Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Omapatrilat, the most clinically advanced member of a new class of cardiovascular agents, vasopeptidase inhibitors, is under development at Bristol-Myers Squibb Pharmaceutical Research Institute for the treatment of hypertension and heart failure. An electrospray LC/MS/MS method has been developed and validated for the simultaneous determination of omapatrilat and its four metabolites in human plasma. Since omapatrilat and two of the metabolites are sulfhydryl-containing compounds, methyl acrylate was used to stabilize these compounds in human blood and plasma samples. Methyl acrylate reacted instantly with the sulfhydryl group to form a derivative that was stable in blood and plasma. Extraction of the analytes from plasma samples was achieved by semiautomated liquid-liquid extraction, where a robotic liquid handler performed the liquid-transferring steps. The mass spectrometer was operated in the negative ion selected-reaction-monitoring mode. The calibration curve ranges were 0.5-250 ng/mL for omapatrilat and one metabolite and 2.0-250 ng/mL for the other three metabolites.
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PMID:LC/MS/MS determination of omapatrilat, a sulfhydryl-containing vasopeptidase inhibitor, and its sulfhydryl- and thioether-containing metabolites in human plasma. 1181 72

The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial is a large clinical trial of omapatrilat, a vasopeptidase inhibitor, in patients with stage 1 isolated systolic hypertension (ISH). OPERA is the first study to examine whether effective antihypertensive treatment can provide survival and clinical end point benefits in older persons with this common condition. This 5-year multinational, randomized, double-blind, parallel-group, placebo-controlled, forced-titration study will be conducted in approximately 12,600 subjects randomized by approximately 1100 study centers worldwide over a recruitment period of approximately 2 years. The primary objective of OPERA is to determine whether treatment with once-daily omapatrilat (target dose 40 mg) will reduce cardiovascular (CV) morbidity and mortality in older (> or = 65 years) men and women with enhanced risk for atherosclerotic events due to stage 1 ISH plus other risk factors for which currently there is no evidence-based requirement for treatment. Blood pressure inclusion criteria are systolic blood pressure (SBP) 140 to 159 mm Hg (SBP 125 to 139 mm Hg in diabetic individuals) and diastolic blood pressure (DBP) <90 mm Hg. The primary end point is defined as the composite of fatal/nonfatal stroke, fatal/nonfatal myocardial infarction, fatal/nonfatal heart failure, and other CV mortality. Secondary end points include the individual components of the primary end point, CV mortality, and major cardiovascular end points, as well as effects on cognitive function and initiation of treatment for diabetes. Additional analyses will be conducted in men and women, in diabetic patients, in different risk classes and according to prior evidence of vascular disease.
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PMID:Design of the Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial. 1186 57

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

The morbidity and mortality of cardiac insufficiency remains such that it justifies the pursuit of finding new drugs and new sensitive techniques to slow or abolish its evolution. Bringing the vasopeptidases, such as omapatrilat, up to date results in a rational process aimed at simultaneously modulating certain interactive humoral systems. They represent drugs which simultaneously inhibit neutral endopeptidase and angiotensin converting enzyme with the effect of potentiating the natiuretic peptide system and bradykinin, and blocking the conversion of angiotensin I and angiotensin II. In the IMPRESS study, omapatrilat has been evaluated in patients with cardiac insufficiency versus lisinopril; there was no significant difference on the principal outcome measure which was exercise tolerance, however it was significantly more effective than lisinopril on the outcome measure combining death and hospital admission for deteriorating cardiac insufficiency. A wider study is underway, the OVERTURE study, which is evaluating omapatrilat versus enalapril on hospital admission and all-cause mortality. The Vanlev dossier has not yet been submitted to the regulatory authorities for obtaining its authorisation to be put on the market.
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PMID:[Heart failure and vasopeptidase inhibitors]. 1193 58

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

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

Considerable attention has recently focused on the vasopeptidase inhibitors (VPI), a new class of drug that combines angiotensin-converting enzyme (ACE) inhibitor activity with inhibition of natriuretic peptide breakdown. In theory, a drug with these properties may be beneficial both in hypertension and in heart failure. Whilst the efficacy of VPIs in hypertension has been consistently demonstrated in pre-clinical and clinical studies, the role of VPIs, if any, in heart failure is less clear, since numerous small studies have produced conflicting results. Furthermore, preliminary results from the recently completed Omapatrilat Versus Enalapril Randomised Trial of Utility in Reducing Events (OVERTURE) study have failed to establish the VPI, omapatrilat, as a first line therapy in the treatment of chronic heart failure. We review the literature on VPIs in heart failure and discuss possible reasons for the reported lack of benefit over ACE inhibitors.
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PMID:Vasopeptidase inhibitors in heart failure. 1256 65

Omapatrilat belongs to the vasopeptidase inhibitors, ie, drugs that possess the ability to inhibit simultaneously the membrane-bound zinc metalloproteases, angiotensin-converting enzyme (ACE), and the neutral endopeptidase EC 3.4.24.11 (NEP). Omapatrilat was targeted to treat patients with hypertension and congestive heart failure. The preclinical and early clinical studies conducted with omapatrilat were very promising. Indeed, omapatrilat appeared to be a very potent antihypertensive agent with very favorable effects on cardiac function in heart failure patients. In contrast to these early studies, the large clinical trials were more disappointing. The results of the OCTAVE trial confirmed the antihypertensive efficacy of omapatrilat, but at the price of an angioedema rate more than threefold higher than that of an ACE inhibitor in the overall population (2.17% vs 0.68%), and close to fourfold higher in the black population. In OVERTURE, a large randomized control trial in heart failure, angioedema was also more common with omapatrilat, but the incidence was much lower (0.8% with omapatrilat vs 0.5% with enalapril). However, omapatrilat was not convincingly superior to the ACE inhibitor. Because angioedema is probably a class side effect of vasopeptidase inhibitors, the higher incidence of this potentially life-threatening complication with omapatrilat has likely stopped the development of this new class of agents. The future of vasopeptidase inhibitors will depend on the ability to improve the risk/benefit ratio either by developing agents that produce less angioedema, or by defining more precisely a high-risk population that could take advantage of dual ACE/NEP inhibition.
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PMID:Recent clinical trials with omapatrilat: new developments. 1284 71


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