Effects of Cisapride, Buprenorphine, and Their Combination on Gastrointestinal Transit in New Zealand White Rabbits.

Due to their effective analgesic properties, opioids are worthy of consideration for pain management in rabbits. However, this class of drugs causes undesirable effects including reduced gastrointestinal (GI) motility, reduced fecal output, and delays GI transit times and thus increases the risk of GI stasis. The risk of stasis discourages the use of opioids in rabbits, which could affect animal welfare. Gastroprokinetic agents such as cisapride are effective in promoting gastric emptying in many species, but whether this effect occurs in rabbits is unknown. This study assessed the efficacy of cisapride when administered as a single agent and in combination with buprenorphine in rabbits; efficacy was assessed by measuring GI transit times, fecal output, body weight, and food and water intake. Female New Zealand White rabbits (n = 10) were studied in a crossover, randomized design and received either vehicle and buprenorphine, cisapride and saline, cisapride and buprenorphine, or vehicle and saline (control) every 8 h for 2 d. Rabbits were anesthetized and administered radio-opaque, barium-filled spheres via orogastric tube. Feces was assessed via radiography for detection of the barium-spheres to determine GI transit time. GI transit time was significantly longer in buprenorphine groups than in control groups, regardless of the use of cisapride. Fecal output and food and water intake were lower for buprenorphine groups than control groups. Cisapride did not significantly alter GI transit, fecal output, or food and water intake. In addition, treatment group did not significantly affect body weight. In conclusion, buprenorphine treatment (0.03 mg/kg TID) prolonged GI transit time and reduced fecal output and food and water consumption in rabbits. Coadministration of buprenorphine and cisapride (0.5 mg/kg) did not ameliorate these effects, and the administration of cisapride at this dose did not appear to affect GI motility in female rabbits.

Thorough QT/QTc Study Shows That a Novel 5-HT4 Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation.

Minesapride (drug code: DSP-6952) is a potential gastrointestinal prokinetic agent with high selectivity for 5-hydroxytryptamine 4 (5-HT4 ) receptor that acts as a partial agonist. Although 5-HT4 receptor agonists are expected to show efficacy in patients with irritable bowel syndrome with constipation, only tegaserod is available for female patients, with limitations, in the United States. Previously, another 5-HT4 receptor agonist, cisapride, was widely used for the treatment of upper gastrointestinal diseases, but was withdrawn from the market because of arrhythmia with QT prolongation. Chemically, benzamide is one of the most common structures among 5-HT4 receptor agonists. Some benzamide derivatives, such as cisapride, are responsible for QT prolongation, while some, such as mosapride, are not. Thus, we planned a thorough QT/QTc study to investigate the effects of minesapride, a newly designed benzamide derivative, on the QT/QTc. This was a randomized, placebo-controlled, 4-arm, 4-period, crossover study conducted in healthy adults, with administration of single oral doses of minesapride (40 mg and 120 mg), placebo, and moxifloxacin in the fasted state. Minesapride and placebo were administered in a double-blind fashion, while the positive control moxifloxacin was administered in an open-label fashion. Japanese subjects (48 total: 24 males and 24 females) were randomized, and 47 subjects completed all treatment periods. A review of other electrocardiographic data revealed that neither therapeutic (40 mg) nor supratherapeutic (120 mg) doses of minesapride were associated with increased risk of prolonged QT interval.

Systematic review and meta-analysis of traditional Chinese medicine in the treatment of constipation-predominant irritable bowel syndrome.

