No abstract

Intraperitoneal injection of zymosan (1 mg in 0.5 ml saline) in mice induces a transient writhing response accompanied by the synthesis of small amounts of prostaglandin E2 (PGE2, < 2 ng) and larger amounts of PGI2 (200 ng per mouse), measured as its non‐enzymatic breakdown product, 6‐keto‐PGF1α. Although both centrally‐acting analgesics (morphine, clonidine) and prostaglandin biosynthesis inhibitors (aspirin, indomethacin, ibuprofen) blocked the writhing response to intraperitoneal injection of zymosan, only the latter reduced prostaglandin levels in the peritoneal cavity. The writhing response correlated equally well with PGE2 levels and 6‐keto‐PGF1α levels when data from mice treated with centrally‐acting analgesics were excluded. However, intraperitoneal injection of PGI2, but not PGE2, reversed the analgesia induced by indomethacin in zymosan‐injected mice. Centrally‐acting agents, but not ibuprofen, blocked the ability of PGI2 to reverse the analgesic activity of indomethacin. PGI2 (2 μg per mouse), injected intraperitoneally in otherwise untreated mice, induced writhing. These data indicate that PGI2 is the prostaglandin involved in mediation of the writhing response to zymosan and that prostaglandin biosynthesis inhibitors, but not centrally‐acting analgesics, exert their analgesic activity by reducing the peritoneal level of PGI2. It is possible that PGI2 may have the ability to stimulate pain receptors directly in the mouse peritoneal cavity, in addition to its previously recognized ability to sensitize pain receptors to other pain‐producing stimuli.

Oral administration of MDL 19,301 (N-(l,3-dithiolan-2-ylidene)-4-hexyl-benzenamine) inhibited rat paw edema induced by carrageenan (ED30 4.8 mg/kg) or an Arthus reaction (ED30 8.2 mgikg p.0.). The oral dose which induced gastric ulceration in 50% of fasted rats (UD50) was greater than 1,000 mgikg, demonstrating a more favorable therapeutic ratio than conventional nonsteroidal anti-inflammatory agents. Its major metabolite (MDLI 6,861, 4[( 1,3-dithiolan-2-yliden)arnino]-benzeneacetic acid) was also a potent inhibitor of carrageenan paw edema (ED50 5.5 mgikg P.o.), although it was more ulcerogenic (UD50 52 mgikg p.0.). The anti-inflammatory activity of MDL 19,301, but not that of MDL 16,861, was attenuated by co-administration of an inhibitor of drug metabolism (SK&F525A 30 mgikg i.p.). This suggests that MDL 19,301 is a prodrug of MDL 16,861 and this phenomenon would explain its lack of ulcerogenicity. Additional anti-inflammatory properties of MDL 19,301 included inhibition of carrageenan pleurisy, adjuvant arthritis, and acetic-acid-induced writhing. Other pharmacological data indicate that MDL 19,301 administration results in inhibition of prostaglandin synthesis; inhibition of arachidonic-acidinduced, but not prostaglandin-E2-induced, diarrhea in mice; and inhibition of ex vivo arachidonic-acid-induced, but not adenosine-diphosphate-induced, rat platelet aggregation. MDL 19,301 and MDL 16,861 were unexpectedly weak antipyretic agents in rats. In summary, MDL 19,301 is an anti-inflammatory, analgesic prodrug which, unlike conventional agents, is devoid of ulcerogenic activity at therapeutic doses.