Gut, 1991,32, 1355-1359 1355 Absorptive and motor components ofthe
antidiarrhoeal action ofloperamide: an in vivo study Gut: first published as 10.1136/gut.32.11.1355 on 1 November 1991. Downloaded from in pigs
V Theodorou, J Fioramonti, T Hachet, L Bueno
Abstract Studies in humans indicate that loperamide does The effects of loperamide (0.1 mg/kg orally) not modify net intestinal or colonic water and on net colonic water absorption, orocolonic electrolyte absorption,2'10 but these were per- transit time, and intestinal motility were formed in subjects in whom the digestive tract investigated in pigs chronically fitted either had been emptied of contents and cleansed. We with two cannulas in the proximal colon and a have recently developed a technique in pigs that catheter in the duodenum and the ileum or with allows us to determine colonic water absorption intraparietal electrodes on the duodenum, in more normal physiological conditions - in the jejunum, caecum, and proximal colon and a presence of digesta and taking into account the duodenal catheter. Loperamide, given 20 fluctuations associated with eating." minutes before a meal reduced significantly This study aimed to determine in pigs the colonic net water absorption for 10 hours after action ofloperamide on colonic water absorption eating. It also reduced colonic flow rate, in the presence of faecal material, in basal increased orocolonic transit time, modified the conditions or during diarrhoea induced by a postprandial intestinal motility by inducing duodenal infusion of a hypertonic solution of supplementary phase 3 motor complexes and mannitol. Because of differences between did not affect caecocolonic motility. Intraduo- species in the effects of loperamide,'2 1" intestinal denal infusion of a hypertonic solution of motility and transit time were monitored to mannitol (900 mOsmfl; 0.6 mi/minute) for determine whether the stimulation ofthe migrat- the first postprandial hour strongly reduced ing motor complexes and the increased transit or reversed net colonic water absorption, time found in humans23 0 is reproduced in pigs. increased the colonic flow rate, accelerated the orocolonic transit, and induced profuse diar-
rhoea. After loperamide administration, all Methods http://gut.bmj.com/ these effects were blocked and the relative colonic water absorption, expressed as the ANIMALS fraction of flow entering the colon, was Eight large white pigs, each weighing approxi- strongly increased. Mannitol did not modify mately 40 kg at the beginning ofthe experiments motility of the small and large intestine, and were studied. The animals were housed in supplementary phase 3 motor complexes were individual cages. They were on a standard diet observed when mannitol infusion was pre- for growing pigs (30 g/kg body weight per day) on September 23, 2021 by guest. Protected copyright. ceded by loperamide administration. It is con- comprising concentrates of barley, wheat, and cluded that in experimental osmotic diarrhoea fish meal (Rental, 31770 Colomiers, France) loperamide causes a reduction in digesta flow given twice daily and had free access to water. entering into the colon, mediated by its action Under thiopental anaesthesia, four pigs were on small intestinal motility, and an increase in fitted with two silicone catheters - one in the colonic water absorption. lumen of the duodenum (15 cm from the pylorus) and one in the ileum (20 cm from the ileocaecal junction), and two silicone cannulas Loperamide, a synthetic opiate derivative, is one (internal diameter 8 mm) were inserted in the of the most commonly used antidiarrhoeal helicoidal (proximal) colon. The proximal drugs. Its mechanism of action, however, still cannula was placed in the first colonic coil 20 cm remains controversial since it may stimulate the from the ileocaecal junction, and the distal rate of absorption by intestinal epithelial cells or cannula, about 50 cm from the first one in the modify intestinal motility to slow down the second coil. The two cannulas and the catheters transit of intestinal contents. ' Its action on were brought to the exterior on the left flank. intestinal motility and transit is well docu- The remaining four pigs were fitted with an Department of mented. In humans, loperamide has been found intraduodenal catheter (15 cm from the pylorus) Pharmacology, INRA, to stimulate jejunal motility by increasing the and term Toulouse, France prepared for long bipolar electromyo- V Theodorou frequency of the phase 3 migrating motor com- graphic recordings of intestinal motility accord- J Fioramonti plexes23 and to delay orocaecal transit time.4 Its ing to a previously described technique.'4 T Hachet action on intestinal fluid absorption, however, is