treatment.

Example XVIII TPA protects mice from radiation damage

Adult C57BL/6 NHsd females (20-20 g Harlan Sprague Dawley, Chicago, IL) (n=15/group) were administered 9.5 Gy of TBI irradiation to achieve a dose ratio of Gamma beta radiation (74 cGy/min) ( A dose of LD 50/30) and an intraperitoneal injection of 0.125 mg/m ² of TPA after 10 minutes. Survival rates of these mice were monitored (Rigwema, 2011).

Example XIX Treatment of individuals with stroke

The patient, NC, male, 68 years old, suffered a stroke for 18 months prior to TPA treatment. At the beginning of the TPA treatment, the patient relied on a cane for walking, and it was difficult to use the left and left feet, and was tired and weak. The patient received 0.19 mg of TPA (0.125 mg/m ² ) injection per other day for 4 weeks, followed by 0.24 mg of TPA (1.25 x 0.125 mg/m ² ) injection per other day for 2 weeks. Then, 0.26 mg of TPA (1.5 x 0.125 mg/m ² ) was injected/every day for 3 weeks. The patient recovered completely.

The patient, MC, male, 65 years old, suffered a stroke for 7 months prior to TPA treatment. The patient received 0.19 mg of TPA (0.125 mg/m ² ), three to four injections per week for a total of 10 weeks for a total of 35 injections. The patient's face regained mobility and 80% of the activity on the right side improved.

Example XX TPA treatment of embolic stroke (Embolic Stroke) mode

Male Sprague-Dawley rats (Charles River Japan) weighing 280-350 g were used. The embolic stroke was induced by a method modified by Kudo, et al. (1982). Rats with blood for in case of spontaneous breathing 1.0% halothane ^{(halothane (Fluorothane TM; Takeda,} Osaka, Japan)) anesthesia. 24- measuring conduit ^{(Surflo TM (Terumo Medical Products,} Elkton, MD)) lines were placed in the femoral artery, and the arterial line to 0.1ml of 1-ml syringe (Terumo Medical Products, Elkton, MD ) for injecting the Collected. The arterial blood line in the syringe was cultured at 30 ° C for 2 days to form coagulation. Thereafter, 0.1 ml of physiological saline was added to the syringe for injection, and the coagulation was pulverized by 26-measuring the injection needle (Terumo Medical Products, Elkton, MD) twice.

Rats that induced cerebral embolic stroke were anesthetized with 1.0% halothane in the case of spontaneous breathing. The cervical line of the rat was incision and the external carotid artery, thyroid artery, occipital artery, and pterygopalatine artery were bipolar coagulator (T-45; Keisei Medical Industrial Co.Ltd) , Tokyo, Japan) cauterization. Cerebral embolism was induced by injecting 0.1 ml of comminuted coagulation into the internal carotid artery.

The development and formation of cerebral embolism was performed using Laser Doppler Flowmetry (FloCl; Omegawave, Tokyo, Japan). A decrease in cerebral blood flow to 30% or less is considered positive evidence of embolization. After injection of coagulation, cerebral blood flow was monitored for 30 minutes, while blood flow was monitored to be maintained at 50% or less than before blood injection. Thereafter, the cannula (PE50) for administering the drug is fixed to the internal jugular vein, and the experimental animal is awakened.

Successful animal models that form cerebral embolism are divided into four groups. The first group of rats was administered saline injection/every other day. The second to fourth groups were administered with 0.125 mg/m ² of TPA injection per other day for 4 weeks. Then the second group will be sacrificed. The third to fourth groups were administered an additional 0.156 mg/m ² of TPA injection per other day for 2 weeks and then sacrificed the third group. The fourth group was re-injected with 0.18775 mg/m ² of TPA injection per other day for three weeks and then sacrificed.

The brain was excised after the animal was sacrificed, and sliced into 10 portions every 1 mm using a McIwain tissue chopper (Mickle Laboratory Engineering, UK), and immersed at 2% at 37 ° C. 2,3,5-triphenyltetrazolium chloride (TTC) (Tokyo Kasei) was stained for 20 minutes. The images of the sections stained with TTC were downloaded to a computer using a digital camera (HC-2500; Fuji Photo Film) and Phatograb-2500 (Fuji Photo Film), and the volume of the infarct was calculated using a Mac Scope (Mitani, Japan). The volume of the infarct is represented by the mean ± standard deviation. The statistical test on the results of the volume of the infarction was performed by the Dunnett's Test in the control group and each of the TPA-administered groups compared with the control group, and then in the group administered with TPA. Perform t-test.

The nervous system symptoms of the rats were observed daily until sacrifice, and then the rats were evaluated according to three tests: (1) Gently grasping the tail of the rat, hanging at a distance of 1 m from the ground, and observing the forelimb flexion State; (2) Rats were placed on large sheets of soft, plastic coated paper, which was a paper that could be firmly grasped by rats. The hand was grasped by the tail of the rat, and the direction of pressure was applied slightly to the shoulder of the rat until the forelimb fell a few inches; (3) the rat was allowed to move freely and observe the behavior of the circle. The scores for neurological symptoms were based on the criteria developed by Bederson et al. (1986) as follows: 0: no defects were observed; 1: forelimb flexion; 2: in the absence of a circle, Resistance to lateral shift decreases; 3: Same behavior as level 2 in the case of a circle.

Nervous system symptoms were performed using the Steel's test in the control group, and each of the TPA-administered groups compared to the control group, and then evaluated by performing a Wilcoxon test on the TPA administration group. In any test, a value of p < 0.05 was defined as substantially significant.

Example XXI Therapeutic effect of TPA on stroke in a permanent middle cerebral artery occlusion model

Wistar male rats (250-320 g) were used for this study. Animals were anesthetized with isoflurane (3% induced, 1 to 2% maintenance). The anesthesia is monitored by the toes. Sterile techniques were used for all procedures in this study. The surgical site was cut open and cleaned with alcohol and surgically. Animals were placed in a warm water heating pad to maintain body temperature. A central opening is made in the neck of the carotid artery. The tissue is directly isolated to expose the carotid artery and its branches. The suture is surrounded by a proximal part or a common carotid or external carotid artery. The suture was tied. The incision is made in the common carotid artery and is ligated distally. A pre-prepared filament (4-0 monofilament suture or the like) is placed in the carotid artery and more advanced in the internal carotid artery. The filaments were passed through the carotid artery branches for about 20 mm until a slight resistance was felt as if they were stuck in the central carotid artery. When the filament is inserted, the carotid artery must be protected from rupture. The filament is tied to this position and the skin incision is closed. When the successfully embolic animal is awakened, it is evaluated using a Bederson scale (See Bederson et al., (1986) Stroke, 17: 1304-1308.) as previously described. Body temperature was measured every 15 minutes to maintain normal temperature. Animals undergoing cerebral artery occlusion surgery have difficulty maintaining body temperature for several hours after surgery. Depending on the body temperature of the animal, it is placed in a cooled or heated box. The body temperature was maintained at 37.5 °C. monitor The carotid artery was placed in the animal for 6 hours and placed in a cage overnight.

Rats were divided into four groups. The first group of rats was administered saline injection/every other day. The second to fourth groups were administered with 0.125 mg/m ² of TPA injection per other day for 4 weeks. Then the second group will be sacrificed. The third to fourth groups were administered an additional 0.156 mg/m ² of TPA injection per other day for 2 weeks and then sacrificed the third group. The fourth group was re-injected with 0.18775 mg/m ² of TPA injection per other day for three weeks and then sacrificed.

