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Ole Vesterqvist - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor Omapatrilat in healthy subjects
British Journal of Clinical Pharmacology, 2003Co-Authors: Wei-chi Liao, Ole Vesterqvist, Carol L Delaney, Mohammed Jemal, Irene Ferreira, Neville F Ford, B N Swanson, Howard UdermanAbstract:Aims To determine the pharmacokinetics, pharmacodynamics and tolerability of Omapatrilat, a vasopeptidase inhibitor, in healthy subjects. Methods The effects of oral Omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received Omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days. Results In the multiple-dose study, peak plasma concentrations (Cmax = 10–895 ng ml−1; tmax = 0.5–2 h) of Omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14–19 h), attaining steady state in 3–4 days. In the single-dose study, Cmax (1–1009 ng ml−1) and AUC(0,t) (0.4–1891 ng ml–1 h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, Cmax but not AUC(0,t) was linear at the lower doses on day 10. The lowest dose of Omapatrilat (2.5 mg) almost completely inhibited (> 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of Omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, Omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 ± 4.1 (± SD) ng 24 h−1 in the placebo group to 60.0 ± 18.2 ng 24 h−1 in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, Omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single- and multiple-dose studies. Conclusions Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of Omapatrilat are consistent with once-daily dosing.
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effects of Omapatrilat on the renin angiotensin system in salt sensitive hypertension
American Journal of Hypertension, 2002Co-Authors: Carlos M Ferrario, Wei-chi Liao, Ole Vesterqvist, Vito M Campese, Michael C Ruddy, Ronald D Smith, Mark C Chappell, Bridget Brosnihan, Clarence E GrimAbstract:The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of Omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either Omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given Omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which Omapatrilat induces an antihypertensive response in salt sensitive hypertension.
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Omapatrilat versus lisinopril efficacy and neurohormonal profile in salt sensitive hypertensive patients
Hypertension, 2001Co-Authors: Vito M Campese, Kenneth C Lasseter, Carlos M Ferrario, William B Smith, Michael C Ruddy, Clarence E Grim, Ronald D Smith, Ramon Vargas, Michael F Habashy, Ole VesterqvistAbstract:Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of Omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind Omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both Omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, Omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure ( P =0.008), ambulatory systolic blood pressure ( P =0.004), and ambulatory mean arterial pressure ( P =0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly ( P P
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pharmacodynamics and pharmacokinetics of Omapatrilat in heart failure
The Journal of Clinical Pharmacology, 2001Co-Authors: John B Kostis, Ole Vesterqvist, Carol L Delaney, Mohammed Jemal, Marc Klapholz, J Manning, Marvin Cohen, Georgia D Kollia, Wei-chi LiaoAbstract:The purpose of this study was to determine the pharmacodynamics and pharmacokinetics of Omapatrilat, administered orally (25 mg) or intravenously (10 mg) in 19 New York Heart Association class II and class III congestive heart failure (CHF) patients versus 17 healthy controls matched for age, race, gender, and weight. The plasma concentrations of atrial natriuretic peptide (ANP) increased by approximately 20% and 30% in CHF and control subjects, respectively, at 4 hours after intravenous or oral Omapatrilat administration. Similar elevation in the cyclic guanosine monophosphate concentration (25% to 35%) and ANP urinary excretion (21 ng/24 h to 22 ng/24 h) was seen in all treatment groups after Omapatrilat administration. Angiotensin-converting enzyme activity was > 90% inhibited at 4 hours after dosing and remained approximately 60% to 70% inhibited at 24 hours after dosing. The levels of endothelin-1 and endothelin-2 remained unchanged after oral or intravenous administration of Omapatrilat. The maximal reduction in seated blood pressure compared with baseline was similar for CHF and control subjects. Clinical pharmacokinetic parameters were similar in both groups after intravenous dosing, but maximum concentration and area under the concentration-time curve were elevated in CHF patients compared with controls after oral dosing. Omapatrilat was well tolerated; differences in systemic exposure and metabolism between CHF patients and controls did not appear to be clinically significant.
