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At least 19 recordsLinked to original sources
PubMed2000

Cisapride treatment for gastro-oesophageal reflux in children.

BACKGROUND: Gastro-oesophageal reflux (GOR) is an extremely common and usually self limiting condition in infants. When treatment is required, Cisapride, a pro-kinetic agent, has been commonly prescribed for the symptomatic management of GOR. There have been recent reports of possibly serious adverse events e.g. an increased QTc interval, cardiac arrhythmias, and death, associated with the use of Cisapride. OBJECTIVES: To determine the effectiveness of Cisapride for symptoms of GOR in children compared with placebo or any other non-surgical treatments. SEARCH STRATEGY: Searches were conducted of the Cochrane Central Trials Register and the specialised Trials register of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group, MEDLINE and Embase. Reference lists of relevant review articles and identified trials were scrutinised and forward citation searches were performed in the Science Citation Index on all trials identified. SELECTION CRITERIA: Randomised controlled trials that compared oral Cisapride therapy with placebo or with other non-surgical treatments for children with a diagnosis of GOR were included. Only studies in which Cisapride was administered orally for a minimum of one week and which documented at least one of the primary outcomes were included. DATA COLLECTION AND ANALYSIS: The primary outcomes were defined as a change in symptoms at the end of treatment, presence of adverse events, occurrence of clinical complications, and weight gain. The secondary outcomes included physiological measures of GOR or histological evidence of oesophagitis. We dichotomised symptoms into 'same or worse' vs 'improved' and calculated summary odds ratios. Continuous measures of GOR (e.g. reflux index) were summarised as a weighted mean difference. All outcomes were analysed using a random effects method. Sensitivity analyses were also performed. MAIN RESULTS: Searches identified eight trials which met the inclusion criteria. Seven trials (a total of 236 participants) compared Cisapride with placebo. The odds ratio for 'same or worse' vs 'improved symptoms' at the end of treatment was 0.34 (95%CI 0.10, 1.19), thus showing no statistically significant difference between the two interventions. There was significant heterogeneity between the studies and the funnel plot suggested substantial publication bias. In the sensitivity analysis, the definition of outcomes was changed to 'any symptoms' vs 'no symptoms'. This resulted in the exclusion of three trials (one of them the largest, best quality trial). The resulting pooled odds ratio showed a significant effect of Cisapride (OR 0.19, 95%CI 0.08, 0.44). There were fewer adverse events with placebo than with Cisapride, but the difference was not statistically significant (OR 1.80, 95%CI 0.87, 3.70) and the result was based on small numbers. Cisapride compared with placebo produced a statistically significant reduction in the reflux index (weighted mean difference -6.49, 95%CI -10.13, -2.85), but as reflux index and clinical symptoms are poorly correlated, the clinical importance of this finding is uncertain. Other measures of oesophageal pH monitoring did not reach significance. One included study compared Cisapride with Gaviscon (or Gaviscon and Carobel). The odds ratio for 'same or worse' vs 'improvement' in the Cisapride group compared with Gaviscon was 3.26 (95%CI 0.93, 11.38). REVIEWER'S CONCLUSIONS: We found no clear evidence that Cisapride reduces symptoms of GOR. The results suggested substantial publication bias favouring studies showing a positive effect of Cisapride. Due to reports of serious adverse events, the company will stop marketing the drug as of July 14th, 2000 and therefore a larger study to provide more conclusive evidence of the effect of Cisapride is no longer possible.

Alginates↗
PubMed1997

A double-blind randomized study of cisapride in the treatment of nonulcer dyspepsia. The Canadian Cisapride Nud Study Group.

Cisapride is a substituted benzamide with gastrointestinal prokinetic effects presumed to be due to the enhancement of the physiological release of acetylcholine at the myenteric plexus. In a multicentre study, 189 patients with nonulcer dyspepsia (NUD) received single-blind placebo treatment for two weeks. A total of 123 patients with no or minimal response to placebo and epigastric pain of at least moderate severity and frequency were randomly assigned to one of the three parallel double-blind treatments for six weeks: cisapride 10 mg tid, cisapride 20 mg tid or placebo. The severity and frequency of individual symptoms (epigastric pain, heartburn, nausea, vomiting anorexia, postprandial discomfort, regurgitation, lower abdominal pain, bloating and constipation) were assessed on a four- and five-point categorical scale, respectively, by the investigator at three on treatment visits and by patients in a daily diary. Analysis of investigator and patient assessments for differences in symptom severity x frequency composite scores among the three treatment groups showed no statistically significant differences for individual symptoms or symptom clusters. As assessed by the investigator, and compared with baseline, cisapride 20 mg tid significantly (P < 0.05) improved epigastric pain, bloating and early satiety as well as improved the total symptom cluster. Investigator evaluation of the five most severe and frequent symptoms for each patient showed statistically significant improvement in each treatment group. For patient diary assessments, statistically significant within-treatment improvement of the total symptom cluster, the five most severe symptoms cluster, bloating and early satiety was observed for both cisapride 20 mg and placebo, whereas epigastric pain significantly (P < 0.05) improved in all three treatment groups. Investigator evaluation of global response (good+excellent) rate at the end of the six week treatment period was 38% for cisapride 20 mg, 47% for cisapride 10 mg and 33% for placebo. No statistically significant difference in this parameter among treatments was noted. Cisapride was well tolerated at both doses with a side effect profile comparable with that of placebo. It is concluded that in this double-blind multicentre study with a single-blind two-week placebo run in phase, cisapride 10 mg tid and 20 mg tid were not effective compared with placebo in improving symptoms in NUD patients. This study re-emphasizes the good prognosis of patients with NUD, with 14% of patients improving in the two-week placebo run-in phase and a further 33% improving in the next six weeks while on placebo. Within-treatment analysis of investigator assessments showed improvement for cisapride 20 mg tid suggesting a trend of efficacy at this dose.