Nichrome wire electrodes (Microfil Industrie, L Bueno not clearly established. In vitro or in anaesthe- Renens, Switzerland) 1 m in length and 120 Correspondence to: [tm Dr J Fioramonti, Department tised animals, loperamide has been found to in diameter were implanted in the wall of the of Pharmacology, INRA, 180 inhibit intestinal secretion induced by thermo- jejunum (at 50, 150, and 250 cm from the Chemin de Tournefeuille, BP 3, 31931 Toulouse, France. stable Escherichia coli,' cholera toxin,6 deoxy- ligament of Treitz), the caecum (10 cm from the Accepted for publication cholic acid,7 and prostaglandin89 but not by apex), and the proximal colon (in the first and December 1990 vasoactive intestinal polypeptide or mannitol.8 second coil). The free ends of the electrodes and 1356 Theodorou, Fioramonti, Hachet, Bueno
the catheter were brought to the exterior on the MOUTH TO COLON TRANSIT TIME MEASUREMENT left flank. The animals were allowed to recover Orocolonic transit time was determined using a for 10 days before beginning the experiments. rigid probe, 15 cm long and 6 mm in diameter, Gut: first published as 10.1136/gut.32.11.1355 on 1 November 1991. Downloaded from introduced into the colonic lumen through the proximal cannula. At the tip of the probe was a NET COLONIC WATER FLUX MEASUREMENT samarium-cobalt magnet (Bregma 17, Arelec, Saline solution containing a marker specific for Pau, France) and 2 mm behind was a magnetic the liquid phase of the digesta, radioactive field detector (KMZ 10A RTC, Rhonalco, labelled chromium ethylenediaminetetra-acetic Toulouse, France). The value of the magnetic acid (51Cr-EDTA, Dupont de Nemours, field, recorded on a potentiometric recorder Dreieich, Germany), at a concentration of (Linear A86, Strasbourg, France) was constant. approximately 0d1 RCilml, was continuously The animals received 2 g ofiron powder (40-160 infused (24 hours/day) at a constant rate of20 ml/ ,um) mixed with the morning meal. The passage hour through the ileal catheter. Determination of iron particles near the probe changed the of the 51Cr-EDTA concentration in colonic magnetic field produced by the magnet. samples (about 2 g) taken from the two cannulas Orocolonic transit time was defined as the time and in the perfused solution was performed elapsing between ingestion of the meal and the using a y counter (MR 252 C, Kontron, Basel, first change in the magnetic field detected on the Switzerland). Dry weight of colonic samples was recorder. determined by heating about 1 g at 100°C for 24 hours. Net water flux in the colonic segment situated between the two cannulas corresponded MOTILITY RECORDINGS to the difference between the flow of the liquid The electrical activity of the small and large phase of digesta at the level of oral cannula (fl) intestines was recorded with an electro- and the flow ofthe liquid phase at the level ofthe encephalograph (Mini-Huit, Alvar, Montreuil, aboral cannula (f2). Flows were calculated as France) using a short time constant (0.03 second) follows: and a paper speed of 2.4 cm/minute. In addition, FO[C0-(Cl/q1)] concurrent summation of the spiking activity fl= and from three electrode sites was obtained every 20 C,/q, seconds by a linear integrator circuit connected -(CAA2) to a potentiometric recorder (L 6514, Linseis, f=Fo[Co Selb, Germany) with a paper speed of6 cm/hour. CA2 where FO is the rate of51Cr-EDTA infusion, CO is the concentration of 51Cr-EDTA in the perfused EXPERIMENTAL PROCEDURE solution, C, and C2 are the concentrations in the In the first group of pigs, orocolonic transit and http://gut.bmj.com/ samples taken from the oral (C,) and the aboral colonic water absorption were determined by (C2) cannulas and ql and q2 are the percentages taking samples of contents (2 g) through the two of water in the samples taken from the oral (q ) cannulas at two hourly intervals for 10 hours in and the aboral (q2) cannulas. each animal. The first sample was obtained two hours after the morning meal (given at 8 am). In e the second group of pigs, direct records of I wateorpt n E Digesta flow on September 23, 2021 by guest. Protected copyright. intestinal myoelectrical activity were performed for 10 hours after the morning meal, while the 7 Control 75 Loperamide integrated record was continued throughout the day. 5 c Twenty minutes before the morning meal, 3 each animal randomly received placebo or E E * ** * * loperamide (Imodium ND, Janssen, Paris) at a 1 ,Qj 4 M, dose of 0.1 mg/kg, in a capsule mixed with some grams of food. Placebo and loperamide were -1 4 6 8 10 given under the same conditions and diarrhoea was induced by an intraduodenal infusion of a Mannitol 7- hypertonic solution of D-mannitol (360 ml, 900 7 + loperamide mOsm/l) during the first postprandial hour. c 5 E 5 Each experiment was repeated twice in each E animal. Experiments in the same animal were 3 -E 3 + performed at minimal intervals of 72 hours. 