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effects of Omapatrilat on pharmacodynamic biomarkers of neutral endopeptidase and angiotensin converting enzyme activity in humans
Current Hypertension Reports, 2001Co-Authors: Ole Vesterqvist, Richard A ReevesAbstract:Vasopeptidase inhibition is a new concept in blood pressure management. A single molecule simultaneously inhibits two enzymes that regulate cardiovascular function: neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) [1]. Development of vasopeptidase inhibitors stemmed from the need for new and more efficacious antihypertensive agents that not only reduce blood pressure but also treat hypertension as part of a larger syndrome involving endothelial dysfunction [2]. By inhibiting NEP and ACE, vasopeptidase inhibitors enhance the natriuretic peptide and kallikrein-kinin systems and inhibit the renin-angiotensinaldosterone system. This article outlines the pharmacodynamic effects of the vasopeptidase inhibitor Omapatrilat on biomarkers of NEP and ACE activity in humans.
Wei-chi Liao - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor Omapatrilat in healthy subjects
British Journal of Clinical Pharmacology, 2003Co-Authors: Wei-chi Liao, Ole Vesterqvist, Carol L Delaney, Mohammed Jemal, Irene Ferreira, Neville F Ford, B N Swanson, Howard UdermanAbstract:Aims To determine the pharmacokinetics, pharmacodynamics and tolerability of Omapatrilat, a vasopeptidase inhibitor, in healthy subjects. Methods The effects of oral Omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received Omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days. Results In the multiple-dose study, peak plasma concentrations (Cmax = 10–895 ng ml−1; tmax = 0.5–2 h) of Omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14–19 h), attaining steady state in 3–4 days. In the single-dose study, Cmax (1–1009 ng ml−1) and AUC(0,t) (0.4–1891 ng ml–1 h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, Cmax but not AUC(0,t) was linear at the lower doses on day 10. The lowest dose of Omapatrilat (2.5 mg) almost completely inhibited (> 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of Omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, Omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 ± 4.1 (± SD) ng 24 h−1 in the placebo group to 60.0 ± 18.2 ng 24 h−1 in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, Omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single- and multiple-dose studies. Conclusions Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of Omapatrilat are consistent with once-daily dosing.
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effects of Omapatrilat on the renin angiotensin system in salt sensitive hypertension
American Journal of Hypertension, 2002Co-Authors: Carlos M Ferrario, Wei-chi Liao, Ole Vesterqvist, Vito M Campese, Michael C Ruddy, Ronald D Smith, Mark C Chappell, Bridget Brosnihan, Clarence E GrimAbstract:The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of Omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either Omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given Omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which Omapatrilat induces an antihypertensive response in salt sensitive hypertension.
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pharmacodynamics and pharmacokinetics of Omapatrilat in heart failure
The Journal of Clinical Pharmacology, 2001Co-Authors: John B Kostis, Ole Vesterqvist, Carol L Delaney, Mohammed Jemal, Marc Klapholz, J Manning, Marvin Cohen, Georgia D Kollia, Wei-chi LiaoAbstract:The purpose of this study was to determine the pharmacodynamics and pharmacokinetics of Omapatrilat, administered orally (25 mg) or intravenously (10 mg) in 19 New York Heart Association class II and class III congestive heart failure (CHF) patients versus 17 healthy controls matched for age, race, gender, and weight. The plasma concentrations of atrial natriuretic peptide (ANP) increased by approximately 20% and 30% in CHF and control subjects, respectively, at 4 hours after intravenous or oral Omapatrilat administration. Similar elevation in the cyclic guanosine monophosphate concentration (25% to 35%) and ANP urinary excretion (21 ng/24 h to 22 ng/24 h) was seen in all treatment groups after Omapatrilat administration. Angiotensin-converting enzyme activity was > 90% inhibited at 4 hours after dosing and remained approximately 60% to 70% inhibited at 24 hours after dosing. The levels of endothelin-1 and endothelin-2 remained unchanged after oral or intravenous administration of Omapatrilat. The maximal reduction in seated blood pressure compared with baseline was similar for CHF and control subjects. Clinical pharmacokinetic parameters were similar in both groups after intravenous dosing, but maximum concentration and area under the concentration-time curve were elevated in CHF patients compared with controls after oral dosing. Omapatrilat was well tolerated; differences in systemic exposure and metabolism between CHF patients and controls did not appear to be clinically significant.
