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Cisapride Therapy for Gastrointestinal Disease

1996; Lippincott Williams & Wilkins; Volume: 22; Issue: 3 Linguagem: Inglês

10.1097/00005176-199604000-00007

1536-4801

Salvatore Cucchiara,

Helicobacter pylori-related gastroenterology studies

Gastrointestinal motility consists of highly coordinated neuromuscular processes, responsible for propagation of intraluminal contents through the gut (1-3). The complexity of the control of gastrointestinal motility has made the development of therapeutic agents for patients with motility disorders a substantial challenge. The most commonly employed agents for treating these patients are the prokinetics, which are drugs facilitating the transit of material through the digestive system (4). The prokinetic agents can be divided into four subclasses according to the mechanism of action: drugs with direct cholinergic activity; drugs with pronounced antidopaminergic properties; drugs that are agonists at neural 5-HT4 receptors; and drugs acting through gastrointestinal motilin receptors. This article focuses on cisapride, a relatively new prokinetic drug, and reviews its effects on gastrointestinal motility and its role in clinical practice. MECHANISMS OF ACTION Cisapride is a substituted piperinidyl benzamide chemically related to metoclopramide (Fig. 1) and devoid of antidopaminergic or direct cholinomimetic effects, which are characteristic of the previously developed substituted benzamides (5). Cisapride promotes motor activity at all levels of the gastro-intestinal tract. It increases the amplitude of the lower esophageal sphincter and esophageal body peristalsis and the force and incidence of gastric and antral contractions, it improves antroduodenal coordination to enhance gastric emptying, and it stimulates small-intestinal and colonic propulsion (6). Cisapride causes the release of acetylcholine from enteric neurons by stimulating a subpopulation of neural serotonin receptors (7). Early studies suggested that the prokinetic effect of cisapride might be due to antagonism of 5-HT3 receptors (8). However, other known 5-HT3 antagonists have relatively little effect on motor activity and propulsion along the gastrointestinal tract (8). Experimental studies in guinea pig ileum and colon have shown that cisapride activity is mainly mediated via 5-HT4 receptors and that acetylcholine release from varicosities on motor neurons of the myenteric plexus is promoted (9). As acetylcholine is the final mediator of the stimulating effects of cisapride, the latter can be blocked by atropine and other antimuscarinic drugs (8). Experimental studies have shown that cisapride enhances the amplitude of fast nicotinic excitatory postsynaptic potentials (EPSPs), which are components of the synaptic events in the enteric microcircuits (10). The effects of cisapride on the fast EPSPs can be antagonized by ICS 205-930, which blocks 5-HT4 receptors, but not by ondansetron, a 5-HT3 receptor antagonist (11). Fast EPSPs are responsible for rapid transfer and transformation of coded signals between elements of the integrated neural circuits and are mediated by acetylcholine acting at nicotinic-cholinergic postsynaptic receptors (11). There is experimental evidence that cisapride enhances the amplitude of nicotinic fast EPSPs by increasing nicotinic ganglionic transmission (12). Several experiments in animals clarified both the drug's mechanism of action and the contractile patterns evoked by its administration. Studies on smooth-muscle circular strips of the feline have shown that cisapride enhances the amplitude of electrically induced contractions in a dose-dependent fashion; pretreatment with tetrodotoxin or atropine abolishes this effect (13). In guinea pig gastroduodenal preparations and in conscious dogs, cisapride increases both the amplitude of antral motor waves and the number of antral waves followed by phasic doudenal activity. This combination results in an increased rate of gastric emptying of liquid and solid meals (5,14). In fasted dogs, intravenous cisapride stimulates motor activity of the upper-gastrointestinal tract and elicits contractile patterns similar to those recorded during the inter-digestive period, even though cisapride-induced contractions do not always migrate aborally through the small intestine (15,16). In the fed state, cisapride increases the amplitude of contractions and their length of spread along the small intestine (16). Cisapride has also been shown to induce tonic contractions of guinea pig right colon (13) and to enhance in conscious dogs ileocolonic motility and colonic transit (17,18). PHARMACOKINETICS Almost all the pharmacokinetic data are related to adults. There are few data on the pharmacokinetics of cisapride on children; nevertheless, there are no reasons to expect great differences from adults. After oral administration