Clinical and Experimental Gastroenterology Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Profile of acotiamide in the treatment of functional dyspepsia Masahiro Ueda1 Abstract: Efficacy of acotiamide for improving symptoms in patients with functional dyspepsia Eisuke Iwasaki1 was shown by several clinical trials. In a randomized, double-blind, placebo-controlled, parallel- Hidekazu Suzuki2 group comparative Phase III trial conducted in Japan, 100 mg of acotiamide three times a day for 4 weeks was more effective than a placebo for improving symptoms, and quality of life. 1Department of Internal Medicine, Division of Gastroenterology and Acotiamide was well-tolerated treatment, with no significant adverse events. The aim of this Hepatology, 2Medical Education review was to summarize the current evidence of the efficacy of acotiamide in the treatment of Center, Keio University School of patients with functional dyspepsia. Medicine, Tokyo, Japan Keywords: functional dyspepsia, acotiamide, acetylcholinesterase, Rome III For personal use only. Introduction Acotiamide, a novel oral prokinetic drug, was developed by Zeria Pharmaceutical Co., Ltd. (Tokyo, Japan) for treatment of patients with functional dyspepsia (FD).1,2 FD is a functional gastrointestinal disorder with upper abdominal symptoms, such as postpran- dial fullness, upper abdominal distension, and early satiety from the gastroduodenal area despite any existence of organic disorders. Additionally, FD is divided into two classes: postprandial distress syndrome (PDS) and epigastric pain syndrome. Duration of symptom is defined by an international diagnostic criteria (Rome III criteria). Cri- teria should be fulfilled for the last 3 months. Onset should be at least 6 months before diagnosis. Acotiamide modulates upper gastrointestinal motility to alleviate abdominal symptoms resulting from hypomotility. Acotiamide was launched in Japan in June 2013 as a therapeutic agent for FD. A Phase III trial was commenced in Europe, and a Phase Clinical and Experimental Gastroenterology downloaded from https://www.dovepress.com/ by 137.108.70.13 on 14-May-2019 II trial was finished in the USA. This review was conducted to summarize the updated current evidence just after the publication of meta-analysis,3 and to critically evaluate the efficacy as well as adverse effects of acotiamide in the treatment of patients with FD. Treatment for FD The name of clinical conditions that present symptoms such as epigastric pain and epigastric distress have been changing. In the 1960s, along with advancement of Correspondence: Hidekazu Suzuki endoscopic diagnosis, the concept of “chronic gastritis” was intensively used. In the Medical Education Center, Keio 1980s, prokinetic dysfunction attracted attention, and it was then called as non-ulcer University School of Medicine, dyspepsia. And in 1999, it was called FD. Disorders of gastrointestinal motility are 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan considered a major pathophysiological mechanism underlying symptoms of FD.4 Tel +81 3 5363 3914 Many agents have been designed to stimulate muscle activity to improve hypomotility- Fax +81 3 5363 3967 Email [email protected] associated symptoms with gastrointestinal disorders such as delayed gastric empting, submit your manuscript | www.dovepress.com Clinical and Experimental Gastroenterology 2016:9 83–88 83 Dovepress © 2016 Ueda et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/CEG.S72172 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Ueda et al Dovepress slow-transit constipation. Activation of 5-hydroxytryptamine 100-fold less than that of neostigmine and physostigmine.7 type 4 (5-HT4) receptors on cholinergic nerve endings in the Receptor-binding studies have shown that acotiamide has enteric nervous system or acetylcholinesterase inhibitors affinity for the dopamine D2 receptor but not for the serotonin enhances the release of acetylcholine (ACh) from motor 5-HT2, 5-HT3, or 5-HT4 receptors. Perhaps one mechanism neurons, thereby stimulating gastrointestinal propulsive acotiamide facilitates ACh release from cholinergic nerve motility. From these pharmacological observations, 5-HT terminals is by blocking presynaptic muscarinic M1 and M2 receptor agonists are mainly developed, and other gastric autoreceptors.8 prokinetic agents such as dopamine receptor antagonists have It had been reported that acotiamide altered the expres- also been