1)jjjjf: 4* Values were expressed as mean (SD) and com- 1 1 parisons were performed using the Wilcoxon's t - 1 -1 test for paired values. 2 4 6 8 10 2 4 6 8 10 Hours after meal Results Figure 1: Postprandial pattern ofnet water absorption andflow ofdigesta (liquid phase) in the pigproximal colon (means (SD), n=8). Loperamide (0 1 mglkggiven orally 20 minutes before NET COLONIC WATER ABSORPTION AND flow the meal) decreased water absorption and digesta flow rate. Mannitol (900 mOsm/l infused OF DIGESTA intraduodenally at a rate of6 ml/minutesfor thefirst postprandial hour) decreased or reversed In control studies, two hours after the meal, net water absorption and increased theflow rate. Loperamide given before mannitol attenuated mannitol induced changes but most ofthe values remained significantly lower than in controls. water was absorbed by the colonic segment *tSignificantly different (p<0 05)from control (*) orfrom mannitol (t) values. between the two cannulas at a rate of 0.83 (0.18) Absorptive and motorcomponents ofthe antidiarrhoeal action ofloperamide: an in vivo study inpigs 1357
100 cantly (p<0 05) increased compared with values
observed after mannitol without loperamide but Gut: first published as 10.1136/gut.32.11.1355 on 1 November 1991. Downloaded from 80 * * remained significantly (p<0 05) lower than con- 0- trol values. The flow of colonic digesta was -0 significantly (p<005) reduced compared with a) 60 q Mannitol + loperamide that in pigs given mannitol alone and also compared with controls between hours six and
32-0 (7.3)% ofthe digesta flow during the second In fasted pigs (15 hours after a meal), the myo- http://gut.bmj.com/ postprandial hour to 50.8 (11 1)% during the electrical activity of the small intestine was eighth hour (Fig 2). organised into migrating myoelectric complexes Loperamide, given orally 20 minutes before recurring at 60-90 minute intervals as previously the meal at a dose of 0O1 mg/kg, produced a described.'5 Each migrating myoelectric com- significant (p<005) decrease in the net plex consisted ofirregular spiking activity (phase colonic postprandial water absorption over 10 2) followed by a short (five minute) period of
hours (0.26 (0.20) ml and 0 45 (0.18) ml/minute, intense and regular activity (phase 3). These two on September 23, 2021 by guest. Protected copyright. two and eight hours after the meal respectively). phases of activity were separated by a quiescent Similarly the flow of digesta at the level of the period (phase 1) lasting 20-30 minutes. After proximal cannula was significantly (p<0 05) ingestion of a meal of concentrates (15 g/kg body reduced: 0.90 (0.54) ml/minute and 1.04 (0.39) weight), no phase 3 activity was observed for 174 ml/minute two and eight hours after eating (37) minutes in the duodenum and 132 (28) respectively (Fig 1). In comparison with con- minutes in the jejunum. Migrating myoelectric trols, the relative water absorption, expressed as complexes then recurred with a short phase 1 a percentage ofthe digesta flow, was significantly lasting 5-10 minutes. (p<005) decreased only at six and eight hours (Fig 2). ,- 12 Intraduodenal infusion of a hypertonic 0 - 10 solution of D-mannitol (900 mOsm/l, 6 ml/ a) minute) during the first postprandial hour, *_- 8. induced a profuse diarrhoea, beginning four to six hours after starting the infusion. Absolute and relative colonic water absorption were strongly reduced (0.48 (0.25) ml/minute, 17.5 ., (8.4)%, two hours after eating) or reversed to net water secretion (-0 45 (0.24) ml/minute, -8.0 2 (4 0)%, six hours after the meal). At the same was time, the flow of digesta increased, reaching Control Loperamide Mannitol Mannitol a value of 5.71 (0.34) ml/minutes six hours after + loperamide the meal, which corresponded to an increase of Figure 3: Postprandial mouth to colon transit time (means 79-6% in comparison with controls. (SD), n=8). Loperamide (0 1 mglkg, orally) increased Oral administration ofloperamide (0. 1 mg/kg) orocolonic transit time, while mannitol (900 mOsm/l infused intraduodenally at a rate of6 mllminutefor 1 hour) accelerated prevented the diarrhoea induced by the duo- it. The effect ofmannitol was blocked by previous denal infusion of mannitol. Values of net water administration ofloperamide. *tSignificantly different absorption between hours six and 10 were signifi- (p<005from control (*) orfrom mannitol (f) values. 1358 Theodorou, Fioramonti, Hachet, Bueno