to human subjects, cisapride is almost completely absorbed, and only 4-6% of the oral dose is detected in stools. Peak plasma levels are reached within 2 h, and the absorbed dose is proportional to the amount administered. Steady-state plasma concentrations after multiple oral dosing are reached within 2-3 days. Absorption may be postponed or decreased because of delayed gastric emptying. Ingestion of cisapride 15 min before meals does not change the rate of absorption but increases the total amount absorbed. Under these conditions, the systemic availability of the drug is significantly higher (≈30%) than when the meal is given 2 h after administration of cisapride (19). Hypochlorhydria induced by H2 receptor antagonists in fasting subjects results in reduced systemic bioavailability of cisapride; however, the bioavailability is restored if cisapride is given 15 min before meals. Thus, cisapride should be given 15 min before meals to ensure optimal absorption under all conditions of gastric acidity. Cisapride is extensively bound (98%) to plasma protein, and albumin is the main binding protein. It undergoes an extensive metabolism by N-dealkylation and aromatic hydroxylation, metabolites have negligible pharmacologic activity compared with the parent compound and are excreted in the urine and feces. The drug has a half-life of 7-10 h, which is prolonged in elderly subjects and in those with impaired liver function (20). After intramuscular dosing, absorption is rapid and complete, and peak concentrations in the plasma are reached within 10-30 min. After rectal administration, there is a rapid rise in plasma concentration, and absorption is sustained over ≥8 h. The recommended oral dose in infants and children is 0.1-0.3 mg/kg every 6-8 h (suspension); the adult dose of 10 mg three times a day should not be exceeded. Because a liquid preparation of cisapride is not currently available in the United States, recently an extemporaneously prepared cisapride suspension from crushed tablets has been proposed for infants and patients unable to swallow the tablets (21). This extemporaneous suspension is formulated with propylene glycol to enhance solubility and is buffered with sodium bicarbonate to give a pH between 6.5 and 7.5; this formulation has been shown to be stable for 3 weeks. At a daily dose of 30 mg in adults, cisapride has no effect on microsomal liver enzymes; however, enhanced gastrointestinal motility due to cisapride may accelerate the absorption rate of other substances, such as diazepam, cimetidine, acetaminophen, alcohol, and oral anticoagulants. Excretion of cisapride into breast milk is very limited (≈0.1% of the original dose), and maternal ingestion of the drug is unlikely to affect the nursing infant. EFFECTS ON THE ESOPHAGUS AND ESOPHAGEAL MOTILITY DISORDERS Studies in children with gastroesophageal reflux (GER) corroborate findings in adult patients. In 14 children (ages 2-38 months) with GER disease, cisapride given intravenously at a dose of 0.15 mg/kg significantly increased lower esophageal sphincter pressure (LESP) and the amplitude and duration of esophageal peristaltic waves (22); LESP rose 15 min after the infusion, reaching a peak value at 60 min (32.4 ± 10 mm Hg vs. baseline 14.5 ± 3.08, p < 0.01) and remaining significantly elevated through-out a 90-min period. The maximum amplitude of peristaltic waves also occurred at 60 min (67.1 ± 35.7 vs. baseline 39.7 ± 23.7, p < 0.01). The duration of peristaltic waves was also increased by in-travenous cisapride, with the peak occurring 60 min after infusion (3.51 ± 1.09 s vs. baseline 2.8 ± 0.72 s, p < 0.05). While the effects on LESP have been corroborated in many studies, cisapride's effects on esophageal peristalsis are controversial. Depending on testing conditions, an increase in contraction amplitude and duration or no change has been documented (23). Although clinical symptoms and side effects of GER disease depend on acid peptic injury of esophageal mucosa, reflux events occur as a consequence of phasic or prolonged LESP failure, furthermore, defective esophageal peristalsis and delayed gastric emptying can contribute to the development of esophagitis and enhance the incidence and volume of reflux events, respectively. Therefore, cisapride should be efficacious for treating GER disease, since it influences motility variables implicated in the pathogenesis of GER disease (4). A growing body of evidence emphasizes the efficacy of cisapride in the treatment of GER in infants and children, although few data come from well-controlled double-blind studies (see Table 1). When given to infants and toddlers with uncomplicated GER disease for 8 weeks at a dose of 0.3 mg/kg/dose t.i.d., cisapride proved more effective than placebo in relieving symptoms, reducing esophageal acid exposure, and improving esophagitis (24). Good relief of symptoms and a decreased number of