Administration, Oral↗
PubMed1989

Cisapride-cimetidine interaction: enhanced cisapride bioavailability and accelerated cimetidine absorption.

The pharmacokinetic interaction between the gastrointestinal motility-stimulating substance cisapride and the H2-antagonist cimetidine was examined in 8 healthy volunteers (25 +/- 2 years of age). Steady-state kinetics of both substances were investigated after separate 1-week treatments of oral cisapride, 10 mg t.i.d., cimetidine, 400 mg t.i.d., and the two drugs combined. Cimetidine increased the cisapride peak plasma concentration from 58 +/- 25 ng/ml to 84 +/- 19 ng/ml (p = 0.01) and AUC0-24 from 509 +/- 289 ng/ml.h to 738 +/- 148 ng/ml.h (p = 0.02). Cisapride shortened the time to the peak concentration of cimetidine from 1.3 +/- 0.6 h to 0.6 +/- 0.2 h (p = 0.005) and reduced the cimetidine AUC0-24 from 11.0 +/- 2.3 micrograms/ml.h to 9.0 +/- 2.0 micrograms/ml.h (p = 0.05). It is concluded that cimetidine inhibits cisapride metabolism, whereas cisapride enhances the gastrointestinal absorption of cimetidine.

Adult↗
PubMed1991

Effect of single doses of cisapride and ranitidine administered simultaneously on plasma concentrations of cisapride and ranitidine.

We have studied in 12 volunteers the effect of single doses of cisapride and ranitidine, administered simultaneously, on plasma concentrations of cisapride and ranitidine. Median maximum plasma concentration of ranitidine was achieved 1 h earlier when ranitidine was taken with cisapride compared with ranitidine alone (P = 0.012). There was a 24% decrease in plasma ranitidine AUC8h when ranitidine was taken with cisapride compared with ranitidine alone (P less than 0.005). Ranitidine had no effect on absorption of cisapride.

Adult↗
PubMed1993

Effectiveness of cisapride in gastric ulcer. Results of a double-blind randomized trial versus ranitidine and versus cisapride plus ranitidine.

Among the factors involved in the pathogenesis of gastric ulcer, the reduced clearing capacity of the stomach seems to play an important role. On this basis, cisapride, which improves gastrointestinal motility, enhances gastric emptying, and prevents duodenogastric reflux, may be effective in the treatment of the gastric ulcer. We randomly allocated 60 consecutive patients, with uncomplicated antral gastric ulcer (diameter 5-25 mm), into three groups of treatment: cisapride 20 mg b.i.d. (C), ranitidine 150 mg b.i.d. (R), cisapride 20 mg b.i.d. + ranitidine 150 mg b.i.d. (C+R). Endoscopic examination with biopsy specimens was performed on admission, after 4 weeks and (if ulcer not healed) after 8 weeks of therapy. Three patients were lost to follow-up (two in C and one in C+R), and three were withdrawn, due to malignant ulcer (one case in R) or to side effects (one case of diarrhea in C, one case of headache in C+R). Healing rates at 4 weeks were 41.1% in C, 52.6% in R, and 50.0% in C+R; at 8 weeks they were 88.2% in C, 89.4% in R, and 94.4% in C+R. Though the lack of a placebo arm makes final considerations difficult, the results were similar in all three groups, with no evident differences. In conclusion, therapy with cisapride appears as effective as H2-blocker alone or combined treatments in healing benign gastric ulcer.

Adult↗
PubMed2001

Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice.

