Yugo Matsunaga

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 D2 or serotonin 5-HT4 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.

Acotiamide hydrochloride (Z-338) enhances gastric motility and emptying by inhibiting acetylcholinesterase activity in rats.

In clinical trials, acotiamide hydrochloride (acotiamide: Z-338) has been reported to be useful in the treatment of functional dyspepsia. Here, we investigated the effects of acotiamide on gastric contraction and emptying activities in rats in comparison with itopride hydrochloride (itopride) and mosapride citrate (mosapride). We also examined in vitro the compounds inhibitory effect on acetylcholinesterase (AChE) activity derived from rat stomach. In in vivo studies, acotiamide (30 and 100mg/kg s.c.) and itopride (100mg/kg s.c.) markedly enhanced normal gastric antral motility in rats. In gastric motility dysfunction models, acotiamide (100mg/kg s.c.) and itopride (100mg/kg s.c.) improved both gastric antral hypomotility and the delayed gastric emptying induced by clonidine, an α(2)-adrenoceptor agonist. In contrast, mosapride (10mg/kg s.c.) had no effect on these models. Like the AChE inhibitors itopride (30 mg/kg s.c.) and neostigmine (10 μg/kg s.c.), acotiamide (10mg/kg s.c.) also clearly enhanced gastric body contractions induced by electrical stimulation of the vagus, which were abolished by atropine and hexamethonium, whereas mosapride (3 and 10mg/kg s.c.) did not. In in vitro studies, acotiamide concentration-dependently inhibited rat stomach-derived AChE activity (IC(50)=2.3 μmol/l). In addition, stomach tissue concentrations of acotiamide after administration at 10mg/kg s.c. were sufficient to produce inhibition of AChE activity in rat stomach. These results suggest that acotiamide stimulates gastric motility and improves gastric motility dysfunction in rats by inhibiting AChE activity, and may suggest a role for acotiamide in improving gastric motility dysfunction in patients with functional dyspepsia.

Mechanism of motilin-induced contractions in isolated perfused canine stomach

BACKGROUND Motilin is known to induce gastric phase III contractions via neural pathways in vivo, but the local mechanism of action is not clearly determined. METHODS An isolated perfused canine stomach was used to demonstrate the mechanism of motilin. Synthetic canine motilin at doses of 0.1, 0.3, 1.0, and 3.0 micrograms/h was infused intra-arterially, and effects of several receptor antagonists on motilin-induced contractions were examined. RESULTS The immunoreactive motilin concentration of venous effluent showed that motilin at doses of 0.1 and 0.3 microgram/h was within the physiological range. Each dose of motilin induced phasic contractions in the isolated stomach, and a dose-related increase in frequency was observed, but not their mean amplitude. Atropine, hexamethonium, ICS205-930, BRL43694, phentolamine, yohimbine, and propranolol significantly inhibited motilin-induced contractions. Naloxone, methysergide, and timolol did not affect the response of motilin. Prazosin significantly increased the mean amplitude of motilin-induced contractions. CONCLUSIONS Physiological dose of motilin can initiate phasic contractions in the stomach independently of the presence of the extrinsic nerves. The results suggest that cholinergic pathway, 5-hydroxytryptamine (HT)3 receptors, and alpha receptors are involved in the motilin-induced contractions.

Inhibition of phase III activity by acid in canine stomach

Very few phase III activity of the interdigestive migrating contractions (phase III) occurs in the stomach of fasted duodenal ulcer patients. But the mechanism is not well understood. In this study, we studied the effect of gastric and duodenal acidification on the spontaneous phase III activity in the upper gastrointestinal tract of conscious dogs. Gastric and duodenal motor activity in 5 conscious dogs was monitored by means of chronically implanted force transducers. Intragastric pH changes were measured by placing a pH glass electrode in the gastric antrum. Intragastric and intraduodenal acidification was achieved by i.v. infusion of histamine, and by intragastric and intraduodenal instillation of acidic solutions of different pHs. The plasma motilin concentrations were measured by radioimmunoassay. Histamine (40 micrograms/kg/h) inhibited spontaneous phase III activity, but the histamine-induced inhibition was completely prevented by pretreatment with famotidine, a potent histamine H2 receptor antagonist (0.3 mg/kg, i.v.). Intragastric acidification at pH 1.0 strongly inhibited spontaneous phase III activity, but an acidic solution at pH 2.0 had no effect in inhibiting phase III activity. Intraduodenal acidification at pH 1.0 also inhibited spontaneous phase III activity. Histamine injection and gastric and duodenal acidification at pH 1.0 strongly suppressed motilin release. It is concluded that gastric and duodenal acidification at pH 1.0 inhibits the occurrence of the spontaneous phase III activity, and the suppression of endogenous release of motilin due to gastric and duodenal acidification at pH 1.0 is involved in this inhibitory mechanism.