The brain was excised after the animal was sacrificed, and sliced into 10 portions every 1 mm using a McIwain tissue chopper (Mickle Laboratory Engineering, UK), and immersed at 2% at 37 ° C. 2,3,5-triphenyltetrazolium chloride (TTC) (Tokyo Kasei) was stained for 20 minutes. The images of the sections stained with TTC were downloaded to a computer using a digital camera (HC-2500; Fuji Photo Film) and Phatograb-2500 (Fuji Photo Film). Brain sections were used to capture and analyze infarct size, infarct volume, penumbra, and edema.

The nervous system symptoms of the rats were observed daily until sacrifice. The neurological symptoms of the rats were observed daily until sacrifice and then the rats were evaluated according to three trials. (1) Gently grasp the tail of the rat, suspend it at a distance of 1 m from the ground, and observe the flexion state of the forelimb. (2) Rats were placed on large sheets of soft, plastic coated paper, which was a paper that could be firmly grasped by rats. The rat's tail was grasped by the hand and the directional pressure was applied slightly to the shoulder of the rat until its forelimb fell a few inches. (3) Let the rat move freely and observe its behavior around the circle. The scores for neurological symptoms were based on the criteria developed by Bederson et al. (1986) as follows: 0: no defects were observed; 1: forelimb flexion; 2: in the case of uncircled, for lateral Resistance to decline decreases; 3: In the case of a circle, it has the same behavior as the second level.

Nervous system symptoms were performed using the Steel's test in the control group, and each of the TPA-administered groups compared to the control group, and then evaluated by performing a Wilcoxon test on the TPA administration group. In any test, a value of p < 0.05 was defined as substantially significant.

Example XXII The effectiveness of TPA in the stroke of the transient middle cerebral artery occlusion model

C57B16 male mice (25-30 g) were used for this study. Animals were anesthetized with isoflurane (3% induced, 1 to 2% maintenance). The surgical site was cut open and cleaned with alcohol and surgically. The neck on the carotid artery creates a median opening and the artery is dissected to its branches. The monofilament suture is pulled to the internal carotid artery until it is hosted in the middle carotid artery. The suture is tied to this position and the incision is closed. Two hours after occlusion of the mice, the mice will be anesthetized again and the suture removed. Body temperature is maintained by using a heating pad during or after surgery. Animals were monitored 4 hours after occlusion of the middle cerebral artery.

The mice were divided into four groups. The first group of mice was administered saline injections / every other day. The second to fourth groups were administered with 0.125 mg/m ² of TPA injection per other day for 4 weeks. Then the second group will be sacrificed. The third to fourth groups were administered an additional 0.156 mg/m ² of TPA injection per other day for 2 weeks and then sacrificed the third group. The fourth group was re-injected with 0.18775 mg/m ² of TPA injection per other day for three weeks and then sacrificed.

The brain was excised after the animal was sacrificed, and sliced into 10 portions every 1 mm using a McIwain tissue chopper (Mickle Laboratory Engineering, UK), and immersed at 2% at 37 ° C. 2,3,5-triphenyltetrazolium chloride (TTC) (Tokyo Kasei) stained for 20 minutes. The images of the sections stained with TTC were downloaded to a computer using a digital camera (HC-2500; Fuji Photo Film) and Phatograb-2500 (Fuji Photo Film). Brain sections were used to capture and analyze infarct size, infarct volume, penumbra, and edema.

The neurological symptoms of the rats were observed daily until sacrifice, and the rats were evaluated according to three trials. (1) Gently grasp the tail of the rat, suspend it at a distance of 1 m from the ground, and observe the flexion state of the forelimb. (2) Rats were placed on large sheets of soft, plastic coated paper, which was a paper that could be firmly grasped by rats. The rat's tail was grasped by the hand and the directional pressure was applied slightly to the shoulder of the rat until its forelimb fell a few inches. (3) Let the rat move freely and observe its behavior around the circle. The scores for neurological symptoms were based on the criteria developed by Bederson et al. (1986) as follows: 0: no defects were observed; 1: forelimb flexion; 2: in the case of uncircled, for lateral The resistance to the shift is reduced; 3: the same behavior as the second level in the case of the circle.

Nervous system symptoms were performed using the Steel's test in the control group, and each of the TPA-administered groups compared to the control group, and then evaluated by performing a Wilcoxon test on the TPA administration group. In any test, a value of p < 0.05 was defined as substantially significant.

Example XXIII Clinical efficacy of TPA in the treatment of stroke

Men and women with strokes between the ages of 30 and 72 were enrolled in a 10-week TPA trial.

Recruited individuals signed informed consent and used computed tomography (CT), physiological and neurological testing, neurological testing, sedation, National Institute of Health Stroke Survey (NIHSS) , 12-lead electrocardiogram, telemetry of electrocardiogram, pulse oximetry, vital signs, weight, patient background, pregnancy test, urine drug test, blood test, coagulation status, general clinical test Evaluation by urine test. Clinical laboratory tests include Comprehensive Metabolic Panel (Na, K, Cl, CO2, Glu, BUN, Cr, Ca, TP, Alb, TBili, AP, AST, ALT), Blood Metabolism Instrumentation (Hematology CBC) (Hgb, Hct, RBC, WBC, Plt, Diff) and all female serum human chorionic hormone (HCG).

The system was administered at 0.125 mg/m ² of TPA or placebo / every other day for 4 weeks, followed by 1.25 x 0.125 mg/m ² of TPA or placebo/every day at weeks 5 and 6, and 1.5 x 0.125 mg/m ² of TPA or placebo/every day was administered from week 7 to week 9. The system was monitored between TPA or placebo and two hours after dosing.

From week 5 to week 10, the system was evaluated using the NIH Stroke Scale (NIHSS), the Barthel ADL Index (Granger, 1979), and the adjusted Rankin table (Farrell, 1991).

The effectiveness was determined by measuring changes in the NIHSS5 baseline for individuals who were dosed with TPA and with placebo. Secondary efficacy variants were the Barthel ADL index and the adjusted Rankin table. Safety measures are controlled by trials, especially at the 5th week. These measurements include Reports of adverse events, physiological tests, signs of life, body weight measurements, electrocardiograms, clinical laboratory test results, and scores of suicidal behavior and/or ideation. Adverse events are any adverse medical events that occur in the individual being administered, whether or not related to the study drug. Adverse events can therefore be any adverse or unintended signs (eg, containing abnormal laboratory findings), symptoms, or transient illnesses associated with the study drug, whether or not related to the study drug.

Individuals who completed all visits were considered to have completed the study. Those individuals who are unable to be included/excluded to the standard; have an adverse event; have an ineffective treatment response; withdraw consent; violate the agreement; stop attending; or the death can suspend the study.

Example XXIV Reduction of pigmentation around the eyes

Six women with severe periocular pigmentation and one male TPA were treated. These treatments reduce inflammation and pigmentation in the periocular area.

Example XXV Treatment of carpal tunnel syndrome

A female patient, 50 years old, has symptoms of burning, tingling, pain, and numbness on her fingers. The patient was treated with TPA and regained his hand function.

Example XXVI Anti-aging properties of TPA

The patient, WL, male, 82 years old, was treated with a dose of 1.25 doses of TPA of 0.125 mg/m ² / every other day for 2 months. After treatment with TPA, the patient's skin became smoother and wrinkles decreased.

Example XXVII Treatment of Parkinson's disease

The patient, SK, 55 years old, was diagnosed with Parkinson's disease. The patient was administered a dose of 1 injection containing 0.19 mg (0.125 mg/m ² ) of TPA. TPA/ every other day for 2 weeks, followed by 0.24 mg (1.25 x 0.125 mg/m ² ) of TPA per other day for 2 weeks, and 0.26 mg (1.5 x 0.125 mg/m ² ) TPA / every other day, another 3 weeks. The patient no longer showed symptoms of tremor.