AIMS: To determine whether the pharmacokinetics of cisapride and its interaction with grapefruit juice are stereoselective. METHODS: The study was a randomized, two-phase cross over design with a washout period of 2 weeks. Ten healthy volunteers were pretreated with either water or 200 ml double strength grapefruit juice three times a day for 2 days. On the 3rd each subject ingested a single 10 mg dose of rac-cisapride tablet. Double strength grapefruit juice (200 ml) or water was administered during cisapride dosing and 0.5 and 1.5 h thereafter. Blood samples were collected before and for 32 h after cisapride administration. Plasma concentrations of cisapride enantiomers were measured by a chiral h.p.l.c. method. A standard 12-lead ECG was recorded before cisapride administration (baseline) and 2, 5, 8, and 12 h later. RESULTS: This study showed that cisapride pharmacokinetics are stereoselective. In control (water treated) subjects, the mean Cmax (30 +/- 13.6 ng ml-1; P = 0.0008) and AUC(0, infinity) (201 +/- 161 ng ml-1 h; P = 0.029) of (-)-cisapride were significantly higher than the Cmax (10.5 +/- 3.4 ng ml-1) and AUC(0, infinity) (70 +/- 51.5 ng ml-1 h) of (+)-cisapride. There was no marked difference in elimination half-life between (-)-cisapride (4.7 +/- 2.7 h) and (+)-cisapride (4.8 +/- 3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (-)-cisapride from 30 +/- 13.6-55.5 +/- 18 ng ml-1 (95% CI on mean difference, -33, -17; P = 0.00005) and of (+)-cisapride from 10.5 +/- 3.4 to 18.4 +/- 6.2 ng ml-1 (95% CI on mean difference, -11.8, -3.9, P = 0.00015). The mean AUC(0, infinity) of (-)-cisapride was increased from 201 +/- 161 to 521.6 +/- 303 ng ml-1 h (95% CI on mean difference, -439, -202; P = 0.0002) and that of (+)-cisapride from 70 +/- 51.5 to 170 +/- 91 ng ml-1 h (95% CI on mean difference, -143, -53; P = 0.0005). The tmax was also significantly increased for both enantiomers (from 1.35 to 2.8 h for (-)-cisapride and from 1.75 to 2.9 h for (+)-cisapride in the control and grapefruit juice group, respectively; P < 0.05). The t(1/2) of (-)-cisapride was significantly increased by grapefruit juice, while this change did not reach significant level for (+)-cisapride. The proportion of pharmacokinetic changes brought about by grapefruit juice was similar for both enantiomers, suggesting non-stereoselective interaction. We found no significant difference in mean QTc intervals between the water and grapefruit juice treated groups. CONCLUSIONS: The pharmacokinetics of cisapride is stereoselective. Grapefruit juice elevates plasma concentrations of both (-)- and (+)-cisapride, probably through inhibition of CYP3A in the intestine. At present, there are no data on whether the enantiomers exhibit stereoselective pharmacodynamic actions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict the degree of drug interaction, cardiac safety and prokinetic efficacy of cisapride.

Administration, Oral↗
PubMed2003

Cisapride: a potential model substrate to assess cytochrome P4503A4 activity in vivo.

OBJECTIVES: Cisapride was compared with midazolam in vivo to determine its potential applicability as a cytochrome P450 (CYP) 3A4 "probe." As well, we evaluated whether cisapride was transported by P-glycoprotein. METHODS: Bidirectional transport assays were conducted in LLC-PK1 cells and the derivative cell line L-MDR1 to determine whether cisapride was a substrate for P-glycoprotein. A pharmacokinetic study was also conducted in 17 healthy adults (n = 8 women) who received intravenous midazolam (0.025 mg/kg), oral midazolam (0.15 mg/kg), and oral cisapride (0.07 mg/kg) in a randomized crossover design. Plasma concentrations were quantitated from repeated after-dosing blood samples by HPLC with ultraviolet detection for midazolam and HPLC with tandem mass spectrometry detection for cisapride and norcisapride. Pharmacokinetic parameters were determined by noncompartmental methods. Both linear and nonlinear regression analyses were used to examine the association between the apparent plasma clearance of midazolam and cisapride and the cisapride/norcisapride plasma concentration ratios. RESULTS: Although not a substrate for P-glycoprotein, cisapride inhibited P-glycoprotein with an apparent inhibition constant (K(i)) of 16.1 micromol/L. Linear correlations between cisapride clearance and both intravenous and oral midazolam clearance (P =.01, r(2) = 0.43 and P =.001, r(2) = 0.46, respectively) were found. Cisapride/norcisapride plasma concentration ratios at 8 hours (P =.001, r(2) = 0.90) and 12 hours (P =.001, r(2) = 0.96), as well as cisapride plasma concentrations at these time points, were shown to accurately predict the area under the plasma concentration versus time curve for cisapride. CONCLUSIONS: CYP3A4 activity reflected by the total body clearance after oral administration of cisapride should be independent of transport by P-glycoprotein. Concordance between the pharmacokinetics for cisapride and midazolam support the applicability of oral cisapride as a pharmacologic substrate to assess total CYP3A4 activity in vivo. Cisapride plasma concentration ratios at 8 or 12 hours after a single oral cisapride dose may prove useful as a single-point determination to reflect the area under the plasma concentration versus time curve and the plasma clearance of cisapride and, as well, total CYP3A4 activity in vivo.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1999

Cisapride: a survey of the frequency of use and adverse events in premature newborns.

