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.

In the present study, we have shown that Z-360 combined with gemcitabine can inhibit pancreatic tumor growth and prolong survival in a pancreatic carcinoma xenograft model, on a possible mode of action being the inhibition of gastrin-induced PKB/Akt phosphorylation through blockade of the CCK-2 receptor. Our results suggest that Z-360 may be a useful adjunct to gemcitabine for the treatment of pancreatic carcinoma and a therapeutic option for patients with advanced pancreatic cancer.

The effect of polaprezinc, a chelate compound consisting of zinc ion and L-carnosine, on abnormalities of taste sensation induced by feeding a zinc-deficient diet to rats was examined by using the two-bottle preference test (quinine hydrochloride as a bitter taste and sodium chloride as a salty taste). Rats were fed either a zinc-deficient or a zinc-sufficient diet. The zinc-deficient diet increased the preference for both taste solutions, while polaprezinc (at doses of 3 and 10 mg/kg) restored the altered taste preferences. We also evaluated the proliferation of taste bud cells using 5-bromo-2'-deoxyuridine (BrdU). The BrdU incorporation into taste bud cells was significantly reduced in rats fed a zinc-deficient diet compared with rats fed a zinc-sufficient diet (from 50.8% to 45.0%, p<0.05) and this reduction was reversed by polaprezinc at doses of 1, 3, and 10 mg/kg, increasing to 50.2%, 53.5%, and 52.5%, respectively. These findings indicate that zinc deficiency induces the delayed of proliferation of taste bud cells, while polaprezinc improves cell proliferation. In conclusion, polaprezinc had a therapeutic effect in a rat model of abnormal taste sensation. Its mechanism of action was suggested to involve improvement of the decrease in taste bud cell proliferation caused by zinc deficiency.

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It has been reported that pain occurs in 30% of patients with early cancer, 60 to 70% of patients with advanced cancer, and 75% or more of those with terminal cancer. 1) Pain is one of the most prevalent conditions that diminish the quality of life. A three-step pain elimination ladder has been established by the World Health Organization as a worldwide standard therapeutic program for cancer pain, but there is still pain that remains beyond control with opioids and nonsteroidal antiinflammatory drugs. Therefore, to achieve a breakthrough in combating cancer pain, energetic efforts have been made to develop novel analgesics with fewer adverse effects and new mechanisms of action., an orally active cholecystokinin 2 (CCK 2 ) receptor antagonist, is under development for the treatment of pancreatic cancer. In our previous studies, Z-360 inhibited pancreatic tumor growth and prolonged survival by combination with gemcitabine, a first-line drug for pancreatic cancer, in mouse models of pancreatic cancer xenograft. 5,6) In a phase Ib/IIa clinical trial in patients with advanced unresectable pancreatic cancer, pain relief was observed with Z-360 administration.7) Pain is experienced by most patients with advanced pancreatic cancer and limits their daily activity. Z-360 might be useful in achieving pain relief for patients with pancreatic cancer. However, the analgesic action of Z-360 is not yet elucidated in animal models. In this study, we evaluated the antinociceptive and anti-allodynic effects of Z-360 in mouse models of formalin-induced pain and cancer pain, respectively. MATERIALS AND METHODS AnimalsFour to five-week-old male Crlj:CD1 (ICR) mice and five-week-old male C57BL/6NCrlCrlj (C57BL/6) ones and male Crl:CD (SD) rats were purchased from Charles River Laboratories Japan Inc. (Yokohama). They were kept under controlled temperature (23Ϯ3°C) and humidity (55Ϯ20%). The room was lighted from 7:00 a.m. to 7:00 p.m. Food and water were freely available. Pain studies were carried out in accordance with guidelines outlined by the Committee for Research and Ethical Issues of International Association for the Study of Pain. Z-360, a novel cholecystokinin 2 (CCK 2 ) receptor antagonist, has been developed as a therapeutic drug for pancreatic cancer and showed pain relief action in phase Ib/IIa clinical trial. This study was attempted to elucidate the analgesic efficacy of Z-360 in mice. Oral administration of Z-360 (30-300 mg/kg) showed a dose-dependent inhibitory effect on the late phase of nociceptive responses to formalin. YF476, another CCK 2 receptor antagonist, was without effects at 1 and 10 mg/kg. In contrast, the CCK 1 receptor antagonist devazepide inhibited the nociceptive responses to formalin. In a mouse model of cancer pain, significant anti-allodynic effect of Z-360 was observed after single and repeated oral administration of 100 and 300 mg/kg doses. Anti-allodynic effect was also observed after repeated administration of devazepide. Combined single treatment with morphine and Z-360 caused an increase ...