Example XXVIII Treatment of prostatic hypertrophy

The patient, WL, male, 82 years old, was diagnosed with prostate hypertrophy. The patient was injected with 0.1 dose of 0.19 mg (0.125 mg/m ² ) of TPA per other day for 4 weeks, followed by administration of 0.24 mg (1.25 x 0.125 mg/m ² ) of TPA per other day. A total of 2 weeks, and 0.26 mg (1.5 x 0.125 mg / m ² ) of TPA / every other day, another 3 weeks. The patient's PSA index is now below 3.0. The patient also has a younger appearance.

Example XXIX Treatment of rheumatoid arthritis

The patient received multiple injections of TPA and found that the stiffness of his joints decreased and his hand function increased.

Instance XXX Collagen-induced arthritis with TPA

Collagen induced arthritis (CIA) was initiated as previously described (Rosloniec 2001). Briefly, 100 μg of type II chicken collagen (Chondrex, Redmond, WA) emulsified in 0.05 M acetic acid emulsified in Freund's adjuvant (Difco, Detroit, MI) was subcutaneously injected into the tail of a male DBA/1J mouse. Twenty-one days after the initial immunization, an additional injection of collagen of the same dose of type II chicken was administered.

At 18 days after the first injection, mice with visible arthritic symptoms in the peripheral joints were carefully examined daily. The clinical severity of arthritis was scored as follows: except for the big toe, each finger was swollen by 1 point (up to 4 points); the tarsal or wrist joint was 1 point; and the hind limbs were metatarsal (metatarsal) ) or the metacarpal joint is swollen with a maximum score of 6 points and a forelimb of 5 points. Each paw is individually graded and the cumulative clinical arthritis score for each mouse is up to 22 points.

After receiving the additional injection, the mice were divided into two groups and each received a placebo or 0.125 mg/m ² of TPA on days 0, ^{2, 4} , 6 and 8 by subcutaneous injection. At 30 days after the initial injection, the mice were sacrificed and their knees were dissected and fixed in 10% formalin buffer for 7 days. The fixed tissue was decalcified in 15% EDTA for 3 weeks, dehydrated and embedded in paraffin. Sagittal sections (8 μm) of the entire knee joint were stained with Safranin-O and counterstained with fast green/iron hematoxylin. Tissue sections were independently graded (from 0, no hyperplasia, to 3, most severe hyperplasia), and synovial membranes by treatment with two observers blinded by the scoring system for the establishment of synovial hyperplasia. Inflammatory cells (from 0, no inflammation, to 3, severely inflamed joints). Cartilage damage was determined by Safranin-O staining (from 0, normal non-arthritic knee joints did not change, fully stained cartilage, to 3, Safranin-O staining was completely lost), as described by Marty, 2001.

Example XXXI Treatment of myasthenia gravis

The patient, CL, male, 63 years old, suffered from myasthenia gravis for more than 40 years. The patient took dexamethasone and simultaneously injected a dose of 0.19 mg (0.125 mg/m ² ) of TPA per other day for 4 weeks, followed by administration of 0.24 mg (1.25 x 0.125 mg/m ² ). TPA / every other day for 2 weeks, and ^{0.26mg (1.5 x 0.125mg / m 2} ) of the TPA / every other day for another 3 weeks, a total of 35 injections TPA. The patient no longer needs to take dexamethasone and is now asymptomatic.

Example XXXII Treatment of urinary incontinence

The patient, WC, female, 61 years old, has suffered from urinary incontinence for more than 30 years. The patient received 6 injections of 0.18 mg (0.125 mg/m ² ) of TPA and had regained normal urination frequency.

Patient, LL, female, 48 years old, suffered from urinary incontinence for 15 years. The patient received 9 injections of 0.18 mg (0.125 mg/m ² ) of TPA and the normal frequency of urination was regained.

references

Abrahm JL, Gerson SL, Hoxie JA, Tannenbaum sh, Cassileth p. A., Cooper RA. Different effects of phorbol esters on normal myeloid precursors and leukemic cells. (Cancer Res.) 46, 3711-3716 (1986).

Altuwaijri S, Lin HK, Chuang KH, Lin WJ, Yeh S, Hanchett LA, Rahman MM, Kang HY, Tsai MY, Zhang Y, Yang L, and Chang C. Interfering with nuclear transcription factors mediated by androgen receptors kappaB to promote 12-O-tetradecanoylphorolate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells (Interruption of nuclear factor kappaB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis In androgen-sensitive prostate cancer LNCaP cells.) Cancer Research (Cancer Res) 2003; 63: 7106-12.

Ando I., Crawfor DH et al. Phorbol ester-induced expression and function of the interleukin 2 receptor in human B lymphocytes. European immunology Journal (Eur J Immunol.) 15(4), 341-4 (1985).

Opesing effects of 12-O-tetradecanoylphorbol 13-acetate on human myeloid and lymphoid cell proliferation Aye MT, Dunne JV 12-O-tetradecane crotonol-13-acetate .) J Cell Physiol. 114(2), 209-14 (1983).

Bauer I., Al Sarraj J. et al. The synthesis of tumor necrosis factor alpha induced by interferon beta and tetradecyl decyl crotonol acetate in human hepatoma cells involves transcription factors ATF2 and c-Jun and stress Interleukin-I beta and tetradecanoylphorbol acetate-induced biosynthesis of tumor necrosis factor alpha in human hepatoma cells involved in transcription factors ATF2 and c-Jun and stress-activated protein kinases. J Cell Biochem. (1), 242-255 (Epub ahead of print), (2006).

Beaupre DM and Kurzrock R. RAS and Leukemia: From basic mechanisms to gene-directed therapy. Journal of Clinical Oncology (J Clin Oncol 1999); 17: 1071-9.

Becker Y. The balance of TH1 cytokines and TH2 cytokines in HIV infection indicates an allergic reaction to viral proteins transcribed by TH2 cytokine inhibitors and immune response modifiers - Review and The T helper I (TH1) and T helper (TH2) cytokine balance during HIV infection are indicative of an allergic response to viral proteins that may be reversed by TH2 cytokine inhibitors and immune response modifiers -a review and hypothesis.) Viral Genes 28 ( 1). 5-18 (2004).

Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. (Stroke). 1986; 17: 472-476.

Beetz A., Messer G. et al. Induced Interleukin 6 by Ionizing Radiation of Human Epithelial Cell Lines: Controlled by Corticosteroids (Induction of interldukin 6 by Ionizing radiation in a human epethelial cell line: controlk by corticosteroids.) Int j Radiat Biol 72(1), 33-43 (1997).

Berenblum I. A re-evaluation of the concept of co-carcinogenesis. Prog. Exp. Tumor Res. 11, 21-30 (1969).

Blockland S. et al. activates potential HIV-1 expression by potent anti-tumor promoter 12-deoxy crotyl-13-phenyl acetate (Activation of latent HIV-1 expression by the potent anti-tumor promoter 12) -dexyphorbol-13-phenylacetate.) Antiviral Res. 59, 89-98 (2003).

Blumberg PM., Protein kinase C as a receptor for croton ester tumor promoters: Protein kinase C as the receptor for the phorbol ester tumor promoters: Rhoads memorial award lecture. Cancer research Res.) 1988 Jan 1;48(1):1-8.

Boutwell RK Tumor Promotes Biochemical Mechanism, Tumor Promotion and Co-carcinogenesis. Eds. Slaga, TJ, Sivak, AJ and Boutwell, RK Raven, New York , 49-58 (1978).

Boundwell R.K. The function and mechanism of promoters of carcinogensis. CRC Crit. Rev. Toxicol 2, 419-443 (1974).

