Inotropic effects of prokinetic agents with 5-HT4 receptor agonist actions on human isolated myocardial trabeculae

Chai, Wenxia; Chan, Kayi Y.; Vries, René de; Bogeardt, Antoon J. van den; Maeyer, Joris H. De; Schuurkes, J. A. J.; Villalón, Carlos M.; Saxena, Pramod R.; Danser, A.H. Jan; MaassenVanDenBrink, Antoinette

doi:10.1016/j.lfs.2012.01.009

Cited by 12 publications

(5 citation statements)

References 42 publications

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“…This effect was also reported in the minesapride nonclinical study 9 . Similar HR increases by other 5‐HT 4 receptor agonists in nonclinical studies were reported as well 19,20 . In addition, a previous study using human atrial cells showed that prucalopride acted as a partial agonist on the L‐type calcium current and action potential early repolarization via 5‐HT 4 receptors 21 .…”

Section: Discussionsupporting

confidence: 80%

“…9 Similar HR increases by other 5-HT 4 receptor agonists in nonclinical studies were reported as well. 19,20 In addition, a previous study using human atrial cells showed that prucalopride acted as a partial agonist on the L-type calcium current and action potential early repolarization via 5-HT 4 receptors. 21 In fact, prucalopride had tendency to increase HR slightly in the thorough QT study and phase 3 study.…”

Section: Discussionmentioning

confidence: 99%

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Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Hamatani

Noda

Takagaki

et al. 2020

Clinical Pharm in Drug Dev

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Minesapride (drug code: DSP-6952) is a potential gastrointestinal prokinetic agent with high selectivity for 5-hydroxytryptamine 4 (5-HT 4) receptor that acts as a partial agonist. Although 5-HT 4 receptor agonists are expected to show efficacy in patients with irritable bowel syndrome with constipation, only tegaserod is available for female patients, with limitations, in the United States. Previously, another 5-HT 4 receptor agonist, cisapride, was widely used for the treatment of upper gastrointestinal diseases, but was withdrawn from the market because of arrhythmia with QT prolongation. Chemically, benzamide is one of the most common structures among 5-HT 4 receptor agonists. Some benzamide derivatives, such as cisapride, are responsible for QT prolongation, while some, such as mosapride, are not. Thus, we planned a thorough QT/QTc study to investigate the effects of minesapride, a newly designed benzamide derivative, on the QT/QTc. This was a randomized, placebo-controlled, 4-arm, 4-period, crossover study conducted in healthy adults, with administration of single oral doses of minesapride (40 mg and 120 mg), placebo, and moxifloxacin in the fasted state. Minesapride and placebo were administered in a double-blind fashion, while the positive control moxifloxacin was administered in an open-label fashion. Japanese subjects (48 total: 24 males and 24 females) were randomized, and 47 subjects completed all treatment periods. A review of other electrocardiographic data revealed that neither therapeutic (40 mg) nor supratherapeutic (120 mg) doses of minesapride were associated with increased risk of prolonged QT interval.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Hamatani

Noda

Takagaki

et al. 2020

Clinical Pharm in Drug Dev

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“…We failed to find reports of specific haemodynamic mechanisms supporting these findings in the literature for pimozide, haloperidol and sertindole. Alternatively, positive inotropic effects related to stimulation of 5‐HT 4 receptors were reported for cisapride (Chai et al, 2012). This molecule supports the hypothesis of a positive inotropic mechanism causing a baroreflex parasympathetic activation responsible for the enhancement of HFHR oscillations.…”

Section: Discussionmentioning

confidence: 98%

Contribution of haemodynamic side effects and associated autonomic reflexes to ventricular arrhythmias triggering by torsadogenic hERG blocking drugs

Champéroux

Fares

Bastogne

et al. 2022

British J Pharmacology

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Declaration of transparency and scientific rigour: This Declaration acknowledges that this paper adheres to the principles for transparent reporting and scientific rigour of preclinical research as stated in the BJP guidelines for Design and Analysis, and Animal Experimentation, and as recommended by funding agencies, publishers and other organisations engaged with supporting research. Short title: Hemodynamic side effects of torsadogenic hERG blocking drugs Author contribution: Data analysis was performed by P.C. Manuscript was written by P.C., J.T. and J.Y.L. and critically evaluated by R.F. and S.R. Principal components analysis and hierarchical clustering analysis were performed by T.B.

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“…However, the target structure must be optimized to meet its possible future directions regarding veterinary uses of cisapride ( 31 , 32 ). Second, cisapride was reported to be an antagonist of 5-hydroxytryptamine (5-HT) 4 receptor (5-HT 4 R) ( 33 ). We should exclude this effect on pancreatic β-cells in future work.…”

Section: Discussionmentioning

confidence: 99%

Cisapride induced hypoglycemia via the KCNH6 potassium channel

Lü

Shi²,

Yuan³

et al. 2022

Front. Endocrinol.

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Mutations in KCNH6 has been proved to cause hypoinsulinemia and diabetes in human and mice. Cisapride is a stomach–intestinal motility drug used to treat gastrointestinal dysfunction. Cisapride has been reported to be a potential inhibitor of the KCNH family, but it remained unclear whether cisapride inhibited KCNH6. Here, we discovered the role of cisapride on glucose metabolism, focusing on the KCNH6 potassium channel protein. Cisapride reduced blood glucose level and increased serum insulin secretion in wild-type (WT) mice fed standard normal chow/a high-fat diet or in db/db mice, especially when combined with tolbutamide. This effect was much stronger after 4 weeks of intraperitoneal injection. Whole-cell patch-clamp showed that cisapride inhibited KCNH6 currents in transfected HEK293 cells in a concentration-dependent manner. Cisapride induced an increased insulin secretion through the disruption of intracellular calcium homeostasis in a rat pancreatic β-cell line, INS-1E. Further experiments revealed that cisapride did not decrease blood glucose or increase serum insulin in KCNH6 β-cell knockout (Kcnh6-β-KO) mice when compared with WT mice. Cisapride also ameliorated glucose-stimulated insulin secretion (GSIS) in response to high glucose in WT but not Kcnh6-β-KO mice. Thus, our data reveal a novel way for the effect of KCNH6 in cisapride-induced hypoglycemia.

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Inotropic effects of prokinetic agents with 5-HT4 receptor agonist actions on human isolated myocardial trabeculae

Cited by 12 publications

References 42 publications

Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Contribution of haemodynamic side effects and associated autonomic reflexes to ventricular arrhythmias triggering by torsadogenic hERG blocking drugs

Cisapride induced hypoglycemia via the KCNH6 potassium channel

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Inotropic effects of prokinetic agents with 5-HT4 receptor agonist actions on human isolated myocardial trabeculae

Cited by 12 publications

References 42 publications

Thorough QT/QTc Study Shows That a Novel 5‐HT4 Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Thorough QT/QTc Study Shows That a Novel 5‐HT4 Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Contribution of haemodynamic side effects and associated autonomic reflexes to ventricular arrhythmias triggering by torsadogenic hERG blocking drugs

Cisapride induced hypoglycemia via the KCNH6 potassium channel

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Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation