The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans

Aims - Inhibition of neutral endopeptidases (NEP) results in a beneficial increase in plasma concentrations of natriuretic peptides such as ANP. However NEP inhibitors were ineffective anti-hypertensives, probably because NEP also degrades vasoconstrictor peptides, including endothelin-1 (ET-1). Dual NEP and endothelin converting enzyme (ECE) inhibition may be more useful. The aim of the study was to determine whether SLV-306 (daglutril), a combined ECE/NEP inhibitor, reduced the systemic conversion of big ET-1 to the mature peptide. Secondly, to determine whether plasma ANP levels were increased. Main methods - Following oral administration of three increasing doses of SLV-306 (to reach an average target concentration of 75, 300, 1200 ng ml− 1 of the active metabolite KC-12615), in a randomised, double blinded regime, big ET-1 was infused into thirteen healthy male volunteers. Big ET-1 was administered at a rate of 8 and 12 pmol kg− 1 min− 1 (20 min each). Plasma samples were collected pre, during and post big ET-1 infusion. ET-1, C-terminal fragment (CTF), big ET-1, and atrial natriuretic peptide (ANP) were measured. Key findings - At the two highest concentrations tested, SLV-306 dose dependently attenuated the rise in blood pressure after big ET-1 infusion. There was a significant increase in circulating big ET-1 levels, compared with placebo, indicating that SLV-306 was inhibiting an increasing proportion of endogenous ECE activity. Plasma ANP concentrations also significantly increased, consistent with systemic NEP inhibition. Significance - SLV-306 leads to inhibition of both NEP and ECE in humans. Simultaneous augmentation of ANP and inhibition of ET-1 production is of potential therapeutic benefit in cardiovascular disease

The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.

Background Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI. Purpose We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H2RAs) and CDI. Data source We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H2RAs and CDI. Study selection Two authors independently reviewed the studies for eligibility. Data extraction Data about studies characteristics, adjusted effect estimates and quality were extracted. Data synthesis Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H2RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22–1.7), I2 = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15–1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H2RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097). Conclusion In this rigorous systematic review and meta-analysis, we observed an association between H2RAs and CDI. The absolute risk of CDI associated with H2RAs is highest in hospitalized patients receiving antibiotics