Cisapride: What can we learn from the rise and fall of a prokinetic?

Abstract

Cisapride, the prototype serotonergic agent, evolved from a body of research that defined the key roles of serotonergic receptors in gastrointestinal motor and sensory function. Impressed by its in vitro properties and encouraged by clinical trial data, cisapride became the drug of choice for the treatment of a wide range of motility disorders and clinicians appeared impressed by its efficacy and comfortable with its side-effect profile. Once serious cardiac events began to be reported in association with cisapride therapy, dark clouds rapidly gathered and soon enveloped the drug, leading to its widespread withdrawal from markets. What lessons can we learn from the story of cisapride? How can its brief but spectacular rise and equally sensational demise inform the development of new drugs which are so sorely needed in the management of motility and functional gastrointestinal disorders? This review explores the background to the development of cisapride, its history in clinical trials and the experience with adverse events and, in so doing, attempts to identify lessons for the future in the therapeutics of enteric neuromodulatory drugs.KEY WORDS: cisapride, gastroesophageal reflux, gastrointestinal motility, gastroparesis, prokinetic, serotonin.Cisapride, introduced worldwide in the 1990s, is a serotonin 5-HT4 agonist with 5-HT3 antagonist activity that stimulates the release of acetylcholine from postsynaptic neurons in the enteric nervous system. It therefore had quite widespread prokinetic effects throughout the gastrointestinal tract: stimulating salivary secretion, increasing esophageal peristaltic amplitude, augmenting lower esophageal sphincter pressure, enhancing gastric emptying and stimulating small bowel and colonic transit. It was, however, devoid of antidopaminergic and direct cholinomimetic effects; the former avoiding the central nervous system and hyperprolactinemia-related side effects of metoclopramide, the latter avoiding the bladder and other side effects of traditional cholinergics, such as bethanechol. Though ultimately employed in a wide range of motility disorders from gastroparesis and pseudo-obstruction to colonic inertia, cisapride was actually approved by the Food and Drug Administration (FDA) in the USA for nocturnal heartburn based on the results of pivotal clinical trials. In primary care, cisapride soon came to be prescribed, either on its own or in combination with a histamine H2 receptor antagonist or a proton pump inhibitor, for a range of upper gastrointestinal symptoms including heartburn and dyspepsia. Its use was especially advocated for children with gastroesophageal reflux disease (GERD) based on the premise that dysmotility was predominant in the etiology of reflux in this patient population. Though trials in gastroparesis did not always show a consistent relationship between symptom improvement and an enhanced gastric emptying rate,

Increased expression of tight junction protein�occludin is associated with the protective effect of mosapride against aspirin‑induced gastric injury

“…In this study, gastric ulceration was significantly relieved and the hexosamine content of gastric mucus was significantly increased, as were the gastric mucosal levels of PGE2 (12,17). However, cisapride is associated with adverse cardiovascular events and has therefore been replaced by mosapride, a novel selective 5-HT4 receptor agonist with safer profiles (18,19). A study by Fujisawa et al (11) found that treatment with a low dose of mosapride inhibited gastric mucosa injury induced by indomethacin, and their results showed that 0.5 mg/kg mosapride was the optimal dose.…”

Response to Arnold and Beaves

“…Th e consensus guideline did not support the use of cisapride, which was never approved for gastroparesis and was withdrawn due to cardiac side eff ects ( 7 ). Other 5-HT 4 receptor agonists, without eff ects on potassium or hERG channels and the associated cardiac arrhythmias, are being investigated for gastroparesis.…”

Prokinetics in the Management of Functional Gastrointestinal Disorders

“…In the latter example the effect was an unexpected one; an interaction with the Human Ether-a-go-go-Related Gene (hERG) channel led to the occurrence of hERG channel-mediated cardiac arrhythmias, such as Torsades de Pointes and ventricular tachycardia. 4 Though many of these adverse events were related to preexisting cardiac disease or the co-administration of cisapride with drugs that either had similar effects on cardiac electrophysiology (prolongation of the Q-T interval) or that altered the metabolism of cisapride, a few occurred in individuals who did not have obvious risk factors and led to the withdrawal of the drug world-wide. All new compounds are now tested for Q-T effects.…”