The results obtained from this cohort indicate that thiopurine use during pregnancy is not associated with increased risks, including congenital abnormalities.

Atrial natriuretic factor (ANF) might be beneficial in several cardiovascular disorders, but its poor oral absorption and rapid inactivation in vivo have so far prevented its use in therapeutics. We have assessed the role of enkephalinase (membrane metallo-endopeptidase, EC 3.4.24.11) in the in vivo inactivation of ANF in mice and healthy human volunteers by evaluating the effects of acetorphan, a potent inhibitor.In mice, the degradation of 125I-labeled ANF was markedly delayed, as shown by the levels of the intact peptide in the plasma and the kidney, a major target organ. The effect of acetorphan was due to the inhibition of enkephalinase activity, since it occurred at an EDs5 very close to this drug's ID50 for the inhibition of the specific binding of radioactive material to the kidney or lung peptidase that was measured after administration of [3H]acetorphan. The effects ofacetorphan were also studied in eight healthy human volunteers by using a randomized double-blind, placebo-controlled design. Oral administration of acetorphan elicited a lasting elevation of plasma ANFlike immunoreactivity, with a time course parallel to that of the inhibition of plasma enkephalinase activity. These effects were accompanied by significant increases in urinary volume and sodium excretion, two well-established renal responses to ANF peptides. These results indicate that enkephalinase plays a critical role in ANF degradation in vivo and that its inhibition enhances the levels of circulating endogenous ANF, which, in turn, results in diuresis and natriuresis. Enkephalinase inhibition may constitute another therapeutic approach to the treatment of cardiovascular diseases, such as congestive heart failure or essential hypertension, on which ANF is postulated to have a beneficial effect.

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.

Background Racecadotril (acetorphan), a potent enkephalinase inhibitor, protects endogenous enkephalins from degradation. Racecadotril exhibits experimental and clinical antidiarrhoeal activity without any effect on intestinal motility, suggesting selective antisecretory activity. The antisecretory effect of racecadotril was directly assessed in the present study. Methods A 1 m, jejunal, Thiry–Vella loop was created in six mongrel dogs, and water and ionic fluxes were evaluated during infusion (2 mL/min) of Tyrode solution labelled with 14C‐polyethylene glycol. Fluxes were determined both in the basal state and 5–6 h after commencement of a 2‐h infusion of cholera toxin (0.4 μg/mL). Racecadotril (10 mg/kg) or vehicle was given orally with and without prior intravenous administration of naloxone (0.1 mg/kg) or phentolamine (0.2 mg/kg). Results Basal absorption remained unchanged following racecadotril administration; however, racecadotril significantly decreased (P = 0.01) cholera toxin‐induced water, sodium, and potassium hypersecretion, from 0.73 ± 0.15 to 0.37 ± 0.13 mL/min; from 125.0 ± 16.1 to 14.7 ± 9.5 μMol/min; and from 3.41 ± 0.66 to 1.66 ± 0.61 μMol/min, respectively. This antisecretory activity of racecadotril was suppressed by naloxone but not by phentolamine. Conclusions This study directly demonstrates the antisecretory activity of racecadotril in relation to the protection of endogenous enkephalins.