Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Omapatrilat was designed to inhibit simultaneously angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The ubiquitous involvement of the renin-angiotensin-aldosterone system, originally conceived as an axis of sodium and fluid metabolism in inflammation, thrombosis and cardiac and smooth muscle hypertrophy, is a major factor in disease progression for conditions as diverse as hypertension, heart failure, coronary artery disease and diabetes. Interruption of angiotensin II generation and bradykinin degradation by ACE inhibition is a major therapeutic advance in the management of these diseases. NEP metabolizes both bradykinin and the natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide, c-type natriuretic peptide and adrenomedullin). These peptides counter the adverse effects of angiotensin II by their vasodilator, natriuretic, diuretic and autonomic neural actions; by their antitrophic effects; and by suppressing plasma renin activity. These two systems can be considered key components of a cardiorenal axis that maintains blood pressure and cardiopulmonary blood volume within a stable range. This balance is compromised in the setting of heart failure and primary hypertension. The combination of ACE and NEP inhibition should augment the beneficial hemodynamic and tissue effects of bradykinin and the natriuretic peptides. Vasopeptidase inhibition, therefore, is a novel approach to cardiovascular therapy, with implications for hypertension, heart failure, renal function and ischemic heart disease.
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PMID:Vasopeptidase inhibition: a novel approach to cardiovascular therapy. 1187 87

Bristol-Myers Squibb (BMS) is developing the vasopeptidase inihibitor, omapatrilat, a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), for the potential treatment of cardiovascular diseases such as hypertension and heart failure [306287]. An NDA for the use of omapatrilat in hypertension was filed with the FDA and the regulatory authorities in the EU in December 1999 [351207], [353287]. In April 2000, BMS voluntarily withdrew the NDA in response to questions raised by the FDA regarding the comparative incidence and severity of an infrequent side effect (angioedema) reported within the NDA database. Prospective controlled clinical studies in patients with hypertension and heart failure were to continue. In May 2001, BMS reported that its blinded omapatrilat hypertension study was continuing and, pending supportive results from a data analysis anticipated in late summer/early autumn 2001, the company expected to refile an NDA with the FDA [409203]. In July 2000, BMS reported that it planned to conduct a multinational, 25,000 patient study (OCTAVE - Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) to compare the efficacy and safety of omapatrilat against enalapril in the treatment of hypertension [374909]. The OCTAVE trial was expected to generate data by mid-2001, which could allow for a launch by early 2002 [380280]. Phase III trials for hypertension had commenced by January 1998 [273646]. In January 2001, Merrill Lynch expected BMS to refile its NDA with the FDA in the second half of 2001 [395423]. In February 2001, Credit Suisse First Boston made a similar prediction, adding that it believed BMS would launch the drug in late 2002 or early 2003. The analysts also predicted peak sales for the drug of $585 million in 2005 [399484]. In May 2001, Merrill Lynch estimated sales of $1.8 billion in 2005 [411811].
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PMID:Omapatrilat. Bristol-Myers Squibb. 1189 Mar 57

Omapatrilat simultaneously inhibits neutral endopeptidase and angiotensin-converting enzyme, increasing levels of vasodilatory peptides while decreasing production of angiotensin II. This study evaluated the clinical effects of withdrawal of omapatrilat after a patient's hypertension had been controlled (seated diastolic blood pressure <90 mm Hg) on omapatrilat for at least 6 months, with or without adjunctive antihypertensive medications. This double-blind study randomized 83 patients to receive either their established omapatrilat dose or placebo for 8 weeks; any concomitant antihypertensive medications were kept constant. Patients continuing on omapatrilat had no change in blood pressure. Patients whose chronic omapatrilat treatment was replaced by placebo had clinically important increases in both systolic (+16.5 mm Hg) and diastolic ((+9.6 mm Hg) blood pressures (both p<0.001). An increase in blood pressure was also seen in patients who were taking adjunctive antihypertensive medications prior to withdrawal of omapatrilat. This study demonstrates that when compared to withdrawal placebo, omapatrilat maintains clinically and statistically significant blood pressure reductions.
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PMID:Omapatrilat provides long-term control of hypertension: a randomized trial of treatment withdrawal. 1204 65

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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PMID:Effects of omapatrilat on the renin-angiotensin system in salt-sensitive hypertension. 1207 59

