td-5108 and Dyspepsia

Studies have reported a lack of association between improvements in gastric emptying (GE) and upper gastrointestinal (UGI) symptoms with promotility drugs. However, GE test methods were suboptimal in some studies. We assessed improvements in GE and UGI symptoms in patients given promotility agents in studies with optimal or moderate test methods (scintigraphy or breath test, solid meal, >2 hours duration) compared to studies with suboptimal GE test methods.. With an expert librarian, we completed an extensive search of publications in the Ovid MEDLINE (1946 to present), EMBASE (1988 to January 2018), and EBM Reviews Cochrane Central Register of Controlled Trials, without restrictions on language or year. Two independent reviewers evaluated the following inclusion criteria: randomized, blinded, parallel, or crossover trials of 5HT. Of 899 studies considered, 22 studies assessed change in GE; 23 evaluated UGI symptoms; and 14 evaluated GE and UGI symptoms. Promotility agents significantly accelerated GE (T. In a meta-analysis of published trials, we found promotility agents to significantly accelerate GE (when optimal test methods were used) and to produce significant improvements in UGI symptoms.

Topics: Breath Tests; Cisapride; Domperidone; Dopamine D2 Receptor Antagonists; Dyspepsia; Gastric Emptying; Gastroparesis; Ghrelin; Humans; Macrocyclic Compounds; Oligopeptides; Radionuclide Imaging; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists; Symptom Assessment

Abnormalities of gastroduodenal motility are considered key players in the pathogenesis of upper gastrointestinal symptoms in disorders such as functional dyspepsia and gastroparesis. Abnormalities of sensory control are considered another important factor that contributes to symptom generation. This review summarizes recent progress in our understanding of gastroduodenal motility and sensitivity in health and in disease.. Although gastric and small intestinal motility remain an important focus of research, including the application of the SmartPill (SmartPill Corp., Buffalo, New York, USA) wireless motility monitoring capsule, duodenal sensitivity and low-grade duodenal inflammation are new areas of interest in the pathogenesis of functional dyspepsia. A number of genetic polymorphisms associated with functional dyspepsia are being investigated, but large-scale studies are still lacking. Central processing of visceral stimuli, and its role in the pathogenesis of functional dyspepsia, is another important emerging topic. Therapeutic studies have reported on novel pharmacological approaches in functional dyspepsia and gastroparesis, as well as gastric electrical stimulation in the treatment of refractory gastroparesis.. There is gradual progress in our understanding of the pathogenesis of gastroduodenal symptoms. Areas of recent advances including the recognition of low-grade duodenal inflammation, the role of central nervous system processing in visceral hypersensitivity and the exploration of novel pharmacotherapeutic approaches.

Topics: Dyspepsia; Gastrointestinal Motility; Gastroparesis; Humans; Intestines; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptors, Ghrelin; Sensation; Serotonin 5-HT4 Receptor Agonists; Stomach

Levosulpiride is a sulpiride isomer that exerts its prokinetic action through a dual mechanism: 1) as a D(2) dopamine receptor antagonist and 2) as a serotonin 5HT(4) receptor agonist, conferring this drug with a cholinergic effect. At a dosage of 25mg three times daily, levosulpiride accelerates gastric and gallbladder emptying. Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia, while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists. The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D(2) dopamine antagonists. Therefore, this drug is a useful therapeutic option in the management of patients with functional dyspepsia, as well as in those with delayed gastric emptying.

Topics: Animals; Clinical Trials as Topic; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Evaluation, Preclinical; Dyspepsia; Gallbladder Emptying; Gastric Emptying; Gastrointestinal Agents; Gastroparesis; Guinea Pigs; Humans; Molecular Structure; Serotonin 5-HT4 Receptor Agonists; Sulpiride

Functional dyspepsia is a highly common disorder. The physiopathological mechanisms of this entity are not yet completely known and prokinetic drugs seem to be useful. The aim of this study was to evaluate the prokinetic effect of cinitapride in patients with dysmotility-like dyspepsia and delayed gastric emptying.. Nineteen patients were randomized to receive 1mg of an oral solution of cinitapride t.i.d or placebo for 4 weeks in two consecutive periods, following a crossover and double-blind design. The main variable was the mean change from baseline after 4 weeks of treatment in gastric-emptying half-time after a liquid test meal, measured by real-time ultrasonography.. At the end of treatment, the mean gastric-emptying half-time decreased with both treatments, with no statistically significant differences between them (ANOVA, p=0.8720). This decrease was greater for cinitapride than for placebo (ANOVA, p=0.0169) in patients with mild-to-moderate delayed gastric emptying. In this group of patients, cinitapride was also superior to placebo in the percentage AUC of the antral area and the percentage of days free of nausea. Cinitapride was well tolerated, with a safety profile comparable to that of placebo.. Oral cinitapride is safe and effective in improving gastric emptying and symptoms in patients with dysmotility-like dyspepsia and mild-to-moderate delayed gastric emptying.