Number ofsmall intestinal phase 3 migrating myoelectric motor complexes and colonic phases of loperamide reduces the postprandial flow of contractile activity during a period of10 hours after a meal (values, means (SD), n=8) digesta entering into the colon and the absolute
Intestinal phase 3 activity net colonic water absorption, while the relative Gut: first published as 10.1136/gut.32.11.1355 on 1 November 1991. Downloaded from Phases of absorption, expressed as the percentage of Duodenum Jejunum colonic motility digesta flow, remains unchanged or is transiently Control 7-7 (0.5) 9-2 (0.5) 84-3 (7.7) reduced. During osmotic diarrhoea, loperamide Loperamide (0-1 mglkg orally) 8-6 (0.6) 13-1 (0.6)* 88-6 (8.5) Mannitol (900 mOsm/l, 6 m/min, intraduodenally) 8-1 (0.5) 9.4 (0.5) 90-1 (8.8) also reduces the flow of digesta but strongly Mannitol after loperamide (0-1 mg/kg orally) 8-8 (0.5) 12-7 (08)* 86-6 (7.4) stimulates both absolute and relative colonic water absorption. The techniques we used for motility studies Intraduodenal infusion of mannitol during the and colonic water absorption measurements first postprandial hour did not change the post- have already been validated." ' The technique prandial pattern ofduodenal and jejunal motility for orocolonic transit time measurement has (Fig 3, Table). When loperamide was given been used for the first time in this study and has orally (0. 1 mg/kg) 20 minutes before the meal, not been validated against another technique. In irrespective of whether or not an intraduodenal control experiments, however, the arrival of the infusion of mannitol was given, the number of first iron particles in the colon was detected 51 episodes ofphase 3 activity determined for the 10 (1 3) hours after the meal and this value is within postprandial hours was significantly increased in the range of transit time values measured with the jejunum (Table, Fig 3) and the first phase 3 different liquid or particulate markers.'61 7 migrating motor complex occurred sooner after Both in vitro58 and in vivo2 '1 studies have the meal (69 (12) minutes in the duodenum and shown that loperamide did not affect or in some 59 (9) minutes in the jejunum). instances stimulate7 basal intestinal fluid absorp- In the caecum and proximal colonj the elec- tion. Our results show that in basal conditions trical activity was characterised by long spike loperamide paradoxically reduced absolute bursts grouped in phases lasting three to five values of net colonic water absorption. This minutes and occurring at a frequency of 8-7 discrepancy may be the result ofdifferent experi- (0.7)/hour (determined for 10 hours after the mental procedures. In studies performed in morning meal). The frequency and duration of humans,2 10 the digestive tract was emptied and the phases of contractile activity did not change perfused at a constant rate with a test solution. after intraduodenal mannitol infusion or when Our study was performed under more normal loperamide was given 20 minutes before a meal physiological conditions since colonic water whether or not followed by intraduodenal absorption was determined in animals whose infusion of mannitol (Table). colons contained digesta, and the rate ofinfusion of the marker into the ileum was negligible in
comparison with the rate of flow of digesta. In a http://gut.bmj.com/ Discussion previous study" we showed a positive correlation Our results indicate that in basal conditions between the net colonic water absorption and the flow of digesta. Indeed, the decrease in absolute water absorption induced by loperamide may be Control 12 [tC a consequence ofthe reduction in the flow rate of .I..1 JIAL. 1 1.1.iii .1 ,1 L,I digesta entering into the colon. This is confirmed
by the fact that the relative water absorption, on September 23, 2021 by guest. Protected copyright. 0 corresponding to the fraction absorbed of the digesta flow, remains unchanged or is slightly decreased. The decrease in colonic flow rate is in agree- Loperamide i ment with that observed through the whole digestive tract in humans."' Moreover, our
a. L -1 .. results indicate that this effect is a consequence of the action of loperamide orad to the colon since it increases orocolonic transit time, as already shown in humans.4 The effects of Mannitol loperamide on orocolonic transit may be attri- buted to a decrease in gastric emptying but it has been shown in humans that loperamide does not - modify gastric emptying.'8 This effect is prob- T Mannitol ably the result of an increase in small intestinal transit time as already shown in humans.2 18 The main effect of loperamide that we + mannitol i observed on small intestinal motility was the induction of supplementary phase 3 motor com- j ma... Aa1 plexes as has already been found in humans in both the fasted23 and fed