Omapatrilat Compared With Lisinopril in Treatment of Hypertension as Assessed by Ambulatory Blood Pressure Monitoring

Asmar, Roland; Fredebohm, W.; Senftleber, I.; Chang, Peng; Gressin, Virginie; Saini, R.P.

doi:10.1097/00004872-200006001-00316

Cited by 14 publications

(15 citation statements)

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“…12,13,25 Preliminary investigations conducted with omapatrilat have shown that this compound effectively lowers blood pressure. 12,13 In accordance with these observations, we found that even though the study was conducted in normotensive subjects, both doses of omapatrilat lowered blood pressure, and the effect of the 80 mg dose was significantly greater than that obtained with the FOS/HCTZ combination. The fall in blood pressure induced by omapatrilat was dose-dependent and persisted during repeated administration.…”

Section: Systemic and Renal Hemodynamic Effectsmentioning

confidence: 99%

“…9 Thus, omapatrilat simultaneously decreases angiotensin II generation by inhibiting ACE activity and reduces the metabolic degradation of natriuretic peptides by inhibiting NEP. In experimental hypertension, omapatrilat has been found to lower blood pressure in low-, normal-, and high-renin hypertension models, 10,11 and in humans, preliminary dose-finding studies have shown that omapatrilat reduces blood pressure dose-dependently at doses ranging between 5 and 80 mg. 12,13 Experimental and preliminary clinical studies also suggest that omapatrilat has favorable effects in heart failure. 10,14,15 Because of its ability to inhibit angiotensin II generation and to prevent the degradation of natriuretic peptides, oma-patrilat is expected to have a major impact on renal function, particularly on sodium excretion.…”

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confidence: 99%

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Renal Hemodynamic and Natriuretic Effects of Concomitant Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Men

et al. 2002

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Abstract-This double-blind placebo-controlled study was designed to investigate the acute and sustained hormonal, renal hemodynamic, and tubular effects of concomitant ACE and neutral endopeptidase (NEP) inhibition by omapatrilat, a vasopeptidase inhibitor, in men. Thirty-two normotensive subjects were randomized to receive a placebo, omapatrilat (40 or 80 mg), or the fosinopril/hydrochlorothiazide (FOS/HCTZ; 20 and 12.5 mg, respectively) fixed combination for 1 week. Blood pressure, renal hemodynamics, urinary electrolytes and atrial natriuretic peptide excretion, and several components of the renin-angiotensin system were measured for 6 hours on days 1 and 7 of drug administration. When compared with the placebo and the FOS/HCTZ combination, omapatrilat induced a significant decrease in plasma angiotensin II levels (PϽ0.001 versus placebo; PϽ0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (PϽ0.01). These hormonal effects were associated with a significant fall in blood pressure (PϽ0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (PϽ0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (PϽ0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (PϽ0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (PϭNS versus FOS/HCTZ). In conclusion, the results of the present study in normal subjects demonstrate that omapatrilat has favorable renal hemodynamic effects. Omapatrilat combines potent ACE inhibition with a sustained natriuresis, which explains its well-documented potent antihypertensive efficacy. Key Words: hemodynamics, renal Ⅲ sodium Ⅲ angiotensin-converting enzyme Ⅲ neutral endopeptidase Ⅲ omapatrilat Ⅲ vasopeptidase Ⅲ human A ngiotensin II is an important physiological modulator of renal function through its hemodynamic, glomerular, and tubular effects. 1 Hence, under most circumstances, interruption of the renin-angiotensin cascade with ACE inhibitors or angiotensin II type 1 receptor antagonists in humans promotes sodium excretion and increases renal blood flow without affecting glomerular filtration rate (GFR). As a result, filtration fraction decreases. 2 Atrial natriuretic peptide (ANP), the brain natriuretic peptide, and the C-type natriuretic peptide represent another family of peptides that have an important impact on renal function. 3,4 Indeed, in addition to a peripheral vasodilation, these peptides elicit diuresis and natriuresis, an attenuation of the release of renin and aldosterone and of the sympathetic nervous activity. 3 High plasma ANP and brain natriuretic peptide levels have been measured under several clinical conditions in which sodium and water retention occur, such as congestive heart failure or chronic renal failure. 3,4 In humans, the administration of exogenous ANP and the inhibition of natriuretic peptide...

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Section: Systemic and Renal Hemodynamic Effectsmentioning

confidence: 99%

mentioning

confidence: 99%

Renal Hemodynamic and Natriuretic Effects of Concomitant Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Men

et al. 2002

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“…In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5)(6)(7)(8). Omapatrilat was shown to have a greater antihypertensive efficacy in hypertensive patients than ACE inhibitors, such as lisinopril (9,10) or enalapril (11). Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure.…”

mentioning

confidence: 99%

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Azizi

Lamarre-Cliché²,

Labatide-Alanore³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodiumdepleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.Omapatrilat is a vasopeptidase inhibitor that has a similar nanomolar inhibitory constant for both neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) in vitro (1). This drug is designed to treat hypertension (2) and congestive heart failure (3,4). In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5-8). Omapatrilat was shown to have a greater antihypertensive efficacy in hypertensive patients than ACE inhibitors, such as lisinopril (9,10) or enalapril (11). Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure. However, the beneficial effect of omapatrilat on cardiovascular morbidity compared with lisinopril in patients with congestive heart failure suggested by the IMPRESS study (4) has not been confirmed by the results of the OVERTURE study (12), in which no significant difference in terms of cardiovascular morbidity or mortality between 40 mg of omapatrilat daily and 10 mg of enalapril twice daily was reported.We have previously reported the BP and hormonal effects of a single oral dose of 10 mg of omapatrilat in sodium-depleted normotensive subjects (13). Omapatrilat (10 mg) had a shorter BP-lowering effect than a single oral dose of 20 mg of fosinopril, despite the fact that, at the dose used, both drugs appeared to have a similar potency in inhibiting ACE, whereas omapatrilat, by inhibiting NEP, increased urinary atrial natriuretic peptide (ANP) and blunted the decrease in plasma ANP due to ACE inhibition (13).The doses of omapatrilat subsequently used in the clinical development program were high...

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“…At the end of the placebo run-in period, patients were randomized to either GW665011X or placebo (1:1 ratio) treatment in a double-blind manner. Patients in the active treatment group received two consecutive 3-day dose titration periods of GW660511X 50 mg once daily (days 1-3) and then 100 mg once daily (days 4-6) followed by GW660511X 200 mg once daily for 14 days (days [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Patients in the placebo treatment group received the same dosing regimen with a matched placebo.…”

Section: Methodsmentioning

confidence: 99%

“…7,8 Clinical evidence thus far has shown that omapatrilat, sampatrilat and fasidotril are effective in the management of hypertension in different patient populations. [9][10][11][12][13][14] However, adverse events (AE) associated with omapatrilat, especially angioedema, raised a concern for the safety of vasopeptidase inhibitors. 15 GW660511X is a novel potent and selective dual inhibitor of ACE (IC 50 3.2 nM) and NEP (IC 50 1.8 nM) both in vitro and ex vivo.…”

Section: Introductionmentioning

confidence: 99%

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

Pearce²,

Danoff

2006

J Hum Hypertens

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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.

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Omapatrilat Compared With Lisinopril in Treatment of Hypertension as Assessed by Ambulatory Blood Pressure Monitoring

Cited by 14 publications

References 0 publications

Renal Hemodynamic and Natriuretic Effects of Concomitant Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Men

Renal Hemodynamic and Natriuretic Effects of Concomitant Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Men

Physiologic Consequences of Vasopeptidase Inhibition in Humans

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

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