Cisapride

Critical evaluations of published reports on the efficacy of different prokinetics (cisapride, domperidone and metoclopramide) concluded that cisapride was the preferred agent.117,118 According to these assessments, the vast majority of clinical trials on the efficacy of cisapride demonstrated that at least one of the end-points changed favorably as a result of the interven-tion.117 Cisapride is more effective than metoclopramide.118 A Cochrane review on cisapride in children analyzed data from seven trials, including 236 patients; they compared the effect of cisapride to that of placebo on symptom presence and improvement.119 It was concluded that there was a statistical difference in the parameter symptoms 'present/absent' but that there was no statistically significant difference for 'symptom change' between placebo and cisapride. The Cochrane review also concluded that cisapride compared to placebo significantly reduced the number and duration of acid reflux episodes, since there was a significant decrease in reflux index, which is the percentage of time that esophageal pH is below 4.0.119 In general, cisapride is well tolerated. The most common adverse events at therapeutic doses are transient diarrhea and colic (in about 2%). The effect of cisapride on relevant cardiac events such as QT prolongation and arrhythmia is related to dose and risk factors. More serious adverse events such as extrapyramidal reactions, seizures in epileptic patients, and cholestasis in very premature infants have been the objects of isolated reports.

The relation between cisapride, the P450 cytochrome and cardiac effects was considered in 1996.120 The cytochrome P450 system and especially CYP3A4 metabolizes cisapride in the liver.121 There is little doubt that cisapride has a QT-prolonging effect,117 as do many other drugs or clinical situations.122 Cisapride possesses class III antiarrhythmic properties and prolongs the action potential duration, delaying cardiac repolariza-tion,123 although many studies do not report an increase in duration of QTc, in neonates or in older children. Torsades de pointes have been reported with cisapride use, especially in those receiving high doses or macrolides.124 Co-treatment of cisapride and macrolides such as clarithromycin and erythromycin clearly prolongs the QT dura-tion.125 Underlying cardiac disease, drug interactions and electrolyte imbalance are clearly interfering factors.126 Cisapride causes prolongation of ventricular repolarization without causing increased heterogeneity of repolarization (QT dispersion), but all patients in the study remained asymptomatic without dysrhythmia.127 The QT-prolonging effect of cisapride may be related to age.128 The cytochrome P4503A4, which is involved in the metabolism of cisapride, is immature at birth and reaches adult activity by the age of 3 months. Cisapride accumulation occurs in newborns because of enzymatic immaturity. A significant QTc prolongation occurs, especially in infants younger than 3 months, but not in older infants.129,130 This effect was related to higher plasma levels. A more frequent administration of lower doses (resulting in a recommended daily dose of 0.8mg/kg per day) in premature infants results in lower peak levels.131 Consumption of grapefruit juice also alters cisapride meta-bolism.132 According to recent data, gene mutation may be the fundamental culprit.133 Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers.134

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