prolonged episodes of GER were achieved in 29 infants who participated in a double-blind study of the administration of cisapride (0.2 mg/kg four times daily) for 13-16 days (25). In a controlled study in 14 infants and toddlers with uncomplicated GER, oral cisapride given for 4 weeks both improved symptoms and lessened intraesophageal acid exposure to a greater extent than positioning or dietary measures (22). There are few clinical studies that have compared the effect of cisapride with that of other drugs. Cisapride, given at a dose of 0.8 mg/kg/day for 4 weeks, was as effective as a combination of Gaviscon and Carobel (a thickening agent) in improving both intraesophageal pH variables and clinical symptoms (26). In two double-blind studies, cisapride (0.2-0.6 mg/kg/day) was as effective as the same dose of metoclopramide in improving symptoms of reflux, but cisapride induced a more rapid symptomatic improvement than metoclopramide (27,28). In a double-blind randomized study of 17 infants, cisapride (0.2 mg/kg four times daily) was as effective as cimetidine (5 mg/kg four times daily) in combination with Gaviscon in improving intraesophageal pH scores after 6 weeks (29). Other clinical trials have been conducted to examine the efficacy of cisapride in children with GER disease complicated by chronic pulmonary disease. Cisapride has been shown to be superior to placebo in a double-blind crossover trial in 14 patients with pathologic GER and chronic bronchopulmonary disease (30); the drug, given at a dose of 0.3 mg/kg before the start of pH monitoring, followed by three doses given at 4-h intervals (0.15 mg/kg), was effective in lowering the intraesophageal pH scores both during daytime and nocturnal recording periods. A marked reduction in respiratory symptoms, including bronchospasm and stridor, was seen in concert with the improvement in intraesophageal pH scores (31-33). Vandenplas et al. have evaluated the effect of cisapride (0.2 mg/kg four times daily) in an open trial in 22 infants (4-26 weeks old) affected by GER associated with apnea and sleep disturbances (34). Eight of the patients had had at least one episode of ALTE (apparent life-threatening event). Continuous intraesophageal pH monitoring was performed before and after 13-16 days of treatment with cisapride; reflux parameters declined significantly during treatment, and the disrupted sleep pattern improved significantly or disappeared in all infants. Children with central nervous system (CNS) disease are prone to severe GER disease and require an intensive therapeutic program. A group of seven children with neurodevelopmental abnormalities has been treated with cisapride and compared with a group of infants with GER but no CNS abnormalities who were similarly treated (35). There was no significant change in the parameters measured by pH monitoring and no improvement in gastrointestinal symptoms in the neurologically impaired group, whereas patients with GER alone improved both in the pH variables measurement and in symptoms. Thus, the efficacy of cisapride in treating GER in the neurologically handicapped child has not been established. Studies in adults with erosive esophagitis have shown that a combination of cisapride (10 mg q.i.d. or 20 mg b.i.d.) with H2-receptor antagonists increases the healing rate compared with a combination of cisapride with placebo or to single H2-receptor-antagonist therapy (36-38). Other studies in adults have shown that cisapride (10-20 mg twice daily) prevents the relapse of previously healed reflux esophagitis more effectively than placebo (39-41). The working group on GER of the European Society for Pediatric Gastroenterology and Nutrition recommended the use of cisapride in uncomplicated cases of symptomatic GER in addition to positioning and dietary measures; cisapride was also recommended in combination with H2-receptor blockers for children with moderate to severe esophagitis (42). In conclusion, cisapride is currently the first-line prokinetic agent for patients with reflux disease, whether or not they have esophagitis. However, studies in children are needed that compare cisapride with drugs known to be effective in healing severe esophagitis, such as H2-receptor blockers and proton pump inhibitors. Recently, attention has been drawn to the high prevalence of GER in patients with cystic fibrosis (CF). Several studies have now shown that treatment of CF patients with cisapride has generally been successful in limiting esophageal acid exposure, improving reflux symptoms, and minimizing respiratory complaints (43-46). TREATMENT OF GASTROPARESIS AND GASTRODUODENAL MOTOR DISORDERS Gastroparesis is a motor disorder of the stomach that essentially consists of an impaired transit of intraluminal content from the stomach to the duodenum, without mechanical causes. It can be an idiopathic condition or associated with other diffuse motility