The cardiovascular safety profile of renzapride, a novel treatment for irritable bowel syndrome.
The cardiac safety of renzapride, a novel benzamide currently under clinical development for the treatment of irritable bowel syndrome, was investigated in a four-way randomized crossover electrocardiographic clinical study in healthy human subjects and also in an in vitro cardiac conductivity study in sheep isolated Purkinje fibres. The primary endpoint in the clinical study was prolongation of the individually corrected QT interval (QTci). No clinically or statistically significant prolongation of QTci after 4 or 20 mg renzapride compared with placebo was observed. The relative effects of renzapride and cisapride in the in vitro study showed that the cardiac action potential duration was unaltered by 0.2 and 2 microM renzapride, shortened by 20 microM renzapride, and prolonged by 1 microM cisapride. Cisparide was also a 1000-fold more potent inhibitor of human ether-a-go-go related gene (hERG) channels in HEK293 cells than renzapride. These studies indicate that therapeutic doses of renzapride are unlikely to prolong cardiac action potentials and, therefore, are also unlikely to cause cardiac arrhythmias in clinical use.
Meyers
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NL
Alizyme Therapeutics Limited, Cambridge, UK. nick@alizyme.co.uk
Hickling
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RI
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001372:Aza Compounds / Q000494:pharmacology; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D020117:Cisapride / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D018592:Cross-Over Studies; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D024841:Fluoroquinolones; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008297:Male; D000077266:Moxifloxacin; D010919:Placebos; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D012756:Sheep
D000890:Anti-Infective Agents; D001372:Aza Compounds; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D005765:Gastrointestinal Agents; D010919:Placebos; D011804:Quinolines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C053006:renzapride; D000077266:Moxifloxacin; D020117:Cisapride