td-5108 and Gastroparesis

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

Parkinson's disease (PD) affects the nerves of the entire gastrointestinal (GI) tract and may result in profound gastrointestinal (GI) dysfunction leading to poor patient outcomes. Common GI disturbances in patients with PD include gastroparesis (GP), constipation and small intestinal bacterial overgrowth syndrome (SIBO). In particular, GP is difficult to treat due to the limited options available and precautions, contraindications and adverse effects associated with the approved treatments. Moreover, some commonly used medications can worsen pre-existing PD.. Our review will focus on treatment options for GP and SIBO with motilin agonists, dopamine receptor antagonists, Ghrelin agonists muscarinic agonists, 5-HT4 receptor agonists, antibiotics, probiotics and herbal formulation such as iberogast. Constipation occurs in the majority of patients with PD and fortunately many treatments are now available. Our review is based on original papers or reviews selected from PUBMED search and Cochrane reviews.. Motility disorders of the GI tract are found frequently in patients with PD and treating the underlying GI disorders caused by PD with various prokinetics and laxatives is paramount in achieving improvements in patient's motor function. Various prokinetics and laxatives are now available to provide some relief of the GI morbidity caused by PD leading even to better absorption of even the PD treatments.

Topics: Anti-Bacterial Agents; Blind Loop Syndrome; Constipation; Dopamine Antagonists; Gastroparesis; Humans; Laxatives; Muscarinic Agonists; Parkinson Disease; Plant Extracts; Probiotics; Serotonin 5-HT4 Receptor Agonists

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

Gastroparesis is a chronic disorder of gastric motility that is characterized by delayed emptying of either solids or liquids from the stomach in the absence of any mechanical obstruction. Nausea, vomiting, early satiety and bloating are some of the manifestations of gastroparesis. Idiopathic, diabetes mellitus and postsurgical states account for the majority of cases. Gastroparesis is a difficult condition to treat. Prokinetic drugs like metoclopramide and erythromycin form the mainstay of therapy but are less than ideal. Some patients may benefit from endoscopic botolinium toxin injection. Gastric electrical stimulation, though promising, is not ready for prime time yet.

Topics: Antiemetics; Diet Therapy; Dopamine Antagonists; Electric Stimulation Therapy; Endoscopy; Gastroparesis; Humans; Nutritional Support; Psychotherapy; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Serotonin 5-HT4 Receptor Agonists; Severity of Illness Index

This study assessed the efficacy and safety of velusetrag-a 5-HT. In this multicenter, double-blind, randomized, placebo-controlled study, subjects with diabetic or idiopathic gastroparesis received velusetrag 5, 15, or 30 mg or placebo for 12 weeks. The primary efficacy outcome was a 7-day mean Gastroparesis Cardinal Symptom Index 24-h composite score (GCSI-24H) change from baseline at week 4; GE was evaluated using scintigraphy (GES) and breath tests, and safety from adverse events (AEs).. 232 subjects (183 females; 113 idiopathic gastroparesis) received treatment from February 2015 through June 2017. Least-squares mean improvement from baseline GCSI-24H (primary endpoint) at week 4 was -1.5 following velusetrag 5 mg vs -1.1 following placebo (treatment difference, -0.4; 95% confidence interval, -0.75 to -0.03; nominal p = 0.0327; Hochberg-adjusted p = 0.0980 [not significant]). Symptom improvement from baseline was achieved only with velusetrag 5 mg, which resulted in greater improvement from baseline vs placebo in all gastroparesis core symptoms, especially in subjects with idiopathic gastroparesis. Improvement from baseline GE by GES was greater in subjects receiving velusetrag (all doses) vs placebo; >70% of subjects receiving velusetrag 30 mg had GE normalization at 4 h. Treatment-emergent AEs were generally mild.. Velusetrag treatment was generally well-tolerated and associated with improved GE vs placebo in subjects with diabetic or idiopathic gastroparesis; however, only the lowest dose, velusetrag 5 mg, was associated with short-term improvement in gastroparesis symptoms.. GOV: NCT02267525.