Brose N, Rosenmund C. Transfer cytokines C, you can get ally: Erqi Gigan Move over protein kinase C, you’ve got company: alternative effectors of diacylglycerol and phorbol esters. JCell Sci; 115: 4399-411 (2002).

Cancer Chemother Pharmacol. Jun; 57(6): 789-95 (2006).

Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ, and et al. National Cancer Institute-sponsored workshop to report the diagnosis of acute myeloid leukemia Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990; 8: 813-9.

Chun TW, Siliciano RF et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387 (Quantity of latent tissue reservoirs and total body viral load in HIV-1 infection.) 8), 183-188 (1997).

Clerici M., Sheare GM A TH1→TH2 is a clinical step in the process of HIV infection (TH1→TH2 switch is a critical step in the etiology of HIV infection.) Immunology (Immunol.) Today 14(3), 107-110 (1993).

Cui XX, Chang RL, Zheng X, Woodward D, Strair R, and Conney A H. Sensitive organisms for measuring 12-O-tetradecane crotonol-13-acetate (TPA) levels in patients' blood A sensitive bioassay for measuring blood levels of 12-O-tetradecanoylphorbol-13-acetate (TPA) in patients: preliminary pharmacokinetic studies. (Oncol Res) 2002; 13: 169-74.

Deegan MJ, Maeda k. Immunization of chronic lymphocytic leukemia cells after in vitro treatment with Epstein-Barr virus or phorbol ester. in vitro treatment with Ebstein-Barr virus or crotonate Immunologic and morphologic studies. Am J Hermatol. 17(4), 335-47 (1984).

Epperly MW, Gretton JE, Sikora CA, et al. Mitochondrial localization of superoxide dismutase is required for reducing radiation-induced cellular damage. (Radiat Res). 2003;160:568-578.

Epperly MW, Gretton JA, DeFilippi SJ, et al. Regulation of radiation-induced cell evolution associated with esophagitis and esophageal stenosis due to manganese superoxide dismutase- plasto /liposome ( SOD2- PL) gene therapy (Modulation of Radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutase-plasmid/liposome ( SOD2 -PL) gene therapy) Radiation Research (Radiat Res). 2001;155:2-14.

Falcioni F., Rautmann A. et al. TPA (12-O-tetradecanequinone-crotonol-13-acetate) interferes with B lymphocyte function in humans (Influence of TPA (12-O-tetradodecanoyl-phorbol) -13-acetate) on human B lymphocte function) Clin Exp Immunol. 62(3), 163-2 (1985).

Farrell B, Godwin J, Richards S, Warlow C, et al. (1991). British Aspirin Attack (UK-TIA) Aspirin Trial: Final Results ("The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. "J Neurol Neurosurg Psychiatry 54 (12): 1044-1054.

Forbes IJ, Zalewski PD, Letarte M. Human B-lymphocyte maturation sequence revealed by TPA-induced differentiation of leukaemi cells. Immunobiology 163 (1) ), 1-6 (1982).

Fujisawa K., Nasu K. et al. Production of interleukin (IL)-6 and IL-8 by a chorio-carcinama cell line, Placenta (BeWo. Placenta) 21 (4), 354-60 (2000).

Gunjan Goel, Harinder PS Makkar, George Francis, and Klaus Becker. Croton Esters: Structure, Bioactivity, and Toxicity to Animals (Phorbol Esters: Structure, Biological Activity, and Toxicity in Animals. International Journal of Toxicology , 26:279-288, 2007. Gogusev J., Barbey S., Nezelof C. Regulation of TNF-α and IL-1 gene expression during differentiation of TPA-induced "malignant histiocytosis" DEL cell lines (Regulation of TNF-alpha and IL-1 gene expression during TPA-induced differentiation of "Malignant histiocyosis" DEL cell line t(5:6) (q35:P21).Anticancer Res. 16(1), 455-60 (1996).

Granger CV, Devis LS, Peters MC, Sherwood CC, Barrett JE. Stroke rehabilitation: analysis of repeated Barthel Index measures. Physical Therapy and Rehabilitation Literature ( Arch Phys Med Rehabil. ) 1979; 60: 14-17.

Gulakowski RJ, McMahon JB, Bukheit Jr., et al. 12-Deoxycrotonol-13-acetate, non-tumor-promoting crotonyl ester antagonizes HIV anti-cytopathic activities of prostratin (Antireplicative and anti-cytopathic activities of prostratin, a non-tumor-promoting phorbol ester against human immunodefeciency virus (HIV). Antiviral Research 33, 87-97 (1997).

Hamburger, A. W., and Salmon, S. E. Primary bioassay of human tumor stem cells. Science (Wash. DC), 797: 461-463, 1977.

Han ZT, Zhu XX, Yang RY, Sun JZ, Tian GF, Liu XJ, Cao GS, Newmark HL, Conney AH, and Chang R L. 12-O-tetradecane croton for patients with myeloid leukemia Benefits of intravenous infusion of alcohol-13-acetate (TPA): preliminary study of therapeutic infusions of 12-O-tetradecanoylphorbol-13-acetate (TPA) in patients with myelocytic leukemia: preliminary Studies on therapeutic efficacy and toxicity. Proc Natl Acad Sci USA 1998; 95: 5357-61.

Han ZT, Tong YK, He LM, Zhang Y., Sun JZ, Wang TY, Zhang H., Cui YL, Newmark HL, Conney AH, Chang RL 12-O-Ten of patients treated with cytotoxic cancer chemotherapy drugs 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) - induced increase in depressed white blood cell counts in patients With cytotoxic Cancer chemotherapeutic drugs.) Proc. Natl. Acad. Sci. 95, 5363-5365 (1998).

Han ZT, Zhu XX, Yang RY, Sun JZ, Tian GF, Liu XJ, Cao GS, NewMark HL, Conney AH, and Chang RL 12-O-tetradecane oxime-crotonol in patients with myeloid leukemia Effect of intravenous infusion of -13-acetate (TPA): Effect of intravenous infusion of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in patients with myelocytic leukemia: Preliminary studies on therapeutic efficacy and toxicity.) Pro. Natl. Acad. Sci. 95, 5357-5361 (1998).

Harada S. et al.: Tumor Promoter, TPA, Enhances HTLV-III/LAV Replication (Tumor Promoter, TPA, Enhances Replication of HTLV-III/LAV). Virology 154, 249-258 (1986) .

Harrigan, PR, Whaley, M., Montaner, JSG Stopping HIV-1 RNA rebound upon stopping antiretroviral therapy. AIDS 13, F59-F62 (1999).

Hecker E. Introduction to Pathology (In handbuch der allgemeinen patholgie), ed. Grundmann, E. (Springer-Verlag, Berlin-Heideiberg, Vol. IV 16, 651-676 (1975).

Structure-activity relationships in deterpene esters irritant and co-carcinogenic to mouse skin, in mechanisms of Hecker E. diterpene ester irritating and co-carcinogenic to mouse skin, in mechanisms of Tumor promotion and co-carcinogenesis. Eds. Slaga, T. J., Sevak, A. j. and Boutwell, R.K. Raven, New York, 11-49 (1978).

The potential for isoenzyme-selective modulation of protein kinase C. (FASEB J.) 11, 649-669 (1997).

Huberman E., Callaham MF Induction of terminal differentiation in human promyelocytic leukemia cells by tumor-promoting agents. Proc. Natl. Acad. Sci .76, 1293-1297 (1979).

Hunter T. Signal 2000 and beyond (Signaling 2000 and beyond.) Cytology (Cell) 100, 113-117 (2000).

Jordan C T. Unique molecular and cellular features of acute myelogenous leukemia stem cells. Leukemia 2002; 16: 559-62.

