Compositions and methods of use of phorbol esters

Abstract

Methods and compositions containing a phorbol ester or a derivative of a phorbol ester are provided for the treatment of cytopathic diseases. Cytopathic diseases may be caused by a variety means such as viral infections like HIV and AIDS, or the development of neoplasms in a mammalian subject. The methods and compositions of the invention are effective for inhibiting de novo HIV infections upregulating viral expression from latent provirus, inhibiting HIV-induced cytopathic effects, down regulating the HIV receptor, increasing Th1 cytokine expression, decreasing Th2 cytokine expression, increasing ERK phosphorylation, inducing apoptosis in malignant cells, inducing remission, maintaining remission, as chemotherapeutic agents, as well as for decreasing symptoms of cytopathic diseases and opportunistic infections that may accompany such diseases. Additional compositions and methods are provided which employ a phorbol ester or derivative compound in combination with at least one additional agent such as those used in HAART protocols, therapeutic agents used to treat opportunistic infections due to HIV, or chemotherapeutic agents to yield more effective treatment tools against cytopathic diseases in mammalian subjects.

1 . A method for preventing or treating HIV infection or disease in a mammalian subject comprising administering an effective amount of a phorbol ester or derivative of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are selected from the group consisting of hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof, and R 3  is selected from hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof. 
     
     
         2 . The method of  claim 1 , wherein R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       the remaining R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       and R 3  is hydrogen. 
     
     
         3 . The method of  claim 1 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate. 
     
     
         4 . The method of  claim 1 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate. 
     
     
         5 . The method of  claim 1 , further comprising administering at least one secondary anti-retroviral or other adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to treat or prevent HIV in said subject. 
     
     
         6 . The method of  claim 5 , wherein the at least one secondary anti-retroviral or other adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject. 
     
     
         7 . The method of  claim 5 , wherein the at least one secondary anti-retroviral or other adjunctive therapeutic agent is selected from the group consisting of: protease inhibitors, nucleoside reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, combination drugs, entry and fusion inhibitors, acyclovir, adefovir dipivoxil, aldesleukin, amphotericin b, azithromycin, calcium hydroxylapatite, clarithromycin, doxorubicin, dronabinol, entecavir, epoetin alfa, etoposide, fluconazole, ganciclovir, immunoglobulins, interferon alfa-2, isoniazid, itraconazole, megestrol, paclitaxel, peginterferon alfa-2, pentamidine, poly-1-lactic acid, ribavirin, rifabutin, rifampin, somatropin, testosterone, trimetrexate, valganciclovir; integrase inhibitors, microbicides, and IL-2. 
     
     
         8 . The method of  claim 1 , wherein said effective amount comprises between about 10 and 1500 μg of said phorbol ester or derivative compound of Formula I every other day. 
     
     
         9 . The method of  claim 1 , wherein said effective amount comprises between about 150 to 500 μg of said phorbol ester or derivative compound of Formula I every other day. 
     
     
         10 . The method of  claim 1 , wherein said effective amount of said phorbol ester compound or derivative compound of Formula I is administered once per day. 
     
     
         11 . A method for preventing or treating one or more symptoms or conditions of HIV infection or AIDS in a mammalian subject comprising administering an effective amount of phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are selected from the group consisting of hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof, and R 3  is selected from hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof. 
     
     
         12 . The method of  claim 11 , wherein R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       the remaining R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       and R 3  is hydrogen. 
     
     
         13 . The method of  claim 11 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate. 
     
     
         14 . The method of  claim 11 , wherein the phorbol ester is 12-O-tetradecanoylphobol-13-acetate. 
     
     
         15 . The method of  claim 11 , further comprising administering at least one secondary anti-retroviral or other adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to treat symptoms or conditions of AIDS in said subject. 
     
     
         16 . The method of  claim 11 , wherein the at least one secondary anti-retroviral or other adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject. 
     
     
         17 . The method of  claim 11 , wherein the at least one secondary anti-retroviral or other adjunctive therapeutic agent is selected from the group consisting of: protease inhibitors, nucleoside reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, combination drugs, entry and fusion inhibitors, acyclovir, adefovir dipivoxil, aldesleukin, amphotericin b, azithromycin, calcium hydroxylapatite, clarithromycin, doxorubicin, dronabinol, entecavir, epoetin alfa, etoposide, fluconazole, ganciclovir, immunoglobulins, interferon alfa-2, isoniazid, itraconazole, megestrol, paclitaxel, peginterferon alfa-2, pentamidine, poly-1-lactic acid, ribavirin, rifabutin, rifampin, somatropin, testosterone, trimetrexate, valganciclovir; integrase inhibitors, microbicides, and IL-2. 
     
