A-906119

The inhibitory action of a novel xanthine derivative, 3-ethyl-1-(6-hydroxy-6-methylheptyl)-7-propylxanthine (A90 6119) on gastric acid secretion was studied in rats. In conscious pylorus-ligated rats, A90 6119 (3 mg/kg intraduodenally, i.d.), inhibited gastric acid output stimulated by carbachol and by 2-deoxy-D-glucose by 49% and 100% respectively. Basal acid secretion was inhibited by 61% by 10 mg/kg, i.d. A90 6119. In urethane anesthetized stomach-lumen-perfused rats, A 90 6119 at 1 and 3 mg/kg, i.d. significantly reduced the acid secretion stimulated by 2-deoxy-D-glucose, by 83% and 100%, respectively. The stable thyrotropin-releasing hormone (TRH) analog, RX 77368, injected intracisternally (i.c.) at a 30 ng dose, induced concomitant increases in acid secretion and gastric mucosal blood flow. A90 6119 (10 micrograms/rat, i.c.) inhibited by 93% and 132% the increase in acid secretion and gastric mucosal blood flow induced by i.c. injection of TRH analog, respectively. These data suggest that the anti-secretory effect of A90 6119 involves inhibition of both central and peripheral vagal cholinergic pathways.

The effects of the novel xanthine derivative 3-ethyl-1-(6-hydroxy-6-methylheptyl)-7-propylxanthine (A90 6119, CAS 134072-58-5) on various experimentally induced ulcers was investigated in rats. A90 6119 produced a dose-dependent inhibition of gastric ulcers induced by water immersion stress and absolute ethanol with ED50- values of 2.4 and 2.8 mg/kg, p.o., respectively. The erosion induced by oral administration of 1.5% NH4OH (3 ml/rat) was significantly reduced by A90 6119 at 10 and 30 mg/kg, p.o. Likewise, A90 6119 caused a dose-dependent inhibition of gastric erosions and intestinal hemorrhage induced by platelet activating factor (PAF) with ED50- values of 8.7 and 11.9 mg/kg p.o., respectively. Duodenal ulcer induced by cysteamine was also dose-dependently inhibited by A90 6119 with an ED50-value of 0.3 mg/kg, i.p. When doses of cimetidine (200 mg/kg) and A90 6119 (10 mg/kg), equipotent in the water immersion stress model, were orally given twice daily for 5 consecutive days before the induction of gastric ulcers by stress, the H2-receptor antagonist aggravated significantly the ulcer formation while the xanthine derivative did not show such an effect. These data suggest that the 3-ethylxanthine A90 6119 possesses pronounced anti-ulcer activity and that its repeated administration might not aggravate ulcer formation and might reduce the incidence of recurrence.