Kassel O, Sancono A, Kratzschmar J, Kreft B, Stassen M, and Cato A C. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation by increasing MKP-1 expression and decreasing MKP-1 degradation. Of MKP-1.) European Journal of Molecular Biology (Embo J 2001); 20: 7108-16.

Kawakami A., Eguchi K. et al. Inhibitory effects of interleukin-10 on synovial cells of rheumatoid arthritis. Immunology (Immumonolgy) 81 ( 2), 252-9 (1997). Kazanietz MG opens its eyes: protein kinase C isozyme is not a croton ester cancer promotion Eyes Wide Shut: protein kinase C isoenzymes are not the only receptors for the phorbol ester tumor promoters. Mol. Carcinog. 28, 5-12 (2000).

Phorbol ester effect on differentiation of human myeloid leukemia cells lines blocked at different stages of maturation. .) Cancer Research (Cancer Res. 4) 1, 919-926 (1981).

Kim SC, Hahn JS, Min YH, Yoo NC, Ko YW, and Lee W J. Continuous activation of extracellular signal-regulated kinases in human acute leukemia: activation of MEK, excessive expression of extracellular signal-regulated kinases, and phosphatase PAC1 Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK, hyperexpression of extracellular signal-regulated kinase, and downregulation of a phosphatase, PAC1. Blood (Blood) 1999; 93: 3893-9.

Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R , and Ueda R. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood (Blood) 1999; 93: 3074-80.

Kobayashi M., Okada N. et al. Intracellular interference in human gingival fibroblasts Intracellular interleukin-1 alpha production in human gingival fibroblasts is differentially regulated by various cytokines. J Dent Res. 78(4), 840-9 (1999).

Phorbol diester-induced macrophge differentiation of leukemic blasts from patients with human myelogenous leukemia. Journal of Clinical Investigation (J. Clin. Invest.) 66, 1101-1108 (1980).

Kulkosky J., Merantz RJ et al. 12-Deoxycrotonol-13-acetate; activation of latent HIV-1 expression is shown as a promising HAART activation adjuvant (Prostratin: activation of latent HIV-1 expression suggested a Potential inductive adjuvant therapy for HAART.) Blood (B) 98 (10), 3006-3015 (2001).

Kudo M., Aoyama A., Ichimori S. and Fukunaga N. Animal pattern of cerebral infarction: An animal model of cerebral infarction: homologous blood clot emboli in rats. Stroke 13: 505 -508 (1982)

Lebien TW, Bollum FJ et al. Non-T lymphocyte strain, non-B leukemia cell line crotonate-induced differentiation: Phorbol ester-induced differentiation of a non-T, non-B leudemic cell Line: model for human lymphoid progenitor cell development.) J Immunol. 128(3), 1316-20 (1982).

Lehrman G., Hogue IB, Palme S. et al. Depletion of Latent HIV-V infection in vivo: a proof-of-concept study. Lancet ) 366 (9485), 523-524 (2005).

Lotem J., Sachs L. Regulation of normal differentiation in mouse and human myeloid leukemia cells by phorbol esters and the mechanism of tumor Promotion.) Pro. Natl. Acad. Sci. 76 5158-5162 (1979).

MD Iqbal Hossain Chowdhury et al. Crotonyl TPA strongly inhibits HIV-1 induced intercellular fusion but increases viral production: The Phorbol Ester TPA Strongly Inhibits HIV-1 Induced Syncytia Formation but Enhances Virus Production: possible Involvement of protein kinase C pathway.) Virology 176, 126-132, (1990).

Marty, Ingrid et al., Amelioration of collagen-induced arthritis by thrombin inhibition. J Clin Invest. 2001 March 1; 107(5): 631-640.

Protein kinase C activation modulates pro- and anti-apoptotic signaling pathways Biol 2000); 79: 824-33.

Meinhardt G., Roth J., Hass R. Activation of protein kinase C in the same kind of cell differentiation signal pathway: differentiation of apoptosis and apoptosis in the same cell type (Activation of protein kinase C relays distinct signaling pathways in the same cell type: Differentiation and caspase-mediated apoptosis. Cell Death Differ. 7, 795-803 (2000).

Milella M, Kornblau SM, Estrov Z, Carter BZ, Lapillonne H, Harris D, Konopleva M, Zhao S, Estey E, and Andreeff M. Therapeutic targeting of the MEK/MAPK signal delivery module in acute myeloid leukemia MEK/MAPK signal transduction module in acute myeloid leukemia.) J Clin Invest 2001; 108: 851-9.

Mochty-Rosen D., Kauvar L. M. Modulating protein kinase C signal transduction. Adv. Pharmacol. 44, 91-145 (1998).

Morgan MA, Dolp O, and Reuter C W. Cell cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signals (Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling.) Blood (Blood) 2001; 97: 1823- 34.

Nagasawa K., Chechgik BE et al. Modulation of human T-cell differentiation markers by 12-O-tetradecanoylphorbal-13 by 12-O-tetradecane crotonol-13-acetate -acetate.) Thymus. (3-5), 307-18, (1981).

Nakao Y., Matsuda S. et al. Paradoxical anti-leukemic effects of anti-leukemia effects of herbal tumor promoters on human thymic lymphocyte cell lines Plant-derived tumor promoters on a human thymic lymphoblast cell line.) Int J Cancer 30(6), 687-95 (1982).

Nakao Y., Matsuda S. et al. Phorbol ester-induced differentiation of human T-lymphoblastic cell line HPB-ALL. Cancer Research (Cancer Res.) 42 (9), 33843-50 (1982).

Newton A.C. Protein Kinase C: Structure, Function and Regulation. J. Biol. Chem. 270, 28495-28499 (1995).

Niederman TMJ, Ratner L. et al. Human Immunodeficiency Virus Type I Nef Protein Inhibits NF-KB Induction in Human T Cells. (J. Virology) 66 (10), 6313-6219 (1992).

Proliferation, differentiation and cytogenetics of chronic leukemic B lymphocytes cultured with mitomycin-treated by Norwell P., Shankey TV et al., with chronic leukemia B lymphocytes co-cultured with normal cells given mitomycin Normal cells.) Blood 57(3), 444-51 (1981).

O'Banion MK, Miller JC et al. Interleukin-1 beta induces prostaglandin G/ in astrocytes cultured in primary mouse astrocytes. H synthase-2 (cyclooxygenase-2) in primary murine astrocyte cultures.) J Neurochem 66(6), 2532-40 (1996).

Okamura J., Geffand EW, Letarte M. Heterogenneity of the response of chronic lymphocytic leukemia cells to phorbol ester. Blood 60(5), 1082-8 (1982) .

Palella FJ, Jr, Delaney KM, Moorman AC, et al. Reduced morbidity and mortality in patients with advanced human immunodeficiency virus infection. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 338: 853-860 (1998).

Palombella VJ, Rando OJ, Goldberg AL, and Maniatis T. The ubiquitin-proteasome pathway is required for cleavage of NF-kappa B1 precursor protein and activation of NF-kappa B (The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 Precursor protein and the activation of NF-kappa B.) Cell (1994) 78: 773-85.

Persaud D., Theodore P., Siliciano RF et al. A stable latent reservoir for HIV-1 in resting CD4+ T lymophocytes in infected children. Journal of Clinical Investigation (J. Clini, Invest.) 115 (7), 995-1003 (2000).

Platanias L C. Map kinase signaling pathway and hematologic malignancies. Hematology (Blood) 2003; 101: 4667-79.

Polliack A., Leizerowitz R., Korkesh A., Gurfel D., Gamliel H., Galili U. Induction of TPA exposure in vitro for the classification of human bone marrow and lymphoid leukemia (Exposure to TPA in vitro as an aid in the classification of blasts in human myelogenous and lymphoid leukemias.) American Journal of Hematology (Am. J. Hematol.) 13, 199-211 (1982).