Inhibition of phase III activity by acidifying stomach in vagally denervated and innervated dogs with gastric pouches

BACKGROUND/AIMS Intragastric acidification at pH 1.0 strongly inhibits phase III contractions in the dog, but this mechanism is not well known. We studied the mechanism in conscious dogs. METHODS Vagally denervated and innervated gastric pouch dogs were prepared. Force transducers were chronically implanted on the serosa of the pouch, main stomach, and mid-duodenum. The pH of the perfusate was monitored. RESULTS Administration of histamine (40 micrograms.kg-1.h-1 intravenously [i.v.]) and instillation of acidic saline at pH 1.0, but not pH 2.0, into the main stomach strongly inhibited the motilin-induced (0.1 microgram/kg i.v.) phase III activity in the main stomach and the innervated pouch but did not influence contractions in the extrinsically denervated pouch. Famotidine completely reversed the histamine-induced inhibition of phase III in the main stomach and Pavlov pouch. Acidification of the pouch itself or duodenum at pH 1.0 did not affect contractions in the main stomach and pouch of either type. CONCLUSIONS The mechanism of inhibition of motilin-induced phase III activity by acid in the stomach involves the intact vagovagal reflex, but sympathetic participation is not completely ruled out. The inhibition of motilin-induced phase III activity may originate in the antral mucosa of the stomach.

Acotiamide Hydrochloride, a Therapeutic Agent for Functional Dyspepsia, Enhances Acetylcholine-induced Contraction via Inhibition of Acetylcholinesterase Activity in Circular Muscle Strips of Guinea Pig Stomach

Acotiamide is a first-in-class prokinetic drug approved in Japan for the treatment of functional dyspepsia. Given that acotiamide enhances gastric motility in conscious dogs and rats, we assessed the in vitro effects of this drug on the contraction of guinea pig stomach strips and on acetylcholinesterase (AChE) activity in stomach homogenate following fundus removal. We also investigated the serotonin 5-HT4 receptor agonist mosapride, dopamine D2 receptor and AChE inhibitor itopride, and representative AChE inhibitor neostigmine. Acotiamide (0.3 and 1 μM) and itopride (1 and 3 μM) significantly enhanced the contraction of gastric body strips induced by electrical field stimulation (EFS), but mosapride (1 and 10 μM) did not. Acotiamide and itopride significantly enhanced the contraction of gastric body and antrum strips induced by acetylcholine (ACh), but not that induced by carbachol (CCh). Neostigmine also significantly enhanced the contraction of gastric body strips induced by ACh, but not that by CCh. In contrast, mosapride failed to enhance contractions induced by either ACh or CCh in gastric antrum strips. Acotiamide exerted mixed inhibition of AChE, and the percentage inhibition of acotiamide (100 μM) against AChE activity was markedly reduced after the reaction mixture was dialyzed. In contrast, itopride exerted noncompetitive inhibition on AChE activity. These results indicate that acotiamide enhances ACh-dependent contraction in gastric strips of guinea pigs via the inhibition of AChE activity, and that it exerts mixed and reversible inhibition of AChE derived from guinea pig stomach.

Acotiamide (Z-338), a Novel Gastroprokinetic Agent for the Treatment of Functional Dyspepsia, Enhances Gastric Motility Without Prolonging QT Interval in Dogs and Rats

G A A b st ra ct s and jejunum after Rikkunshito administration was significantly higher than that in the control and increased in a dose-dependent manner. In the postprandial state, Rikkunshito had no significant effect on the motor activity. Intragastric administration of Rikkunshito accelerated gastric emptying. Atropine and hexamethonium significantly diminished Rikkunshito-induced contractions. After administration of Rikkunshito, plasma acylated-ghrelin gradually increased, and the increase was much more significant than in the control at 3h after administration. Conclusions: Intragastric administration of Rikkunshito stimulated gastrointestinal contractions in the interdigestive state and accelerated gastric emptying. Moreover, Rikkunshito increased plasma acylated-ghrelin levels. Rikkunshito, a traditional herbal medicine, may alleviate gastrointestinal tract disorders through its prokinetic effect.