AIM: This meta-analysis analyzed the efficacy and safety of traditional Chinese medicine (TCM) for the treatment of irritable bowel syndrome with constipation (IBS-C). METHODS: We searched seven electronic databases for randomized controlled trials investigating the efficacy of TCM in the treatment of IBS-C. The search period was from inception to June 1, 2017. Eligible RCTs compared TCM with cisapride and mosapride. Article quality was evaluated with the Cochrane Risk Bias Tool in the Cochrane Handbook by two independent reviewers. Begg's test was performed to evaluate publication bias. Review Manager 5.3 and Stata 12.0 were used for analyses. RESULTS: Eleven eligible studies comprising a total of 906 participants were identified. In the primary outcome, TCM showed significant improvement in overall clinical efficacy compared with cisapride and mosapride (odds ratio [OR] = 4.00; 95% confidence interval [CI]: 2.74,5.84; P < 0.00001). In terms of secondary outcomes, TCM significantly alleviated abdominal pain (OR = 5.69; 95% CI: 2.35, 13.78; P = 0.0001), defecation frequency (OR = 4.38; 95% CI: 1.93, 9.93. P = 0.0004), and stool form (OR = 4.96; 95% CI: 2.11, 11.65; P = 0.0002) in the treatment group as compared to the control group. A lower recurrence rate was associated with TCM as compared to cisapride and mosapride (OR = 0.15; 95% CI: 0.08, 0.27; P < 0.00001). No adverse effects were observed during TCM treatment. CONCLUSIONS: TCM showed greater improvement in terms of clinical efficacy in the treatment of IBS-C than cisapride and mosapride, although it was not possible to draw a definitive conclusion due to the small sample size, high risk, and low quality of the studies. Large multi-center and long-term high-quality randomized control trials are needed.

High-resolution manometric evaluation of the effects of cisapride on the esophagus during administration of solid and liquid boluses in awake healthy dogs.

OBJECTIVE To validate the use of high-resolution manometry (HRM) in awake, healthy dogs and compare the effects of bolus type (liquid vs solid) and drug treatment (saline [0.9% NaCl] solution [SS] vs cisapride) on esophageal pressure profiles. ANIMALS 8 healthy dogs. PROCEDURES In a crossover study, each dog received SS (10 mL) IV, and HRM was performed during oral administration of 10 boluses (5 mL each) of water or 10 boluses (5 g each) of canned food. Cisapride (1 mg/kg in 60 mL of SS) was subsequently administered IV to 7 dogs; HRM and bolus administration procedures were repeated. Two to 4 weeks later, HRM was repeated following administration of SS and water and food boluses in 4 dogs. Pressure profile data were obtained for all swallows, and 11 outcome variables were statistically analyzed. RESULTS After SS administration, predicted means for the esophageal contractile integral were 850.4 cm/mm Hg/s for food boluses and 660.3 cm/mm Hg/s for water boluses. Predicted means for esophageal contraction front velocity were 6.2 cm/s for water boluses and 5.6 cm/s for food boluses after SS administration. Predicted means for residual LES pressure were significantly higher following cisapride administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that HRM was feasible and repeatable in awake healthy dogs of various breeds and sizes. Stronger esophageal contractions and faster esophageal contraction velocity occurred during solid bolus and liquid bolus swallows, respectively. Lower esophageal sphincter pressure increased significantly following cisapride administration. Esophageal contractions and bolus transit latency should be further evaluated by HRM in clinically dysphagic dogs.

High-resolution manometric evaluation of the effects of cisapride and metoclopramide hydrochloride administered orally on lower esophageal sphincter pressure in awake dogs.

OBJECTIVE: To evaluate the effects of cisapride and metoclopramide hydrochloride administered orally on the lower esophageal sphincter (LES) resting pressure in awake healthy dogs. ANIMALS: 6 adult Beagles. PROCEDURES: Each dog was evaluated after administration of a single dose of cisapride (0.5 mg/kg), metoclopramide (0.5 mg/kg), or placebo (empty gelatin-free capsule) in 3 experiments performed at 3-week intervals. To measure LES pressure, a high-resolution manometry catheter equipped with 40 pressure sensors spaced 10 mm apart was used. For each experiment, LES pressure was recorded during a 20-minute period with a virtual electronic sleeve emulation before treatment (baseline) and at 1, 4, and 7 hours after drug or placebo administration. A linear mixed-effects model was used to test whether the 3 treatments affected LES pressure differently. RESULTS: In the cisapride, metoclopramide, and placebo experiments, median baseline LES pressures were 29.1, 30.5, and 29.0 mm Hg, respectively. For the cisapride, metoclopramide, and placebo treatments, median LES pressures at 1 hour after administration were 44.4, 37.8, and 36.6 mm Hg, respectively; median LES pressures at 4 hours after administration were 50.7, 30.6, and 31.1 mm Hg, respectively; and median LES pressures at 7 hours after administration were 44.3, 28.5, and 33.3 mm Hg, respectively. The LES pressures differed significantly only between the placebo and cisapride treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that orally administered cisapride may be of benefit in canine patients for which an increase in LES pressure is desirable, whereas orally administered metoclopramide did not affect LES resting pressures in dogs.