developed. Dopamine receptor antagonists such as sions of stress-related genes such as GABA receptors, GABA domperidone are effective for treatment of gastroparesis or transporters, and neuromedin U in medulla oblongata or nausea, but induce extrapyramidal syndrome and increase hypothalamus in restrain stress rats.9 It suggests that acoti- plasma prolactin levels as adverse effects. Non-selective amide has potential role in the regulation of stress through 5-HT4 receptor agonists such as cisapride were subsequently the hypothalamic–pituitary–adrenocortical axis activity. withdrawn from the global market in 2000 because of their cardiovascular adverse events. A newer generation of selec- Trends in clinical trials tive 5-HT receptor agonists such as mosapride is being 4 The total number of clinical trials using acotiamide that are developed for the treatment of chronic gastritis. We have registered in PubMed and Japan Medical Abstracts Society looked forward to the effective oral prokinetic agent with continue to grow from year to year (Figure 2). From 2011 no adverse effect for long time. to 2014, the total number of trials increased by more than three times. Reports written in Japanese were significantly Pharmacological data of acotiamide increased after the launch of acotiamide for the treatment Acotiamide is a new prokinetic agent which performs its of FD in 2013. For personal use only. gastroprokinetic function by enhancing ACh release by act- ing as an antagonist of the M and M muscarinic receptors 1 2 Systematic review in the enteric nervous system and inhibiting acetylcholin- Systematic review and meta-analysis about the efficacy of 5,6 esterase activity (Figure 1). It is known that acotiamide acotiamide on FD has been reported by Xiao et al.3 In the has various pharmacological effects on the gastrointestinal meta-analysis, six publications including seven random- tract. Acotiamide enhances electrically stimulated contrac- ized controlled trials were evaluated.5,10–12 The summary 3 tions and the release of Ach in the [ H]-choline-preincubated risk ratio of overall improvement of FD symptoms in gastric antrum and body at doses .10–6 M from a guinea pig’s stomach in vitro. Acotiamide reversibly inhibits human 25 erythrocyte AChE activity, although the IC50 is approximately Review Japanese Excitatory cholinergic nerves 20 Review English Clinical and Experimental Gastroenterology downloaded from https://www.dovepress.com/ by 137.108.70.13 on 14-May-2019 Clinical Japanese M1R, M2R 15 Clinical English Acotiamide ACh Acotiamide 10 ACh Negative feedback Number of articles Acetic acid AChE + choline 5 ACh Surface of smooth muscle cell 0 2010 2011 2012 2013 2014 Figure 1 Pharmacologically effective site of acotiamide. Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; M1R, muscarinic Figure 2 Number of scientific articles on acotiamide published between 2010 and acetylcholine receptor m1; M2R, muscarinic acetylcholine receptor m2. 2014. 84 submit your manuscript | www.dovepress.com Clinical and Experimental Gastroenterology 2016:9 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Efficacy of acotiamide in functional dyspepsia patients receiving acotiamide vs placebo was 1.29 (95% these trials, a randomized controlled treatment period lasted confidence interval [CI] 1.19–1.40, P,0.00001). The risk for 28 days, during which a placebo or different doses of ratio of improvement of patients with PDS was 1.29 (95% acotiamide were allocated to patients during 4 weeks. Study CI: 1.09–1.53, P=0.003) and epigastric pain syndrome was 1: 323 patients were randomized to a placebo group, 100mg 0.92 (95% CI: 0.76–1.11, P=0.39). Adverse events were not group and 300mg group. Eight upper-abdominal symptoms significantly different between both groups. Acotiamide had (upper abdominal pain, upper abdominal discomfort, post- the potential to relieve the symptoms of patients with FD, prandial fullness, upper abdominal bloating, early satiety, particularly of patients with PDS without major adverse nausea, vomiting, and excessive belching) were recorded. events. Improvement rate of the overall symptoms was 41.7% in the placebo group, 51.5% in 100mg the group, and 38.1% in the Determination of optimal dose 300mg group. The 100 mg group looks better for improve- of acotiamide for FD ment rates, but there were no statistically significant differ- A multicenter, randomized, double-blind, placebo-controlled ence. Elimination rate