disorders (47). Several defects in motility of the antroduodenal region lead to delayed gastric emptying: fed antral hypomotility, disordered antropyloroduodenal coordination, and duodenal phasic activity uncoordinated with antropyloric waves. The rationale behind treating gastric and duodenal motor disorders with cisapride is based on the drug's ability to increase the amplitude of antral contractions and the relationship between antral and pyloroduodenal contractions (48). Gastroduodenal motor disorders and gastroparesis are often present in patients with recurrent symptoms of vomiting, nausea, anorexia, abdominal pain, and early satiety. This clinical syndrome is more commonly described in adults than in children and is known as functional or nonulcer dyspepsia (49). Cisapride is thought to accelerate gastric emptying by increasing both the number and amplitude of antral contractions that propagate into the duodenum (48). By measuring antropyloroduodenal motor activity, it has been shown that patients with gastroparesis had fewer long antropyloroduodenal waves (>6 cm) than controls. After administration of intravenous cisapride, there was an increase in the number of long waves as well as in the gastric emptying rate of solid food (50). A controlled double-blind study in adults with proven gastroparesis showed an acceleration of gastric emptying for both solids and liquids documented by a dual radionuclide technique (51). Interestingly, acceleration of gastric emptying occurred in the proximal portion of the stomach, suggesting that it is an important site of action of cisapride. There are few studies on the use of cisapride in children with gastric or gastroduodenal motor abnormalities. Twelve infants with gastroparesis and abnormal gastroesophageal reflux (age range 3-13 months) were treated with cisapride syrup, given in an open fashion at a dose of 0.3 mg/kg/t.i.d. for 8 weeks. Gastroparesis had been documented by ultrasound scanning of the gastric antrum. Cisapride lessened final gastric emptying time and the antral area at all the various study times; there was also a correlation between the improvement in the gastric motor variables and that in the esophageal exposure acid time (52). Recently, 16 children (age range 3-12 years) with chronic intermittent symptoms of nonulcer dyspepsia underwent both double-blind intravenous and oral treatment with cisapride with monitoring of interdigestive antroduodenal motility, gastric emptying of a liquid meal, and dyspeptic symptoms (53). Intravenous cisapride induced a very active phase-2-like motor pattern at the antroduodenal level, characterized by a greater number and amplitude of contractions and by a high proportion of waves propagated aborally when compared with baseline tracings. At the end of the treatment period, symptoms improved both in the cisapride and in the placebo group; however, patients on cisapride showed a greater decrease in the symptomatic score than the placebo group, and only cisapride resulted in a faster gastric emptying time. Chronic administration of oral cisapride also normalized gastric electrical activity recorded by cutaneous electrogastrography in children affected by gastroparesis and functional dyspepsia (54). In a recent study, 10 children (age range 4-11 years) with functional dyspepsia, gastroparesis, and gastric dysrhythmias were treated for 8 weeks with oral cisapride at a dose of 0.6 mg/kg/day. At the end of the trial there was a marked improvement in dyspeptic symptoms; furthermore, a reduction of gastric emptying time and gastric dysrhythmias was recorded (55). Cisapride normalized gastric electrical activity measured by electrogastrography in patients with juvenile diabetes mellitus (56). However, in some adults with severe refractory gastroparesis stemming from diabetes, cisapride at a dose of 20 mg three times a day significantly accelerated gastric emptying of a solid meal but failed to reduce symptoms (57). A recent study described three children with diabetes and dyspeptic symptoms (nausea, vomiting, chronic abdominal pain, constipation), beginning 1-7 years after diagnosis (58). All three had gastroparesis documented by scintigraphic technique and postprandial antral hypomotility measured by manometric techniques. These patients had considerable difficulty in achieving satisfactory glycemic control. Treatment with cisapride resulted in improvement of dyspeptic symptoms and, in one child, metabolic control. Delayed gastric emptying also occurs commonly in patients with primary anorexia nervosa (59), who often complain of postprandial epigastric fullness and discomfort that can be relieved by spontaneous or self-induced vomiting. Cisapride given to adults with primary anorexia nervosa either by slow intravenous injection (8 mg) or orally (10 mg t.i.d.) improved gastric emptying of a semisolid meal and increased the amplitude of contractions in some