Redondo P., Garci-Foncillas J. et al. regulates the differentiation of interleukin-8 and TNF-α in human keratinocytes by buffomedil chlorhydrate and pentoxifylline (Differential modulation of IL-8 and TNF-alpha) Expression in human keratinocytes by buffomedil chlorhydrate and pentoxifylline.) Exp. Dermatol. 6(4), 186-94 (1997).

Rosloniec EF, Cremer M, Kang A, Myers LK. Collagen-induced arthritis. In: Coligan JE, KruisbeekAM, MarguliesDH, ShevachEM, StroberW, editors. Current protocols in immunology. New York: John Wiley &Sons; 2001. p. 15.5.1.

Rovera G., Santoli D., Damsky C. Cultured human promyelocytic cells in culture differentiated into macrophage-like cells treated with a phorbol diester. Pro. Natl. Acad. Sci. 7, 2779-2783 (1979).

Rullas J., Alcami J. et al. Receptors in peripheral blood lymphocytes. Antivir. Ther. 9 (4). 545-554 (2004).

Rwigema JC, Beck B, Wang W, Doemling A, Epperly MW, Shields D, Goff JP, Franicola D, Dixon T, Frantz MC, Wipf P, Tyurina Y, Kagan VE, Wang H, Greenberger JS. Small molecule spoke Two strategies for the development of mitochondrion-targeted small molecule radiation damage mitigators. Int J Radiat Oncol Biol Phys. 2011 Jul 1;80(3): 860-8.

Epub 2011 Apr 13Sahar El-Mekkawy et .al. Phytochemistry, Phytochemistry, from crotonic acid extracted from croton seeds, Phytochemistry 53, 457-464 (2000).

Schaar D, Goodell L, Aisner J, Cui XX, Han ZT, Chang R, Martin J, Grospe S, Dudek L, Riley J, Manago J, Lin Y, Rubin EH, Conney A, Strair RK. 12-O-Ten Phase II clinical trial of 12-O-tetradecanoylphorbol-13-acetate for patients with relapsed/refractory malignancies in patients with relapsed/refractory malignancies .)

Role of Transcriptional Activation of Ikappa Balpha in Mediation of Immunosuppression by Glucocortic oids. 270: 283-286.

Shkolnick T., Schlossman SF, Griffin JD Acute Undifferentiated Leukemia: Induction of partial differentiation by phorbol ester. Leuk. Res. 9, 11- 17 (1985).

Shwarz M. et . al. stimulates high yield of T cells by monoclonal antibodies High-level IL-10 production by monoclonal antibody-stimulated human T cells. Immunology 86, 364-371 (1995).

Siliciano JD, Siliciano RF et al. Long-term follow-up study confirming the stability of HIV-1 latent virus pools in dormant CD4+ T cells. confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Med. 9(6) 727-728 (2003).

Staber PB, Linkesch W, Zauner D, Beham-Schmid C, Guelly C, Schauer S, Sill H, and Hoefler G. Common changes in gene expression and increased proliferation in acute myeloid leukemia (Common alterations in gene Expression and increased proliferation in recurrent acute myeloid leukemia.) Oncogene 2004; 23: 894-904.

Steube KG, Meyer C., Drexler HG The persistent excretion of hematopoietic cytokines in human cancerous cells and its regulation by interleukin-1 and crotonin (Constitutive excretion of hematopoietic cytokines by human carcinoma cell lines and its up-regulation) By interleukin-1 and phorbol ester.) Oncol. Rep. 6(20), 427-32 (1999).

Strair RK, Schaar D, Goodell L, Aisner J, Chin KV, Eid J, Senzon R, Cui XX, Han ZT, Knox B, Rabson AB, Chang R, and Conney A. Crotonic acid in patients with malignant blood diseases: Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O -tetradecanoylphorbol-13-acetate). Clin Cancer Res 2002; 8: 2512-8

Sumitomo M, Shen R, Goldberg JS, Dai J, Navarro D, and Nanus D M. Neutral endopeptidase promotes crotonyl ester in pancreatic cancer cells induced by inhibition of neuropeptide-induced degradation of protein kinase CΔ Neutral endopeptidase promotes phorbol ester-induced apoptosis in prostate cancer cells by inhibiting neuropeptide-induced protein kinase C delta degradation. Cancer Research 2000; 60: 6590-6.

Totterman T. H., Nilsson K., Sundstrom C. Phorbol ester-induced differentiation of chronic lymphoctic leukaemia cells. Nature 288 (5787), 176-8 (1980)

Towatari M, Iida H, Tanimoto M, Iwata H, Hamaguchi M, and Saito H. Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells. Leukemia 1997; 11: 479-84.

Van Duuren, B.L. Tumor-promoting agents in two-stage carcinogenesis. Prog. Exp. Tumor Res. 11, 31-68 (1969).

Williams SW et al. 12-Deoxycrotonol-13-acetate by Promoting Antagonize HIV Latency by Activating NF-KB. J. Biol. Chem. 279, 42008-42017 (2004).

Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H , Ueda R, Ohno R, and Naoe T. Activation of FLT3A in human hematological malignancies Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434-9.

YIP, Y.K. et al. Stimulation of human gamma interferon production by diterpene esters. Infection and Immunity 34(1) 131-139 (1981).

Zhao J., Sharma Y., Agarwal R. Flavonoid-resistant antioxidant silymarin 12-O-tetradecane-crotonol 13-acetate-mediated regulation of antioxidants and inflammatory enzymes and cyclooxygenase 2 Significant inhibition of interleukin-Iα expression in SENCAR mouse epidermis: Significant inhibition by the flavonoid antioxidant silymarin against 12-O-tetradecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes and cyclooxygenase2 And interleukin-I alpha expression in SENCAR mouse epidermis: implications in the prevention of stage 1 tumor promotion.) Mol Carcinog. 26(4), 321-33 (1999).

Claims (63)