OBJECTIVE: This survey estimated the frequency of use and adverse events associated with cisapride treatment of premature newborns in intensive care units. It was initiated in response to a warning issued in Canada cautioning against cisapride treatment of premature infants of <36 weeks' gestation and <3 months of age. METHODOLOGY: Surveys were mailed to 105 neonatology training program directors to obtain the total number of neonatal intensive care unit (NICU) admissions, the number of admissions of infants of <36 weeks' gestation, the number of years that cisapride had been used, the estimated percent/number of premature patients treated with cisapride per year, and the frequency and nature of arrhythmias or other adverse events associated with cisapride treatment. Of 105 programs, 46 responded to a single mailing of the first survey. A second survey mailed to the 45 respondents to the first survey sought to determine the indications, diagnostic tests, and dosages used with cisapride treatment of premature newborns. Of the 45 programs, 26 responded to the second survey. RESULTS: More than 58 000 premature newborns of <36 weeks' gestation were admitted to the NICUs we surveyed, and approximately 19% were treated with cisapride. No deaths attributable to cisapride were reported among >11 000 preterm newborns treated. Three nonfatal arrhythmias were reported; two associated with 10-fold dosing errors and one with co-treatment with erythromycin, a macrolide antibiotic that reduces the metabolism of cisapride. Diarrhea was reported in 12 patients, and reversible liver enzyme changes were noted in one patient. Typically, cisapride treatment was started in dosages of 0.1 to 0.2 mg/kg/dose, repeated every 6 to 8 hours. Treatment usually was begun empirically, without a preceding study to document gastroesophageal reflux. The most frequent indications for cisapride treatment were choking or gagging, with associated apnea, bradycardia, and desaturation. Approximately 50% of patients had discontinued cisapride treatment before discharge. Eighty-four percent of clinicians judged cisapride to be effective for the problems being treated. CONCLUSIONS: Cisapride treatment of premature infants of <36 weeks' gestation and <3 months of age in NICUs appears to be widespread in the United States. Complications and adverse events were seen when cisapride was administered in excessive dosages or in combination with a drug that inhibits its metabolism and leads to increased serum concentrations. Severe toxicities such as arrhythmias were reported with a frequency of <1/11 000 NICU admissions. However, in a retrospective survey, episodes of toxicity, including mortality, attributable to cisapride may not have been recognized or reported.

Cisapride↗
PubMed2001

Cisapride decreases gastroesophageal reflux in preterm infants.

OBJECTIVE: Gastrointestinal prokinetic agents, such as cisapride, are commonly used in pediatric practice to improve gastric emptying, to decrease emesis, to improve lower esophageal sphincter tone, and to improve irritability and feeding aversion associated with gastroesophageal reflux (GER). Although cisapride seems to be effective in infants from 2 months to 14 years old, data for younger and preterm infants are not available. Whether reflux is a significant cause of reflex apnea or feeding intolerance in the preterm infant is controversial. The objective of this 1-year prospective study, started in 1998, was to determine the efficacy of cisapride for treatment of reflux and reflux-associated apnea (RAAP) in preterm infants. Before this study, the diagnosis of reflux was often made clinically and the effect of therapy on reflux or the decision to increase the dose of cisapride was made empirically. The clinical bias was that persistent apnea, not responding to caffeine, was caused by GER. We reasoned that a systematic approach to the diagnosis and treatment of reflux would improve the care of preterm infants and reduce the risk of toxicity, especially if an increased dose of cisapride showed no improvement in reflux or apnea. STUDY DESIGN: Twenty-four preterm infants (24-36 weeks' gestational age) had clinical apnea/pH studies when they were referred by the attending neonatologist for suspected GER. These infants were born at 28.8 +/- 3.1 weeks with birth weight of 1169 +/- 387 g (range: 631-2263 g). Each infant was studied before and 8 days after starting cisapride treatment. Cisapride dose was 0.09 to 0.25 mg/kg every 6 hours enterally. Treatment decisions regarding dose of cisapride were the responsibility of the attending neonatologist. The pH was recorded continuously for 24 hours at 0.25 Hz and was analyzed using EsopHogram software. A single sensor pH catheter was inserted to ~2 cm above the esophageal gastric junction. GER was defined as a drop in esophageal pH below 4.0 for a least 5 seconds, or pathologic GER was defined as a reflux index (RI) >2 standard deviation (SD) from the mean based on published norms for term infants. The following parameters were calculated from the pH recording: number of reflux events per 24 hours, duration of the longest episode, number of episodes >5 minutes per 24 hours, and RI, ie, percentage of time with pH <4.0. Each study had a combined time-lapse video recording and multichannel digital recording. Recorded parameters were: continuous pulse oximetry, electrocardiogram, respiratory effort (piezo sensor), and airflow (temperature sensor at nostrils and mouth). The recording was scored for central apneas of 10 to 14 seconds and >/=15 seconds (prolonged) and >/=10 seconds for obstructive and mixed apneas. RAAP was scored when an apnea (irrespective of the type) occurred within 1 minute of a GER event. Baseline, after cisapride, and follow-up electrocardiograms were performed because of concern about prolonged QTc and cardiac arrhythmias. The infants were 35.6 +/- 4.5 weeks postconceptional age when first studied. Twelve infants (mean birth weight: 1821 +/- 749 g; gestational age: 32 +/- 2 weeks; postconceptional age: 35.6 +/- 2.6 weeks) were identified retrospectively as controls because their baseline GER parameters were within the normal range using Vandenplas' criteria. RESULTS: Overall, cisapride treatment significantly improved the RI from 16.6 +/- 15.2 to 9.1 +/- 8.4 SD. The number of reflux episodes >/=5 minutes was reduced from 7.1 +/- 5.8 to 4.3 +/- 4.4 SD. No significant effect was seen on the total number of refluxes (/24 hours). Eight infants (33%) had no decrease in the RI after a week of treatment. Three of these infants improved after cisapride dose was increased from 0.09 to 0.25 mg/kg/dose every 6 hours. Although 0.09 mg/kg/day is the minimum effective dose, 67% of our infants did respond to this low dose. Cisapride was discontinued in 3 infants because of prolonged QTc >/=0.450 seconds (0.473 in 1 and 0.470 in 2). More data about the effect of cisapride on QTc interval are reported in Pediatrics in a separate article. Only 1 infant showed no improvement with increased dose. Caffeine treatment had no effect on the baseline or follow-up GER values. Although apnea indexes for central and obstructive apnea were similar before and after cisapride, mixed apnea was less during treatment. There was a significant decrease (0.32 +/- 0.40 to 0.12 +/- 0.17/hour) in RAAP when the one infant who had increased reflux on increased dose of cisapride was excluded as an outlier. The statistical difference, before and after cisapride, for the group is significant with the outlier omitted. The clinical significance is unclear because ~50% of the infants had minimal changes in their apnea indexes. Furthermore, ~40% of infants did not have RAAP. (ABSTRACT TRUNCATED)