studies but not in others (60-62). Thus, there is convincing evidence that cisapride may be efficacious in treatment of several groups of patients with gastroparesis. It appears that cisapride may be beneficial in patients with primitive idiopathic gastroparesis, but there is a need for further studies in patients with gastroparesis due to autonomic neuropathies or systemic disorders or endocrinopathies. However, improvement in motility varibles does not invariably parallel subjective amelioration, as dyspeptic symptoms often arise more from abnormal visceral sensitivity than from abnormal motility patterns (49). CHRONIC INTESTINAL PSEUDOOBSTRUCTION The effects of cisapride on symptoms and gastro-intestinal motility have also been investigated in children with chronic intestinal pseudoobstruction. In an early study, both intravenous and oral cisapride stimulated postprandial amplitude and number of contractions in the proximal duodenum in nine of 13 patients; in two patients with low amplitude waves the drug increased the strength of contractions and permitted discrimination of a typical phase 3 of the interdigestive migrating motor complex (63). However, in a subsequent study in 20 children, the effect of cisapride on gastric emptying of a radiolabeled liquid meal and on gastrointestinal motility was disappointing (64). Cisapride did not influence the discrete, qualitative abnormalities in individual records and did not significantly increase the percentage of propagated duodenal waves. It did increase the postfeeding duodenal motility index, but had no significant effect on the antral motility index. Furthermore, it did not induce phase 3 of the migrating motor complex in patients in whom it was absent during the placebo session. The drug did not improve the marked delay in gastric emptying. A recent retrospective study of a large group of children with chronic intestinal pseudoobstruction has isolated two main variables that predict the therapeutic response to the drug (65). A beneficial response to cisapride was predicted by the presence of migrating motor complexes and postprandial duodenal hypomotility, as well as by the absence of bowel dilatation. Patients with a neuropathic form did better than those with a myopathic form of pseudoobstruction. In children with absent migrating motor complexes, parenteral nutrition was often required in order to maintain adequate nutrition, and cisapride was generally ineffective. Of 49 patients followed, 17 were judged improved, and seven were able to convert from total parenteral nutrition to tube feeding or from tube feeding to oral alimentation. The study supports the notion that a therapeutic response to cisapride can be predicted by a pretrial assessment of radiographic and manometric findings in each patient. The most severe derangement of intestinal motility occurs in chronic intestinal pseudoobstruction, and administration of prokinetic agents is often disappointing. Cisapride is the first prokinetic drug that has shown a consistent efficacy in some patients with intestinal pseudoobstruction, particularly in those in mild to moderate stages of the disorders, characterized by absence of extensive dilatation at radiography, presence of migrating motor complexes at manometry, and absence of findings of autonomic dysfunction (6). Patients with neurogenic pseudoobstruction are usually more responsive to cisapride than those with the myogenic type of the disorder (8). In several cases oral cisapride might not be appreciably absorbed because of severe gastric dilatation and stasis; in these cases the drug may be given through a nasojejunal tube with good absorption (66). In patients on total parenteral nutrition, cisapride administration must be initiated in the absence of acute illness and malnutrition and be coincident with administration of enteral feeding (66). CHRONIC CONSTIPATION Nonorganic constipation usually results from impaired propulsive contractions and transit through the colon or from a disturbed mechanism of defecation at the level of the rectoanal region (67). The latter mechanism predominates in childhood. Cisapride has been shown to produce a marked prokinetic effect on colonic transit in normal subjects (68). The effects of cisapride on colonic motility and scintigraphic transit were studied in 10 constipated adult patients (69). Motility and transit were measured before and after 12 weeks of cisapride administration (80 mg/day). Cisapride improved symptoms in patients who previously had shown a postprandial increase in colonic motility, whereas it was not effective in patients with no significant increase in postprandial colonic motility. A previous report had shown that cisapride could enhance the rectoanal inhibitory reflex by increasing conscious rectal sensation and by lessening rectal compliance (70). It is also possible that cisapride may raise the water content of