1. The present study compared the acute efficacies of vasopeptidase inhibition with omapatrilat, nitroglycerin and angiotensin-converting enzyme (ACE) inhibition in exercise-induced myocardial dysfunction. Omapatrilat, a vasopeptidase inhibitor, inhibits both neutral endopeptidase and ACE. Whereas vasopeptidase inhibitors have demonstrated clinical efficacy in hypertension and heart failure, their effects in myocardial ischaemia remain unclear. 2. Omapatrilat (0.3 mg/kg) was compared with vehicle (saline), an ACE inhibitor (fosinoprilat; 0.44 mg/kg) and nitroglycerin (8.0 microg/kg per min), in an established canine model of exercise-induced myocardial dysfunction induced by progressive closure of an ameroid constrictor placed about the proximal circumflex coronary artery. Maximal treadmill exercise tests, terminated when heart rate failed to increase with increasing workload or failure to continue exercise, were performed in chronically instrumented dogs. 3. During exercise, omapatrilat and nitroglycerin similarly increased ischaemic wall thickening (P< or = 0.0001, ANOVA, 12 d.f.), whereas fosinoprilat and vehicle were without effect. Ischaemic zone ST changes were decreased with nitroglycerin (P = 0.0006, ANOVA, 12 d.f.) and tended to decrease with omapatrilat (P = 0.07, ANOVA, 12 d.f.). Peak exercise capacity was increased with nitroglycerin (9.7 +/- 1.1 vs 11.2 +/- 1.0 kcal, control vs 4 h, respectively; n = 6) and omapatrilat (9.7 +/- 0.8 vs 11.4 +/- 0.6 kcal, control vs 4 h, respectively; n = 6) and was unchanged with ACE inhibition (9.0 +/- 1.2 vs 9.5 +/- 1.1 kcal, control vs 4 h, respectively; n = 7). Omapatrilat differentially increased double product during exercise (P = 0.001, ANOVA, 12 d.f.) compared with other treatments. 4. During exercise-induced myocardial dysfunction, acute ACE inhibition did not attenuate ischaemic changes and failed to improve exercise capacity. Increased exercise capacity with omapatrilat was accompanied by a differential increase in double product, consistent with increased oxygen supply and demand. Improvements in ischaemic function were comparable between omapatrilat and nitroglycerin, suggesting that omapatrilat may represent a novel therapy in demand-induced ischaemia.
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PMID:Vasopeptidase inhibition in a canine model of exercise-induced left ventricular dysfunction. 1210 2

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 (P<0.001 versus placebo; P<0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (P<0.01). These hormonal effects were associated with a significant fall in blood pressure (P<0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (P<0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (P<0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (P<0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (P=NS 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.
Hypertension 2002 Sep
PMID:Renal hemodynamic and natriuretic effects of concomitant Angiotensin-converting enzyme and neutral endopeptidase inhibition in men. 1221 65

Vasopeptidase inhibitors are a new class of drugs that have dual inhibitory effects on two key enzymes involved in the metabolism of vasoactive peptides. Essentially, they inhibit angiotensin-converting enzyme (ACE), thereby blocking the generation of angiotensin II (Ang II); at the same time they prevent the breakdown of natriuretic peptides by the enzyme neutral endopeptidase. The combination of reduction of Ang II on a background of increased natriuretic peptide activity has several potential advantages for the treatment of cardiovascular and renal disease and in particular, hypertension and congestive heart failure (CHF). Several vasopeptidase inhibitors, such as sampatrilat, fasidotril, gemopatrilat and omapatrilat (Vanlev, the most clinically developed vasopeptidase inhibitor to date) are under intensive clinical investigation. Recent clinical trials have demonstrated effective antihypertensive activity in hypertension, independent of age, renin and salt status or ethnic origin, and have also highlighted the potential for vasopeptidase inhibition as a new therapeutic modality for the treatment of CHF. Moreover, ongoing research suggests that this new class of drugs may be an important approach, not only for the treatment of hypertension and of conditions associated with overt volume overload but also for ischaemic heart disease.
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PMID:Vasopeptidase inhibitors. 1222 48

