Digestive Diseases and Sciences, Vol. 35, No. 12 (December 1990), pp. 1500-1504

Effects of Cisapride on Gastrointestinal Transit in Healthy Humans J A N L Y S G A R D M A D S E N , MD

It was the aim o f this study to assess the effects o f cisapride on gastrointestinal transit o f solids in healthy humans. Twelve men received cisapride 10 mg or placebo orally four times a day in random, double-blind, crossover fashion. Transit measurements were performed with a new gamma camera technique. Cisapride reduced mean gastric emptying time o f 99'~Tc-labeled cellulose fiber {0.77 (0.69-1.12) hr [median (range)] vs 0.98 (0.63-1.95) hr; P < 0.05} and 1- to 2-mm lllln-labeled plastic particles [1.08 (0.50-1.42) hr vs 1.69 (0.59-3.03) hr; P < 0.01]. Cisapride also decreased mean small intestinal transit time o f cellulose fiber [2.11 (0.80-5.08) hr vs 2.82 (0.78-7.12) hr; P < 0.05] and plastic particles [2.06 (1.13-5.13) hr vs 2.64 (1.18-7.04) hr; P < 0.05]. However, cisapride increased mean large intestinal transit time of plastic particles [31 (13-75) hr vs 23 (12-36) hr; P < 0.05]. In conclusion, oral cisapride 10 mg four times a day accelerates gastric emptying and small intestinal transit whereas this dose of cisapride seems to delay large intestinal transit o f solids in healthy humans. cisapride; gastric emptying; small intestinal transit; large intestinal transit; 99mTc-labeled cellulose fiber; rain-labeled plastic particles. KEY WORDS:

Cisapride is a n e w gastrointestinal prokinetic drug acting mainly b y enhancing cholinergic neurot r a n s m i t t e r release selectively in the m y e n t e r i c plexus. In c o n t r a s t with o t h e r prokinetic drugs, it has no a n t i d o p a m i n e r g i c or direct cholinergic effects (1). Both animal and h u m a n studies h a v e indicated that cisapride intensifies p r o p a g a t i n g motility p a t t e r n s along the gastrointestinal tract (2-6). A new technique was u s e d to assess the effects o f cisapride on gastrointestinal transit rates in healthy volunteers.

Manuscript received February 23, 1990; revised manuscript received July 11, 1990; accepted July 12, 1990. From the Department of Clinical Physiology and Nuclear Medicine, Glostrup Hospital, Glostrup; and Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet, Copenhagen, Denmark. Tablets of cisapride and placebo were provided by Janssen Pharmaceutica, Beersee, Belgium. Address for reprint requests: Dr. Jan Lysgfird Madsen, Department of Clinical Physiology and Nuclear Medicine, Glostrup Hospital, DK-2600 Glostrup, Denmark.

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MATERIALS AND METHODS Subjects. Twelve healthy male volunteers of median age 25 years (range 21-30 years) and median body mass index 21.2 kg/m 2 (range 19.6-25.1 kg/m2), who were not taking drugs at the time of the experiment, had regular bowel movements, and did not have a history of gastrointestinal disease or previous abdominal surgery, were studied. The protocol for the experiments was approved by the local ethical committee. Study Design. This study was a randomized, doubleblind, crossover comparison of the effects of oral cisapride 10 mg and placebo four times a day, 30 min before meals on gastric emptying, small intestinal transit, and large intestinal transit. Each subject was studied twice-once on placebo and once on cisapride--and each served as his own control. In each study session the transit measurements began on the fifth day of medication to attain steady-state plasma levels of cisapride (7). The medication was continued until the transit measurements had finished. The cisapride and the placebo study sessions were separated by at least two weeks. During the studies, the energy distribution and the fiber fraction of the diet were maintained (44% carbohydrate; 33% fat; 23% protein; 3.6 g fiber/1000 kJ). The total daily energy Digestive Diseases and Sciences, Vol. 35, No. 12 (December 1990)

