Effects of acetorphan, an enkephalinase inhibitor, on experimental and acute diarrhoea.

Abstract

Acetorphan is an orally active inhibitor of enkephalinase (EC 3.4.24.11) with antidiarrhoeal activity in rodents apparently through protection of endogenous enkephalins and a purely antisecretory mechanism. Its antidiarrhoeal activity in man was assessed in an experimental model of cathartic induced secretory diarrhoea as well as in acute diarrhoea. of presumed infectious origin. In six healthy volunteers receiving castor oil and pretreated with acetorphan or placebo in a crossover controlled trial, the drug significantly decreased the number and weight of stools passed during 24 hours. About 200 outpatients with severe acute diarrhoea (more than five stools per day) were included in a randomised double blind study of acetorphan against placebo. The significant antidiarrhoeal activity of acetorphan was established using a variety of criteria: (i) the duration of both diarrhoea and treatment were diminished; (ii) no acetorphan treated patient withdrew from the study whereas five dropped out because of worsening in the placebo group; (iii) the frequency of symptoms associated with diarrhoea -for example, abdominal pain or distension, nausea and anorexia -remaining after two weeks was nearly halved; (iv) using visual analogue scales acetorphan treatment was found more effective than placebo by both investigators and patients. There was statistically no significant difference between acetorphan and placebo in respect of side effects, particularly constipation, which often accompanies the antidiarrhoeal activity of mu opioid receptor agonists this difference is attributable to the lack of antipropulsive activity of acetorphan in man. The efficacy and tolerance of acetorphan suggest that enkephalinase inhibition may represent a novel therapeutic approach for the symptomatic management of acute secretory diarrhoea without impairing intestinal transit.

Racecadotril Efficacy in the Symptomatic Treatment of Adult Acute Diarrhoea: A Systematic Review and Meta-Analysis

“…The excluded studies were: duplicate or translation of previous published trials [15], and review or meta-analysis [16]- [18], studies performed in infants or in children, in patients suffering from cholera [19], from HIV-related chronic diarrhoea [20] [21] or from subacute or recurrent diarrhoea induced by anticancerous chemotherapy [22]- [26] studies comparing 100 mg capsules RC to domestic Chinese 100 mg RC [27], to the RC isomer, dexecadotril [28], and to 175 mg tablets RC [29]- [31], due to the lack of a third comparator.…”

“…The initial dosing regimen of RC in the first randomized clinical trial performed in adults suffering from acute diarrhoea [35], was: "two capsules at first, followed by one capsule after each unformed stool, with treatment lasting until production of the first formed stool, up to 10 days". This regimen differs from the dosages in the next trials and from recommended dosages in SmPC, but the number of RC capsules ingested, day by day, were very closed to the number of capsules if SmPC dosage was prescribed: 4.3 ± 2.1 on day 1 (instead of 4), 2.8 ± 1.9 on day 2 (instead of 3).…”

“…Loperamide doses differ from SmPC dose and seem to be not optimized: During Rogé study [35], loperamide doses (1.33 mg per capsule, two capsules initially, followed by 2 capsules during the next 12 hours, thereafter, one capsule 3 times a day until recovery) seem to be not optimized. But this dosage induced similar efficacy (for instance, time to recovery was 2.2 ± 0.2 days in the RC group and 2.3 ± 0.2 days in the loperamide group), and significantly worse tolerance as compared to RC group: secondary constipation was significantly more frequent in the loperamide group (31.3% vs. 8.1%, p < 0.02).…”

“…Miscellaneous definitions were adopted within RCTs, from 48 hours without any stool [39] to a reported adverse event [35] [40]- [42], [Lin Sanren & Coulden: personal data]. As previously discussed, frequency of antitransit complications are too low to be compared within hundreds of patients.…”

A Three-dimensional Model of the Neprilysin 2 Active Site Based on the X-ray Structure of Neprilysin

“…thiorphan (21)(22)(23)(24). These functions of NEP and the design of specific inhibitors thereof are of considerable interest, because the inhibitors of NEP have recently been introduced in human gastroenterologic (25) and cardiovascular (26) therapeutic fields.…”