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oral bioavailability and disposition of 14c Omapatrilat in healthy subjects
The Journal of Clinical Pharmacology, 2001Co-Authors: Bimal Malhotra, Wei-chi Liao, Ramaswamy A Iyer, James Mitroka, Kathy M Soucek, Douglas Behr, Sanjeev Kaul, Marvin B Cohen, Catherine A KnuppAbstract:The objective of this study was to determine the absolute oral bioavailability and disposition of Omapatrilat. This single-dose, randomized, crossover study of 20 mg intravenous and 50 mg oral [ 14 C]Omapatrilat was conducted in 12 healthy male subjects to determine the disposition and oral bioavailability of Omapatrilat, an orally active vasopeptidase inhibitor. Blood samples were collected up to 120 hours, and the excreta were collected over 168 hours postdose. Plasma concentrations of Omapatrilat were determined by a validated LC/MS/MS procedure. Radioactivity in blood, plasma, urine, and feces was determined by liquid scintillation counting. Urinary excretion of radioactivity averaged 80% and 64% of intravenous and oral doses, respectively; < 1% of oral dose was excreted unchanged in urine. The absolute oral bioavailability of Omapatrilat averaged 31%. Total body clearance of Omapatrilat (80 L/h) exceeded liver plasma flow. Apparent steady-state volume of distribution of Omapatrilat (21 L/kg) was extremely high compared with total body water. Omapatrilat undergoes substantial presystemic first-pass metabolism after oral administration. Omapatrilat is eliminated primarily by metabolism, and its metabolites are eliminated primarily in urine. Extrahepatic organs may be involved in the elimination of Omapatrilat. Plasma concentrations of Omapatrilat exhibit a prolonged terminal elimination phase, which represents elimination from a deep compartment.
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The cardiovascular actions of Omapatrilat in spontaneously hypertensive rats
Current Hypertension Reports, 2001Co-Authors: Yafeng Dong, Eric Shaffer, Nickolai Atamas, Hui Zhou, Wei-chi LiaoAbstract:Omapatrilat is a newly developed vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase and has potent antihypertensive efficacy. However, the specific effect of Omapatrilat on cardiac function and left ventricular hypertrophy with hypertension remains controversial. Therefore, we investigated the effect of Omapatrilat on blood pressure, cardiac hypertrophy, and cardiac function in spontaneously hypertensive rats (SHR). Studies were performed in SHR that received vehicle (n=9), Omapatrilat (n=10), or fosinopril (ACE inhibitor, n=7) by daily gavage for 56 days. Systolic blood pressure (SBP) and mean blood pressure (MBP) were measured by tail plethysmography. Left ventricular fractional shortening and left ventricular mass were measured by echocardiography at day 56. Omapatrilat and fosinopril significantly decreased SBP and MBP from day 1 through day 56, and Omapatrilat markedly reduced SBP and MBP compared with fosinopril from day 21 to day 56. Although both Omapatrilat and fosinopril decreased left ventricular mass and left ventricular mass-tobody weight ratio with increased LV fractional shortening, Omapatrilat had a more potent effect on the reduction of left ventricular mass and improvement of cardiac function. This study shows that in SHR, Omapatrilat mediated a potent and stable antihypertensive effect and a reduction in left ventricular mass with improvement of cardiac function, compared with ACE inhibition alone.
Marc A Pfeffer - One of the best experts on this subject based on the ideXlab platform.
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comparison of the effects of Omapatrilat and lisinopril on circulating neurohormones and cytokines in patients with chronic heart failure
American Journal of Cardiology, 2002Co-Authors: Tej Sheth, Albert Adam, Marc A Pfeffer, Chunlin Qian, Alan J Block, Thomas Parker, Christian Hall, Duncan Stewart, Jean L RouleauAbstract:Angiotensin-converting enzyme (ACE) inhibitors exert their effects by modulating the neurohumoral milieu. Vasopeptidase inhibitors (VPI) are ACE and neutral endopeptidase inhibitors and may increase natriuretic peptides, bradykinin, and perhaps endothelin-1 in patients with congestive heart failure. Patients (n = 107) with ischemic or dilated cardiomyopathy, New York Heart Association functional class II to III, with left ventricular ejection fraction <40%, and on ACE inhibitor therapy were randomized to either the VPI Omapatrilat 40 mg/day or the ACE inhibitor lisinopril 20 mg/day. Trough levels of neurohormones (24 hours after dosing) were assessed at baseline, and at 12 and 24 weeks of follow-up. C-terminal atrial natriuretic peptide (C-ANP) levels decreased with lisinopril (p = 0.035), but not with Omapatrilat. In contrast, N-terminal ANP levels did not change, and brain natriuretic peptide (BNP) levels tended to decrease similarly in both groups. Endothelin-1 levels increased in both groups, the increase reaching statistical significance with Omapatrilat (p = 0.008). Levels of the proinflammatory cytokine interleukin-6 tended to decrease, and the anti-inflammatory cytokine interleukin-10 increased in both groups, with statistical significance only for interleukin-10 with Omapatrilat therapy. Neither agent changed catecholamines or angiotensin II. Thus, even at trough levels, Omapatrilat potentiates C-ANP more than lisinopril. Potentially important effects of Omapatrilat on endothelin-1 and anti-inflammatory cytokines were identified, providing potential explanations for differences in clinical outcome.
