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Effects of Acetorphan, an Enkephalinase Inhibitor, On Gut, 1992, 33, 753-758 753 Effects ofacetorphan, an enkephalinase inhibitor, on experimental and acute diarrhoea Gut: first published as 10.1136/gut.33.6.753 on 1 June 1992. Downloaded from Ph Baumer, E Danquechin Dorval, J Bertrand, J M Vetel, J C Schwartz, J M Lecomte Abstract and reduce the discomfort. Their beneficial Acetorphan is an orally active inhibitor of effect, however, has become a matter of contro- enkephalinase (EC 3.4.24.11) with antidiar- versy in view of their limited efficacy and poten- rhoeal activity in rodents apparently through tial side effects. These drugs disrupt forward protection of endogenous enkephalins and a propulsive motility, increase capacitance of the purely antisecretory mechanism. Its antidiar- gut and delay passage of fluid through the rhoeal activity in man was assessed in an intestine allowing, in turn, more time for net experimental model of cathartic induced absorption of water and electrolytes to occur.68 secretory diarrhoea as well as in acute diar- The fact that their antidiarrhoeal activity is rhoea. of presumed infectious origin. In six always associated with an antimotility effect is healthy volunteers receiving castor oil and probably responsible for some of the major pretreated with acetorphan or placebo in a gastrointestinal side effects - that is, pooling of crossover controlled trial, the drug signific- fluid in the distended bowel lumen and enhance- antly decreased the number and weight of ment of bacterial colonisation.8"'3 This has led to stools passed during 24 hours. About 200 the idea that antidiarrhoeal drugs with a purely outpatients with severe acute diarrhoea (more mucosal antisecretory activity, should lead to a than five stools per day) were included in a therapeutic improvement.3 Two main strategies randomised double blind study of acetorphan were used to reach this aim: design weak a2- against placebo. The significant antidiarrhoeal adrenergic receptor blocks devoid of cardiovas- activity of acetorphan was established using a cular effects'45 and enkephalin like pentapep- variety of criteria: (i) the duration of both tides'"'8 but, so far, the resulting investigational diarrhoea and treatment were diminished; (ii) drugs have not gained therapeutic application. no acetorphan treated patient withdrew from Another strategy was recently suggested the study whereas five dropped out because of by the observations that inhibition of enkepha- http://gut.bmj.com/ worsening in the placebo group; (iii) the fre- linase (membrane metalloendopeptidase, EC quency ofsymptoms associated with diarrhoea 3.4.24.11) delays the inactivation of endogenous - for example, abdominal pain or distension, enkephalins in the brain which, in turn, results nausea and anorexia - remaining after two in a series of naloxone reversible biological weeks was nearly halved; (iv) using visual responses.'9 21 The peptidase is present all along analogue scales acetorphan treatment was the gastrointestinal tract2223 and its inhibition found more effective than placebo by both delays the inactivation of exogenous enkephalins on September 23, 2021 by guest. Protected copyright. investigators and patients. There was statistic- by the guinea pig ileum.2>26 Moreover, enkepha- ally no significant difference between acetor- linase inhibitors exert potent, naloxone revers- phan and placebo in respect of side effects, ible antidiarrhoeal activity in the rodent castor Laboratoire Bioprojet, particularly constipation, which often accom- oil induced model of diarrhoea.2728 Interestingly, Marnes la Coquette, panies the antidiarrhoeal activity of mu opioid this action was not associated with any detectable France this difference is attribut- antitransit effect,27 30 which clearly differentiates Ph Baumer receptor agonists J M Lecomte able to the lack of antipropulsive activity of this class of compounds from mu opiate receptor acetorphan in man. The efficacy and tolerance agonists.3'-36 Centre Hospitalier of acetorphan suggest that enkephalinase In the present study we have assessed the Universitaire Trousseau, Tours, France inhibition may represent a novel therapeutic antidiarrhoeal activity of the enkephalinase E Danquechin Dorval approach for the symptomatic management of inhibitor acetorphan in man in two randomised J Bertrand acute secretory diarrhoea without impairing placebo controlled double blind trials. The first trial on six healthy volunteers Centre Hospitalier intestinal transit. was a crossover Regional, Le Mans, receiving castor oil, a validated model of experi- France mental 'secretory' diarrhoea in man,'6 37 whereas J M Vetel It is generally admitted that acute infectious the second one was a parallel study on two groups Unite de Neurobiologie et diarrhoea