Cisapride↗
PubMed1993

The effect and mechanism of the prokinetic action of cisapride on gastrointestinal smooth muscle.

Cisapride is a new prokinetic agent which can facilitate or restore motility throughout the entire gastrointestinal tract. Although facilitation of acetylcholine release has been suggested, the mechanism of action of cisapride is not clear. To investigate the effect and mechanism of action of cisapride, we used isolated muscle strips (with mucosa and submucosa removed) of guinea pig antrum, ileum and colon to study: (1) the dose response to cisapride, (2) the effect of antagonists (atropine and tetrodotoxin) on the stimulatory effect of cisapride. Besides these studies, we also used 3H-acetylcholine release method to investigate the acetylcholine release effect of cisapride. Cisapride elicited a dose-related enhancement of baseline activity (motility index) on the antrum and contraction on the ileum and colon at the dose of 4, 40 and 400 nM. At higher doses (4 microM) cisapride caused inhibition. This bell-shaped dose response curve suggested that cisapride might be autoinhibitory or that the receptors of cisapride might consist of high affinity stimulatory and low affinity inhibitory sites. The stimulatory responses elicited by cisapride (400 nM) were not significantly inhibited by atropine and tetrodotoxin in the antrum, ileum and colon. This suggested that cisapride might act directly on the smooth muscle. Cisapride (400 nM) evoked a rather small increase of 3H-acetylcholine release on the antrum, ileum and colon. Because the percentage of increase was small and we had demonstrated that the stimulatory effects of cisapride were not blocked by atropine and tetrodotoxin, the acetylcholine release effect of cisapride was considered unimportant.

Acetylcholine↗
PubMed1995

A risk-benefit assessment of cisapride in the treatment of gastrointestinal disorders.

Cisapride is a substituted benzamide compound that stimulates motor activity in all segments of the gastrointestinal tract by enhancing the release of acetylcholine from the enteric nervous system. Cisapride is administered orally in the treatment of gastro-oesophageal reflux disease, functional dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction syndromes and chronic constipation. In gastro-oesophageal reflux disease in both adults and children, cisapride provides symptomatic improvement and mucosal healing. Long term treatment with cisapride is effective in the prevention of relapse of oesophagitis. Cisapride improves gastric emptying rates and improves symptoms in patients with gastroparesis of various origins. Unlike domperidone and metoclopramide, long term administration of cisapride seems to result in persistently enhanced gastric emptying. Cisapride is also effective in improving symptoms in patients with functional dyspepsia. In comparative studies in patients with functional dyspepsia, cisapride was at least as effective as metoclopramide, domperidone, clebopride, ranitidine and cimetidine. Cisapride increases stool frequency and reduces laxative consumption in patients with idiopathic constipation. Severe cases of slow transit constipation seem refractory to cisapride. Clinical studies also indicate that cisapride might be effective in the treatment of chronic intestinal pseudo-obstruction, postoperative ileus, peptic ulcer and irritable bowel syndrome. Further clinical studies are warranted to define the role of cisapride in these conditions. The dosage of cisapride ranges from 5mg 3 times daily to 20mg twice daily. Cisapride is generally well tolerated, both during short and long term treatment. In children, cisapride is also well tolerated in doses of 0.2 to 0.3 mg/kg, 3 to 4 times daily.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Ulcer Agents↗
PubMed2000

Drug interactions with cisapride: clinical implications.

Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend avoiding coadministration of cisapride with amiodarone, cimetidine (alternatives are famotidine, nizatidine, ranitidine or one of the proton pump inhibitors), diltiazem and verapamil (the dihydropyridine calcium antagonists are alternatives), grapefruit juice, isoniazid, metronidazole, quinine, quinupristin/dalfopristin and zileuton (montelukast is an alternative). Pharmacodynamic interactions with cisapride involve drugs that have the potential to have additive effects on the QT interval. We do not recommend use of cisapride with class Ia and III antiarrhythmic drugs or with adenosine, bepridil, cyclobenzaprine, droperidol, haloperidol, nifedipine (immediate release), phenothiazine antipsychotics, tricyclic and tetracyclic antidepressants or vasopressin. Vigilance is advised if anthracyclines, cotrimoxazole (trimethoprim-sulfamethoxazole), enflurane, halothane, isoflurane, pentamidine or probucol are used with cisapride. In addition, uncorrected electrolyte disturbances induced by diuretics may increase the risk of torsade de pointes. Patients receiving cisapride should be promptly treated for electrolyte disturbances.

Animals↗
PubMed2003

A comparison of the pharmacokinetics of two dosing regimens of cisapride and their effects on corrected QT interval in premature infants.

OBJECTIVE: To compare the pharmacokinetics of two dosing regimens of cisapride and their effects on QT(c) interval. DESIGN: Thirty-one pre-term infants were enrolled in two neonatal intensive care units. In 16 infants, cisapride was started at 0.2 mg/kg orally every 6 h (group A) and in 15 infants at 0.1 mg/kg orally every 3 h (group B). Electrocardiograms were performed before and after 72 h of treatment to calculate the QT(c) interval according to the Bazett formula. After 72 h of treatment, cisapride and norcisapride trough concentrations, and concentrations 1 h after the next cisapride administration were quantified in serum. A linear regression analysis was performed to analyse the effect of postnatal and postconception age. RESULTS: At the start of cisapride treatment, mean postnatal age was 22.9+/-13.9 days (mean+/-SD) for group A and 23.3+/-15.0 days for group B, and mean postconception age was 34.0+/-1.8 weeks for group A and 33.3+/-0.8 weeks for group B. The QT(c) interval increased equally in both groups (group A: +37+/-20 ms, and group B: + 38+/-25 ms; P=0.9). Mean concentration of cisapride 1 h after administration was, as expected from the dosing regimen, significantly higher in group A than in group B (123.7+/-43.2 ng/ml versus 86.7+/-27.8 ng/ml; P=0.03).The difference in trough concentration was not significant (107.4+/-44.3 ng/ml versus 78.2+/-35.4 ng/ml; P=0.09). There was a positive correlation between QT(c) prolongation and cisapride serum concentration (peak: R(2)=0.20, P=0.015; trough: R(2)=0.24, P=0.008) and an inverse correlation between postnatal age and concentration 1 h after administration concentration of cisapride (R(2)=0.19, P=0.02). No correlation was found for postconception age. CONCLUSION: Postnatal age has an inverse relationship with cisapride serum concentration in premature infants, whereas postconception age is not correlated. The maturation process of the biotransformation system of cisapride during the first weeks of life, triggered by birth, but independent of gestational age at birth can explain this observation. The effect of cisapride on cardiac repolarisation is positively related with the cisapride serum concentration. Administering cisapride every 3 h instead of every 6 h could be advantageous, as it is associated with lower peak cisapride serum concentrations. Further investigations are required to confirm this and its potential clinical benefit on QT(c )and arrhythmia risk.

Age Factors↗
PubMed2001

Red wine-cisapride interaction: comparison with grapefruit juice.

