Method and Composition for Potentiating the Antipyretic Action of a Nonopiod Analgesic

Abstract

A composition and method of treating fever, and optionally treating pain, is disclosed. The composition and method utilize a nonopioid analgesic and an endothelin antagonist as active agents to treat fever in mammals, including humans. The composition also is useful in the prevention and treatment of stroke and other cardiovascular disorders, like myocardial infarction.

1 . A method of treating fever comprising administering to a mammal in need thereof (a) a therapeutically effective amount of a nonopioid analgesic, and (b) a therapeutically effective amount of an endothelin antagonist. 
     
     
         2 . The method of  claim 1  wherein the nonopioid analgesic and endothelin antagonist are administered simultaneously. 
     
     
         3 . The method of  claim 2  wherein the nonopioid analgesic and endothelin antagonist are administered from a single composition. 
     
     
         4 . The method of  claim 2  wherein the nonopioid analgesic and endothelin antagonist are administered from separate compositions. 
     
     
         5 . The method of  claim 1  wherein the nonopioid analgesic and endothelin antagonist are administered sequentially. 
     
     
         6 . The method of  claim 5  wherein the nonopioid analgesic is administered prior to the endothelin antagonist. 
     
     
         7 . The method of  claim 5  wherein the endothelin antagonist is administered prior to the nonopioid analgesic. 
     
     
         8 . The method of  claim 1  wherein the nonopioid analgesic is selected from the group consisting of acetaminophen, phenacetin, ibuprofen, fenoprofen, aspirin, indomethacin, naproxen, oxyphenbutazone, phenylbutazone, allopurinol, cholchicine, carbamazepine, methyl sergide, methotrimeprazine, propoxyphene, probenecid, salsalate, sulfinpyrazone, antipyrine, ethoheptazine, amodiaquine diflunisal, dihydroergotamine, ergotamine, meclofenamate, mefenamic acid, piroxican, sulindac, tolmetin, and mixtures, salts, prodrugs, and derivatives thereof. 
     
     
         9 . The method of  claim 1  wherein the nonopioid analgesic comprises acetaminophen, phenacetin, ibuprofen, fenoprofen, aspirin, indomethacin, or a salt, prodrug, or derivative and mixtures thereof. 
     
     
         10 . The method of  claim 1  wherein the nonopioid analgesic comprises acetaminophen. 
     
     
         11 . The method of  claim 1  wherein the endothelin antagonist comprises an endothelin-A antagonist. 
     
     
         12 . The method of  claim 11  wherein the endothelin-A antagonist comprises a specific endothelin-A antagonist. 
     
     
         13 . The method of  claim 11  wherein the endothelin-A antagonist comprises a nonspecific endothelin-A antagonist. 
     
     
         14 . The method of  claim 1  wherein the endothelin antagonist is selected from the group consisting of compounds 1 through 35 of Appendix A. 
     
     
         15 . The method of  claim 1  wherein the endothelin antagonist is selected from the group consisting of compounds 46 through 67 of Appendix B. 
     
     
         16 . The method of  claim 1  wherein the endothelin antagonist is selected from the group consisting of compounds 36 through 45 of Appendix C. 
     
     
         17 . The method of  claim 1  wherein the endothelin antagonist is selected from the group consisting of compounds 68 through 109 of Appendix D. 
     
     
         18 . The method of  claim 1  wherein the endothelin antagonist is selected from the group consisting of atrasentan, tezosentan, bosentan, darnsenten, sitaxsentan, enrasentan, BMS-207940, BMS-193884, BMS-182874, J-104132, VML 588/Ro 61-1790, T-0115, TAK-044, BQ-788, BQ123, YM-598, LU 135252, PD 145065, A-127722, ABT-627, A-192621, A-182086, TBC3711, BSF208075, S-0139, TBC2576, TBC3214, PD156707, PD180988, ABT-546, ABT-627, Z1611, RPR118031A, SB247083, SB217242, S-Lu302872, TPC10950, SB209670, and mixtures thereof. 
     
     
         19 . The method of  claim 1  wherein the endothelin antagonist comprises BQ123. 
     
     
         20 . The method of  claim 10  wherein the endothelin antagonist comprises BQ123. 
     
     
         21 . The method of  claim 1  wherein the endothelin antagonist comprises an endothelin converting enzyme inhibitor. 
     
     
         22 . The method of  claim 21  wherein the endothelin converting enzyme inhibitor is selected from the group consisting of N-((1-((2(S)-(acetylthio)-1-oxopentyl)-amino)-1-cyclopentyl)-carbonyl-S4-phenylphenyl-alanine methyl ester, phosphoramidon, and mixtures thereof. 
     
     
         23 . The method of  claim 1  wherein analgesic properties of the nonopioid analgesic are unaffected. 
     
     
         24 . The method of  claim 1  wherein the mammal is a human. 
     
     
         25 . The method of  claim 1  wherein treating the fever comprises reducing severity of the fever. 
     
     
         26 . The method of  claim 25  wherein the fever is reduced at least 1.5 times longer than a treatment utilizing the nonopioid analgesic alone. 
     
     
         27 . The method of  claim 25  wherein the antipyretic treatment reduces the fever by at least 0.1° C. more than a treatment for fever using the nonopioid analgesic along. 
     
     
         28 . A method of treating a stroke comprising administering to a mammal in need thereof (a) a therapeutically effective amount of a nonopioid analgesic, and (b) a therapeutically effective amount of an endothelin antagonist. 
     
     
         29 . A method of treating a cardiovascular disorder comprising administering to a mammal in need thereof (a) a therapeutically effective amount of a nonopioid analgesic, and (b) a therapeutically effective amount of an endothelin antagonist. 
     
     
         30 . A composition comprising (a) a nonopioid analgesic, (b) an endothelin antagonist, and (c) an optional excipient. 
     
     
         31 . The composition of  claim 30  wherein the endothelin antagonist comprises an endothelin-A antagonist. 
     
     
         32 . An article of manufacture comprising:
 (a) a packaged composition comprising a nonopioid analgesic;   (b) a packaged composition comprising an endothelin antagonist;   (c) an insert providing instructions for a simultaneous or sequential administration of (a) and (b) to reduce fever, and optionally to treat pain, in a mammal; and   (d) a container for (a), (b), and (c).   
     
     
         33 . An article of manufacture comprising:
 (a) a packaged composition comprising a nonopioid analgesic and an endothelin antagonist;   (b) an insert providing instructions for administration of (a) to reduce fever, and optionally to treat pain, in a mammal; and   (c) a container for (a) and (b).