Clinical recovery of chronic intestinal pseudo-obstruction with cisapride in a complex pediatric patient.

Cisapride is a gastrointestinal prokinetic that facilitates or restores motility along the entire gastrointestinal tract. It has been used successfully to treat acute and chronic intestinal pseudo-obstructions (CIPs) in adults, but there is a paucity of literature surrounding the treatment of CIP in pediatric patients and therapies for CIP are limited and their impact is often unsatisfactory. This case report presents the use of cisapride in the management of pseudo-obstruction. Treatment with cisapride substantially improved the patient's symptoms and improved feeding tolerance. It improved his prognosis remarkably and prevented the need for end-of-life care. He experienced no adverse effects throughout the course of therapy. The treatment regimen is discussed in this case report.

Impact of amiodarone and cisapride on simulated human ventricular electrophysiology and electrocardiograms.

AIMS: Amiodarone and cisapride are both known to prolong the QT interval, yet the two drugs have different effects on arrhythmia. Cisapride can cause torsades de pointes while amiodarone is found to be anti-arrhythmic. A computational model was used to investigate the action of these two drugs. METHODS AND RESULTS: In a biophysically detailed model, the ion current conductivities affected by both drugs were reduced in order to simulate the pharmacological effects in healthy and ischaemic cells. Furthermore, restitution curves of the action potential duration (APD), effective refractory period, conduction velocity, wavelength, and the vulnerable window were determined in a one-dimensional (1D) tissue strand. Moreover, cardiac excitation propagation was computed in a 3D model of healthy ventricles. The corresponding body surface potentials were calculated and standard 12-lead electrocardiograms were derived. Both cisapride and amiodarone caused a prolongation of the QT interval and the refractory period. However, cisapride did not significantly alter the conduction-related properties, such as e.g. the wavelength or vulnerable window, whereas amiodarone had a larger impact on them. It slightly flattened the APD restitution slope and furthermore reduced the conduction velocity and wavelength. CONCLUSION: Both drugs show similar prolongation of the QT interval, although they present different electrophysiological properties in the single-cell as well as in tissue simulations of cardiac excitation propagation. These computer simulations help to better understand the underlying mechanisms responsible for the initiation or termination of arrhythmias caused by amiodarone and cisapride.

A case of chronic intestinal pseudo-obstruction secondary to primary visceral myopathy.

BACKGROUND: A 13-year-old girl presented to the emergency room at her local hospital with an acute onset of vomiting, severe abdominal pain and distension. There was evidence of small-bowel obstruction on plain abdominal x-ray. Throughout the girl's adolescent years she was admitted to hospital numerous times for recurrent abdominal symptoms and underwent multiple sequential laparotomies. She had marked weight loss and a poor quality of life. The patient's symptoms were initially managed with intravenous fluids, bowel rest, and nasogastric decompression of the upper gut. INVESTIGATIONS: Peripheral blood tests with biochemistry and measurement of serum folate, vitamin B(12), albumin, 25-hydroxyvitamin D, inflammatory markers, autoantibodies and thyroid function; gastrointestinal imaging (plain abdominal x-ray, small-bowel series, colonic transit study, and abdominal CT with oral contrast); MRI of the brain and lumbar puncture; upper endoscopy; and laparotomy with sero-muscular biopsy of the small bowel. DIAGNOSIS: Chronic intestinal pseudo-obstruction secondary to primary visceral myopathy. MANAGEMENT: Prokinetic agents including oral cisapride and tegaserod, a venting gastrostomy, and total parenteral feeding.

Cisapride and ventricular arrhythmia.