states.' This effect of 4 Mannitol Meal 1 hour loperamide on the small intestinal motor profile Time has not been found in other animal species such Figure 4: Effect ofloperamide on the postprandial pattern ofjejunal motility. The records of as the dog'2 or the calf'3 indicating that the pig is integrated intestinal myoelectric activity obtained in the same animal indicate that loperamide an adequate animal model in which to investigate (0 1 mglkg given orally 20 minutes before the meal) increased the number ofphase 3 motor complexes after a meal, whether or notfollowed by an intraduodenal infusion ofmannitol (900 the effects ofloperamide. In view of the relations mOsmll 6 mllminute). between the flow ofdigesta and the occurrence of Absorptive and motorcomponents ofthe antidiarrhoeal action ofloperamide: an in vivo study in pigs 1359
migrating myoelectric complexes,'9 we can the mechanisms action of other antidiarrhoeal speculate that the loperamide induced episodes compounds. of phase 3 complexes are responsible for the Gut: first published as 10.1136/gut.32.11.1355 on 1 November 1991. Downloaded from increase in small intestinal transit time. This We thank G Bories, G Galy, and R Theisen for their skilful hypothesis is reinforced by recent data showing technical assistance and C Jean for typing the manuscript. This work was supported by Institut National de la Recherche that pharmacological induction of phase 3 motor Agronomique, Departement de Pathologie Animale. complexes after a meal strongly reduced intestinal propulsion in rats.20 On the other 1 Megens AAHP, Canters LLJ, Awouters FHL, Niemegeers hand, intraduodenal infusion of a hypertonic CJE. Is in vivo dissociation between the antipropulsive and solution ofmannitol increased the colonic rate of antidiarrheal properties of opioids in rats related to gut selectivity? Arch Int Pharmacodyn Ther 1989; 298: 220-9. flow. Since this increase was reduced by 2 Kachel G, Ruppin H, Hagel J, Barina W, Meinhardt M, loperamide, which induced intestinal phase 3 Domschke W. Human intestinal motor activity and trans- port: effects of a synthetic opiate. Gastroenterology 1986; 90: motor complexes, the hypothesis that it has a role 85-93. in blocking phase 3 complexes is supported. 3 Remington M, Malagelada JR, Zinsmeister A, Fleming CR. Abnormalities in gastrointestinal motor activity in patients In our study, loperamide had no effect on with short bowels: effects of a synthetic opiate. Castro- colonic motility, but long lasting colonic enterology 1983; 85: 629-36. 4 Basilisco G, Bozzani A, Camboni G, et al. Effects of stimulation has been described in dogs.'2 This loperamide and naloxone on mouth-to-caecum transit time corresponds to the large differences between evaluated by lactulose hydrogen breath test. Gut 1985; 26: in the action of opiates on colonic 700-3. species 5 Hugues S, Higgs NB, Turnberg LA. Antidiarrhoeal activity of motility. 21 loperamide: studies of its influence on ion transport across of action of loperamide in rabbit ileal mucosa in vitro. Gut 1982; 23: 974-9. The mechanism 6 Farack UM, Kautz U, Loeschke K. Loperamide reduces the health and in diarrhoea is based upon the positive intestinal secretion but not the mucosal cAMP accumulation between the flow of colonic digesta induced by cholera toxin. Naunyn Schmiedebergs Arch correlation Pharmacol 1981; 317: 178-9. and the net colonic water absorption" and upon 7 Farack UM, Loeschke K. Inhibition by loperamide of and Phillips,22 which deoxycholic acid induced intestinal secretion. Naunvn the theory of Debongnie Schmiedebergs Arch Pharmacol 1984; 325: 286-9. indicates that diarrhoea occurs when the capacity 8 Beubler E, Lembeck F. Inhibition of stimulated fluid colon to absorb fluid is overcome by an secretion in the rat small and large intestine by opiate of the agonists. Naunyn Schmiedebergs Arch Pharmnacol 1979; 306: input offluid that is above a critical value. In our 113-8. model in loperamide induced 9 Hardcastle J, Hardcastle PT, Read NW, Redfern JS. The experimental pigs, action of loperamide in inhibiting prostaglandin-induced phase 3 motor complexes which slowed down intestinal secretion in the rat. Br 7 Pharmacol 1981; 74: intestinal transit, reduced the colonic rate 563-9. 10 Schiller LR, Santa Ana C, Morawski SG, Fordtran JS. of flow, and consequently reduced absolute Mechanism ofthe antidiarrheal effect of loperamide. Gastro- net colonic water absorption. Intraduodenal enterology 1984; 86: 1475-80. 11 Theodorou V, Fioramonti J, Bueno L. Water absorption from infusion ofhypertonic mannitol in pigs increased the pig proximal colon: relations with feeding and flow of colonic input above the critical value and led to digesta. Qj Exp Physiol 1989; 74: 521-9.
