Compositions and methods for reducing hepatotoxicity associated with drug administration

Abstract

The present invention relates to the discovery that acetylsalicylic acid (ASA or aspirin), salicylic acid (SA) and related salicylate esters and their pharmaceutically acceptable salts, when coadministered in effective amounts with a drug or other bioactive agent which typically (in the absence of the salicylate compound) produces significant hepatotoxicity as a secondary indication, will substantially reduce or even eliminate such hepatotoxicity. Favorable therapeutic intervention results from the use of the present invention having the effect of reducing hepatotoxicity associated with the administration of certain drugs and other bioactive agents and in certain instances of allowing the administration of higher doses of a compound which, without the coadministration, would produce hepatotoxicity which limits or even negates the therapeutic value of the compound.

1 . A pharmaceutical composition comprising a therapeutically effective amount of a hepatotoxicity inducing bioactive agent in combination with an effective amount of a salicylate according to the chemical structure: 
       
         
           
           
               
               
           
         
         where R is H or a C 2 -C 10  acyl group, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, additive or excipient 
         wherein the amount of said salicylate in said composition substantially reduces the hepatotoxicity of said bioactive agent after administration to a patient. 
       
     
     
         2 . The composition according to  claim 1  wherein R is an acetyl group. 
     
     
         3 . The composition according to  claim 1  wherein said salicylate increases the therapeutic index of said bioactive agent at least about 5-10% above the therapeutic index exhibited by said bioactive agent when administered in the absence of said salicylate. 
     
     
         4 . The composition according to  claim 1  wherein R is a C 2  acyl group. 
     
     
         5 . The composition according to  claim 1  wherein said salicylate is acetylsalicylic acid or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The composition according to  claim 1  wherein said bioactive agent is selected from the group consisting of anaesthetic agents, antiviral agents, anticancer agents, organ transplant drugs, antimicrobial agents, anti-diabetes drugs, vitamin A derivatives, steroidal agents, non-steroidal anti-inflammatory drugs (NSAIDs), anti-depressants, glucocorticoids, natural products and herbal and alternative remedies. 
     
     
         7 . The composition according to  claim 6  wherein said steroidal agent is selected from the group consisting of contraceptives, anabolic steroids and androgens. 
     
     
         8 . The composition according to  claim 6  wherein said herbal and alternative remedy is St. John's wort. 
     
     
         9 . The composition according to  claim 6  wherein said antiviral agent is an anti-HIV agent. 
     
     
         10 . The composition according to  claim 6  wherein said antiviral agent is a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or mixtures thereof. 
     
     
         11 . The composition according to  claim 6  wherein said anti-viral agent is selected from the group consisting of indinavir, didanosine, emtricitabine, squinavir, raltegravir, ritonavir, lopinavir, lamivudine, delavirdine, zidovudine, atazanavir, maraviroc, efavirenz, nelfinavir, tenofovir, stavudine, abacavir, tipranavir, darunavir, festinavir, combivir (lamivudine/zidovudine), epzicom (abacavir/lamivudine), kaletra (lopinavir/ritonavir), trizivir (abacavir/lamivudine/zidovudine), truvada (emtricitabine/tenofovir), atripla (efavirenz/emtricitabine/tenofovir) and mixtures thereof. 
     
     
         12 . The composition according to  claim 10  wherein said antiviral agent is a mixture of a nucleoside reverse transcriptase inhibitor and a non-nucleoside reverse transcriptase inhibitor. 
     
     
         13 . The composition according to  claim 6  wherein said antimicrobial agent is an anti-fungal agent or an antibiotic. 
     
     
         14 . The composition according to  claim 13  wherein said anti-fungal agent is selected from the group consisting of diflucan, terbinafine, itraconazole, ketoconazole, voriconazole, posaconazole and mixtures thereof. 
     
     
         15 . The composition according to  claim 6  wherein said antimicrobial agent is an anti-tuberculosis agent selected from the group consisting of isoniazid, ethambutol, pyrazinamide, ethionamide and mixtures thereof. 
     
     
         16 . The composition according to  claim 6  wherein said anti-diabetes drug is selected from the group consisting of rosiglitazone, pioglitazone and mixtures thereof. 
     
     
         17 . The composition according to  claim 1  wherein said bioactive agent is an organ transplant drug selected from the group consisting of cyclosporin, tacrolimus, OKT3 and mixtures thereof. 
     
     
         18 . The composition according to  claim 17  wherein said composition comprises cyclosporine and tacrolimus in combination. 
     
     
         19 . The composition according to  claim 6  wherein said anti-depressant is a tricyclic antidepressant selected from the group consisting of desipramine and imipramine. 
     
     
         20 . The composition according to  claim 1  wherein said bioactive agent is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, amlodipine/atorvastatin (Caduet), rosuvastatin, fluvastatin, fluvastatin ER, niacin/simvastatin (Simcor) and mixtures thereof. 
     
     
         21 . The composition according to  claim 1  wherein said bioactive agent is selected from the group consisting of fenofibrate, ezetimibe, gemfibrozil and mixtures thereof. 
     