AIMS: We aimed to examine the association between cisapride and ventricular arrhythmia, and examine the relationship to dose and CYP3A4 inhibitors. METHODS: A nested case-control study was conducted in Medicaid beneficiaries exposed to cisapride, metoclopramide or a proton pump inhibitor (PPI) from 1999 to 2000. Cases were hospitalized with a principal International Classification of Diseases-9 code indicating sudden cardiac death or ventricular arrhythmia. Controls had at least as much event-free person time following the study prescription as its matched case. RESULTS: A total of 145 cases and 7250 controls were identified. The unadjusted rate ratio for cisapride vs. PPIs was 1.49 (95% confidence interval 0.96, 2.25). The adjusted odds ratio (OR) for cisapride vs. PPIs was 2.10 (1.34, 3.28). Excluding persons in managed care, the adjusted OR for cisapride was 2.92 (1.55, 5.49). In the initial prescription period, the adjusted OR for cisapride vs. PPIs was 7.85 (1.95, 31.60). Non-arrhythmogenic CYP3A4 inhibitors were not associated with an increased risk in users of cisapride or PPI inhibitors. The OR for potentially arrhythmogenic CYP3A4 inhibitors was 3.79 (1.76, 8.15) in cisapride users and 3.47 (2.06, 5.83) in PPI users. CONCLUSIONS: Cisapride was associated with a doubling to tripling of the risk of hospitalization for ventricular arrhythmia, and a nearly eightfold risk in the initial prescription period. Although use of potentially arrhythmogenic CYP3A4 inhibitors was associated with an increased risk, this appears to be due to a direct effect of the drugs themselves rather than an interaction with cisapride.

Diagnostic codes for sudden cardiac death and ventricular arrhythmia functioned poorly to identify outpatient events in EPIC's General Practice Research Database.

PURPOSE: To examine the validity of OXMIS/Read diagnoses of hospitalization for sudden cardiac death and ventricular arrhythmia (SD/VA) for use in studies of arrhythmogenic effects of outpatient medications in the General Practice Research Database (GPRD). METHODS: We identified putative occurrences of hospitalization for SD/VA in patients receiving outpatient prescriptions for cisapride, domperidone, or metoclopramide. We then administered a questionnaire to general practitioners (GPs) caring for these patients, requested hospital discharge consult letters, and examined the positive predictive value (PPV) of diagnostic codes in identifying outpatient events precipitating hospitalization. RESULTS: We identified 84 putative events, 38 (45%) of which occurred in patients cared for by GPs participating in the follow-up scheme. Thirty of 38 questionnaires (79%) were completed. The PPV for the occurrence of any SD/VA was 93% (95% CI, 78-99%). However, the PPV for SD/VA occurrence in an outpatient setting precipitating a hospitalization was only 23% (95% CI, 10-42%). The majority of inpatient diagnostic codes reflected events occurring after hospital admission, not precipitating it. CONCLUSIONS: While computerized codes for SD/VA agreed well with physician diagnosis, they operated poorly to identify events occurring in an outpatient setting. Studies of SD/VA in the GPRD should verify events on a case-by-case basis.

The in vivo gastrointestinal activity of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity.

The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity, was compared to that of the clinically studied gastrointestinal pro-kinetic agents, tegaserod, cisapride and mosapride. The activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT(4) receptor agonist, TD-5108, demonstrates robust in vivo activity in the guinea pig, rat and dog gastrointestinal tracts.

Oral mitemcinal (GM-611), an erythromycin-derived prokinetic, accelerates normal and experimentally delayed gastric emptying in conscious dogs.

1. We examined effects of orally administered mitemcinal, an erythromycin-derived motilin agonist, on gastric emptying and antroduodenal motility in conscious normal dogs and conscious dogs with experimentally delayed gastric emptying. For comparison, we also examined the effects of orally administered cisapride. 2. Gastric emptying was assessed by adding paracetamol to the test meal and determining three of its pharmacokinetic parameters as indices of gastric emptying. Antroduodenal motility was assessed from the output of force transducers chronically implanted in the gastric antrum and duodenum. 3. In normal dogs, mitemcinal (0.25, 0.5 and 1 mg/kg) dose-dependently accelerated gastric emptying, significantly increasing all three indices at doses of 0.5 and 1 mg/kg; cisapride (1, 3 and 10 mg/kg) had no significant effect. Mitemcinal also dose-dependently stimulated antroduodenal motility in the interdigestive and digestive states. Cisapride, at 100-fold the dose, produced similar effects in the interdigestive state, but mixed results in the digestive state. 4. In dogs with delayed gastric emptying induced by subcutaneous clonidine (0.03 mg/kg), mitemcinal (0.25, 0.5 and 1 mg/kg) dose-dependently improved delayed gastric emptying, significantly increasing two of three indices at a dose of 1 mg/kg. Cisapride (1, 3 and 10 mg/kg) caused non-significant increases in the indices of gastric emptying, with roughly bell-shaped dose-response curves. The highest dose of mitemcinal (1 mg/kg) also stimulated antroduodenal motility. 5. In dogs with delayed gastric emptying induced by vagotomy, mitemcinal (0.125, 0.25 and 0.5 mg/kg) dose-dependently improved delayed gastric emptying, significantly increasing all three indices at doses of 0.25 and 0.5 mg/kg. Cisapride (3 mg/kg) restored the indices to roughly prevagotomy levels, but none of the increases was significant. Mitemcinal, at a dose of 0.25 mg/kg, also stimulated antroduodenal motility. 6. Because delayed gastric emptying is the basic characteristic of gastroparesis, the fact that mitemcinal accelerated gastric emptying in dogs with normal and delayed gastric emptying much more robustly than cisapride adds to the evidence that mitemcinal is likely to be useful for the treatment of patients with gastroparesis.