At the American College of Cardiology in March two major trials were presented. The publicity surrounding the two could not have been more different. The LIFE demonstrated clear superiority of losartan-based therapy over atenolol-based therapy for the treatment of hypertension. It was published the same week in the Lancet and received major press coverage all over the world. The OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) study in contrast received a subdued reception, very little publicity and is yet to be published. 5770 NYHA class II-IV heart failure patients (LVEF<or=30%, recent heart failure hospital admission) were randomised and uptitrated to either 10 mg BD of Enalapril or 40 mg once a day Omapatrilat. The primary end-point of all cause mortality or heart failure related hospitalisation did not differ significantly: 914/2884 for Enalapril and 914/2886 for Omapatrilat (hazard ratio 0.94, CI's 0.86-1.03, P=0.187). Mortality was also similar: 509 for Enalapril and 477 for Omapatrilat (hazard ratio 0.94, CI's 0.83-1.07, P=0.339). Omapatrilat was as good as Enalapril but not better. The worrying trend was however, that angioedema was more common with Omapatrilat; 24 (0.8%) versus 14 cases (0.5%). The OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) study was also presented at this time. 25,267 hypertensives were randomised to Omapatrilat or enalapril and a difference of approximately 3 mmHg in favour of Omapatrilat was seen. Significantly more cases of angioedema were seen with Omapatrilat, 274 (2.17%) compared to 86 (0.68%) with enalapril. Overall death rates were similar, 0.18% for enalapril and 0.15% for Omapatrilat. All adverse events were similar, 51.0% for Omapatrilat and 50.4% for enalapril. The rates of angioedema were much higher in blacks, 5.54% for Ompatrilat and 1.62% for enalapril and for smokers, 3.93% for Omapatrilat and 0.81% for enalapril. We were left with a drug that was, for heart failure, not superior to an ACE inhibitor already off patent, and, as an anti-hypertensive, with an angioedema rate more than double that of an ACE inhibitor in a large head to head comparison. The medical community will be watching to make sure these data are published in full in the medical literature in a timely fashion, in the order of end-points specified in the protocol and with appropriate emphasis on the logical points of presentation.
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PMID:Omapatrilat--the story of Overture and Octave. 1295 41

The term vasopeptidase means any peptidase able to generate or to inactivate a vasoactive peptide. This term got a more definitive meaning when a new class of drugs, the vasopeptidase inhibitors, was introduced. These drugs are especially represented by the inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE is now primarily considered a kininase rather than an angiotensinase and ACE-inhibitors have been used successfully in the treatment of many cardiovascular diseases, including hypertension and heart failure. Preliminary results suggest that the use of NEP inhibitors could also contribute to improve prognosis of cardiovascular diseases. Vasopeptidase inhibitors simultaneously inhibiting both NEP and ACE have shown to be more effective than currently available ACE inhibitors. (Omapatrilat is at present the most clinically advanced in these drugs). However, many side-effects of vasopeptidase inhibitors have been reported, but the most dangerous is angioedema which is potentially life threatening. Since this complication is mediated by bradykinin, and both inhibition of ACE and NEP can produce bradykinin increasing, it has been suggested that the incidence of angioedema due to vasopeptidase inhibitors could be higher compared with that related to ACE-inhibitors. The FDA raised concern about this adverse effect, and the manufacturer decided to withdraw the application temporarily. In order to identify patients at risk of angioedema we have recently shown that low plasma levels of aminopeptidase P, another enzyme which cabolises bradykinin, could indicate a predisposition for development of angioedema in some patients treated with vasoinhibitor drugs.
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PMID:[Vasopeptidases and their inhibitors]. 1240 10

Omapatrilat, a novel vasopeptidase inhibitor, is under development for the treatment of hypertension and congestive heart failure. This study describes the comparative biotransformation of radiolabeled [(14)C]- and stable-labeled [(13)C(2)]omapatrilat after administration of single oral doses to rats, dogs, and humans. The metabolites were identified by a combination of methods including reduction, hydrolysis, and comparison of high performance liquid chromatography retention times with those of the synthetic standards. Urinary metabolites were further characterized by liquid chromatography tandem mass spectrometry analysis. Prominent metabolites identified in human plasma, which were also present in rat and dog plasma, were S-methyl omapatrilat and S-2-thiomethyl-3-phenylpropionic acid. Omapatrilat accounted for only a small portion of the extractable radioactivity in plasma in all three species. A portion of the plasma radioactivity was unextractable in all three species (27-53%). The majority of unextractable radioactivity in plasma was characterized after dithiothreitol reduction to be omapatrilat and (S)-2-thio-3-phenylpropionic acid, both apparently bound to plasma proteins by reversible disulfide bonds. The major human urinary metabolites were the amine hydrolysis product, diasteromeric sulfoxide of (S)-2-thiomethyl-3-phenylpropionic acid, acyl glucuronide of S-methyl omapatrilat, and S-methyl omapatrilat. The minor metabolites were acyl glucuronide of (S)-2-thiomethyl-3-phenylpropionic acid, L-cysteine mixed disulfide of omapatrilat, diastereomers of S-methyl sulfoxide of omapatrilat, and S-methyl omapatrilat ring sulfoxide. The metabolic profiles of dog and human urine were qualitatively similar whereas rat urine showed only metabolites arising from hydrolysis of omapatrilat. Unchanged omapatrilat was not found in rat, dog, or human urine samples indicating extensive metabolism in vivo.
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PMID:Comparative biotransformation of radiolabeled [(14)C]omapatrilat and stable-labeled [(13)C(2)]omapatrilat after oral administration to rats, dogs, and humans. 1248 55


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