OBJECTIVES: Our objective was to compare the interactions of red wine and grapefruit juice with cisapride. METHODS: The oral pharmacokinetics of cisapride, its norcisapride metabolite, and electrocardiographic QTc interval were determined over a 24-hour period after administration of cisapride 10 mg with 250 mL grapefruit juice, red wine (cabernet sauvignon), or water in a randomized 3-way crossover study in 12 healthy men. RESULTS: The cisapride area under the concentration-time curve (AUC) and the maximum plasma drug concentration after single-dose administration (C(max)) with grapefruit juice were 151% (P <.01) and 168% (P <.001), respectively, of those with water. The increase in cisapride AUC and C(max) was variable among individuals; however, cisapride AUC and C(max) were enhanced by the same proportion. The time to reach maximum concentration after drug administration (t(max)) and the apparent elimination half-life (t((1/2)) for cisapride and the pharmacokinetics of norcisapride were not altered. Norcisapride/cisapride ratios were reduced. Cisapride AUC and C(max) with red wine were 115% (difference not statistically significant) and 107% (difference not statistically significant), respectively, of those with water. The cisapride t(max) was slightly longer. Cisapride t((1/2)) and norcisapride pharmacokinetics were not different. The norcisapride/cisapride ratio at cisapride C(max) was lower. One subject had a doubling in cisapride AUC and C(max) and a decrease in norcisapride/cisapride ratios with red wine and also had the largest interaction with grapefruit juice. QTc interval was unchanged in all treatment groups and individuals. CONCLUSIONS: A single glass of grapefruit juice produced an individual-dependent variable increase in the systemic availability of cisapride by inhibition of intestinal cytochrome P450 3A4 (CYP3A4) activity. The identical volume of red wine caused only minor changes in cisapride pharmacokinetics despite some inhibition of CYP3A4 in most individuals. However, even this amount of red wine may cause a marked interaction similar to that for grapefruit juice in individuals with a preexisting high intestinal CYP3A4 content.

Adult↗
PubMed2000

Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions.

Cisapride is a prokinetic drug that is widely used to facilitate gastrointestinal tract motility. Structurally, cisapride is a substituted piperidinyl benzamide that interacts with 5-hydroxytryptamine-4 receptors and which is largely without central depressant or antidopaminergic side-effects. The aims of this study were to investigate the metabolism of cisapride in human liver microsomes and to determine which cytochrome P-450 (CYP) isoenzyme(s) are involved in cisapride biotransformation. Additionally, the effects of various drugs on the metabolism of cisapride were investigated. The major in vitro metabolite of cisapride was formed by oxidative N-dealkylation at the piperidine nitrogen, leading to the production of norcisapride. By using competitive inhibition data, correlation studies and heterologous expression systems, it was demonstrated that CYP3A4 was the major CYP involved. CYP2A6 also contributed to the metabolism of cisapride, albeit to a much lesser extent. The mean apparent K(m) against cisapride was 8.6+/-3.5 microM (n = 3). The peak plasma levels of cisapride under normal clinical practice are approximately 0.17 microM; therefore it is unlikely that cisapride would inhibit the metabolism of co-administered drugs. In this in vitro study the inhibitory effects of 44 drugs were tested for any effect on cisapride biotransformation. In conclusion, 34 of the drugs are unlikely to have a clinically relevant interaction; however, the antidepressant nefazodone, the macrolide antibiotic troleandomycin, the HIV-1 protease inhibitors ritonavir and indinavir and the calcium channel blocker mibefradil inhibited the metabolism of cisapride and these interactions are likely to be of clinical relevance. Furthermore, the antimycotics ketoconazole, miconazole, hydroxy-itraconazole, itraconazole and fluconazole, when administered orally or intravenously, would inhibit cisapride metabolism.

Anti-Ulcer Agents↗
PubMed2001

Cisapride plasma levels and corrected QT interval in infants undergoing routine polysomnography.

BACKGROUND: Reported QTc prolongation associated with cardiac arrhythmia in a small number of children undergoing cisapride therapy and lack of pharmacokinetic correlation provided the impetus for this prospective study. The authors evaluated the relation between cisapride plasma concentrations, the electrocardiographic QT interval, and cardiac rhythm in infants undergoing routine 8-hour polysomnography. METHODS: A total of 211 infants were enrolled: 84 (17 born prematurely) undergoing cisapride therapy for at least 4 days for suspected gastroesophageal reflux and 127 controls (10 born prematurely), aged between 1 week and 13.5 months. Infants underwent continuous bipolar limb lead I recording during routine 8-hour polysomnography. QT intervals and heart rate were measured at hourly intervals. The morning after polysomnography, 12-lead electrocardiography was performed (1 hour after cisapride administration). Cisapride plasma concentrations were determined immediately before and 1 to 2 hours after administration. Serum electrolyte concentrations were measured. RESULTS: The administered cisapride dose ranged from 0.35 to 1.55 (mean, 0.81, median 0.79) mg. kg-1. d-1. Cisapride plasma concentrations were significantly higher in infants younger than 3 months of age. Cisapride-treated infants younger than 3 months of age had longer QTc intervals compared with age-matched controls. Heart rate was similar for cisapride-treated and control infants. No arrhythmia or atrioventricular conduction abnormalities were observed. CONCLUSIONS: At comparable doses of cisapride and comparable plasma concentrations, the QTc was significantly higher in infants younger than 3 months of age. This confirms age-dependent cisapride pharmacokinetics in the first 10 to 12 weeks strongly correlated with changes in body weight and may also suggest an altered ability of infants younger than 3 months of age to metabolize cisapride. The clinical significance and risk of the increased QTc interval is unclear. Cisapride should be judiciously prescribed in infants younger than the age of 3 months and electrocardiography should be performed before and during therapy.