12 Fioramonti J, Fargeas MJ, Bueno L. Stimulation of gastro- http://gut.bmj.com/ diarrhoea. This cannot, however, explain by intestinal motility by loperamide in dogs. Dig Dis Sci 1987; the reduction in net water absorption. After 32: 641-6. itself 13 Fioramonti J, Bueno L. Effects of loperamide hydrochloride mannitol infusion the colonic transit was prob- on experimental diarrhoea and gastrointestinal myoelectrical accelerated since diarrhoea occur- activity in calves. AmJ Vet Res 1987; 48: 415-9. ably strongly 14 Ruckebusch Y. The electrical activity of the digestive tract of red four to six hours after the end of infusion the sheep as an indication ofthe mechanical events in various normal mean retention time of digesta regions. J Physiol 1970; 210: 857-82. while the 15 Ruckebusch Y, Bu6no L. The effect of feeding on the motility through the pig's colon averages 40 hours. ofthe stomach and small intestine in the pig. BrJ7 Nutr 1976; as in some diarrhoeal 35: 397-405. on September 23, 2021 by guest. Protected copyright. Consequently, proposed 16 Ishikawa S, Sugimura K. Movement of polyvinylalcohol diseases,23 too rapid transit does not allow normal through the digestive tract as a digestion indicator with absorption of water because the minimum swine. Agricultural and Biological Chemistry 1973; 37: 203-6. 17 Clemens ET, Stevens CE, Southworth M. Sites of organic acid exposure time of the contents to the absorptive production and pattern of digesta movement in the gastro- surface of the colon is not reached. By slowing intestinal tract of swine. 7 Nutr 1975; 105: 759-68. 18 Sninsky CA, Davis RH, Clench MH, Thomas KT, Mathias down small intestinal transit, loperamide JR. Effect of lidamidine hydrochloride and loperamide on reduced colonic flow, restored normal water gastric emptying and transit of the small intestine. A double- blind study. Gastroenterology 1986; 90: 68-73. absorption, and abolished diarrhoea. After a 19 Bueno L, Fioramonti J, Ruckebusch Y. Rate offlow of digesta delay of four hours, however, the relative water and electrical activity of the small intestine in dogs and sheep. J Physiol 1975; 249: 69-85. absorption, which corresponds to the fraction 20 Fargeas MJ, Fioramonti J, Bueno L. Central and peripheral of the digesta flow absorbed, was strongly actions of adenosine and its analogues on intestinal myoelectric activity and propulsion in rats. ] Gastrointest increased. This proabsorptive action is in agree- Motility 1990; 2: 121-7. ment with the efficacy of loperamide in chronic 21 Fioramonti J, Niemegeers CJ, Awouters F. Diarrhea and antidiarrheal drugs. In: Ruckebusch Y, Toutain PL, Koritz diarrhoea24 which cannot be explained by an GD, eds. Veterinary pharmacology and toxicology. Lancaster: action only on motility and transit time. MTP Press, 1983: 283-98. 22 Debongnie JC, Phillips SF. Capacity of the human colon to In conclusion, loperamide abolishes experi- absorb fluid. Gastroenterology 1978; 74: 698-703. mental osmotic diarrhoea by acting on small 23 Read NW, Miles CA, Fisher D, et al. Transit ofa meal through the stomach, small intestine, and colon in normal subjects intestinal motility, and consequently reducing and its role in pathogenesis of diarrhea. Gastroenterology the flow entering the colon, and then by stimulat- 1980; 79: 1276-82. 24 Pelemans W, Vantrappen G. A double blind crossover com- ing colonic water absorption. Moreover, the pig parison of loperamide with diphenoxylate in the sympto- model can be considered as one of the most matic treatment of chronic diarrhea. Gastroenterology 1976; 70: 1030-4. suitable for determining human digestive 25 Miller ER, Ullrey DE. The pig as a model for human nutrition. physiology25 and should be used to investigate Annu Rev Nutr 1987; 7: 361-82