Effects of cisapride on postcibal jejunal motor activity

In the jejunum of fasting humans, cisapride induces a phase 2-like, highly propagative motor pattern. This study investigated cisapride's effects on the fed pattern of the jejunum. Starting 5 min after a phase 3 of the migrating motor complex, 18 healthy men received 5 or 10 mg cisapride or placebo orally in random double-blind fashion and ingested meals containing 1000 and 4200 kJ, respectively. Jejunal pressures were recorded pneumohydraulically with five catheter orifices 10–30 cm aborad the ligament of Treitz. After the 4200-kJ meal, total number and number of propagated contractions as well as area under the curve increased significantly more than after 1000 kJ. Following the 1000-kJ but not the 4200-kJ meal, 10 mg cisapride increased total number of contractions, number of propagated contractions, mean amplitude, and area under curve significantly more than placebo. Fed-pattern duration increased with the meal's caloric content but was not influenced systematically by cisapride. In conclusion, cisapride stimulates jejunal motor activity and induces a propagative pattern after a 1000-kJ but not after a 4200-kJ meal, suggesting that it can produce no further stimulation when motor activity is near maximally enhanced already.     

Cisapride stimulates propulsive motility patterns in human jejunum

The effects of cisapride on upper gut motility were studied in seven healthy volunteers by means of a novel intraluminal electromyographic technique in a placebo-controlled study. In the interdigestive state, cisapride (10 mg intravenous bolus injection) markedly increased the number of spike bursts. The most obvious effect was observed during the first 5-min period when a nonmigrating phase-3-like activity (stationary phase 3) occurred, which lasted for 2.6±0.4 min. This initial pattern was followed by an intense phase 2 activity, characterized by a 10-fold increase in the number of groups of repetitive spike bursts and a sixfold increase in the number of ultrarapid single propagated spike bursts (ultrarapid peristaltic rushes). Cisapride induces in the human upper gut a remarkable pattern of aborally propagated (peristaltic) contractions, which are very likely responsible for the active propulsion of intestinal contents in the interdigestive state.     

Effects of the prodrug loperamide oxide,loperamide, and placebo on jejunal motor activity

This crossover, double-blind study investigated the effects of single oral doses of the prodrug loperamide oxide, which is reduced gradually to loperamide in the intestine, and loperamide on jejunal motor activity in 12 fasting healthy men. Five minutes after a phase III of the migrating motor complex (MMC), 2 mg loperamide oxide, 4 mg loperamide oxide, 4 mg loperamide, or placebo were administered. Thereafter, motor activity 10–30 cm aborad the ligament of Treitz was recorded with five catheter orifices at 3-cm intervals over 4 hr. Number of contractions and area under curve increased significantly with 4 mg loperamide and 4 mg loperamide oxide, the increases with loperamide oxide occurring more gradually. Placebo and 2 mg loperamide oxide had no discernible effects. With both 4 mg loperamide and 4 mg loperamide oxide, phase I of the MMC was slightly prolonged and phase II and the time from drug administration to the onset of the first phase III slightly shortened. The percentage of aborally propagated contractions in phase II increased with all active treatments, whereas the occurrence of phases III was not altered.Presented in poster form at the European Digestive Disease Week, Vienna, Austria, June 5–9, 1990Supported by Janssen Pharmaceutica, Beerse, Belgium.     

Effects of cisapride, a new gastrointestinal prokinetic substance, on interdigestive and postprandial motor activity of the distal oesophagus in man.

Cisapride is a newly developed substance that stimulates gastrointestinal motility, possibly enhancing acetylcholine release in the gut wall. The aim of our study was to investigate the effect of cisapride on oesophageal motor function in man. In a blind fashion and in random order six healthy volunteers received cisapride (0.5 mg/h intravenously, preceded by a three day oral loading at 10 mg tid) and matching placebo. Oesophageal contractions and lower oesophageal sphincter pressure were constantly recorded during a complete cycle of the interdigestive migrating motor complex and during two and half hours after a mixed test meal. Cisapride did not disturb the interdigestive migrating motor complex. In the fasting state the lower oesophageal sphincter pressure showed considerable interdigestive migrating motor complex phase-related variations, whereas amplitude and duration of the oesophageal contractions did not. In the dosis used cisapride was found to increase lower oesophageal sphincter pressure in the interdigestive and in the late postprandial state, but to have no effect in the early postprandial period. Amplitude and duration of oesophageal contractions were not affected by cisapride.     

