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Absorptive and Motor Components Ofthe Antidiarrhoeal Action of Loperamide

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Absorptive and Motor Components Ofthe Antidiarrhoeal Action of Loperamide 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.
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