The anti-inflammatory and analgesic profile of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (Tiopinac)

Abstract

Tiopinac displayed marked anti-inflammatory activity when given p.o. in rat models of acute and chronic inflammation. It inhibited carrageenan-induced paw edema (40 x phenylbutazone), and cotton-pellet-induced granuloma (0.8 x indomethacin). In an 18-day test, tiopinac prevented the development of adjuvant-induced arthritis (10–15 x naproxen) and had similar activity versus pre-induced arthritis. Tiopinac exhibited antiphlogistic activity in adrenalectomized rats. It did not have corticosteroid activity. Depending upon the type of analgesic test used, the potency of tiopinac varied. When given p.o. it inhibited henylquinone-induced writhing in the mouse and rat (respectively 16 and 10 x aspirin). In contrast, tiopinac had ∼ 10 times the potency of indomethacin in increasing the pain threshold when yeast-inflamed paws were compressed. The pain threshold of the noninflamed paw was not increased. Tiopinac was highly active versus pain induced by flexing the adjuvant arthritic-inflamed paw (≥1000 x aspirin). It was inactive in the mouse hotplate test in which opiate-like agents are active. Tiopinac, p.o., lowered yeast-induced pyrexia (130 x aspirin). Tiopinac did not have significant cardiovascular or CNS activity. Whereas the ED₅₀ versus adjuvant arthritis in rats was 0.1 mg/kg/day p.o., rats tolerated up to 20 mg/kg/day p.o. in the 8-day cotton-pellet test. Lack of anorexia and emesis in dogs with up to 30 mg/kg p.o. and mild oral activity in producing gastric erosion in acute and subacute studies in rats suggests that tiopinac may have relatively little gastrointestinal irritating activity.