Effect of cisapride,a new prokinetic agent,on esophageal motor function

In this study, we assessed by a double-blinded, cross-over design the effect of intravenous and oral cisapride on esophageal motor activity during the late fed state in normal subjects. For the intravenous study, subjects were given placebo or 10 mg cisapride randomly, while in the oral study, they randomly received placebo or cisapride at 5, 10, or 20 mg. Cisapride given intravenously or orally caused a significant increase in resting LES pressure. The increase in LES pressure after oral administration was significant only after the 20 mg dose. Esophageal-body peristaltic amplitude, determined for all smooth-muscle sites, showed a modest but significant increase of approximately 10 mm Hg after intravenous cisapride, whereas no significant increase occurred after oral cisapride. Propagation time of peristalsis was unaffected by intravenous or oral cisapride. Side effects of treatment were minimal and at no time necessitated cessation of the study. We conclude that in healthy subjects during the late fed period, (1) cisapride at 10 mg intravenously or 20 mg orally increased resting LES pressure and (2) at 10 mg intravenously, but at no oral dose, cisapride increased peristaltic amplitude without affecting propagation time. The potentiating effect of cisapride on LES pressure suggests that cisapride could have an ancillary role in the therapy of gastroesophageal reflux disease.     

Effects of cisapride on distal esophageal motility in humans

Peristaltic contractions of the distal esophageal body and lower esophageal sphincter tone were evaluated in patients affected by gastroesophageal reflux disease after either acute intravenous (8.0 mg) administration or two oral doses (5.0 mg and 10.0 mg) of cisapride and in healthy controls after a 10.0-mg oral dose of cisapride. Intravenous cisapride administration enhanced the amplitude and duration of primary peristalsis and the lower esophageal sphincter tone, which reached normal control values. Likewise, the 10.0-mg oral dose effectively enhanced the lower esophageal sphincter resting pressure in both controls and in reflux patients, whereas the amplitude and duration of primary peristalsis was improved only in controls. The 5.0-mg oral dose of cisapride proved ineffective on distal esophageal motor activity in reflux patients. To evaluate whether atropine is capable of modifying the effects of cisapride on distal esophageal motor activity, cisapride was administered intravenously before and during intravenous atropine administration. Effects of cisapride on peristaltic contractions were completely blocked by atropine, irrespective of whether atropine was administered before or after cisapride. The lower esophageal sphincter pressure response to cisapride varied according to the sequence of drug administration, showing no effect when cisapride followed atropine administration and, when this sequence was reversed, no significant atropine-induced inhibition on cisapride-stimulated lower esophageal sphincter pressure. It is suggested that cisapride enhances distal esophageal motor activity by means of a muscarinic receptor mechanism at the level of the distal esophageal body and, at least in part, via a muscarinic-independent mechanism at the level of the lower esophageal sphincter.     

Longterm oral cisapride improves interdigestive antroduodenal motility in dyspeptic patients.

We have evaluated the effect of cisapride on interdigestive antroduodenal motility during a prolonged oral therapy in 20 consecutive dyspeptic subjects. Individuals with less than two migrating motor complexes (MMCs) starting from the antral region in 240 minutes and without evidence of upper gastrointestinal tract diseases were randomly treated with either cisapride (10 cases), or placebo (10 cases) for 15 days. Computerised manometry of antroduodenal region was performed for 240 minutes, in basal conditions and on the 15th day of therapy. Symptomatic evaluation of patients was also performed before and after treatment. After cisapride administration, a significant increase in the incidence of antral migrating motor complexes was noticed (p = 0.022); likewise, the motility index, calculated for phase-2 periods, appeared to be significantly higher both in the antrum and in the duodenum (p less than 0.001). Symptomatic improvement was observed in both groups, with a hardly significant (p = 0.049) reduction of dyspeptic symptoms severity only but not of frequency in cisapride treated patients v controls. We conclude that longterm oral therapy with cisapride improves interdigestive antroduodenal motor activity.     