     
         18 . The method of  claim 11 , wherein the one or more symptoms or conditions of AIDS are oral lesions, fatigue, skin thrush, fever, lack of appetite, diarrhea, apthous ulcers, malabsorbtion, thrombocytopenia, weight loss, anemia, and lymph node enlargement,  mycobacterium avium  complex, salmonellosis, syphilis, neuroshyphilis, turberculosis, bacillary angiomatosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, pelvic inflammatory disease, Burkitt's lymphoma, cryptococcal meningitis, histoplasmosis, Kaposi's sarcoma, lymphoma, systemic non-Hodgkin's lymphoma, primary CNS lymphoma, cryptosporidiosis, isosporiasis, microsporidiosis,  pneumocystis carinii  pneumonia, toxoplasmosis, cytomegalovirus, hepatitis, herpes simplex, herpes zoster, human papiloma virus, molluscum contagiosum, oral hairy leukoplakia, and progressive multifocal leukoencephalopathy. 
     
     
         19 . A method for controlling HIV infection in a mammalian subject to reduce or prevent AIDS comprising administering to said subject an effective amount of a phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof, to said subject 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are selected from the group consisting of hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof and R 3  is selected from hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof. 
     
     
         20 . The method of  claim 19 , wherein R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       the remaining R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       and R 3  is hydrogen. 
     
     
         21 . The method of  claim 19 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate. 
     
     
         22 . The method of  claim 19 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate. 
     
     
         23 - 28 . (canceled) 
     
     
         29 . A method for activating latent reservoirs of HIV comprising administering an effective amount of a phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are selected from the group consisting of hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof, and R 3  is selected from hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof. 
     
     
         30 - 38 . (canceled) 
     
     
         39 . A method of increasing the expression of Th1 cytokines comprising administering an effective amount of a phorbol ester or derivative of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are selected from the group consisting of hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof, and R 3  is selected from hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof. 
     
     
         40 . The method of  claim 39 , wherein R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       the remaining R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       and R 3  is hydrogen. 
     
     
         41 . The method of  claim 39 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate. 
     
     
         42 . The method of  claim 39 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate. 
     
     
         43 - 48 . (canceled) 
     
     
         49 . A method of treating or preventing neoplasms in a mammalian subject comprising administering an effective amount of a phorbol ester or derivative of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are selected from the group consisting of hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof, R 3  is selected from hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof; and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to treat or prevent neoplasms in said subject. 
     
     
         50 . The method of  claim 49 , wherein R 1  or R 2  is the 
       
         
           
           
               
               
           
         
       
       the remaining R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       and R 3  is hydrogen. 
     
     
         51 . The method of  claim 49 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate. 
     
     
         52 . The method of  claim 49 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate. 
     
     
         53 . The method of  claim 49 , wherein the at least one secondary or adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject. 
     
     
         54 . The method of  claim 49 , wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of: doxorubicin, vitamin D3, cytarabine, cytosine arabinoside, daunorubicin, cyclophosphamide, gemtuzumab ozogamicin, idarubicin, mercaptopurine, mitoxantrone, thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, fludarabine, methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate. 
     
     
         55 - 58 . (canceled) 
     
     
         59 . The method of  claim 49  wherein the neoplasm is caused by a hematological malignancy/bone marrow disorder. 
     
     
         60 . The method of  claim 59 , wherein the hematological malignancy/bone marrow disorder is leukemia. 
     
     
         61 . The method of  claim 60 , wherein the leukemia is acute myeloid leukemia. 
     
     
         62 . The method of  claim 49 , wherein the neoplasm is a solid tumor. 
     
     
         63 - 77 . (canceled) 
     
     
         78 . A method for inducing apoptosis in a neoplasm in a mammalian subject suffering from neoplastic disease comprising administering to said subject an effective amount of a phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof, to said subject 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are selected from the group consisting of hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof, R 3  is hydrogen, 
       
         
           
           
               
               
           
         
       
       and substituted derivatives thereof, and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester of derivative compound of Formula I to induce apoptosis in a neoplasm in said subject. 
     
     
         79 . The method of  claim 78 , wherein R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       the remaining R 1  or R 2  is 
       
         
           
           
               
               
           
         
       
       and R 3  is hydrogen and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to treat or prevent malignancy in said subject. 
     
     
         80 . The method of  claim 78 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate. 
     
     
         81 . The method of  claim 78 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate. 
     
     
         82 - 90 . (canceled)