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Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension results of the conduit hemodynamics of Omapatrilat international research study
Circulation, 2002Co-Authors: Gary F Mitchell, Chunlin Qian, Alan J Block, Joseph L Izzo, Yves Lacourciere, Jeanpascal Ouellet, Joel M Neutel, Linda J Kerwin, Marc A PfefferAbstract:Background—Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension. Methods and Results—We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor Omapatrilat 80 mg daily (n80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be 160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Zc), a direct measure of the stiffness of the central aorta, was calculated from the ratio of changes in carotid pressure and aortic flow in early systole. Omapatrilat compared with enalapril produced greater reductions in peripheral (8.212.2 versus 4.012.2 mm Hg, P0.05) and central (10.216.2 versus 3.216.9 mm Hg, P0.01) pulse pressures and Zc (23783 to 20870 versus 22587 to 23194 dyne · s/cm 5 , P0.001); the latter remained significant ( P0.05) after adjusting for change in mean pressure. Conclusions—Greater reductions in pulse pressure and Zc in hypertensive subjects treated with Omapatrilat compared with enalapril suggest that aortic stiffness is maintained by specific, partially reversible mechanisms and underscore a potential role for pharmacological modulation of natriuretic peptides in the treatment of hypertension. (Circulation. 2002;105:2955-2961.)
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Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension results of the conduit hemodynamics of Omapatrilat international research study
Circulation, 2002Co-Authors: Gary F Mitchell, Chunlin Qian, Alan J Block, Joseph L Izzo, Yves Lacourciere, Jeanpascal Ouellet, Joel M Neutel, Linda J Kerwin, Marc A PfefferAbstract:Background— Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension. Methods and Results— We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n=87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor Omapatrilat 80 mg daily (n=80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be ≥160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Zc), a direct measure of the stiffness of the central aorta, was calculated from the ratio of change...
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Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension
Circulation, 2002Co-Authors: Gary F Mitchell, Chunlin Qian, Alan J Block, Joseph L Izzo, Yves Lacourciere, Jeanpascal Ouellet, Joel M Neutel, Linda J Kerwin, Marc A PfefferAbstract:Background— Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension. Methods and Results— We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n=87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor Omapatrilat 80 mg daily (n=80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be ≥160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Zc), a direct measure of the stiffness of the central aorta, was calculated from the ratio of change...
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or 37 Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension results of the conduit hemodynamics of Omapatrilat international research choir study
American Journal of Hypertension, 2002Co-Authors: Gary F Mitchell, Chunlin Qian, Alan J Block, Joseph L Izzo, Yves Lacourciere, Jeanpascal Ouellet, Joel M Neutel, Linda J Kerwin, Marc A PfefferAbstract:Background—Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension. Methods and Results—We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor Omapatrilat 80 mg daily (n80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be 160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Zc), a direct measure of the stiffness of the central aorta, was calculated from the ratio of changes in carotid pressure and aortic flow in early systole. Omapatrilat compared with enalapril produced greater reductions in peripheral (8.212.2 versus 4.012.2 mm Hg, P0.05) and central (10.216.2 versus 3.216.9 mm Hg, P0.01) pulse pressures and Zc (23783 to 20870 versus 22587 to 23194 dyne · s/cm 5 , P0.001); the latter remained significant ( P0.05) after adjusting for change in mean pressure. Conclusions—Greater reductions in pulse pressure and Zc in hypertensive subjects treated with Omapatrilat compared with enalapril suggest that aortic stiffness is maintained by specific, partially reversible mechanisms and underscore a potential role for pharmacological modulation of natriuretic peptides in the treatment of hypertension. (Circulation. 2002;105:2955-2961.)
Carlos M Ferrario - One of the best experts on this subject based on the ideXlab platform.