Effect of six weeks of treatment with cisapride in gastroparesis and intestinal pseudoobstruction

We have investigated the effect of oral cisapride (10 mg t.i.d.) in a double-blind, placebo-controlled trial in 26 patients with upper gut dysmotility: 11 with gastroparesis (8 diabetic, 3 idiopathic) and 15 with chronic idiopathic intestinal pseudoobstruction. Patients were evaluated at entry and at the end of the 6-wk study by upper gastrointestinal manometry, scintigraphic evaluation of gastric emptying of solids and liquids, measurement of body weight, and scoring of the following symptoms: abdominal pain, nausea, vomiting, early satiety, bloating, and distention. Cisapride and placebo groups were strictly comparable for all parameters assessed. Cisapride resulted in a significant increase in the gastric emptying of solids (p less than 0.05) compared with placebo; cisapride also tended to increase the postcibal antral motility and normalize the abnormal manometric features in the patients with intestinal dysmotility, particularly the characteristics of fasting interdigestive motor complexes and the fed motor pattern. Both cisapride and placebo groups showed an improvement in total symptom scores and there was no significant difference in overall symptom response between the two groups. However, the change in abdominal pain was greater with cisapride (p = 0.07). Cisapride facilitates gastric emptying in patients with upper gut dysmotility. The overall symptomatic benefit during a 6-wk trial of cisapride, 10 mg t.i.d., was not greater than that of placebo, and dose-response as well as longer term trials are necessary to determine the clinical efficacy of this medication.     

Oral prostaglandin E analogues induce intestinal migrating motor complexes after a meal in dogs. Evidence for a central mechanism

The effects of oral, intravenous, and intracerebroventricular administration of synthetic derivatives of prostaglandins E1 (misoprostol) and E2 (enprostil) on postprandial gastrointestinal motility were investigated in dogs chronically fitted with strain gauge transducers on the antrum and the proximal and middle jejunum. Synthetic prostaglandin E analogues administered orally at a dose of 20-50 micrograms/kg 15 min before the meal did not modify the postprandial pattern of gastric contractions but suppressed the spontaneous postprandial irregular activity on the jejunum and induced a cyclic pattern of migrating motor complexes for 4-6 h after the meal. These postprandial migrating motor complexes induced by prostaglandin E were propagated between the two recording sites and had a period similar to that observed in the fasted state. However, the duration of phase 2 was significantly increased and the amplitude of the phase 3 decreased. This jejunal cyclic motor pattern was reproduced by administration of synthetic prostaglandin E derivatives either intravenously (4-10 micrograms/kg) 15 min before the meal or intracerebroventricularly (50 ng/kg) 1 h after the meal. The intestinal migrating motor complex activity observed after oral administration of synthetic prostaglandin E derivatives was abolished by the previous intracerebroventricular (40 micrograms/kg) but not intravenous (200 micrograms/kg) administration of SC-19220, a receptor antagonist of prostaglandin E. These results suggest that oral administration of synthetic prostaglandin E1 (misoprostol) or prostaglandin E2 (enprostil) analogues before a meal induces postprandial migrating motor complexes on the jejunum in dogs through a mechanism involving central prostaglandin receptors.     

Effect of erythromycin on gastric motility in controls and in diabetic gastroparesis.