Use of a crotonyl ester of the formula I or a pharmaceutically acceptable salt thereof, Wherein R ₁ and R ₂ are selected from the group consisting of hydrogen and hydroxyl groups. , , , And a group of substituted derivatives thereof, R ₃ is hydrogen, And substituted derivatives thereof for use in the manufacture of a medicament for reducing signs of aging in a mammalian subject; wherein the crotonyl ester of Formula I is present in an effective amount. The use of claim 1 wherein R ₁ or R ₂ is , the other of R ₁ or R ₂ is And R ₃ is hydrogen. The use of claim 1, wherein the crotonate is crotyl-13-butyrate, crotyl-12-decanoate, crotyl-13-decanoate, crotyl-12,13-diacetate , crotyl alcohol-13,20-diacetate, crotyl-12,13-dibenzoate, crotyl-12,13-dibutyrate, crotyl-12,13-dicaprate, Crotonyl-12,13-dihexanoate, crotyl-12,13-dipropionate, crotyl-12-myristate, crotyl-13-myristate, crotyl-12,13 , 20-triacetate, 12-deoxy crotyl alcohol-13-angelate, 12-deoxy crotyl-13-angelate-20-acetate, 12-deoxy crotyl-13-isobutyrate , 12-deoxy crotyl alcohol-13-isobutyrate-20-acetate, 12-deoxyba Bean alcohol-13-phenyl acetate, 12-deoxy crotyl-13-phenyl acetate-20-acetate, 12-deoxy crotyl-13-tetradecanoate, crotyl-12-cis acid Ester-13-phthalate, 12-deoxy crotyl-13-acetate, crotyl-12-acetate or crotyl-13-acetate. The use of claim 1, wherein the crotonate is 12-O-tetradecyldecylcrotonol-13-acetate. The use of claim 1, wherein the drug is administered with further at least one secondary or adjunctive therapeutic agent. The use of claim 1, wherein the medicament comprises between about 10 μg and about 1500 μg of a crotonate or derivative compound of formula I, and the medicament is administered daily. The use of claim 6, wherein the drug comprises between about 125 μg and about 500 μg of a crotonate or derivative compound of formula I, and the drug is administered daily. Use of a crotonyl ester of the formula I or a pharmaceutically acceptable salt thereof, Wherein R ₁ and R ₂ are selected from the group consisting of hydrogen and hydroxyl groups. , , , And a group of substituted derivatives thereof, R ₃ is hydrogen, And substituted derivatives thereof for use in the manufacture of a medicament for the treatment or prevention of one or more symptoms of a carpal tunnel syndrome in a mammalian subject; wherein the crotonyl ester of formula I is present in an effective amount. The use of claim 8, wherein R ₁ or R ₂ is , the other of R ₁ or R ₂ is And R ₃ is hydrogen. The use of claim 8, wherein the crotonate is crotyl-13-butyrate, crotyl-12-decanoate, crotyl-13-decanoate, crotyl-12,13-diacetate , crotyl alcohol-13,20-diacetate, crotyl-12,13-dibenzoate, crotyl-12,13-dibutyrate, crotyl-12,13-dicaprate, Crotonyl-12,13-dihexanoate, crotyl-12,13-dipropionate, crotyl-12-myristate, crotyl-13-myristate, crotyl-12,13 , 20-triacetate, 12-deoxy crotyl alcohol-13-angelate, 12-deoxy crotyl-13-angelate-20-acetate, 12-deoxy crotyl-13-isobutyrate , 12-deoxy crotyl alcohol-13-isobutyrate-20-acetate, 12-deoxy crotyl alcohol-13-phenyl acetate, 12-deoxy crotyl alcohol-13-phenyl acetate-20-acetic acid Ester, 12-deoxy crotyl alcohol-13-tetradecanoate, crotyl-12-cis decyl-13-decanoate, 12-deoxy crotyl-13-acetate, crotyl-12-acetic acid Ester or crotyl-13-acetate. The use of claim 8, wherein the crotonate is 12-O-tetradecyldecylcrotonol-13-acetate. The use of claim 8, wherein the drug is administered with further at least one secondary or adjunctive therapeutic agent. The use of claim 8, wherein the drug comprises between about 10 μg and about 1500 μg of a crotonate or derivative compound of formula I, and the drug is administered daily. The use of claim 13, wherein the drug comprises between about 125 μg and about 500 μg of a crotonate or derivative compound of formula I, and the drug is administered daily. Use of a crotonyl ester of the formula I or a pharmaceutically acceptable salt thereof, Wherein R ₁ and R ₂ are selected from the group consisting of hydrogen and hydroxyl groups. , , , And a group consisting of the substituted derivatives thereof, R ₃ is selected from the group consisting of hydrogen, And a group of substituted derivatives thereof for use in the manufacture of a medicament for the prevention or treatment of one or more side effects of a chemotherapeutic treatment; wherein the crotonyl ester of the formula I is present in an effective amount. The use of claim 15 wherein R ₁ or R ₂ is , the other of R ₁ or R ₂ is And R ₃ is hydrogen. The use of claim 15, wherein the crotonate is crotyl-13-butyrate, crotyl-12-decanoate, crotyl-13-decanoate, crotyl-12,13-diacetate , crotyl alcohol-13,20-diacetate, crotyl-12,13-dibenzoate, crotyl-12,13-dibutyrate, crotyl-12,13-dicaprate, Crotonyl-12,13-dihexanoate, crotyl-12,13-dipropionate, crotyl-12-myristate, crotyl-13-myristate, crotyl-12,13 , 20-triacetate, 12-deoxy crotyl alcohol-13-angelate, 12-deoxy crotyl-13-angelate-20-acetate, 12-deoxy crotyl-13-isobutyrate , 12-deoxy crotyl alcohol-13-isobutyrate-20-acetate, 12-deoxy crotyl alcohol-13-phenyl acetate, 12-deoxy crotyl alcohol-13-phenyl acetate-20-acetic acid Ester, 12-deoxy crotyl-13-tetradecanoate, crotyl-12-cis phthalate-13-phthalate, 12- Deoxycrotonol-13-acetate, crotyl-12-acetate or crotyl-13-acetate. The use of claim 15, wherein the crotonyl ester is 12-O-tetradecyldecylcrotonol-13-acetate. The use of claim 15, wherein the drug is in a secondary or at least one of a combination or synergistic treatment with the crotonate or derivative of Formula I effective for treating or preventing one or more side effects of the chemotherapeutic or Auxiliary therapeutic agents are co-administered. The use of claim 19, wherein the at least one secondary or adjunctive therapeutic agent is administered concurrently with, prior to, or after administration of the drug, according to a synergistic dosing schedule. The use of claim 20, wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of pegfilgrastim, erythropoietin (epoeitn alfa), darbepoetin alfa, alendronate Sodium, risedronate, ibandronate, G-CSF, 5-HT3 receptor antagonist, NK1 antagonist, olanzapine, corticosteroid, dopamine antagonist, serotonin antagonist, benzene A group consisting of benzodiazepines, aprepitant, and cannabinoids. The use of claim 15, wherein the effective amount comprises the crotonate or derivative of formula I between about 10 [mu]g and about 1500 [mu]g per day. The use of claim 22, wherein the effective amount comprises the crotonate or derivative of formula I between about 125 [mu]g and about 500 [mu]g per day. The use of claim 15, wherein the one or more side effects of the chemotherapy are hair loss, nausea, vomiting, loss of appetite, soreness, neutropenia, anemia, thrombocytopenia, dizziness, fatigue, constipation, oral ulcers Itchy skin, peeling, nerve and muscle leprosy, hearing changes, weight loss, diarrhea, immunosuppression, indocyanine, tendency to easily bleed, heart damage, liver damage, kidney damage, dizziness or brain lesions. Use of a crotonyl ester of the formula I or a pharmaceutically acceptable salt thereof, Wherein R ₁ and R ₂ are selected from the group consisting of hydrogen and hydroxyl groups. , , , And a group consisting of the substituted derivatives thereof, R ₃ is selected from the group consisting of hydrogen, And a group of substituted derivatives thereof for use in the manufacture of a medicament for preventing or treating one or more side effects of radiation. The use of claim 25, wherein R ₁ or R ₂ is , the other of R ₁ or R ₂ is And R ₃ is hydrogen. The use of claim 25, wherein the crotonate is crotyl-13-butyrate, crotyl-12-decanoate, crotyl-13-decanoate, crotyl-12,13-diacetate , crotyl alcohol-13,20-diacetate, crotyl-12,13-dibenzoate, crotyl-12,13-dibutyrate, crotyl-12,13-dicaprate, Crotonyl-12,13-dihexanoate, crotyl-12,13-dipropionate, crotyl-12-myristate, crotyl-13-myristate, crotyl-12,13 , 20-triacetate, 12-deoxy crotyl alcohol-13-angelate, 12-deoxy crotyl-13-angelate-20-acetate, 12-deoxy crotyl-13-isobutyrate , 12-deoxy crotyl alcohol-13-isobutyrate-20-acetate, 12-deoxy crotyl alcohol-13-phenyl acetate, 12-deoxy crotyl alcohol-13-phenyl acetate-20-acetic acid Ester, 12- Deoxycrotonol-13-tetradecanoate, crotyl-12-cis