Topics: Diabetes Mellitus; Double-Blind Method; Female; Gastric Emptying; Gastroparesis; Humans; Treatment Outcome

Gastroparesis, defined by delayed gastric emptying in the absence of mechanical outlet obstruction, is a frequent neuropathic complication of diabetes mellitus, and effective treatments are lacking. Prucalopride is a pan-gut prokinetic with selective agonist effects on serotonin 5-HT4 receptors in the gut. This study aimed to assess the effect of prucalopride 4 mg daily on Gastroparesis Cardinal Symptom Index (GCSI), meal-related symptom score (MRSS), and gastric emptying rate in diabetic or connective tissue disease (CTD)-related gastroparesis patients.. This was a double-blind crossover trial of four-week treatment periods with prucalopride or placebo divided by two weeks of washout. GSCI, MRSS, gastric emptying scintigraphy, PAGI-SYM, and PAGI-QoL were assessed at baseline and the end of each treatment period. Daily bowel movement (BM) frequency and gastrointestinal symptoms were recorded in each period.. Fifteen gastroparesis patients (13 diabetic, 2 CTD) were enrolled. GCSI scores were lower than baseline but not different between treatment arms. MRSS scores over time or cumulative score were not significantly different between groups. Gastric emptying was more rapid in the prucalopride treatment period, with mean four-hour meal retention of 22 ± 6% in PRU period vs 40 ± 9% in the placebo period (P = 0.05). Weekly BM frequency was significantly higher in prucalopride than placebo periods (10.5 ± 1.8 vs 7.5 ± 0.8, P < 0.0001). Perception of weight loss was higher in patients on prucalopride. Analysis of diabetic gastroparesis (n = 13) population did not change the conclusions.. Prucalopride at 4 mg accelerates gastric emptying and bowel movement frequency but does not appear to ameliorate gastroparesis or meal-related symptoms in this study.

Topics: Adult; Benzofurans; Cross-Over Studies; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Gastroparesis; Humans; Male; Middle Aged; Mitral Valve Prolapse; Myopia; Pilot Projects; Quality of Life; Radionuclide Imaging; Scleroderma, Systemic; Serotonin 5-HT4 Receptor Agonists; Skin Diseases; Treatment Outcome

Gastroparesis is a serious gastrointestinal (GI) condition characterised by delayed gastric emptying (GE). Velusetrag-a potent, selective, pan-gastrointestinal 5-hydroxytryptamine type 4 receptor agonist-is under investigation for treatment of GI motility disorders including gastroparesis.. To assess the efficacy and safety of velusetrag for accelerating GE in subjects with diabetic or idiopathic gastroparesis.. In this multicentre, randomised, double-blind, placebo-controlled, three-period fixed-sequence crossover phase 2 study, subjects with diabetic or idiopathic gastroparesis received oral velusetrag (5, 15 or 30 mg) or placebo once daily for 7 days each. The primary outcome was proportion of subjects achieving ≥20% reduction in GE half-time (GE t. Thirty-four subjects (67.6% female; mean age, 46.3 years; 52.9% with diabetic gastroparesis) were included. Treatment with velusetrag 30 mg significantly increased the proportion of subjects with ≥20% reduction from baseline GE t. Velusetrag accelerates GE in subjects with diabetic or idiopathic gastroparesis and is generally well tolerated in this population (Clinicaltrials.gov NCT01718938).