Effects of oral mitemcinal (GM-611), erythromycin, EM-574 and cisapride on gastric emptying in conscious rhesus monkeys.

We assessed and compared the effects of oral mitemcinal (an orally active, erythromycin-derived motilin-receptor agonist; Code name: GM-611), erythromycin, EM-574 and cisapride on gastric emptying in conscious Rhesus monkeys using the acetaminophen method. Mitemcinal and erythromycin induced significant, dose-dependent increases in indices of gastric emptying, but mitemcinal required a much lower dose for the same effect. Cisapride induced a bell-shaped dose response, and EM-574, a potent erythromycin derivative and originally developed as an enteric coated formulation, had little effect when it was given orally uncoated. Since our previous study showed that response to motilin is similar in Rhesus monkeys and humans, these results suggest that oral mitemcinal may be effective for the treatment of symptoms in human disorders related to delayed gastric emptying (e.g., functional dyspepsia and gastroparesis). Combined with the results of other studies, these results suggest that mitemcinal may be able to replace the withdrawn drug, cisapride, as the drug of choice for treating delayed gastric emptying.

The 5-HT(4) agonists cisapride, mosapride, and CJ-033466, a Novel potent compound, exhibit different human ether-a-go-go-related gene (hERG)-blocking activities.

The blocking effect of three 5-HT(4) agonists, cisapride, mosapride, and the newly discovered CJ-033466 on the human ether-a-go-go-related gene (hERG) channel was studied using a whole cell patch-clamp technique in HEK293 cells. Cisapride was found to be the most potent of the hERG blockers. CJ-033466 had the widest safety margin between its hERG blocking activity and 5-HT(4) agonism among the tested compounds. This suggests a lower clinical risk of cardiac arrhythmia in CJ-033466 compared with the other 2 agonists. Therefore, CJ-033466 has the potential to be a drug with higher therapeutic efficacy and less cardiac risk than both cisapride and mosapride.

Comparison of the QT interval response during sinus and paced rhythm in conscious and anesthetized beagle dogs.

INTRODUCTION: The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different pharmacological and pharmacokinetic profiles. METHOD: Dofetilide and moxifloxacin were tested in all models, whereas cisapride and terfenadine were tested in the conscious telemetered and paced models. All substances were given as two consecutive 1.5-h intravenous infusions (infusions 1 and 2). The individual concentration-time courses of dofetilide, moxifloxacin, and cisapride were linked to the drug-induced effects on the QT interval and described with a pharmacokinetic-pharmacodynamic model to obtain an estimate of the unbound plasma concentrations at steady state that give a 10- and 20-ms drug-induced QT interval prolongation (CE10ms and CE20ms). RESULTS: In the conscious telemetered, conscious paced, and anesthetized dog models, the mean CE10ms values were 1.4, 4.0, and 2.5 nM for dofetilide and 1300, 1800, and 12,200 nM for moxifloxacin. For cisapride, the CE10ms values were 8.0 and 4.4 nM in the conscious telemetered and conscious paced dog models. The drug-induced QT interval prolongation during the last 30 min of infusions 1 and 2 was comparable in the conscious models, but smaller in the anesthetized dog model. Terfenadine displayed a marked delay in onset of response, which could only be detected by the extended ECG recording. DISCUSSION: All dog models investigated detected QT interval prolongation after administration of the investigated test substances with similar sensitivity, except for a lower sensitivity in the anesthetized dogs following moxifloxacin administration. The conscious telemetered dog model was favorable, mainly due to the extended continuous ECG recording, which facilitated detection and quantification of delayed temporal differences between systemic exposure and drug-induced QT interval prolongation.

