Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride.

Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D(2) or serotonin 5-HT(4) receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents.

Differential effects of intraplantar capsazepine and ruthenium red on capsaicin-induced desensitization in mice.

Intraplantar injection of capsaicin (1.6 microg/paw) into the mouse hindpaw produced an acute paw-licking/biting response. This study was designed (1) to investigate the antinociceptive effects of intraplantar administration of capsazepine, a competitive vanilloid receptor antagonist, and ruthenium red, a noncompetitive antagonist, in the nociceptive licking/biting response induced by intraplantar injection of capsaicin, and (2) to determine whether these compounds were able to prevent capsaicin-induced desensitization in mice. Both capsazepine and ruthenium red produced a dose-dependent reduction in the capsaicin-induced nociceptive response. In licking/biting response to intraplantar capsaicin, ruthenium red was more potent than capsazepine in producing antinociceptive activity as assayed by the capsaicin test. The first injection of capsaicin induced a profound desensitization to the second and third injections of capsaicin at the interval of 15 or 30 min. The capsaicin-induced desensitization was prevented dose-dependently by antinociceptive doses of capsazepine, whereas ruthenium red in doses exhibiting antinociceptive activity was without effect on capsaicin-induced desensitization. The present results suggest that both capsazepine and ruthenium red can produce a local peripheral antinociceptive action, which may be mediated by inhibiting the membrane ion channel activated by capsaicin. In addition, these data suggest that capsazepine may act in the mechanism clearly different from ruthenium red in the capsaicin-induced nociceptive desensitization.