The effect of three doses of erythromycin on interdigestive gastrointestinal motility and on plasma motilin levels was studied in healthy volunteers and patients with diabetic gastroparesis. Abnormalities of interdigestive motility were observed in 40% of the patients. In healthy volunteers, 40 mg erythromycin elicited a premature phase 3 that started in the stomach. In contrast to the spontaneous gastric phase 3, this erythromycin-induced phase 3 was not accompanied by a motilin peak. In patients with diabetic gastroparesis, 40 mg erythromycin induced a premature phase 3 in three patients, no response in one patient, and a burst of antral contractions in another patient. Doses of 200 and 350 mg erythromycin elicited a burst of antral phase-3-like contractions in both volunteers and patients, which was not accompanied by a motilin peak. This phase-3-like activity did not migrate to the small intestine and was not followed by a phase 1, but by a prolonged period of antral contractile activity. The number and amplitude of antral contractions after 200 or 350 mg erythromycin were significantly higher than after 40 mg. The motor patterns induced by different doses of erythromycin offer potential therapeutic applications.     

Effects of acute psychologic stress on small-intestinal motility in health and the irritable bowel syndrome.

Psychologic stress may be a provoking factor in the alterations in phase-2 motor activity of the migrating motor complex (MMC) which have been recorded in patients with the irritable bowel syndrome (IBS). To test this, changes in phase-2 duodenojejunal motor activity during 20 min of psychologic stress in 10 patients with IBS were compared with those shown by 10 healthy subjects. Autonomic arousal in response to the stressor was assessed by cardiovascular responses and self-reported levels of anxiety and tension. IBS and controls showed a significant cardiovascular and subjective response to stress which was comparable in the two groups. In general, duodenal phase-2 motor activity was suppressed during stress in both IBS and controls. Jejunal motor activity showed a similar inhibitory response in both groups, but the change in motility index was significant for controls only. Qualitatively, stress did not cause clustered contractions in either the IBS or the control group. However, in IBS patients with clustered contractions in the basal period there was inhibition of this pattern during stress. These findings suggest that acute psychologic stress profoundly suppresses, rather than enhances, duodenojejunal MMC phase-2 motility in healthy subjects. IBS patients, irrespective of their underlying phase-2 motor pattern show similar, although less marked, changes in motility.     

Effects of oral cyclotropium bromide, hyoscine N-butylbromide and placebo on gastric emptying and antral motor activity in healthy man

Cyclotropium bromide, a new antimuscarinic agent, inhibits gastrointestinal motility in animals at lower doses than those required to inhibit gastric acid secretion and salivation. In man, cyclotropium bromide suppresses fasting and meal stimulated colonic motility. This study investigated the effects of single oral doses of 60 mg cyclotropium bromide, 60 mg hyoscine N-butylbromide and placebo on gastric emptying and on antral motor activity. Twenty four healthy men (mean age 25 years) participated in three experiments one week apart. The drugs were administered, in random double blind fashion, 30 minutes before the ingestion of a semisolid test meal labelled with 74 MBq (2 mCi) 99mTc sulphur colloid. A gamma camera coupled to a computer monitored gastric emptying together with amplitude, frequency, and propagation velocity of antral contractions. Cyclotropium bromide and, to a lesser degree, hyoscine N-butylbromide delayed gastric emptying and reduced contraction amplitude, but did not affect frequency and propagation velocity of antral contractions. Cyclotropium bromide was significantly more active than hyoscine N-butylbromide; the effects of hyoscine N-butylbromide differed significantly from placebo. Antral contractile activity was present all the time. After cyclotropium bromide, there was a significant correlation between antral contraction amplitude and gastric emptying. No adverse side effects occurred with any one treatment. In conclusion, cyclotropium bromide markedly inhibits gastric emptying and reduces antral contraction amplitude.     

Effect of cisapride on postprandial gastro-oesophageal reflux.