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vasopeptidase inhibition and ang 1 7 in the spontaneously hypertensive rat
Kidney International, 2002Co-Authors: Carlos M Ferrario, David B Averill, Bridget K Brosnihan, Mark C Chappell, Samy S Iskandar, Richard H Dean, Debra I DizAbstract:Vasopeptidase inhibition and Ang-(1-7) in the spontaneously hypertensive rat . Background Omapatrilat, a new vasopeptidase inhibitor, inhibits the activity of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). Because these two enzymes participate in the degradation of the vasodilator and natriuretic peptide, angiotensin-(1-7) [Ang-(1-7)], we assessed whether Omapatrilat treatment is associated with changes in the plasma and urinary excretion rates of the angiotensins. Methods We investigated in spontaneously hypertensive rats (SHR) (0.24kg body weight) the effect of Omapatrilat on plasma and urinary concentrations of angiotensin (Ang) I, Ang II and Ang-(1-7) during 17 days of administration of either the drug ( N = 15, 100 μmol/kg/day) or vehicle ( N = 14) in the drinking water. Hemodynamic and renal excretory function studies were associated with histological examination of the expression of Ang-(1-7) in the kidneys of both vehicle and Omapatrilat-treated SHRs. Results Omapatrilat induced a sustained lowering of systolic blood pressure (-68mm Hg) without changes in cardiac rate. The mild positive water balance produced by Omapatrilat did not cause natriuresis or kaliuresis, although it was associated with a significant decrease in urine osmolality. Blood pressure normalization was accompanied by increases in plasma Ang I (2969%), Ang II (57%), and Ang-(1-7) (163%) levels, paralleling pronounced increases in urinary excretion rates of Ang I and Ang-(1-7) but not Ang II. Detection of Ang-(1-7) immunostaining in the kidneys of five other SHR exposed either to vehicle ( N = 3) or Omapatrilat ( N = 2) ascertained the source of the Ang-(1-7) found in the urine. Intense Ang-(1-7) staining, more pronounced in Omapatrilat-treated SHR, was found in renal proximal tubules throughout the outer and inner regions of the renal cortex and the thick ascending loop of Henle, whereas no Ang-(1-7)-positive immunostaining was found in glomeruli and distal tubules. Conclusions Omapatrilat antihypertensive effects caused significant activation of the renin-angiotensin system associated with increases in urinary excretion rates of Ang I and Ang-(1-7). Combined studies of Ang-(1-7) metabolism in urine and immunohistochemical studies in the kidney revealed the existence of an intrarenal source, which may account for the pronounced increase in the excretion rate of the vasodilator heptapeptide. These findings provide further evidence for a contribution of Ang-(1-7) to the regulation of renal function and blood pressure.
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effects of Omapatrilat on the renin angiotensin system in salt sensitive hypertension
American Journal of Hypertension, 2002Co-Authors: Carlos M Ferrario, Wei-chi Liao, Ole Vesterqvist, Vito M Campese, Michael C Ruddy, Ronald D Smith, Mark C Chappell, Bridget Brosnihan, Clarence E GrimAbstract:The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of Omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either Omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given Omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which Omapatrilat induces an antihypertensive response in salt sensitive hypertension.
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Omapatrilat versus lisinopril efficacy and neurohormonal profile in salt sensitive hypertensive patients
Hypertension, 2001Co-Authors: Vito M Campese, Kenneth C Lasseter, Carlos M Ferrario, William B Smith, Michael C Ruddy, Clarence E Grim, Ronald D Smith, Ramon Vargas, Michael F Habashy, Ole VesterqvistAbstract:Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of Omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind Omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both Omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, Omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure ( P =0.008), ambulatory systolic blood pressure ( P =0.004), and ambulatory mean arterial pressure ( P =0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly ( P P
Clarence E Grim - One of the best experts on this subject based on the ideXlab platform.
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effects of Omapatrilat on the renin angiotensin system in salt sensitive hypertension
American Journal of Hypertension, 2002Co-Authors: Carlos M Ferrario, Wei-chi Liao, Ole Vesterqvist, Vito M Campese, Michael C Ruddy, Ronald D Smith, Mark C Chappell, Bridget Brosnihan, Clarence E GrimAbstract:The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of Omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either Omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given Omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which Omapatrilat induces an antihypertensive response in salt sensitive hypertension.
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Omapatrilat versus lisinopril efficacy and neurohormonal profile in salt sensitive hypertensive patients
Hypertension, 2001Co-Authors: Vito M Campese, Kenneth C Lasseter, Carlos M Ferrario, William B Smith, Michael C Ruddy, Clarence E Grim, Ronald D Smith, Ramon Vargas, Michael F Habashy, Ole VesterqvistAbstract:Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of Omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind Omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both Omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, Omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure ( P =0.008), ambulatory systolic blood pressure ( P =0.004), and ambulatory mean arterial pressure ( P =0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly ( P P