decyl-13-decanoate, 12-deoxy crotyl-13-acetate, crotyl-12-acetate or crotyl alcohol -13-acetate. The use of claim 25, wherein the crotonyl ester is 12-O-tetradecyldecylcrotonol-13-acetate. The use of claim 25, wherein the drug is co-administered with at least one secondary or adjunctive therapeutic agent effective in treating or preventing side effects of radiation in a combination formulation or synergistic treatment with the crotonyl ester or derivative of Formula I; versus. The use of claim 29, wherein the at least one secondary or adjunctive therapeutic agent is administered concurrently with, prior to, or after administration of the drug, according to a synergistic dosing schedule. The use of claim 30, wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of steroids, amifostatin, chlorhexidine, benzydamine, sucralfate, KGF , a group consisting of palifermin, Cu/Zn superoxide dismutase, interleukin 11 or prostaglandins. The use of claim 25, wherein one or more of the side effects of the radiation are wet peeling, pain, diarrhea, nausea, vomiting, loss of appetite, constipation, itching of the skin, peeling, mouth and sore throat, edema, infertility, fibrosis , hair removal or mucous membrane drying. The use of claim 25, wherein the effective amount comprises the crotonate or derivative of formula I between about 10 [mu]g and about 1500 [mu]g per day. The use of claim 33, wherein the effective amount comprises the crotonate or derivative of formula I between about 125 [mu]g and about 500 [mu]g per day. Use of a crotonyl ester of the formula I or a pharmaceutically acceptable salt thereof, Wherein R ₁ and R ₂ are selected from the group consisting of hydrogen and hydroxyl groups. , , , And a group consisting of the substituted derivatives thereof, R ₃ is selected from the group consisting of hydrogen, And a group of substituted derivatives thereof for the manufacture of a medicament for treating or preventing one or more symptoms of prostatic hypertrophy. The use of claim 35, wherein R ₁ or R ₂ is , the remaining R ₁ or R ₂ is And R ₃ is hydrogen. The use of claim 35, wherein the crotonate is crotyl-13-butyrate, crotyl-12-decanoate, crotyl-13-decanoate, crotyl-12,13-diacetate , crotyl alcohol-13,20-diacetate, crotyl-12,13-dibenzoate, crotyl-12,13-dibutyrate, crotyl-12,13-dicaprate, Crotonyl-12,13-dihexanoate, crotyl-12,13-dipropionate, crotyl-12-myristate, crotyl-13-myristate, crotyl-12,13 , 20-triacetate, 12-deoxy crotyl alcohol-13-angelate, 12-deoxy crotyl-13-angelate-20-acetate, 12-deoxy crotyl-13-isobutyrate , 12-deoxy crotyl alcohol-13-isobutyrate-20-acetate, 12-deoxy crotyl alcohol-13-phenyl acetate, 12-deoxy crotyl alcohol-13-phenyl acetate-20-acetic acid Ester, 12-deoxy crotyl-13-tetradecanoate, crotyl-12-cis phthalate-13-phthalate, 12- Deoxycrotonol-13-acetate, crotyl-12-acetate or crotyl-13-acetate. The use of claim 35, wherein the crotonate is 12-O-tetradecyldecylcrotonol-13-acetate. The use of claim 35, wherein the drug is in a secondary or auxiliary effect effective for treating or preventing the one or more symptoms of prostatic hypertrophy in combination with at least one combination or synergistic treatment with the crotonate or derivative of formula I; Therapeutic agents are co-administered. The use of claim 39, wherein the at least one secondary or adjunctive therapeutic agent is administered concurrently with, prior to, or after administration of the drug, according to a synergistic dosing schedule. The use of claim 39, wherein the at least one secondary or adjunctive therapeutic agent is finasteride, dutasteride, terazosin hydrochloride, doxazosin, tamsulosin Tasulosin or alpha receptor blocker. The use of claim 35, wherein the drug is combined with surgery to treat or prevent the one or more symptoms of prostatic hypertrophy. The use of claim 42, wherein the surgical procedure is transurethral resection of the prostate, transurethral resection of the prostate, laser surgery, or prostatectomy. The use of claim 35, wherein the effective amount comprises the crotonate or derivative of formula I between about 10 [mu]g and about 1500 [mu]g per day. The use of claim 44, wherein the effective amount comprises the crotonate or derivative of formula I between about 125 [mu]g and about 500 [mu]g per day. The use of claim 35, wherein the one or more symptoms of prostatic hypertrophy are dripping at the end of urination, urinary retention, incomplete bladder emptying, urinary incontinence, frequent urination, painful urination, hematuria, slow or delayed urination, urinary flow Suspension, urination needs to be strong, weak urine flow, sudden urgency. Use of a crotonyl ester of the formula I or a pharmaceutically acceptable salt thereof, Wherein R ₁ and R ₂ are selected from the group consisting of hydrogen and hydroxyl groups. , , , And a group consisting of the substituted derivatives thereof, R ₃ is selected from the group consisting of hydrogen, And a group of substituted derivatives thereof for use in the manufacture of a medicament for the treatment or prevention of one or more symptoms of myasthenia gravis; wherein the crotonyl ester of Formula I is present in an effective amount. The use of claim 47, wherein R ₁ or R ₂ is , the other of R ₁ or R ₂ is And R ₃ is hydrogen. The use of claim 47, wherein the crotonyl ester is 12-O-tetradecyldecylcrotonol-13-acetate. The use of claim 47, wherein the drug is effective for treating or preventing the one or more symptoms of myasthenia gravis with at least one combination or synergistic treatment with the crotonate or derivative of formula I or Auxiliary therapeutic agents are co-administered. The use of claim 50, wherein the at least one secondary or adjunctive therapeutic agent is administered concurrently with, prior to, or after administration of the drug, according to a synergistic dosing schedule. The use of claim 50, wherein the at least one secondary or adjunctive therapeutic agent is an anticholinergic enzyme, a corticosteroid or an immunosuppressive agent. The use of claim 47, wherein the one or more symptoms of myasthenia gravis are under the eye Divergence, diplopia, speech disorder, fatigue, muscle weakness, difficulty swallowing, dysphonia. The use of claim 47, wherein the effective amount comprises the crotonate or derivative of formula I between about 10 [mu]g and about 1500 [mu]g per day. The use of claim 54, wherein the effective amount comprises the crotonate or derivative of formula I between about 125 [mu]g and about 500 [mu]g per day. Use of a crotonyl ester of the formula I or a pharmaceutically acceptable salt thereof, Wherein R ₁ and R ₂ are selected from the group consisting of hydrogen and hydroxyl groups. , , , And a group consisting of the substituted derivatives thereof, R ₃ is selected from the group consisting of hydrogen, And a group of substituted derivatives thereof for use in the manufacture of a medicament for the treatment or prevention of symptoms of urinary incontinence; wherein the crotonyl ester of formula I is present in an effective amount. The use of claim 56, wherein R ₁ or R ₂ is , the other of R ₁ or R ₂ is And R ₃ is hydrogen. The use of claim 56, wherein the crotonate is 12-O-tetradecyldecylcrotonol-13-acetate. The use of claim 56, wherein the drug is associated with at least one of the crotons of formula I A combination formulation of an ester or derivative or a secondary or adjunctive therapeutic agent effective in treating or preventing the symptoms of urinary incontinence in a synergistic treatment. The use of claim 59, wherein the at least one secondary or adjunctive therapeutic agent is administered concurrently with, prior to, or after administration of the drug, according to a synergistic dosing schedule. The use of claim 59, wherein the at least one secondary or adjunctive therapeutic agent is an anticholinergic drug, a local estrogen, imiline or duloxetine. The use of claim 56, wherein the effective amount comprises the crotonate or derivative of formula I between about 10 [mu]g and about 1500 [mu]g per day. The use of claim 62, wherein the effective amount comprises the crotonate or derivative of formula I between about 125 [mu]g and about 500 [mu]g per day.