Age Factors↗
PubMed2001

Stereoselective metabolism of cisapride and enantiomer-enantiomer interaction in human cytochrome P450 enzymes: major role of CYP3A.

Cisapride is a chiral molecule that is marketed as a racemate consisting of two optical isomers, but little is known about its stereoselective metabolism. Studies with (-)-, (+)-, and (+/-)-cisapride were undertaken in human liver microsomes (HLMs) and recombinant cytochrome P450s (P450s) to determine the stereoselective metabolism and enantiomer-enantiomer interaction. Each enantiomer and racemic cisapride were N-dealkylated to norcisapride (NORCIS) and hydroxylated to 3-fluoro-4-hydroxycisapride (3-F-4-OHCIS) and 4-fluoro-2-hydroxycisapride (4-F-2-OHCIS). The kinetics for the formation of NORCIS from (-)-cisapride (Km = 11.9 +/- 4.8 microM; Vmax = 203 +/- 167 pmol/min/mg of protein) or (+)-cisapride (Km = 18.5 +/- 4.7 microM; Vmax = 364 +/- 284 pmol/min/mg of protein) in HLMs exhibited simple Michaelis-Menten kinetics, while a sigmoidal model characterized those of 3-F-4-OHCIS and 4-F-2-OHCIS. In vitro, NORCIS appears to be the major metabolite of both enantiomers. NORCIS and 3-F-4-OHCIS were preferentially formed from (+)-cisapride rather than (-)-cisapride, but that of 4-F-2-OHCIS was the reverse, suggesting regio- and stereoselective metabolism. The formation rate of each metabolite from each enantiomer (20 microM) in 18 HLMs was highly variable (e.g., NORCIS, >35-fold) and correlated with the activity of CYP3A (r = 0.6-0.85; p < 0.05). Coincubation of troleandomycin (50 microM) with cisapride enantiomers (15 microM) in HLMs resulted in potent inhibition of NORCIS formation (by 75-80%), while other inhibitors showed negligible effect. Of 10 recombinant human P450s tested, CYP3A4 catalyzed the formation of NORCIS, 3-F-4-OHCIS, and 4-F-2-OHCIS from each enantiomer and racemic cisapride (15 microM) with the highest specific activity (Km values close to those in HLMs). We noted that the rate of racemic cisapride metabolism by HLMs and recombinant human CYP3A4 is slower compared with equimolar concentrations of each enantiomer. When incubated simultaneously in HLMs, the enantiomers inhibit each other's metabolism. In conclusion, our data demonstrate for the first time the stereoselective metabolism and enantiomer-enantiomer interaction of cisapride. Provided that the potency or the response of the enantiomers differ, understanding the factors that control their disposition as opposed to that of racemic cisapride may better predict adverse drug interactions and the resulting prokinetic efficacy and cardiac safety of cisapride.

Aryl Hydrocarbon Hydroxylases↗
PubMed2000

Contraindicated use of cisapride: impact of food and drug administration regulatory action.

CONTEXT: Cisapride, a gastrointestinal tract promotility agent, can cause life-threatening cardiac arrhythmias in patients susceptible either because of concurrent use of medications that interfere with cisapride metabolism or prolong the QT interval or because of the presence of other diseases that predispose to such arrhythmias. In June 1998, the US Food and Drug Administration (FDA) determined that use of cisapride was contraindicated in such patients and informed practitioners through additions to the boxed warning in the label and a "Dear Health Care Professional" letter sent by the drug's manufacturer. OBJECTIVE: To evaluate the impact of the FDA's 1998 regulatory action regarding contraindicated use of cisapride. DESIGN AND SETTING: Analysis of data for the 1-year periods before (July 1997-June 1998) and after (July 1998-June 1999) the regulatory action from the population-based, pharmacoepidemiology research databases of 2 managed care organizations (sites A and B) and a state Medicaid program (site C). PARTICIPANTS: Patients with at least 180 days of prior enrollment in 1 of the 3 sites who were prescribed cisapride at least once in the period before (n = 24 840) or after (n = 22 459) regulatory action. Patients could be included in both cohorts. MAIN OUTCOME MEASURES: Proportion of cisapride users in each period for whom cisapride use was contraindicated by the product label, based on computerized patient medical encounter records. RESULTS: In the year prior to regulatory action, cisapride use was contraindicated for 26%, 30%, and 60% of users in study sites A, B, and C, respectively. In the year after regulatory action, use was contraindicated for 24%, 28%, and 58% of users, a reduction in contraindicated use of approximately 2 per 100 cisapride users at each site. When the analysis was restricted to new users of cisapride after regulatory action, only minor reductions in contraindicated use were found. CONCLUSION: The FDA's 1998 regulatory action regarding cisapride use had no material effect on contraindicated cisapride use. More effective ways to communicate new information about drug safety are needed.

Cisapride↗