Compositions and methods for reducing hepatotoxicity associated with drug administration and treating non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and associated cirrhosis

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. The invention also relates to methods of reducing the likelihood of a patient at risk for non-alcoholic fatty liver diseases (NAFLD), including non-alcoholic steatohepatitis (NASH), or treating NAFLD or NASH including primary NASH, NASH secondary to liver transplantation (NASH post-liver transplantation) or cirrhosis represent alternative aspects of the present invention.

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 . (canceled) 
   
   
       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 . (canceled) 
   
   
       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 . (canceled) 
   
   
       13 . (canceled) 
   
   
       14 . (canceled) 
   
   
       15 . (canceled) 
   
   
       16 . (canceled) 
   
   
       17 . (canceled) 
   
   
       18 . (canceled) 
   
   
       19 . (canceled) 
   
   
       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 . (canceled) 
   
   
       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 . The method according to  claim 32  wherein R is an acetyl group. 
   
   
       34 . The method according to  claim 32  wherein said salicylate is acetylsalicylic acid. 
   
   
       35 . The method according to  claim 32  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. 
   
   
       36 . (canceled) 
   
   
       37 . (canceled) 
   
   
       38 . (canceled) 
   
   
       39 . (canceled) 
   
   
       40 . (canceled) 
   
   
       41 . (canceled) 
   
   
       42 . (canceled) 
   
   
       43 . (canceled) 
   
   
       44 . (canceled) 
   
   
       45 . (canceled) 
   
   
       46 . (canceled) 
   
   
       47 . (canceled) 
   
   
       48 . (canceled) 
   
   
       49 . The method according to  claim 32  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. 
   
   
       50 . The method according to  claim 32  wherein said bioactive agent is selected from the group consisting of fenofibrate, ezetimibe, gemfibrozil and mixtures thereof. 
   
   
       51 . The method according to  claim 32  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. 
   
   
       52 . The method according to  claim 32  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. 
   
   
       53 . The method according to  claim 32  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. 
   
   
       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 . The method according to  claim 54  wherein R is an acetyl group. 
   
   
       56 . The method according to  claim 54  wherein said salicylate is acetylsalicylic acid. 
   
   
       57 . The method according to  claim 54  wherein said bioactive agent is selected from the group consisting of anaesthetic agents, antiviral agents, q
 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.   
   
   
       58 . (canceled) 
   
   
       59 . (canceled) 
   
   
       60 . (canceled) 
   
   
       61 . (canceled) 
   
   
       62 . (canceled) 
   
   
       63 . (canceled) 
   
   
       64 . (canceled) 
   
   
       65 . (canceled) 
   
   
       66 . (canceled) 
   
   
       67 . (canceled) 
   
   
       68 . (canceled) 
   
   
       69 . (canceled) 
   
   
       70 . (canceled) 
   
   
       71 . The method according to  claim 54  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. 
   
   
       72 . The method according to  claim 54  wherein said bioactive agent is selected from the group consisting of fenofibrate, ezetimibe, gemfibrozil and mixtures thereof. 
   
   
       73 . The method according to  claim 54  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. 
   
   
       74 . The method according to  claim 54  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. 
   
   
       75 . (canceled) 
   
   
       76 . (canceled) 
   
   
       77 . (canceled) 
   
   
       78 . (canceled) 
   
   
       79 . (canceled) 
   
   
       80 . (canceled) 
   
   
       81 . (canceled) 
   
   
       82 - 89 . (canceled) 
   
   
       90 . A method of inhibiting sterile inflammation of the liver in a patient comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a 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. 
   
   
       91 . (canceled) 
   
   
       92 . (canceled) 
   
   
       93 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a patient in need comprising administering to said patient a composition a comprising an effective amount of a 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. 
   
   
       94 . (canceled) 
   
   
       95 . (canceled) 
   
   
       96 . The method according to  claim 93  wherein said compound is coadministered with a second agent selected from the group consisting of metformin, glibenclamide, gliclazide, rosiglitazone, pioglitazone, troglitazone, acarbose, miglitol, nateglinide, repaglinide, exenatide, sitagliptin, pramlintide and mixtures thereof. 
   
   
       97 . The method according to  claim 93  wherein said NAFLD is non-alcoholic steatohepatitis (NASH). 
   
   
       98 . The method according to  claim 96  wherein said NAFLD is NASH. 
   
   
       99 . The method according to  claim 98  wherein said NASH is primary NASH. 
   
   
       100 . A method of reducing the likelihood of or treating non-alcoholic steatohepatitis (NASH) secondary to post-liver transplantation comprising administering to a patient in need thereof an effective amount of a 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. 
   
   
       101 . (canceled) 
   
   
       102 . The method according to  claim 100  wherein said compound is acetyl-salicyclic acid. 
   
   
       103 . The method according to  claim 100  wherein said compound is coadministered with at least one additional agent selected from the group consisting of cyclosporine, tacrolimus, prednisone, azathioprine, mycophenolate mofetil, daclizumab, basiliximab and mixtures thereof. 
   
   
       104 . The method according to  claim 102  wherein said compound is coadministered with at least one additional agent selected from the group consisting of cyclosporine, tacrolimus, prednisone, azathioprine, mycophenolate mofetil, daclizumab, basiliximab and mixtures thereof. 
   
   
       105 . The method according to  claim 103  wherein said compound and said additional agent are further coadministered with a type II diabetes treating agent selected from the group consisting of metformin, glibenclamide, gliclazide, rosiglitazone, pioglitazone, troglitazone, acarbose, miglitol, nateglinide, repaglinide, exenatide, sitagliptin, pramlintide and mixtures thereof. 
   
   
       106 . A pharmaceutical composition comprising an effective amount of a salicylate 
     
       
         
         
             
             
         
       
     
     where R is H or a C 2 -C 10  acyl group, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient and further in combination with an effective amount of a type II diabetes treatment agent selected from the group consisting of metformin, glibenclamide, gliclazide, rosiglitazone, pioglitazone, troglitazone, acarbose, miglitol, nateglinide, repaglinide, exenatide, sitagliptin, pramlintide and mixtures thereof. 
   
   
       107 - 108 . (canceled) 
   
   
       109 . A pharmaceutical composition comprising 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, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient and further in combination with an effective amount of an additional agent selected from the group consisting of cyclosporine, tacrolimus, prednisone, azathioprine, mycophenolate mofetil, daclizumab, basiliximab and mixtures thereof. 
   
   
       110 - 112 . (canceled) 
   
   
       113 . A method of reducing liver damage in a patient incidental to physical or chemical trauma, comprising administering an effective amount of a salicylate compound to said patient according to the chemical structure: 
     
       
         
         
             
             
         
       
     
     where R is H or a C 2 -C 10  acyl group, or a pharmaceutically acceptable salt thereof, optionally-in combination with a pharmaceutically acceptable carrier, additive or excipient. 
   
   
       114 - 116 . (canceled) 
   
   
       117 . The method according to claim wherein said chemical trauma is acetaminophen-induced liver trauma. 
   
   
       118 . A method of preserving a liver after removal of said liver from a transplant donor and prior to transplantation in a patient, said method comprising exposing said liver after said removal and prior to transplantation to an effective amount of a compound according to the chemical structure: 
     
       
         
         
             
             
         
       
     
     where R is H or a C 2 -C 10  acyl group, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient 
   
   
       119 - 121 . (canceled)