We studied the effect of cisapride on oesophageal motor function and postprandial gastro-oesophageal reflux in a randomised, double blind, placebo controlled crossover study. In 16 patients with symptomatic gastro-oesophageal reflux, cisapride 10 mg orally and placebo were studied on separate days according to identical protocols. Cisapride and placebo were given 30 minutes before a standard meal. Each study day was preceded by corresponding three day oral loading of cisapride (10 mg tds) or placebo. Lower oesophageal sphincter pressure, oesophageal body motility and oesophageal pH were monitored for 30 minutes before and three hours after the meal. Plasma cisapride concentrations were measured before and after dosing on both study days. With cisapride treatment, the plasma cisapride levels ranged from 48.1 (5.0) to 75.9 (6.9) ng/ml. Plasma levels were undetectable during placebo treatment. Cisapride enhanced acid clearance but had no significant effect on the duration of acid exposure, the rate of reflux episodes, the pattern of lower oesophageal sphincter pressure associated with the reflux episodes, basal lower oesophageal sphincter pressure or oesophageal peristalsis. These findings do not suggest a major role for cisapride, at the dosage tested, for the control of troublesome postprandial gastro-oesophageal reflux.     

Differences between jejunal myoelectric activity after a meal and during phase 2 of migrating motor complexes in healthy humans

Using an intraluminal probe with six pairs of annular electrodes, the myoelectric activity of the proximal jejunum was recorded during 48-hr sessions in 16 healthy volunteers receiving evening and noon meals (1000 kcal) and breakfast (400 kcal). In 10 subjects receiving no drug, the characteristics of the migrating motor complexes (period, duration of each phase, velocity of propagation of phase 3, duration of the postprandial disruption) varied markedly between subjects but were relatively constant from the first to the second day of recording. Single spike bursts propagated at a rate of 2–5 cm/sec, clusters of 3–10 spike bursts propagated at a rate of 0.5–1 cm/sec, and similar clusters recurring repetitively each 1.5–2 min were observed after the meals and very rarely in the fasted state during phase 2 of nocturnal migrating motor complexes. In six subjects, oral administration of codeine (50 mg) 1 hr before a meal induced migrating motor complexes in the postprandial state, with characteristics similar to that observed in the fasted state except a longer duration of phase 2. Single spike bursts and isolated and repetitive clusters of spike bursts were observed during phase 2 of the codeine-induced migrating motor complexes and after meals preceded by placebo, but very rarely during the phase 2 of nocturnal (fasted state) migrating motor complexes. It is concluded that the patterns of jejunal contractions consisting of propagated single spike bursts and isolated or repetitive spike bursts characterize the postprandial state in healthy humans and are dependent upon digesta flow.This work was presented in part at the Vth European Symposium on Gastrointestinal Motility, June 13–16, 1990, Augsburg, Germany, and has appeared in abstract form in theJournal of Gastrointestinal Motility 2: 161, 1990.     

Long-Term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function

OBJECTIVES: Altered small-bowel motility, lengthening of the orocecal transit time, and small-intestinal bacterial overgrowth have been described in patients with liver cirrhosis. These changes might be related to the progressive course and poor prognosis of the disease. We investigated the effect of a long-term treatment with cisapride and an antibiotic regimen on small-intestinal motor activity, orocecal transit time, bacterial overgrowth, and some parameters of liver function. METHODS: Thirty-four patients with liver cirrhosis of different etiology entered in the study. They were randomly allocated to receive cisapride (12), an alternating regimen of norfloxacin and neomycin (12), or placebo (10) during a period of 6 months. At entry and at 3 and 6 months, a stationary small-intestinal manometry was performed, and orocecal transit time and small-intestinal bacterial overgrowth were also investigated using the H2 breath test. Liver function was estimated with clinical and laboratory measurements (Child-Pugh score). RESULTS: After 6 months, both cisapride and antibiotics significantly improved fasting cyclic activity, reduced the duration of orocecal transit time, and decreased small-intestinal bacterial overgrowth. Cisapride administration was followed also by an increase in the amplitude of contractions. No statistically significant variations in these parameters were observed with placebo. An improvement of liver function was observed at 3 and 6 months with both cisapride and antibiotics. CONCLUSIONS: Long-term treatment with cisapride or antibiotics reversed altered small-intestinal motility and bacterial overgrowth in patients with liver cirrhosis. These findings suggest a possible role for prokinetics and antibiotics as a modality of treatment in selected cases of decompensated cirrhosis.     

