Life sciences
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Randomized Controlled Trial
The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans.
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. ⋯ 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.
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Randomized Controlled Trial
Clinical efficacy of the selective endothelin A receptor antagonist, atrasentan, in patients with diabetes and chronic kidney disease (CKD).
Progression of chronic kidney disease (CKD) in patients with diabetes is a growing problem. Diabetes is associated with elevated endothelin-1 (ET-1) and enhanced renal expression of the endothelin A receptor (ETAR). Atrasentan, a highly selective ETAR antagonist, reduces albuminuria in patients with DN. KEY METHODS: This was a randomized, double-blind trial of subjects with type 2 diabetes on renin-angiotensin system (RAS) inhibitors having eGFR >20 ml/min, and urine albumin-to-creatinine ratio (UACR) of 100-3000 mg/g, who were allocated to placebo, 0.25, 0.75 or 1.75 mg atrasentan. ⋯ Edema formation was dose-dependent and occurred early. The decrease in urine NGAL warrants further study in renal tubular disease attenuation. UACR responses based on ethnicity need further characterization. Results suggest atrasentan may have additive effects to RAS inhibition in treatment of DN.