the stool in the rectum and facilitate defecation as a consequence of a reduced intestinal transit time (71). Table 2 The results of a small number of placebo-controlled studies in patients with chronic functional constipation tend to support a role for cisapride in the treatment of this disorder. In 126 adult patients with chronic idiopathic constipation, the effect of cisapride on stool frequency and laxative intake was studied in a randomized double-blind fashion (72). Cisapride, but not placebo, significantly increased spontaneous stool frequency (p < 0.01), whereas laxative consumption was decreased more by cisapride (p < 0.01) than by placebo (p < 0.05). The most pronounced effect of active treatment was on stool consistency. Other clinical trials in constipated adults support these findings (23,73,74). Twelve children (ages 2-13 years) with functional fecal retention refractory to vigorous use of emollients, enems, and/or laxatives were treated with cisapride at an initial dose of 0.2 mg/kg/dose q.i.d., subsequently adjusted to a maximum of 0.6 mg/kg/dose or 10 mg q.i.d. (75). Cisapride treatment spanned 26-72 weeks (61 ± 12). On therapy, there was no significant change in stool frequency, but five patients reported softer stools while taking the drug. Encopresis ceased in eight of 10 cases, and the number of episodes declined in the other two cases. The effects of cisapride (0.6 mg/kg/day) have also been studied in a double-blind fashion in a group of 20 children (mean age 5.2 years) with functional constipation; stool frequency, total gastrointestinal transit time, and anorectal motility variables were evaluated (76). Cisapride increased stool frequency (p < 0.05) and produced a significant decrease in the volume required to elicit the rectoanal inhibitory reflex, the conscious rectal sensitivity threshold, and the gastrointestinal transit time. Unlike other prokinetic agents, data from several studies suggest that cisapride will be an effective agent in treating patients with functional fecal retention. First-line medical treatment of nonorganic constipation consists of stool softeners given after evacuation of the rectal fecal masses through enemas. Cisapride may be used if constipation is poorly responsive to high doses of stool softeners and may be of value in reducing laxative use; however, clinical efficacy of the drug in constipation due to neurogenic dysmotility of the colon is uncertain. Furthermore, colonic motility patterns that are responsive to the administration of cisapride have not yet been defined in constipated patients. MISCELLANEOUS INDICATIONS In a double-blind placebo-controlled crossover trial, the effect of a 6-month trial of cisapride was studied in 17 patients with CF (77). Cisapride was more effective than placebo in reducing flatulence (p < 0.005) and fullness and nausea (p < 0.05). During cisapride treatment, physicians judged 11 patients to be improved. However, no significant differences between cisapride and placebo periods was found in patients' nutritional status, radiography scores, pulmonary function, food intake, stool size and consistency, and loss of fecal fat. Cisapride may be effective in treating postoperative paralytic ileus (78). Forty adult patients undergoing cholecystectomy were given either intravenous cisapride or placebo on the day of surgery, and the dose was repeated every 12 h until the third postoperative day. Cisapride induced earlier reappearance of normal motility in the colon, as judged by the movement of radioopaque markers. The study did not address whether the length of hospital stay was shortened or whether patients could resume feeding sooner. The efficacy and the side effect of cisapride have been studied in 20 premature infants without identifiable organic causes for gastrointestinal stasis (79,80). All infants were being ventilated and received standard semielemental formula. Cisapride was given as a bolus infusion through the feeding tube at doses of 0.15 mg/kg every 6 h, 30 min before each feeding. Cholestasis developed in only four patients. In three of them it was already evident before administration of cisapride, and the eventual cholestatic effect of cisapride could not be evaluated; cholestasis arising after the start of treatment was observed in only one subject and was reversible. Because of the risk of GER and the drawbacks of delayed enteral feedings, the use of cisapride in premature neonates with gastric retention and emesis appears to be justified. CONCLUSIONS Cisapride is the first-line prokinetic agent for treating the majority of gastrointestinal motility disorders in children. Unlike other traditional prokinetic agents, it has a favorable side-effect profile without antidopaminergic or direct cholinomimetic effects (6). Cisapride is devoid of extrapyramidal effects and has a very low incidence of central nervous system effects (fatigue, somnolence) (6). Unwanted