is accompanied with an abnormality of ofabout 100 patients each attending their general Pharmacologie, Centre intestinal water and electrolyte transport. ' As a practitioners for severe acute diarrhoea of pre- Paul Broca de l'Institut with replacement of sumed infectious origin. National de la Sante et de consequence rehydration la Recherche Medicale, electrolytes are accepted as the most important Paris, France therapeutic measures. Antimicrobial agents are J C Schwartz also of value in diarrhoea caused by identified Methods Correspondence to: intestinal protozoa but are essentially ineffective Dr J C Schwartz, Unite de Neurobiologie et in the treatment of viral enteric infections which STUDY I: CASTOR OIL INDUCED DIARRHOEA Pharmacologie de l'Institut constitute most cases of acute diarrhoea.245 In National de la Sante et de la Recherche Medicale, Centre addition, mu opiate receptor agonists such as SUBJECTS Paul Broca, 2ter rue d'Alesia, opium derived preparations, diphenoxylate or Six healthy volunteers, three men, three women, 75014 Paris, France. are used to shorten the dura- aged 21 (3) years, with no reported digestive Accepted for publication loperamide widely 16 September 1991 tion of the disease, relieve a variety of symptoms abnormality, particularly no intestinal transit 754 Baumer, Danquechin Dorval, Bertrand, Vetel, Schwartz, Lecomte disorder, and not receiving any drug treatment, TREATMENT were selected. Their mean (SEM) body weights Identical capsules containing 100 mg either were 61-0 (3.7) kg (68 (4) kg for men, 54 (3) kg accetorphan or lactose (placebo) were supplied. for women). Written informed consent was Each patient was assigned a sequential study Gut: first published as 10.1136/gut.33.6.753 on 1 June 1992. Downloaded from obtained and the study was approved by the local number and corresponding bottle containing 60 Ethical Committee. capsules. Treatment had been previously randomised using a random number table with groups of four. STUDY DESIGN Patients were given two capsules at the start of The study was a double blind, randomised, the study and were instructed to take one capsule placebo controlled crossover study ofthe preven- after each unformed bowel movement. Drug tion by acetorphan ofdiarrhoea elicited by a fixed administration was continued until recovery, dose of castor oil. The study comprised two defined as the disappearance of any unformed sessions, performed at one week intervals, stool, or for a maximum of 10 days. The remain- during which the subjects received placebo and ing capsules were returned to the investigators acetorphan capsules in a randomised order. and were counted to determine the actual Neither the subjects nor the clinicians were number of capsules ingested. No other new aware of the nature of treatment. treatment was allowed during the trial, except In the morning ofeach session, generally after for paracetamol. one spontaneous stool, each subject absorbed five capsules and, 45 minutes later, 30 g castor oil (French Pharmacopoeia). The time and weight STUDY DESIGN of each stool was then determined during the The patients were seen twice by clinicians not following 24 hours. informed of the nature oftreatments: for the first The capsules for the placebo session contained time at inclusion (visit 1) and 10-14 days later 200 mg lactose and were undiscernible from (visit 2). For each patient the clinicians had a case those containing acetorphan for which a dosage report form to complete at visits 1 and 2. It close to 10 mg/kg of body weight was selected. included a specific questionnaire with a report of The actual acetorphan dosage received by the clinical examinations. The clinicians remained subjects was 11 1 (4.2) mg/kg, a dosage eliciting blind all over the study. more than 50% inhibitions of plasma enkepha- Patients were requested to keep a diary in linase for at least six hours. which the following information was reported: All side effects were recorded during the 24 time, number and characters of bowel move- hour experimental period. ments, number of capsules taken, possible http://gut.bmj.com/ adverse affects, and their global evaluation of the treatment visual scales 0= STATISTICAL ANALYSIS using analogic (from The evaluation criteria were the cumulative no efficacy, to 100=excellent efficacy). Patients weights of stools, the total number of stools were asked to bring back the diary and remaining during the experimental 24 hour period and the capsules at visit 2 and both were checked by the delay between administration of the cathartic clinicians. and the first stool passage. Data were expressed The duration of diarrhoea was defined as the on September 23, 2021 by guest. Protected copyright. as means (SEM) and analysed by analysis of time from the first dose of the trial drug
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