A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of dual ACE/NEP inhibitor GW660511X in mild-to-moderate hypertensive patients

Abstract

This multicentre, double-blind, placebo-controlled, parallel-group study determined the efficacy and safety of GW660511 200 mg, a dual inhibitor of angiotensinconverting enzyme (ACE) and neutral endopeptidase (NEP), in mild-to-moderate hypertensive patients (diastolic blood pressure (DBP), X90 and p109 mm Hg; systolic blood pressure (SBP), X150 and p180 mm Hg). After a single-blind 2-to 4-week placebo run-in period, 123 patients (aged 18-65 years) were randomized to either placebo (n ¼ 62) or to active treatment (n ¼ 61) consisting of two consecutive 3-day dose titration periods of GW660511X 50 mg once daily and 100 mg once daily followed by GW660511X 200 mg once daily for 14 days. GW660511X 200 mg significantly lowered (baseline and placebo-corrected) both trough mean cuff SBP (À8.00 mm Hg, P ¼ 0.002) and DBP (À5.38 mm Hg, P ¼ 0.003). GW660511X 200 mg significantly reduced placebo-corrected mean 24-h and daytime but not night-time ambulatory SBP and DBP. Over the 0-24 h time period following GW660511X 200 mg, there were significant (Po0.001) reductions in serum ACE activity and significant (Po0.001) increases in plasma ANP concentration compared with placebo in terms of both peak and trough effects. In addition, treatment with GW660511X 200 mg significantly (P ¼ 0.003) increased (placebo-corrected, 1.52-fold) urinary excretion of cGMP over the 0-24 h interval. Treatment-related adverse events were experienced by 43% of the patients administered GW660511X 200 mg and 44% of those dosed with placebo with headache the most commonly reported. In conclusion, GW660511X 200 mg is an effective antihypertensive in mild-to-moderate hypertensive patients with potent effects on biological markers of ACE and NEP inhibition.

Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin‐mediated angioedema

“…Interestingly, the novel dual ACE/NEP inhibitor, GW660511X, with no activity against APP, elicited no angioedema in a small clinical trial. However, this compound was not efficacious at inducing a reduction in blood pressure ( Jandeleit‐Dahm, 2006 ; Johnson et al , 2006 ). Thus, whether concomitant inhibition of APP is necessary to achieve robust blood pressure‐lowering effects with ACE/NEP inhibitors is presently unknown.…”

Concomitant Angiotensin AT1 Receptor Antagonism and Neprilysin Inhibition Produces Omapatrilat-like Antihypertensive Effects Without Promoting Tracheal Plasma Extravasation in the Rat

“…13 To date, attempts to develop other vasopeptidase inhibitors (with varying ACE/NEP potency ratios) have not been successful, and these attempts seem to have been abandoned. 14,15 The angioedema caused by ACE inhibitors and ACE-NEPI occurs with low frequency (0.68% and 2.17% of patients, respectively) but can be life threatening if it involves the upper airways, at times requiring surgical intubation. 13 Although the exact reason for the susceptibility of certain patients to angioedema is unclear, metabolism of bradykinin, which increases microvascular permeability, is believed to be a major causative factor.…”

“…Other zinc-containing metalloproteases such as aminopeptidase P (APP), NEP and dipeptidyl peptidase IV(DPP-IV) also play a role in bradykinin metabolism. [11][12][13][14][15][22][23][24][25] Recently, Fryer et al 26 using bradykinin-evoked hypotensive response in rats as an end point, demonstrated that the rank order for different peptidases in bradykinin metabolism is ACE . APP .. NEP = DPP-IV.…”

Cardiac biomarkers: myths, facts and future horizons

“…Some controversy still exists around the role of natriuretic peptides to guide medical treatments, although this is feasible in some settings [16].…”