td-5108 and levosulpiride

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

Levosulpiride is a 5HT4 agonist/D2 antagonist prokinetic agent used to improve gastric emptying in patients with functional dyspepsia or gastroparesis. The aim of this study was to characterize its effect on the main in vitro motility patterns in the human fundus, antrum, and jejunum.. Circular muscle strips from human stomach (antrum and fundus) and jejunum, obtained from 46 patients undergoing bariatric surgery, were studied using organ baths. Enteric motor neurons (EMNs) were stimulated by electrical field stimulation (EFS).. Levosulpiride, caused an increase in the EFS-induced cholinergic contractions in the gastric antrum (+37 ± 15.18% at 100 μM, pEC50 = 4.46 ± 0.14; p < 0.05, n = 8) and jejunum (+45.4 ± 22.03% at 100 μM, pEC50 = 3.78 ± 6.81; p < 0.05, n = 5), but not in the gastric fundus. It also caused a slight decrease in tone and frequency of spontaneous contractions in the jejunum, but did not have any major effect on tone or spontaneous contractions in the stomach. It did not have any effect on EFS-induced relaxations mediated by nitric oxide (NO) in the stomach (antrum and fundus) and by NO and ATP in the jejunum.. Our results suggest that the prokinetic effects of levosulpiride in humans are mainly due to the facilitation of the release of acetylcholine by enteric motor neurons in the gastric antrum and the jejunum.

Topics: Adult; Dose-Response Relationship, Drug; Female; Gastric Emptying; Gastric Fundus; Gastrointestinal Agents; Humans; Jejunum; Male; Middle Aged; Organ Culture Techniques; Pyloric Antrum; Serotonin 5-HT4 Receptor Agonists; Sulpiride