Pemedolac

PEM-420, the active isomer of pemedolac, inhibited the writhing responses induced by phenylbenzoquinone (PBQ), acetic acid, and acetylcholine in mice with ED50's of 0.80, 0.92, and 0.075 mg/kg p.o., respectively. In the rat acetic acid writhing assay, PEM-420 exhibited an ED50 value of 8.4 mg/kg p.o. In the Randall-Selitto test, PEM-420 raised the pain threshold of the yeast-injected paw (ED50 = 0.55 mg/kg p.o.). Like other NSAIDs, PEM-420 inhibited the PBQ-induced production of PGI2 and PGE2 in the mouse peritoneal cavity, with ED50 values of 0.5 and 1.2 mg/kg p.o., respectively. It had weak ulcerogenic liability in rats (acute UD50 = 99 mg/kg p.o. in fasted rats; subacute UD50 = 74 mg/kg/day for 4 days in fed rats). The data indicate that PEM-420 is a potent and safe peripheral analgesic.

Pemedolac [cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)-pyrano [3,4-b]indole-1-acetic acid; AY-30,715] exhibited potent analgesic effects against chemically induced pain in rats and mice and against inflammatory pain in rats. In each of the animal models used the analgesic potency of pemedolac was defined by an ED50 of 2.0 mg/kg p.o. or less. Significant analgesic activity was detected in rats at 16 hr after administration of 1 mg/kg p.o. (paw pressure test) and at 10 hr after administration of 10 mg/kg p.o. to mice (p-phenylbenzoquinone writhing). Inasmuch as pemedolac was inactive in the hot plate and tail-flick tests; and its analgesic activity was not antagonized by naloxone (1 mg/kg s.c.), and tolerance did not develop upon multiple administration; this drug does not exert its analgesic effects through an opiate mechanism. Pemedolac differed from standard nonsteroidal anti-inflammatory drugs (NSAIDs) in that the doses which produced analgesia were much lower than those required for either anti-inflammatory or gastric irritant effects. In acute anti-inflammatory tests, pemedolac exhibited only weak activity as evidenced by an ED50 approximately 100 mg/kg p.o. in the carrageenan paw edema procedure. This demonstrates for pemedolac a separation of at least 50-fold between the acute analgesic and anti-inflammatory activities, which was greater than that observed with reference NSAIDs. The compound also had a low ulcerogenic liability with an acute UD50 = 107 mg/kg p.o. and a subacute UD50 estimated to be 140 mg/kg/day p.o. In contrast, the reference NSAIDS (piroxicam, indomethacin, naproxen and ibuprofen) exhibited similar dose-response relationships for the analgesic, anti-inflammatory and gastric irritant effects.(ABSTRACT TRUNCATED AT 250 WORDS)