Effect of NS-398, a new nonsteroidal anti-inflammatory agent, on gastric ulceration and acid secretion in rats.

The ulcerogenic activity of NS-398 was compared with that of indomethacin and the effects of NS-398 on stress-induced ulceration, gastric acid secretion and gastric mucosal prostaglandin (PG) contents were investigated in rats. NS-398 in a single dose of up to 1,000 mg/kg, p.o. did not significantly cause gastric ulceration while other nonsteroidal anti-inflammatory drugs such as, loxoprofen, indomethacin, diclofenac and ibuprofen, produced distinct gastric lesions. In cases of stress-induced ulcerations, NS-398 at 30 mg/kg, p.o. had no significant influence while indomethacin markedly potentiated the ulceration in a dose dependent manner. In basal gastric secretion studies, both NS-398 and indomethacin decreased secretion volume and acidity. However, in the 2-deoxy-D-glucose-stimulated gastric acid secretion study, NS-398 had no significant influence on gastric secretions while indomethacin significantly potentiated the secretion. Both NS-398 and indomethacin to much the same extent significantly decreased prostaglandin E2 (PGE2) contents in inflammatory tissue. However, with respect to gastric mucosal PGE2 contents, NS-398 did not decrease PGE2 contents while indomethacin significantly decreased the contents. It would thus appear that the absence of ulcerogenic properties of NS-398 is due to a relative lack of activity in inhibiting gastric PG synthesis.

Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation.

NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl) methane sulphonamide), a newly synthesized potent non-steroidal anti-inflammatory drug (NSAID) has a much lesser degree of toxicity, as compared with presently available NSAIDs. We have investigated the inhibition of prostanoid production in inflammatory exudate, gastric mucosa and renal papillary tissue, following oral administration to carrageenan-air-pouch rats. The ID50 values of NS-398 in the inflammatory exudate, gastric mucosa and renal papillary tissue were 0.18, 62.2 and 261.7 mg kg-1, respectively. In contrast, indomethacin decreased the PGE2 concentration in the inflammatory exudate, gastric mucosa and renal papillary tissue, with the same dose range, the ID50 values being 0.23, 0.14 and 0.15 mg kg-1, respectively. The same tendency was seen for 6-keto-prostaglandin F1 and thromboxane B2. Moreover, NS-398 inhibited excess PGE2 production in inflamed tissue but did not affect physiological production of PGE2 in non-inflamed tissue. Indomethacin, in both inflamed and non-inflamed tissues, inhibited PGE2 production to the same degree. These results indicated that NS-398 has some specificity for inflamed tissue, by inhibiting prostanoid synthesis, and this effect may explain the decreased side-effects of this drug.

NS-398, a novel non-steroidal anti-inflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions.

1. NS-398 (N-[2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide) is a new non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic effects. 2. The anti-inflammatory potency of NS-398 in rat carrageenin-induced edema was as potent as that of indomethacin and 8 times more potent than diclofenac. In rat adjuvant arthritis, NS-398 showed a therapeutic effect comparable to that seen with loxoprofen but less than that seen with indomethacin and diclofenac. 3. The analgesic potency of NS-398 in rat adjuvant arthritic pain was much the same as that of indomethacin, and was about 3-5 times higher than that of diclofenac and loxoprofen. In the Randall-Selitto method in rats, NS-398 was 2-7 times as potent as loxoprofen, diclofenac and indomethacin. In acetic acid-induced writhing in mice, NS-398 was equipotent to indomethacin and diclofenac. 4. In LPS-induced fever in rats, NS-398 was 1.5-4.5 times as potent as loxoprofen and indomethacin, but less potent than diclofenac. 5. NS-398 produced little gastric ulceration in doses of up to 1000 mg/kg, while reference drugs produced distinct stomach lesions in doses of 10-30 mg/kg. 6. NS-398 inhibited prostaglandin (PG) endoperoxide synthase from sheep seminal vesicle microsomes less potent than that of ibuprofen.

A new test for evaluating nonsteroidal anti-inflammatory drugs in vitro: inhibition of prostaglandin E2 production in minced intestinal tissue.

A new method for evaluating the inhibitory effect of nonsteroidal anti-inflammatory drugs on prostaglandin E2 production is presented. Minced rat intestinal tissue was incubated with a nonsteroidal anti-inflammatory drug and homogenized. After centrifugation, prostaglandin E2 in the supernatant was measured by radioimmunoassay. The production of prostaglandin E2 was decreased by nonsteroidal anti-inflammatory drugs, in a concentration-dependent manner, the order of potency being diclofenac greater than loxoprofen greater than indomethacin greater than ibuprofen greater than TA-847 (imidazole derivative). Loxoprofen, a prodrug, inhibited the prostaglandin E2 production. In a classical enzyme assay with sheep seminal vesicle microsomal prostaglandin endoperoxide synthase, the order of inhibitory potency was TA-847 greater than diclofenac greater than indomethacin greater than ibuprofen. The inhibitory effect of loxoprofen was very weak. On the other hand, the potency order of these nonsteroidal anti-inflammatory drugs, with regard to their anti-inflammatory effect as determined in the rat carrageenin-induced paw edema model, was loxoprofen greater than indomethacin greater than diclofenac greater than ibuprofen greater than TA-847. The results of the new method with intestinal tissue showed thus a good correlation with the anti-inflammatory activity in vivo.