Jejunoileal transplantation

This study was designed to determine if extrinsic innervation and intrinsic neural continuity with the duodenum (neuroenteric physiologic pathways disrupted during intestinal transplantation) modulate the characteristics of interdigestive motor activity in the canine small bowel. Five dogs served as neurally intact controls (group 1) and 10 dogs (group 2) underwent a model of jejunal autotransplantation involvingin situ neural isolation of the jejunoileum. Fasting duodenal and jejunal motor activity was recorded on-line to a microcomputer using closely spaced duodenal and jejunal manometry catheters. Characteristics of global motor patterns, the migrating motor complex (MMC), and local motor patterns, including individual contractions and grouped clustered contractions, were determined. Neural isolation of the jejunoileum disrupted coordination of duodenal and jejunal phase III activity, increased the variability of cycling of the MMC, decreased the period of the jejunal MMC, and increased motility indices in the neurally isolated jejunum. In contrast, single pressure waves and clustered contractions in the neurally isolated jejunum were not altered significantly in incidence or direction, distance, or velocity of spread.In situ neural isolation of the jejunoileum leads to temporal dissociation of the MMC between the transplanted segment (jejunum) and the duodenum but does not appear to alter markedly the characteristics of local contractile activity as measured by individual or grouped contractions. The occurrence of interdigestive jejunal motor patterns and the local organization of individual and grouped small intestinal contractions are not controlled by extrinsic innervation or intrinsic neural continuity with the duodenum.     

Effect of the quaternary ammonium compound trospium chloride on 24 hour jejunal motility in healthy subjects.

This study aimed to record 24 hour jejunal motility in healthy ambulant subjects and to analyse changes in motility caused by the oral administration of an anticholinergic agent, the quaternary ammonium compound, trospium chloride. In a placebo-controlled, double blind crossover trial, 24 hour jejunal motility was recorded in 12 healthy volunteers, aged 25 (21-30) years, using a digital data logger connected to two strain-gauge transducers mounted 20 cm apart in a flexible nasojejunal catheter. A computer program was developed to determine contraction parameters. Trospium chloride (15 mg orally thrice daily) prolonged the duration of irregular contractile activity after meals (p < 0.02) and reduced its contraction frequency and amplitude (p < 0.001). In the fasting state, the cycle length of the migrating motor complex was prolonged (p < 0.01) by an extended phase I (p < 0.025). Phase III was shortened (p < 0.005) and showed a slower aboral migration velocity (p < 0.005). Clustered contractions were less frequent during postprandial and fasting periods (p < 0.01). Runs of clustered contractions were completely absent with trospium chloride. Digital manometry was useful for long term recordings of jejunal motility and enabled the motor effects of an anticholinergic agent to be characterised in ambulant subjects.     

Effects of cisapride on parameters of oesophageal motility and on the prolonged intraoesophageal pH test in infants with gastro-oesophageal reflux disease.

The effect of cisapride, a new gastrointestinal prokinetic drug, on oesophageal motility and acid reflux was studied in 14 children with gastro-oesophageal reflux disease, receiving either placebo or cisapride 0.15 mg/kg intravenously. Cisapride significantly (p less than 0.01) increased the lower oesophageal sphincter pressure (+124%), the amplitude (+84%) and duration (+24%) of oesophageal peristaltic waves, whereas the placebo treatment did not produce any changes. Subsequently, all 14 children underwent 24 hour oesophageal pH-monitoring before and after four weeks of treatment with oral cisapride 0.2 mg/kg tid given in addition to postural therapy and thickened feedings. The 24 hour intraoesophageal pH recordings and symptomatic scores were compared with those of 10 control patients treated only by postural therapy and thickened feedings. When compared with baseline pH data, cisapride significantly reduced the oesophageal acid exposure time, the mean duration of each reflux episode, the duration of the longest reflux episode and the number of long lasting reflux episodes; the number of reflux episodes was not influenced. The effect of cisapride was marked and consistent during fasting and sleep periods. Oesophageal acid exposure was reduced more significantly in patients given cisapride (-61%) than in controls (-24%; p less than 0.001). Symptom improvement was greater after four weeks of cisapride treatment (score reduction: 61%) than after postural and dietary therapy alone (score reduction: 42%; p less than 0.01). No adverse effects occurred. These findings suggest that cisapride is a valuable drug in the management of gastro-oesophageal reflux disease in children.     

