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      Effect of DA-9701 on the Normal Motility and Clonidine-induced Hypomotility of the Gastric Antrum in Rats

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          Abstract

          Background/Aims

          DA-9701 is a novel prokinetic agent. In the present study, we investigated the effect of DA-9701 on the motility of the gastric antrum in the normal and clonidine-induced hypomotility in an in vivo animal model.

          Methods

          A strain gauge force transducer was sutured on the gastric antrum to measure the contractile activity in rats. A total of 28 rats were subclassified into the 4 groups: (1) the placebo group, (2) the DA-9701 group, (3) the placebo group in the clonidine-pretreated rats, and (4) the DA-9701 group in the clonidine-pretreated rats. After the basal recording, either placebo (3% [w/v] hydroxypropylmethyl cellulose) or DA-9701 was administered. Contractile signals were measured after the administration and after a meal. In the clonidine-pretreated rats, either placebo or DA-9701 was administered. Contractile signals were measured after the administration and after a meal.

          Results

          Oral administration of DA-9701 did not significantly alter the motility index of the gastric antrum in the preprandial and postprandial periods, compared with the placebo group. The administration of clonidine decreased the motility index of the gastric antrum in the preprandial and postprandial periods, compared with the administration of placebo. This reduction of the antral motility by the administration of clonidine was not observed in the clonidine-pretreated DA-9701 group. The percentage of the motility index in the postprandial period was significantly greater in the clonidine-pretreated DA-9701 group, compared with the clonidine-pretreated placebo group.

          Conclusions

          DA-9701 improves the hypomotility of the gastric antrum induced by clonidine, suggesting its gastroprokinetic effect in the pathologic condition.

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          Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia.

          Hein Janssens, Geert O R J Janssens, Philip Caenepeel … (2003)
          The relationship between functional dyspepsia and delayed gastric emptying of solids or liquids is still unclear. The aim of the present study was to investigate in dyspeptic patients the prevalence of delayed gastric emptying for solids or for liquids and to investigate the relationship to the dyspepsia symptom pattern. In 392 and 330 patients with functional dyspepsia, the solid and liquid gastric emptying, respectively, was measured using breath tests, and the severity of eight dyspeptic symptoms was scored. Gastric emptying of solids and liquids were delayed in 23% and 35% of the patients. Multivariate analysis showed that the presence of vomiting and postprandial fullness was associated with delayed solid emptying (OR 2.65, 95% CI = 1.62-4.35 and OR 3.08, 95% CI = 1.28-9.16, respectively). Postprandial fullness was also associated with the risk of delayed liquid emptying when symptom was present (OR 3.5, 95% CI = 1.57-8.68), relevant or severe (OR 2.504, 95% CI = 1.41-4.65), and severe (OR 2.214, 95% CI = 1.34-3.67). Severe early satiety was associated with the risk of delayed liquid emptying (OR 1.902, 95% CI = 1.90-3.30). A subset of dyspeptic patients has delayed gastric emptying of solids or of liquids. Delayed gastric emptying of solids was constantly associated with postprandial fullness and with vomiting. Delayed emptying for liquids was also associated with postprandial fullness and with severe early satiety.
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            Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders

            C. J. Tack, Géraldine Camilleri, L.-L. Chang … (2012)
            Summary Background The nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride). Conclusions 5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility.
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              A placebo-controlled trial of itopride in functional dyspepsia.

              Nicholas J. Talley, Tobias Liebregts, Mary B. Adam … (2006)
              The treatment of patients with functional dyspepsia remains unsatisfactory. We assessed the efficacy of itopride, a dopamine D2 antagonist with anti-acetylcholinesterase [corrected] effects, in patients with functional dyspepsia. Patients with functional dyspepsia were randomly assigned to receive either itopride (50, 100, or 200 mg three times daily) or placebo. After eight weeks of treatment, three primary efficacy end points were analyzed: the change from baseline in the severity of symptoms of functional dyspepsia (as assessed by the Leeds Dyspepsia Questionnaire), patients' global assessment of efficacy (the proportion of patients without symptoms or with marked improvement), and the severity of pain or fullness as rated on a five-grade scale. We randomly assigned 554 patients; 523 had outcome data and could be included in the analyses. After eight weeks, 41 percent of the patients receiving placebo were symptom-free or had marked improvement, as compared with 57 percent, 59 percent, and 64 percent receiving itopride at a dose of 50, 100, or 200 mg three times daily, respectively (P<0.05 for all comparisons between placebo and itopride). Although the symptom score improved significantly in all four groups, an overall analysis revealed that itopride was significantly superior to placebo, with the greatest symptom-score improvement in the 100- and 200-mg groups (-6.24 and -6.27, vs. -4.50 in the placebo group; P=0.05). Analysis of the combined end point of pain and fullness showed that itopride yielded a greater rate of response than placebo (73 percent vs. 63 percent, P=0.04). Itopride significantly improves symptoms in patients with functional dyspepsia. (ClinicalTrials.gov number, NCT00272103.). Copyright 2006 Massachusetts Medical Society.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Neurogastroenterol Motil
                Journal ID (iso-abbrev): J Neurogastroenterol Motil
                Title: Journal of Neurogastroenterology and Motility
                Publisher: Korean Society of Neurogastroenterology and Motility
                ISSN (Print): 2093-0879
                ISSN (Electronic): 2093-0887
                Publication date (Print): April 2016
                Publication date (Electronic): 30 April 2016
                Volume: 22
                Issue: 2
                Pages: 304-309
                Affiliations
                [1 ]Department of Gastroenterology, Ajou University School of Medicine, Suwon, Gyeonggi-do, Korea
                [2 ]Laboratory Animal Research Center, Ajou University School of Medicine, Suwon, Gyeonggi-do, Korea
                Author notes
                [* ]Correspondence: Kwang Jae Lee, MD, PhD, Department of Gastroenterology, Ajou University Hospital, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do 443-721, Korea, Tel: +82-31-219-5102, Fax: +82-31-219-5999, E-mail: kjleemd@ 123456hotmail.com
                Article
                Publisher ID: jnm-22-304
                DOI: 10.5056/jnm15131
                PMC ID: 4819869
                PubMed ID: 26755679
                SO-VID: 376d9cc6-16a6-4473-90b0-089ac83a3051
                Copyright © © 2016 The Korean Society of Neurogastroenterology and Motility
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 13 August 2015
                Date revision received : 06 December 2015
                Date accepted : 20 December 2015
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Neurology
                Keywords: antrum,da-9701,motility,prokinetic
                Data availability:
                ScienceOpen disciplines: Neurology
                Keywords: antrum, da-9701, motility, prokinetic

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