Topics: Azabicyclo Compounds; Double-Blind Method; Female; Gastric Emptying; Gastroparesis; Humans; Male; Middle Aged

Prokinetics are considered the preferred treatment option for gastroparesis, but evidence of their efficacy is scarce. Prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist used in the treatment of constipation, is able to enhance the gastric emptying rate. In a double-blind, randomized, placebo-controlled crossover study, we evaluated the efficacy of prucalopride to improve the gastric emptying rate and symptoms in patients with gastroparesis.. Thirty-four patients with gastroparesis (28 idiopathic, 7 men, mean age 42 ± 13 years) were evaluated in a double-blind crossover trial of 4-week treatment periods with placebo or prucalopride 2 mg q.d., separated by 2 weeks of washout. The primary end point was the change in symptom severity, assessed by the Gastroparesis Cardinal Symptom Index; secondary end points comprised the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index, the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life, and daily diaries, and the gastric emptying rate was assessed by the C-octanoic acid breath test.. Three patients were lost to follow-up. One serious adverse event occurred (small bowel volvulus in the prucalopride group), and 3 patients dropped out because of adverse events of nausea and headache (all prucalopride). For the entire patient group, compared with placebo, prucalopride significantly improved the total Gastroparesis Cardinal Symptom Index (1.65 ± 0.19 vs 2.28 ± 0.20, P < 0.0001) and the subscales of fullness/satiety, nausea/vomiting, and bloating/distention. Prucalopride significantly improved the overall Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life score (1.15 ± 0.16 vs 1.44 ± 0.16, P < 0.05) and the domains of clothing and diet. The gastric half emptying time was significantly enhanced by prucalopride compared with placebo and baseline (98 ± 10 vs 143 ± 11 and 126 ± 13 minutes, P = 0.005 and <0.001, respectively). These significant improvements were also found when considering only the idiopathic gastroparesis subgroup.. In a cohort of patients with predominantly idiopathic gastroparesis, 4 weeks of prucalopride treatment significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo.

Topics: Adult; Benzofurans; Breath Tests; Cross-Over Studies; Double-Blind Method; Female; Gastric Emptying; Gastroparesis; Humans; Male; Quality of Life; Serotonin 5-HT4 Receptor Agonists; Severity of Illness Index

Gastroparesis is a chronic gastric disorder characterized by delayed gastric emptying without mechanical obstruction, and clinical symptoms as postprandial fullness, early satiety, bloating, nausea, vomiting, and abdominal pain. Prokinetic agents are used for the treatment of gastroparesis. Revexepride, a 5-hydroxytryptamine (serotonin) receptor (5-HT4 R) agonist, could be a good candidate drug for the gastroparesis treatment.. In the current phase II, exploratory, double-blind, randomized, stratified, placebo-controlled, repeated dose trial (EudraCT number 2007-004997-23), the efficacy on gastrointestinal symptoms and gastric emptying rate, safety, and pharmacokinetic profile of three oral doses of revexepride (0.02, 0.1, and 0.5 mg administered orally t.i.d. for 4 weeks) was evaluated in trial participants (diabetic and non-diabetic) with upper gastrointestinal tract symptoms suggestive for gastroparesis.. Eighty participants, enrolled in four parallel treatment groups, were asked to score their symptom diary data, gastroparesis cardinal symptom index (GCSI), patient assessment of upper gastrointestinal disorders-symptom severity index (PAGI-SYM), quality of life questionnaires, and meal-related symptom score. Gastric emptying rate was evaluated by (13) C-octanoic acid breath test.. The severity of the symptoms assessed by means of GCSI and PAGI-SYM decreased at Week 2 and decreased further at Week 4 in all treatment groups including placebo, with similar trends in all treatment groups. Quality of life improved in all treatment groups after 4 weeks of treatment. No differences on gastric emptying rate were shown between any of the active treatment groups and placebo. Revexepride was generally safe and well-tolerated.. Four weeks of revexepride treatment did not improve symptoms or gastric emptying over placebo in patients with symptoms suggestive of gastroparesis.

