Naloxone-reversible antidiarrheal effects of enkephalinase inhibitors

Marcais-Collado, H.; Uchida, Genevieve; Costentin, Jean; Schwartz, Jean‐Charles; Lecomte, Jeanne‐Marie

doi:10.1016/0014-2999(87)90510-3

Cited by 45 publications

(35 citation statements)

References 28 publications

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“…In contrast, acetorphan (3,4), like other enkephalinase inhibitors (3,16) and delta opioid receptor agonists (17), is devoid of antitransit effect in rodents. Its antidiarrhoeal activity seems to result primarily from an antisecretory mechanism, directly evidenced in cholera toxin-treated dogs ( 5 ) and, indirectly, in human volunteers by its efficacy in an experimental model of 'secretory' diarrhoea (7), associated with a lack of antitransit effect (6).…”

Section: Discussionmentioning

confidence: 92%

The Enkephalinase Inhibitor, Acetorphan, in Acute Diarrhoea: A Double-Blind, Controlled Clinical Trial versus Loperamide

Rogé

Bäumer²,

Bérard³

et al. 1993

Scandinavian Journal of Gastroenterology

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The antidiarrhoeal properties of acetorphan, an inhibitor of enkephalinase (EC 3.4.24.11) that prevents endogenous enkephalin degradation, and loperamide, a mu opiate receptor agonist, were compared. The double-blind study included 69 patients with acute diarrhoea of presumed infectious origin, allocated at random to two parallel groups. Acetorphan and loperamide were both rapidly and similarly effective, diarrhoea resolving in both cases in nearly 2 days. With acetorphan, however, abdominal distension vanished significantly more rapidly, and reactive constipation was less frequent (8% versus 31% with loperamide). These differences can be accounted for by the distinct mechanisms of antidiarrhoeal activity of the two drugs--that is, primary antitransit effect for loperamide and antisecretory activity for acetorphan.

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Section: Discussionmentioning

confidence: 92%

The Enkephalinase Inhibitor, Acetorphan, in Acute Diarrhoea: A Double-Blind, Controlled Clinical Trial versus Loperamide

Rogé

Bäumer²,

Bérard³

et al. 1993

Scandinavian Journal of Gastroenterology

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“…This protection presumably occurs at the level of peripheral tissues because (i) acetorphan given by oral route is readily hydrolysed into the active inhibitor thiorphan21 which does not cross the blood brain barrier9 20; (ii) in rats enkephalinase inhibitors are devoid of antidiarrhoeal activity when administered intracerebroventricularly and, when administered intraperitoneally, their action is not blocked by intracerebroventricular naloxone. 27 The diarrhoea induced by castor oil, which appears to result from changes in fluid and electrolyte transport39`4 and not from stimulation of gastrointestinal smooth muscle contractility,4' 42 seems a valid model of experimental hypersecretory diarrhoea. Accordingly delta p<O-01; tp<0-001.…”

Section: Discussionmentioning

confidence: 99%

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

Bäumer

Dorval

et al. 1992

Gut

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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.

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“…of racecadotril or thiorphan or 0.5 mg/kg oral loperamide also did not significantly affect transit time, whereas 10 mg/kg oral or 0.5 mg/kg i.v. loperamide significantly prolonged it (Marcais-Collado et al, 1987). A potential consequence of effects on gastro-intestinal transit time was explored in newborn piglets, in which a 4-day oral treatment with 20 mg/kg racecadotril twice daily did not significantly affect E. coli content of the proximal jejunum, whereas 1 mg/kg oral loperamide twice daily markedly increased it; accordingly, the E. coli content of the stool was significantly reduced by loperamide but not by racecadotril (Duval-Ilfah et al, 1999).…”

Section: Studies In the Gastro-intestinal Tractmentioning

confidence: 99%

“…thiorphan; they were blocked by subcutaneous but not by i.c.v. naloxone, indicating that the opioid receptors mediating this effects are located peripherally (Marcais-Collado et al, 1987). Racecadotril also reduced castor oil-induced diarrhea in human volunteers in a placebo-controlled study (Baumer et al, 1992).…”

Section: Studies In the Gastro-intestinal Tractmentioning

confidence: 99%

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A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril

2012

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Racecadotril, via its active metabolite thiorphan, is an inhibitor of the enzyme neutral endopeptidase (NEP, EC 3.4.24.11), thereby increasing exposure to NEP substrates including enkephalins and atrial natriuretic peptide (ANP). Upon oral administration racecadotril is rapidly and effectively converted into the active metabolite thiorphan, which does not cross the blood–brain-barrier. Racecadotril has mainly been tested in animal models and patients of three therapeutic areas. As an analgesic the effects of racecadotril across animal models were inconsistent. In cardiovascular diseases such as hypertension or congestive heart failure results from animal studies were promising, probably related to increased exposure to ANP, but clinical results have not shown substantial therapeutic benefit over existing treatment options in cardiovascular disease. In contrast, racecadotril was consistently effective in animal models and patients with various forms of acute diarrhea by inhibiting pathologic (but not basal) secretion from the gut without changing gastro-intestinal transit time or motility. This included studies in both adults and children. In direct comparative studies with loperamide in adults and children, racecadotril was at least as effective but exhibited fewer adverse events in most studies, particularly less rebound constipation. Several guidelines recommend the use of racecadotril as addition to oral rehydration treatment in children with acute diarrhea.

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Naloxone-reversible antidiarrheal effects of enkephalinase inhibitors

Cited by 45 publications

References 28 publications

The Enkephalinase Inhibitor, Acetorphan, in Acute Diarrhoea: A Double-Blind, Controlled Clinical Trial versus Loperamide

The Enkephalinase Inhibitor, Acetorphan, in Acute Diarrhoea: A Double-Blind, Controlled Clinical Trial versus Loperamide

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

A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril

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