Does Cisapride Influence Cardiac Rhythm? Results of a United States Multicenter, Double-Blind, Placebo-Controlled Pediatric Study

Levy, Joseph; Hayes, Constance J.; Kern, Jeffrey A.; Harris, Jennifer; Flores, Alex F. C.; Hyams, Jeffrey S.; Murray, R. Charles; Tolia, Vasundhara

doi:10.1097/00005176-200104000-00013

Cited by 33 publications

(47 citation statements)

References 20 publications

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“…The risk of proarrhythmic activity associated with the clinical use of each drug, however, is quite different. Cisapride (Propulsid), a motility enhancer that can be used to treat patients with gastroesophageal reflux disease, and quinidine, a class Ia antiarrhythmic agent, have been shown to prolong the QT interval and to trigger TdP (Roden et al, 1986;Wysowski and Bacsanyi, 1996;Walker et al, 1999;Levy et al, 2001). Cisapride is a potent (IC 50 ϭ 7 nM) I Kr blocker (Walker et al, 1999).…”

mentioning

confidence: 99%

An Increase in Late Sodium Current Potentiates the Proarrhythmic Activities of Low-Risk QT-Prolonging Drugs in Female Rabbit Hearts

Shryock²,

Song³

et al. 2005

J Pharmacol Exp Ther

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Assessment of the proarrhythmic risk associated with drugs that prolong the QT interval is difficult. We hypothesized that the proarrhythmic activities of drugs with very low to moderate risk of causing torsades de pointes would be well differentiated when the late sodium current (I NaL ) was greater than normal. The effects of selected QT-prolonging drugs on electrical activity of female rabbit isolated hearts were determined in the absence and presence of sea anemone toxin (ATX-II; an enhancer of I NaL ). I NaL recorded from ventricular myocytes isolated from female rabbit hearts was slightly increased by 1 and 3 nM ATX-II (n ϭ 13, P Ͻ 0.01). ATX-II (1 nM) prolonged the duration of the monophasic action potential (MAPD 90 ) of the isolated heart by 19 Ϯ 3% (P Ͻ 0.001, n ϭ 31) and shifted the concentration-response relationships for cisapride (1-30 nM), ziprasidone (0.01-3 M), quinidine (0.1-1 M), and moxifloxacin (0.01-1 M) to prolong MAPD 90 to the left by 2-to 12-fold. In contrast, the increases in MAPD 90 caused by 1 nM ATX-II and pentobarbital were only additive, and the increases in MAPD 90 caused by ATX-II and ranolazine [(Ϯ)-N-(2,6-dimethylphenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine] were less than additive. Episodes of arrhythmic activity were commonly observed, and beat-to-beat variability of action potential duration was increased, during exposure of hearts to cisapride, ziprasidone, quinidine, and moxifloxacin but not during exposure of hearts to ranolazine or pentobarbital, in the presence of ATX-II. Thus, in the female rabbit heart, ATX-II potentiated the effects of QT-prolonging drugs to increase MAPD 90 and unmasked the proarrhythmic activities of these drugs at clinically relevant drug concentrations.

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mentioning

confidence: 99%

An Increase in Late Sodium Current Potentiates the Proarrhythmic Activities of Low-Risk QT-Prolonging Drugs in Female Rabbit Hearts

Shryock²,

Song³

et al. 2005

J Pharmacol Exp Ther

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“…Torsade de pointes is the classic form of proarrhythmia which may occur after the administration of any drug that prolongs myocardial repolarization. Although the risk of a clinically significant proarrhythmia appears to be very low (!1:11,000 treated subjects) with low-dose cisapride [12,23], such concerns have most recently led to severe restrictions for clinical use in the United States.…”

Section: Discussionmentioning

confidence: 99%

24-Hour Electrocardiogram before and during Cisapride Treatment in Neonates and Infants

Zamora¹,

Belli²,

Friedli

et al. 2004

Neonatology

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We studied prospectively the effects of cisapride on heart rate and rhythm using standard ECG and 24-hour ECG recordings in term and preterm neonates and infants. We studied subjects with gastroesophageal reflux disease (apparent life-threatening events, apneas, bradycardias) before and 3 days after starting cisapride (0.8 mg/kg/day in 4 doses). We performed standard ECGs for determination of corrected Q-T interval (QTc) and Q-T dispersion (QTd) and 24-hour ECG recordings for analysis of heart rate, heart rate variability, and heart rhythm. Fourteen term and 17 preterm subjects (gestational age range 28–36 weeks) were studied at a median chronological age of 29 (range 3–132) days. Cisapride significantly increased the QTc in preterm infants (before vs. after: 408 ± 7 vs. 433 ± 7 ms, p = 0.001). Two preterm and 1 term infant had a QTc >450 ms before cisapride. Four preterm (4/15 = 27%) and 2 term (2/13 = 15%) subjects had a QTc >450 ms on cisapride. After cisapride the QTd remained normal, and no relevant arrhythmias were documented on Holter recordings. Cisapride significantly decreased peak and mean heart rates of all study subjects without affecting the heart rate variability, while it increased the minimal heart rate of preterm infants only (before vs. after: 66 ± 5 vs. 78 ± 5 bpm, p = 0.02). The maximally measured R-R intervals (pauses) decreased after cisapride in preterm infants (before vs. after: 1.33 ± 0.2 s vs. 1.05 ± 0.2 s, p = 0.04). Although cisapride did cause a significant prolongation of the ventricular action potential duration in preterm infants, the QTd remained unaffected, and no clinically relevant arrhythmias were documented in this small sample. On the other hand, cisapride had a direct lowering effect on the maximal and mean heart rates of both term and preterm infants, while the drug increased the minimal heart rate and reduced the severity of bradycardia episodes in preterm infants.

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“…Arrhythmias have also been reported ranging from notched t waves to torsades de points [ 71,74,76 ] . In a multicenter, double-blind placebo-controlled trial of 49 children (age 6 months-4 years), however, a dose of 0.2 mg/kg given three times a day in patients without cardiac risk factors, for a treatment duration of at least 6 weeks, did not show a statistically signi fi cant increase in QTc interval and no subjects experienced cardiac events [ 62 ] .…”

Section: -Hydroxytryptamine-4 Receptor Agonists Cisapridementioning

confidence: 94%

“…However, more recently the 2010 Cochrane Review did not show any difference in symptom improvement or weight gain when cisapride is compared to placebo [ 61 ] . Nine studies comparing cisapride with placebo or no treatment, that met inclusion criteria, were included in the meta-analysis [62][63][64][65][66][67][68][69] . The authors reviewed fi ve studies comparing results of esophageal pH probe in patients being treated with cisapride vs. placebo and while there was improvement in the re fl ux index, there was no signi fi cant improvement in the number of re fl ux episodes and episodes lasting longer than 5 min.…”

Section: -Hydroxytryptamine-4 Receptor Agonists Cisapridementioning

confidence: 99%

Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives

Har

Croffie

2012

Pediatric Neurogastroenterology

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Does Cisapride Influence Cardiac Rhythm? Results of a United States Multicenter, Double-Blind, Placebo-Controlled Pediatric Study

Cited by 33 publications

References 20 publications

An Increase in Late Sodium Current Potentiates the Proarrhythmic Activities of Low-Risk QT-Prolonging Drugs in Female Rabbit Hearts

An Increase in Late Sodium Current Potentiates the Proarrhythmic Activities of Low-Risk QT-Prolonging Drugs in Female Rabbit Hearts

24-Hour Electrocardiogram before and during Cisapride Treatment in Neonates and Infants

Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives

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