Topics: Adult; Aged; Benzamides; Computer Systems; Cross-Over Studies; Dopamine D2 Receptor Antagonists; Double-Blind Method; Dyspepsia; Electrocardiography; Female; Gastric Emptying; Gastroparesis; Humans; Male; Middle Aged; Pyloric Antrum; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Agents; Ultrasonography; Young Adult

To evaluate the potential role of tegaserod in the management of functional dyspepsia (FD) and gastroesophageal reflux disease (GERD) in patients with chronic constipation and to determine the possible efficacy of tegaserod on solid-phase gastric emptying and gastric hypersensitivity.. This was an exploratory open-label trial of tegaserod therapy for dyspepsia and reflux symptoms in patients with chronic constipation. The study cohort consisted of 90 patients randomized to three treatment groups for a study period of 4 weeks (tegaserod 6 mg, twice daily; esomeprazole 40 mg, once daily; tegaserod 6 mg, twice daily plus esomeprazole 40 mg, once daily). Twenty healthy volunteers provided control values. Clinical symptoms were evaluated by one of the investigators using a Gastrointestinal Symptom Rating Scale (GSRS). Solid-phase gastric emptying and colonic transit were measured by the radiopaque barium marker method, and the water load test (WLT) was used to evaluate gastric sensation and the function of proximal stomach. The proportions of patients with complete relief of epigastric pain /discomfort, epigastric fullness, early satiety and heartburn in the tegaserod group and the tegaserod plus esomeprazole group were compared with the esomeprazole group, respectively.. The mean global gastrointestinal (GI) scores of all three treatment groups reported using the GSRS showed the same trend, with decreasing scores over the 4-week study period indicating a reported decreasing severity of symptoms that was significantly different from baseline values. Patients in the tegaserod plus esomeprazole group reported the lowest global GI scores after 4 weeks, as expected. Solid-phase gastric emptying (GER) and colonic transit (CTT) increased significantly in the tegaserod 6 mg twice daily group compared with baseline. These parameters did not change in the esomeprazole group at week 4 compared with baseline. In terms of gastric sensation, in the tegaserod group, the proportions of patients with hypersensitivity of the first perception threshold did not change at week 2 or week 4 compared with baseline; however, in this group and in the tegaserod plus esomeprazole group, the proportions of patients with hypersensitivity of discomfort threshold decreased significantly at week 4 compared with baseline. In the esomeprazole group, there were no changes in the proportions of patients with hypersensitivity of the first perception threshold and discomfort threshold at week 2 or 4 compared with baseline. No severe adverse events were recorded, and the medications were in general well-tolerated.. Tegaserod is effective and safe at improving dyspepsia and reflux symptoms in patients with chronic constipation, and tegaserod plus esomeprazole is superior to esomeprazole alone in the resolution of epigastric pain/discomfort and heartburn.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analysis of Variance; Anti-Ulcer Agents; Chronic Disease; Cohort Studies; Constipation; Drug Therapy, Combination; Dyspepsia; Esomeprazole; Female; Gastric Emptying; Gastroesophageal Reflux; Gastrointestinal Transit; Heartburn; Humans; Indoles; Male; Middle Aged; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

Mosapride citrate (mosapride), a prokinetic agent with 5-HT(4)-receptor agonistic activity, is known to enhance gastric emptying and alleviate symptoms in patients with functional dyspepsia (FD). As hyperalgesia and delayed gastric emptying play an important role in the pathogenesis of FD, we used in this study balloon gastric distension to enable abdominal muscle contractions and characterized the visceromotor response (VMR) to such distension in conscious rats. We also investigated the effects of mosapride on gastric distension-induced VMR in the same model. Mosapride (3-10 mg/kg, p.o.) dose-dependently inhibited gastric distension-induced VMR in rats. However, itopride even at 100 mg/kg failed to inhibit gastric distension-induced VMR in rats. Additionally, a major metabolite M1 of mosapride, which possesses 5-HT(3)-receptor antagonistic activity, inhibited gastric distension-induced VMR. The inhibitory effect of mosapride on gastric distension-induced visceral pain was partially, but significantly inhibited by SB-207266, a selective 5-HT(4)-receptor antagonist. This study shows that mosapride inhibits gastric distension-induced VMR in conscious rats. The inhibitory effect of mosapride is mediated via activation of 5-HT(4) receptors and blockage of 5-HT(3) receptors by a mosapride metabolite. This finding indicates that mosapride may be useful in alleviating FD-associated gastrointestinal symptoms via increase in pain threshold.

Topics: Abdominal Pain; Analgesics, Non-Narcotic; Animals; Benzamides; Benzyl Compounds; Dose-Response Relationship, Drug; Dyspepsia; Gastric Dilatation; Gastrointestinal Agents; Gastrointestinal Motility; Granisetron; Male; Morpholines; Random Allocation; Rats; Rats, Wistar; Reflex, Abdominal; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Stomach

Topics: Arrhythmias, Cardiac; Aryl Hydrocarbon Hydroxylases; Benzamides; Cisapride; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Drug Interactions; Dyspepsia; Electrocardiography; Gastrointestinal Agents; Humans; Ketoconazole; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists