Novel Therapeutic Treatments Using Centhaquin

Abstract

Methods of treating hypertension, pain, and resuscitative hemorrhagic shock using an adrenergic agent, like centhaquin, are disclosed. The methods treat mammals, including humans.

1 . A method of treating hypertension comprising administering to a mammal in need thereof (a) a therapeutically effective amount of an adrenergic agent and (b) a therapeutically effective amount of an endothelin antagonist. 
     
     
         2 . The method of  claim 1  wherein the adrenergic agent and the endothelin antagonist are administered simultaneously. 
     
     
         3 . The method of  claim 2  wherein the adrenergic agent and the endothelin antagonist are administered from a single composition. 
     
     
         4 . The method of  claim 2  wherein the adrenergic agent and the endothelin antagonist are administered from separate compositions. 
     
     
         5 . The method of  claim 1  wherein the adrenergic agent and the endothelin antagonist are administered sequentially. 
     
     
         6 . The method of  claim 5  wherein the adrenergic agent is administered prior to the endothelin antagonist. 
     
     
         7 . The method of  claim 5  wherein the endothelin antagonist is administered prior to the adrenergic agent. 
     
     
         8 . The method of  claim 1  wherein the adrenergic agent is selected from the group consisting of centhaquin, clonidine, guanfacine, guanabenz, guanoxbenz, methyldopa, prazosin, tamsulosin, doxazosin, terazosin, phentolamine, phenoxybenzamine, mirtazapine, and mixtures thereof. 
     
     
         9 . The method of  claim 1  wherein the adrenergic agent comprises centhaquin, clonidine, or a mixture thereof. 
     
     
         10 . The method of  claim 1  wherein the endothelin antagonist comprises an endothelin-A antagonist. 
     
     
         11 . The method of  claim 10  wherein the endothelin-A antagonist comprises a specific endothelin-A antagonist. 
     
     
         12 . The method of  claim 10  wherein the endothelin-A antagonist comprises a nonspecific endothelin-A antagonist. 
     
     
         13 . The method of  claim 1  wherein the endothelin antagonist is selected from the group consisting of compounds 1 through 35 of Appendix A. 
     
     
         14 . The method of  claim 1  wherein the endothelin antagonist is selected from the group consisting of compounds 46 through 67 of Appendix B. 
     
     
         15 . The method of  claim 1  wherein the endothelin antagonist is selected from the group consisting of compounds 36 through 45 of Appendix C. 
     
     
         16 . The method of  claim 1  wherein the endothelin antagonist is selected from the group consisting of compounds 68 through 109 of Appendix D. 
     
     
         17 . 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. 
     
     
         18 . The method of  claim 1  wherein the endothelin antagonist comprises BMS-182874. 
     
     
         19 . The method of  claim 1  wherein the endothelin antagonist comprises an endothelin converting enzyme inhibitor. 
     
     
         20 . The method of  claim 19  wherein the endothelin converting enzyme inhibitor is selected from the group consisting of N-((1-((2(S)-(acetylthio)-1-oxopentyl)-amino)-1-cyclopentyl)-carbonyl-S-4-phenylphenyl-alanine methyl ester), phosphoramidon, and mixtures thereof. 
     
     
         21 . The method of  claim 1  wherein the mammal is a human. 
     
     
         22 . A composition comprising (a) adrenergic agent, (b) an endothelin antagonist, and (c) an optional excipient. 
     
     
         23 . The composition of  claim 22  wherein the endothelin antagonist comprises an endothelin-A antagonist. 
     
     
         24 . A method of treating pain comprising administering to a mammal in need thereof a therapeutically effective amount of centhaquin. 
     
     
         25 . The method of  claim 24  wherein the centhaquin is administered in a dose range from 10 μg to about 300 μg. 
     
     
         26 . A method of treating pain comprising administering to a mammal in need thereof a therapeutically effective amount of an opiate analgesic and a therapeutically effective amount of centhaquin. 
     
     
         27 . The method of  claim 26  wherein the opiate analgesic is selected from the group consisting of opium, morphine, morphine sulfate, codeine, codeine phosphate, codeine sulfate, diacetylmorphine, morphine hydrochloride, morphine tartate, diacetylmorphine hydrochloride, dextromethorphan hydrobromide, hydrocodone bitartrate, hydromorphone, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloride, oxycodone hydrochloride, fentanyl, meperidine, methodone, propoxyphene, dextromethorphan, hydrocodone, hydromorphone, levorphanol, oxymorphone, oxycodone, levallorphan, salts thereof, and mixtures thereof. 
     
     
         28 . The method of  claim 24  wherein the subject is a mammal. 
     
     
         29 . The method of  claim 29  wherein the subject is human. 
     
     
         30 . The method of  claim 24  wherein the pain is chronic pain. 
     
     
         31 . The method of  claim 24  wherein the pain is acute pain. 
     
     
         32 . A method of treating resuscitative hemorraghic shock or shock due to circulatory failure comprising administering to a mammal in need thereof a therapeutically effective amount of centhaquin. 
     
     
         33 . The method of  claim 32  wherein the centhaquin is administered with Ringer's lactate.