effects, which can be predicted from its pharmacologic profile, have slight clinical consequences and include abdominal colics, borborygmi, and diarrhea (81). In the majority of studies, the overall incidence of adverse effects in cisapride-treated patients was similar to placebo, 14.1% and 12.3%, respectively (81); interestingly, the incidence of adverse events did not appear to be related to the dose of cisapride. Cisapride has been discontinued in ≈2.5% of treated patients (mainly because of abdominal pain or diarrhea), compared with 1.3% of patients on placebo. In recent large studies (82,83) the incidence of adverse events was similar to previous reports (81). In children treated with cisapride the adverse reactions are of a nature similar to those described in adults, and the incidence is not different (22,26-28,84). Recently, increased micturition frequency and urinary incontinence has been described in adults treated with cisapride; these reactions could be due to increased bladder cholinergic activity (85,86). Several aspects of the use of cisapride for treating GER disease in children remain unsettled. New therapeutic trials including children with the most severe degree of esophagitis are warranted. The role of the drug in combination with antisecretory agents in refractory esophagitis should also be assessed. It is also uncertain whether long-term administration of cisapride can be efficacious in treating chronic relapsing esophagitis of childhood. Cisapride seems to be of limited value in children with reflux due to neurological disease; in these patients cisapride should be given for long periods in association with high doses of antisecretory drugs. Cisapride is also the first-line prokinetic agent for gastrointestinal motility disorders. Several reports indicate its effectiveness in improving gastric emptying and abnormal gastroduodenal motility, both in patients with functional gastrointestinal symptoms and in patients with GER disease; the drug can also be effective in ameliorating symptoms of functional dyspepsia. Nevertheless, only a few studies have evaluated the effectiveness of cisapride in childhood gastrointestinal motility disorders. Future clinical trials should be performed with standardized inclusion criteria and methods of motility evaluation; moreover, results of cisapride administration must be related to the motility patterns recorded in the patients. Cisapride might be used in addition to other prokinetic agents, such as metoclopramide and erythromycin, to assess whether combination therapy has a role in refractory gastrointestinal motility disorders; prokinetic drugs with different pharmacologic mechanisms of action might have synergistic effects. Long-term oral cisapride has been reported in adults with functional dyspepsia and gastroparesis (87-90) and as maintenance treatment of healed esophagitis to prolong endoscopic and symptomatic remission (39-41). There are only a few reports on long-term oral use of cisapride in children. The drug was given to 12 children with chronic functional constipation for a period spanning 26-72 weeks (75) and to a population of children with chronic intestinal pseudoobstruction for 1 year (65). Unlike chronic treatment with other prokinetics, the effect of chronic administration of cisapride on gastric emptying and dyspeptic symptoms is retained for ≥ 18-24 months, and tolerance does not seem to develop (6). In European trials on long-term (6-12 months) treatment with cisapride of adult GER disease, the overall incidence of adverse effects ranged from 8 to 20% (vs. 9 to 12% with placebo). The most common adverse events were such gastrointestinal complaints as diarrhea and abdominal pain; the treatment was discontinued in <4% of the treated patients. No changes in hematologic or biochemical variables as well as vital signs were reported (81). The effects of cisapride in improving motility and transit in chronic intestinal pseudoobstruction is variable owing to the complexity of the enteromuscular disease underlying the disease process. Nevertheless, a trial of cisapride is worthwhile for most children with pseudoobstruction, and the drug is more effective if manometry confirms persistence of migrating motor complexes and radiology shows absence of gut dilatation. Since intestinal pseudoobstruction is a chronic (and often progressive) disorder, cisapride should be administered for long periods. Further controlled studies on long-term oral cisapride treatment in children with chronic intestinal pseudoobstruction are warranted. Acknowledgment: The author is grateful to Dr. William R. Treem for critical review and suggestions aimed at improving the text.FIG. 1.: Chemical structures of metoclopramide (2-methoxy-5-chloroprocainamide) and cisapride (cis-4-amino-5-chloron-[1- [3- (4-fluorophenoxil) propyl] 3 methoxy-4-piperidinyl]-2-methoxy-benzamide monohydrate).