Use of inhibitors of soluble epoxide hydrolase to synergize activity of cox and 5-lox inhibitors

Abstract

The invention relates to methods, compositions, and uses of those compositions for making medicaments, for potentiating the beneficial effects of inhibitors of COX-1, COX-2, and 5-LOX, and reducing adverse effects, by also administering inhibitors of soluble epoxide hydrolase (“sEH”), with or without also administering one or more cis-epoxyeicosantrienoic acids. The invention further relates to the use of inhibitors of sEH as analgesics and to methods and compositions of epoxides of eicosapentaenoic acid and docosahexaenoic acid, optionally with an inhibitor of sEH, to reduce pain or inflammation or both.

1 . A method of reducing or preventing pain in a subject, said method comprising administering to said subject an analgesic amount of an inhibitor of soluble epoxide hydrolase (“sEH”). 
     
     
         2 . A method of  claim 1 , wherein said inhibitor of sEH has a primary pharmacophore selected from the group consisting of a urea, a carbamate, and an amide. 
     
     
         3 . A method of  claim 2 , wherein said inhibitor of sEH has a polyether secondary pharmacophore. 
     
     
         4 . A method of  claim 1 , further comprising administering a cis-epoxyeicosantrienoic acid (“EET”) to said subject. 
     
     
         5 . A method of  claim 4 , wherein one or more EETs selected from the group consisting of 14,15-EET, 8,9-EET, 11,12-EET and 5,6 EET are administered. 
     
     
         6 . A method of  claim 1 , further comprising administering an inhibitor of an enzyme selected from the group consisting of cyclo-oxygenase (“COX”)-1, COX-2, and 5 lipoxygenase (“5-LOX”). 
     
     
         7 . A method of  claim 6 , wherein the inhibitor of COX-1, COX-2, or 5 LOX is selected from the group consisting of celecoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, licofelone, tepoxalin, aspirin, acetaminophen, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen sodium, piroxicam, tolmetin sodium, magnesium salicylate, choline salicylate, salsalate, sodium salicylate, and an inhibitor of 5 lipoxygenase activating protein. 
     
     
         8 . A method of  claim 6 , wherein the inhibitor of COX-1, COX-2, or 5 LOX is administered in a subtherapeutic dose. 
     
     
         9 . A method of  claim 6 , wherein the inhibitor of COX-1, COX-2, or 5 LOX is a selective COX-2 inhibitor. 
     
     
         10 . A method of  claim 1 , further comprising administering an epoxide of docosahexaenoic acid (“DHA”) or of eicosapentaenoic acid (“EPA”), or an epoxide of DHA and an epoxide of EPA to said subject. 
     
     
         11 . A method of  claim 1 , wherein the analgesic effects of the inhibitor of sEH are independent of the effect in reducing inflammation.