Effects of laxative and nonlaxative hydrophilic polymers on canine small intestinal motor activity

Bulk-forming laxatives increase fecal volume and elicit aborally directed colonic motility patterns. Recently, it was demonstrated that test meals of the bulk-laxative fibers (cellulose and bran) elicited organized jejunal motor activity while nonlaxative fiber meals (guar) elicited unorganized jejunal motor activity. However, whether bulk-forming laxatives, as a class of compounds, differentially affect small intestinal motility has not been studied. Therefore, a study was made of the effects of the bulk laxatives psyllium and polycarbophil and the nonlaxative pectin on canine jejunal motor activity. Psyllium and pectin are examples of dietary fiber, while polycarbophil is a synthetic polymer. Pectin and psyllium test meals presented as viscous gels. In contrast, polycarbophil meals presented as a combination of discrete particles plus meal water. After each meal, measurements were made of the jejunal motility index, the time of reappearance of interdigestive burst activity, and overall motility patterns. Pectin and psyllium meals increased in viscosity as meal fiber content increased. As meal content and hence viscosity increased, both the laxative (psyllium) and nonlaxative (pectin) fiber meals elicited increasing jejunal motor activity and delays in the reappearance of the burst interval. For both fiber types, motor activity presented as randomly appearing contractions. In contrast, meals of the laxative polycarbophil elicited no more motor activity than the saline control meal. However, this control-level amount of activity presented as propagated clusters of contractions, ie, the laxative-induced pattern. Polycarbophil did not delay the reappearance of burst activity. We conclude: (1) bulk laxatives do not uniformly affect jejunal motility, and (2) differences in these meal-induced jejunal motor effects are related to meal viscosities and probably the physical form of the meal.Support for this research was provided by G.D. Searle & Co.J. Russell performed this research in partial fulfillment of the requirements for the degree of Doctor of Philosophy.     

Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans

BACKGROUND: Serotonin 5-HT(4) receptors are located on enteric cholinergic neurones and may regulate peristalsis. 5-HT(4) receptors on primary afferent neurones have been postulated to modulate visceral sensation. While 5-HT(4) agonists are used as prokinetic agents, the physiological role of 5-HT(4) receptors in the human gut is unknown. AIMS: Our aim was to characterise the role of 5-HT(4) receptors in regulating gastrointestinal motor and sensory function in healthy subjects under baseline and stimulated conditions with a 5-HT(4) receptor antagonist. METHODS: Part A compared the effects of placebo to four doses of a 5-HT(4) receptor antagonist (SB-207266) on the cisapride mediated increase in plasma aldosterone (a 5-HT(4) mediated response) and orocaecal transit in 18 subjects. In part B, 52 healthy subjects received placebo, or 0.05, 0.5, or 5 mg of SB-207266 for 10-12 days; gastric, small bowel, and colonic transit were measured by scintigraphy on days 7-9, and fasting and postprandial colonic motor function, compliance, and sensation during distensions were assessed on day 12. RESULTS: Part A: 0.5, 5, and 20 mg doses of SB-207266 had significant and quantitatively similar effects, antagonising the cisapride mediated increase in plasma aldosterone and acceleration of orocaecal transit. Part B: SB-207266 tended to delay colonic transit (geometric centre of isotope at 24 (p=0.06) and 48 hours (p=0.08)), but did not have dose related effects on transit, fasting or postprandial colonic motor activity, compliance, or sensation. CONCLUSION: 5-HT(4) receptors are involved in the regulation of cisapride stimulated orocaecal transit; SB 207266 tends to modulate colonic transit but not sensory functions or compliance in healthy human subjects.