Topics: Benzofurans; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastric Emptying; Gastroparesis; Humans; Male; Middle Aged; Pilot Projects; Quality of Life; Serotonin 5-HT4 Receptor Agonists; Surveys and Questionnaires

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

Prokinetics have been considered the first-line medicine for treating delayed gastric emptying. The aim of this study was to explore the effects and mechanisms of a new 5-HT. Four experiments were performed in dogs: (i) dose-response effects of YKP10811 on liquid gastric emptying; (ii) effects and mechanisms of YKP10811 on solid gastric emptying delayed by glucagon; (iii) effects of low-dose YKP10811 on antral contractions; and (iv) effects of low-dose YKP10811 on gastric accommodation.. No adverse events or cardiac dysrhythmia was noted. (i) High-dose YKP10811 (30 mg/kg) accelerated liquid gastric emptying from 15 to 90 min without inducing adverse events or cardiac dysrhythmia. YKP10811 at low doses (0.3, 1, and 3 mg/kg) accelerated gastric emptying in a dose-dependent manner. (ii) YKP10811 (0.1 mg/kg), but not tegaserod (0.3 mg/kg), significantly accelerated glucagon-induced delayed gastric emptying of solid, and the effect was completely blocked by GR113808. (iii) YKP10811 (0.3 mg/kg) enhanced antral contractions. (iv) YKP10811 did not alter gastric accommodation.. YKP10811 seems to improve antral contractions and accelerate gastric emptying without altering gastric accommodation in dogs via the 5-HT

Topics: Administration, Oral; Animals; Benzamides; Carbamates; Dogs; Dose-Response Relationship, Drug; Gastric Emptying; Gastrointestinal Motility; Gastroparesis; Glucagon; Pyloric Antrum; Serotonin 5-HT4 Receptor Agonists

Topics: Aged; Atrial Fibrillation; Benzofurans; Catheter Ablation; Cryosurgery; Female; Gastroparesis; Humans; Postoperative Complications; Serotonin 5-HT4 Receptor Agonists; Severity of Illness Index; Tomography, X-Ray Computed

5-Hydroxytryptamine (5-HT) receptors and dopamine(2) (D(2)) receptor modulate gastrointestinal motility. Gastroprokinetic agents that act on several 5-HT receptor subtypes and/or D(2) receptors are used clinically. Although the 5-HT(4) receptor is known to mediate the gastroprokinetic effects of these agents, the absence of highly selective 5-HT(4) receptor agonists has made it difficult to confirm the physiological consequences of selective 5-HT(4) receptor stimulation. In this study, we report the in vitro pharmacological profiles and the in vivo gastroprokinetic effects of 5-amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-alpha]pyridine-8-carboxamide (CJ-033,466), a novel, potent, and selective 5-HT(4) partial agonist. Compared with preceding 5-HT(4) agonists such as cisapride, mosapride, and tegaserod, CJ-033,466 had a superior in vitro profile, with nanomolar agonistic activities for the 5-HT(4) receptor and 1000-fold greater selectivity for the 5-HT(4) receptor over other 5-HT and D(2) receptors. In vivo studies in conscious dogs showed that CJ-033,466 dose-dependently stimulated gastric antral motility in both the fasted and postprandial states at the same dose range and that it was 30 times more potent than cisapride. Furthermore, CJ-033,466 accelerated the gastric emptying rate in a gastroparesis dog model at the minimally effective dose established in the gastric motility study. In conclusion, CJ-033,466 is a potent and highly selective 5-HT(4) agonist that stimulates physiologically coordinated gastric motility, and it has no activity on other 5-HT receptor subtypes and D(2) receptors. Therefore, CJ-033,466 could be used to treat gastroparesis, providing better gastroprokinetics and reduced side effects mediated by the other receptors.

Topics: Aminopyridines; Animals; Dogs; Dose-Response Relationship, Drug; Gastric Emptying; Gastrointestinal Motility; Gastroparesis; Humans; Imidazoles; Radioligand Assay; Rats; Receptors, Dopamine D2; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists