Analgetic activity of SK&F 105809, a dual inhibitor of arachidonic acid metabolism.
The analgetic activity of inhibitors of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) was investigated using rat Randall-Selitto (RS) hyperalgesia and mouse phenylbenzoquinone (PBQ)-induced abdominal constriction assays. Using the RS assay, the CO inhibitors indomethacin, naproxen, and ibuprofen all effectively reduced hyperalgesia; whereas, the inhibitors of leukotriene production, MK886 and phenidone were inactive. SK&F 105809, a dual inhibitor of 5-LO/CO, significantly reduced hyperalgesia. In the PBQ assay, CO inhibitors were active, SK&F 105809 was nearly as potent as naproxen, and MK886 and phenidone were found to be active. Thus, improved analgetic activity appeared to result from inhibition of 5-LO and CO; whereas, in the RS assay, only CO inhibitors and SK&F 105809 were clearly effective. These results suggest that dual inhibitors, and in particular, SK&F 105809 may be more efficient analgesic agents than selective CO inhibitors in clinical situations in which 5-LO products play a significant role.
Griswold
D E
DE
Division of Pharmacological Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, PA.
Marshall
P
P
Martin
L
L
Webb
E F
EF
Zabko-Potapovich
B
B
D000700:Analgesics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D016227:Benzoquinones / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011919:Rats, Inbred Strains
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016227:Benzoquinones; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; C067914:SK&F 105809; D016718:Arachidonic Acid; C029322:phenylbenzoquinone