Evaluation of the guinea pig monophasic action potential (MAP) assay in predicting drug-induced delay of ventricular repolarisation using 12 clinically documented drugs.

INTRODUCTION: While the dog in vivo model is commonly employed in the later phase of discovery for assessing drug-induced QT prolongation, an early screening assay is valuable when selecting compounds for further development and when compound availability usually is low. One such screening assay is the anaesthetised guinea pig monophasic action potential (MAP) model. The aim of the present study was to evaluate the ability of this model to detect proarrhythmic properties by testing a set of reference compounds with known clinical profile. Moreover, these results were compared to data previously obtained using in vivo canine QT assays (QT PRODACT study). METHODS: Anaesthetised and ventilated male guinea pigs were vagotomised and pretreated with propranolol. After thoracotomy, a pacing electrode was clipped to the left atrial appendage and a suction MAP electrode positioned on the left ventricular epicardium. The drug or corresponding vehicle was injected intravenously in cumulative doses and MAP duration at 90% repolarisation (MAPD90) was recorded during cardiac pacing. RESULTS: The 8 drugs known to be proarrhythmic in the clinic all displayed dose-dependent prolongation of MAPD90, while the 4 drugs devoid of dysrhythmia in man had no effect. When comparing doses producing a 10% MAPD90 increase with doses reported to increase QTc by 10% in dogs a strong correlation was seen (R(2) 0.94 and 0.58 for anaesthetised and conscious dogs, respectively). DISCUSSION: The guinea pig MAP assay identified all clinically positive drugs while negative drugs were without effect on ventricular repolarisation. Furthermore, a good concurrence is shown between the guinea pig and dog models in identifying compounds with proarrhythmic properties. Overall, the study reinforces the anaesthetised guinea pig MAP model as a reliable assay predicting QT liability of new chemical entities and as a highly sensitive early screening model for cardiovascular risk.

[Therapeutic innovations in gastroesophageal reflux]. / Nouveautés thérapeutiques dans le reflux gastro-oesophagien.

Proton-pump inhibitors remain the most effective treatment for relieving symptoms, healing lesions and preventing recurrences of gastroesophageal reflux (GER). Drugs inhibiting transient relaxation of the lower esophageal sphincter have an unfavorable benefit/risk ratio. Endoscopic methods developed in recent years have not been shown effective in trials versus sham procedures. Surgical treatment is effective in GER but causes frequent uncomfortable side effects that are difficult to treat.

Usage of the claim database of national health insurance programme for analysis of cisapride-erythromycin co-medication in Taiwan.

PURPOSE: This study aimed to use the National Health Insurance Research Database, Taiwan for risk analysis of concomitant use of cisapride and erythromycin. METHODS: The sample consisted of subjects identified in the Outpatient Sampling Database (OSD) and Longitudinal Health Insurance Database 2000 (LHID 2000), derived from the original claim data of the National Health Insurance Research Database, Taiwan. RESULTS: According to the LHID 2000, a total of 464 individuals experienced 685 episodes of cisapride-erythromycin co-medication prescribed by 295 physicians, revealing a prevalence of 4.5% concomitant use, with higher prevalence in clinics (9.2%) than in other medical institutes (3.7-5.4%). Among the co-medication episodes, 81.9% and 61.2% were prescribed from the same health institutes and by the same physicians, respectively. No medical record of cardiac arrhythmias was found among these patients in 2001 and 2002, probably due to the fact that 78.9% of the 464 individuals were under age 16, 84.0% had short exposure duration (1-4 days) and 98.0% of the episodes were prescribed with a cisapride dose of less than 0.8 mg/kg/day. CONCLUSIONS: Findings from this study suggest that there exists an urgent need for accreditation in terms of pharmacovigilance of clinical sites and their practicing physicians for the prevention of irrational concomitant prescription in Taiwan. Our findings also indicate that it is necessary to investigate other possible conditions of potentially dangerous co-medication in Taiwan and other developing countries.