     
         22 . The composition according to  claim 1  wherein said bioactive agent is a mixture of at least one compound selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, amlodipine/atorvastatin (Caduet), rosuvastatin, fluvastatin, fluvastatin ER and niacin/simvastatin (Simcor) and at least one compound selected from the group consisting of fenofibrate, ezetimibe and gemfibrozil. 
     
     
         23 . The composition according to  claim 1  wherein said bioactive agent is selected from the group consisting of acebutolol, indomethacin, phenylbutazone, allopurinol, isoniazid, phenytoin, atenolol, ketoconazole, piroxicam, carbamazepine, labetalol, probenecid, cimetidine, maprotiline, pyrazinamide, dantrolene, metoprolol, quinidine, diclofenac, mianserin, quinine, quinidine, diltiazem, naproxen, ranitidine, enflurane, para-aminosalicylic acid, sulfonamide antibiotics, ethambutol, penicillin, benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, dicloxacillin, flucloxacillin, nafcillin, cloxacillin, penicillamine, sulindac, ethionamide, phenelzine, desipramine, imipramine, halothane, phenindione, valproic acid, ibuprofen, phenobarbital, verapamil, adrenocorticol steroids, phenothiazines, antithyroid drugs, phenytoin, tetracyclines, valproic acid, methotrexate, actinomycin D, chlorpropamide, erythromycin, azathioprine, cyclophosphamide, flurazepam, diazepam, chlordiazepoxide, captopril, cyclosporine, flutamide, carbamazepine, danazol, glyburide, carbimazole, gold salts, cephalosporins, disopyramide, griseofulvin, enalapril, haloperidol, ketoconazole, norethandrolone, mercaptopurine, tamoxifen, methyltestosterone, testosterone, thiabendazole, nifedipine, tolbutamide, nitrofurantoin, phenothiazines, propoxyphene, verapamil, allopurinol, hydralazine, procainamide, carbamazepine, chlorpromazine, nitrofurantoin, diltiazem, tolbutamide, disopyramide, phenylbutazone, dantrolene, methyldopa, terbinafine HCl, nicotinic acid, chlorpromazine/valproic acid (combination), thorotrast, danazol, labetolol, adriamycin, dacarbazine, thioquanine, vincristine, vitamin A, carmustine, mitomycin, maprotiline, probenecid, piroxicam, diclofenac, enflurane, sulindac, phenindione, glyburide, haloperiodol, norethandolone, amiodarone, felbamate, fenofibrate, femfibrozil, fenofibrate and gemfibrozil (combination), imatinib, leflunomide, nefazodone, niacin, aminosalicyclic acid/aminosalicylate sodium, capreomycin sulfate, clofazimine, cycloserine, clopidogrel, kanamycin sulfate, rifabutin, rifampin, rifapentine, streptomycin sulfate, gatifloxacin, tacrine and riluzole, troglitazone, bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, ximelagatran and mixtures thereof. 
     
     
         24 . The composition according to  claim 1  wherein said bioactive agent is selected from the group consisting of ibuprofen, ibuprofen/oxycodone, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, mecrofenamate, nabumetone, naproxen, naproxen sodium, oxaprozin, salsalate, sulindac, tolmetin, ketorolac, piroxicam, meloxicam, prevacid/naproxen, celecoxib, mefenamic acid, sumatriptan/naproxen sodium and mixtures thereof. 
     
     
         25 . The composition according to  claim 1  wherein said bioactive agent is included in said composition at a high effective dose. 
     
     
         26 . The composition according to  claim 1  wherein said salicylate compound is administered in sustained or controlled release form. 
     
     
         27 . The composition according to  claim 1  wherein said salicylate compound and said bioactive agent is delivered in sustained or controlled release form. 
     
     
         28 . The composition according to  claim 1  in oral dosage form. 
     
     
         29 . The composition according to  claim 1  in parenteral dosage form. 
     
     
         30 . The composition according to  claim 1  in buccal or sublingual dosage form. 
     
     
         31 . The composition according to  claim 1  in transdermal dosage form. 
     
     
         32 . A method of increasing the therapeutic index of a hepatotoxicity inducing bioactive agent comprising combining in a pharmaceutical composition said bioactive agent in combination with an effective amount of a salicylate according to the chemical structure: 
       
         
           
           
               
               
           
         
       
       where R is H or a C 2 -C 10  acyl group, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, additive or excipient, wherein the amount of said salicylate in said composition is effective to substantially increase the therapeutic index of said bioactive agent after administration to a patient. 
     
     
         33 - 53 . (canceled) 
     
     
         54 . A method of reducing the hepatotoxicity of a hepatotoxicity inducing bioactive agent in a patient or subject comprising coadministering to said patient or subject said bioactive agent in combination with an effective amount of a salicylate compound according to the chemical structure: 
       
         
           
           
               
               
           
         
       
       where R is H or a C 2 -C 10  acyl group, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, additive or excipient. 
     
     
         55 .- 89 . (canceled)