0163-2116/90/1200-1500506.00/09 1990PlenumPublishingCorporation

EFFECTS OF CISAPRIDE supply, however, was body weight-dependent (below 70 kg: 7700 kJ; 70-75 kg: 9500 kJ; above 75 kg: 11,000 kJ). The diet was consumed according to a fixed schedule (9:00 AM; 1:00 PM; 5:00 aM; 9:00 PM). The subjects drank about 2000 ml of nonalcoholic liquids per day. Transit Measurements. Gastrointestinal transit measurements were performed with a gamma camera technique described previously (8). As radiolabeled markers of nondigestible solid components, 40 MBq of 99mTclabeled cellulose fiber (thin and flexible) and 2 MBq of 111In-labeled plastic particles (diameter 1-2 mm, density 1. l g/ml) were added to a 1600-kJ standard meal consisting of 400 g of mixed solid and liquid components (80 g of bread; 30 g of cheese; 10 g of butter; 50 g of yogurt; 230 g of water). Transit measurements began at 9:00 AM after an overnight fast. The subjects consumed the labeled standard meal within 10 min. Right after, anterior and posterior images were obtained in the upright position. Imaging was repeated at 30-min intervals until no activity could be detected in the small intestine. Data were stored on a computer for later analyses. Subjects were encouraged to sit upright or walk between imaging for the first 4-hr period. On each image and for each marker, regions of interest were delineated manually around the stomach, the small intestine, and the large intestine. To minimize errors in the interpretation, sequential images were displayed forwards and backwards in time, showing the movement of the markers. The count rates were corrected for physical decay, downscatter, and attenuation. Feces were collected in separate samples until all markers had cleared from the large intestine. This clearance was established by abdominal scintigraphy, first performed after 72 hr and then, if necessary, at 24-hr intervals. The 11lin activity was measured in each sample with the gamma camera. Calculations. The use of a gamma camera technique and a deconvolution procedure made it possible to perform quantitative analyses of gastric emptying, small intestinal transit, and large intestinal transit as described previously (8). For each subject, a balanced mean emptying or a balanced mean transit time was calculated from the time-activity curve obtained for the gastrointestinal segment and the marker in question. As gastric input was almost instant, these curves were obtained directly for the stomach. However, the rate at which material enters the large intestine involves a convolution of the rate of emptying of the stomach and the rate of transit through the small intestine. Therefore, construction of adequate small intestinal time-activity curves involved a deconvolution procedure that made it possible to compute the expected time-activity curves for the small intestine if input from the stomach was instantaneous. Similar assumptions and principles applied to the large intestine. After testing for carryover effect and period effect, the data were analyzed by Wilcoxon's paired rank-sum test. Blood Analyses. Blood sampling was performed at the beginning and at the end of the transit measurements to ensure correct medication. Side Effects. Side effects, as reported spontaneously by the subjects, were recorded. Digestive Diseases and Sciences, Vol. 35, No. 12 (December 1990)

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Fig 1. Effect of cisapride (10 mg four times a day orally) on gastric emptying of 99mTc-labeled cellulose fiber and lllInlabeled plastic particles in 12 healthy humans. RESULTS T r a n s i t M e a s u r e m e n t s . G a s t r i c e m p t y i n g and small intestinal a n d large intestinal transit times are s h o w n in Figures 1-3 and in T a b l e 1. Testing did not reveal a c a r r y - o v e r effect or a p e r i o d effect. Cisapride i n c r e a s e d the gastric e m p t y i n g rate o f cellulose fiber and plastic particles (P < 0.05 and P < 0.01, respectively). Cisapride also a c c e l e r a t e d small intestinal transit o f cellulose fiber and plastic particles (P < 0.05 and P < 0.05, respectively). H o w ever, cisapride d e c r e a s e d the large intestinal transit rate o f plastic particles (P < 0.05). L a r g e intestinal transit times o f cellulose fiber c o u l d n o t be measured o w i n g to the short p h y s i c a l half-life o f 99mTc. During p l a c e b o administration, gastric e m p t y i n g o f cellulose fiber w a s c o n s i d e r a b l y faster than that o f plastic particles (P < 0.05), w h e r e a s no differe n c e w a s f o u n d in small intestinal transit rate o f the t w o m a r k e r s . D u r i n g cisapride administration, there w a s no difference in either gastric e m p t y i n g or small

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Fig 2. Effect of cisapride (10 mg four times a day orally) on small intestinal transit of 99mTc-labeled cellulose fiber and 11lin.labeled plastic particles in 12 healthy humans.

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Fig 3. Effect of cisapride (10 mg four times a day orally) on large intestinal transit of 1HIn-labeled plastic particles.

intestinal transit rate of the two markers. Typical intragastric distributions of the two markers are shown in Figure 4. Blood Analyses. During cisapride treatment, morning predose plasma cisapride concentration ranged between 30 and 150 ng/ml. No sample contained detectable cisapride concentration (

Effects of cisapride on gastrointestinal transit in healthy humans.

It was the aim of this study to assess the effects of cisapride on gastrointestinal transit of solids in healthy humans. Twelve men received cisapride...
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