摘要:

Since angiotensin II is an established target of pharmacological interventions, there is an increasing interest in the biological effects and metabolism of other vasoactive peptides like atrial natriuretic factor (ANF) and endothelin (ET). Exogenous administration of the vasodilatory and natriuretic ANF and of its analogues improved haemodynamics and renal function in cardiovascular disease, including congestive heart failure (CHF). Effects of natriuretic peptides appeared to be attenuated during prolonged infusion and in more severe disease. Promising results were obtained in animal experiments and initial patient studies concerning haemodynamics and kidney function with inhibition of ANF metabolism by inhibitors of the neutral endopeptidase 24.11 (NEP). With further clinical studies, moderately relevant effects of acute intravenous or oral NEP inhibition were observed, but these effects were blunted with prolonged drug administration.There is increasing evidence that NEP inhibitors such as candoxatril, expected to exhibit vasodilatory activity at least at certain doses and in certain clinical settings, even induce vasoconstriction. As well as natriuretic peptides, NEP also metabolises the vasoactive peptides ET, angiotensin II and bradykinin. It now appears to be evident, especially from human experiments on forearm blood flow after intra-arterial infusion of agents, that NEP inhibitor-induced vasoconstriction is mediated by increased ET-1 rather than by angiotensin II.The hypothesis that concurrent ACE inhibition would unmask the benefits of NEP inhibitors was not supported by a recent 10-week study in CHF; with ecadotril given to ACE inhibitor-pretreated patients, there were no clear hints towards improvement of symptoms but troublesome aspects on mortality.Future clinical studies on dual inhibitors of NEP and ACE will have to reveal the place of NEP inhibition in cardiovascular disease in the presence of established therapeutic standards.Remarkable haemodynamic and cardioprotective effects have been obtained with antagonists of the ET receptor. Specific inhibitors of the endothelin converting enzyme (ECE) have only recently been introduced, inhibiting ET generation from its precursor, big ET.If the results previously obtained with ET receptor antagonists can be reproduced with ECE inhibitors, and transferred to clinical medicine, endopeptidase inhibition might open new horizons in cardiovascular treatment strategies.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

All the drugs appearing in the Adis Profile Summary table have been selected based on information contained inR&D InsightTM, a proprietary product of Adis International. As the emphasis ofDrugs in R&Dis on the clinical potential of new drugs, selection of agents for a full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified fromR&D InsightTM, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Candoxatrilat (UK 73967) is a neutral endopeptidase inhibitor that is in phase I of development with Pfizer in the USA. Candoxatrilat is the active form of candoxatril. It is also in clinical trials for the treatment of renal failure.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Ecadotril [sinorphan, (S)-acetorphan] is a neutral endopeptidase inhibitor currently undergoing phase III clinical trials for hypertension and heart failure with Bioprojet in France. Shionogi has licensed ecadotril from Bioprojet, and is conducting phase II trials of the agent for heart failure in Japan. The agent has been exclusively licensed to Bayer AG worldwide except for France and Japan. Bayer is conducting phase II clinical studies with ecadotril in Germany and the US. Ecadotril is the (S)-enantiomer of acetorphan, and is 2 to 3 times more potent than the (R)-enantiomer retorphan.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Fasidotril (BP 1137, alatriopril, aladotril), the prodrug of its active metabolite fasidoprilat, is a mixed inhibitor of ACE and neutral endopeptidase (NEP). It is currently undergoing phase II development with Bioprojet in France for the treatment of congestive heart failure (CHF) and appears to be undergoing clinical investigation for the treatment of hypertension.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;MDL 100240 is the orally-active prodrug of MDL 100173, the most active inhibitor of ACE and neutral endopeptidase known. It is currently undergoing phase I clinical investigation with Hoechst Marion Roussel in the US for the treatment of hypertension and is in preclinical investigation for use in heart failure.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Omapatrilat, a potent dual metalloprotease inhibitor, is currently undergoing phase II clinical studies with Bristol-Myers Squibb in the US as a cardiovascular agent. The company highlights the potential of omapatrilat in organ protection in hypertension that would differentiate it from other antihypertensive agents. Omapatrilat has also potential for similar efficacy in African Americans and Caucasians. In 3 phase II studies the effect of omapatrilat has been at least equivalent in either group. Omapatrilat is currently undergoing phase III clinical trials for hypertension and phase II for heart failure.Bristol-Myers Squibb plans to file a US FDA application for the use of omapatrilat in hypertension and associated heart, kidney and brain problems in late 1999. Omapatrilat is undergoing clinical evaluation for the treatment of congestive heart failure at Christchurch Hospital in New Zealand. Also in Australia and New Zealand, omapatrilat, in association with folic acid, is undergoing clinical evaluation in patients with coronary heart disease (myocardial infarction or angina pectoris). Known as the PACIFIC study, it is expected to recruit about 900 patients. The company also plans to develop the drug for the treatment of postmyocardial infarction.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Sampatrilat (UK 81252) is a potent dual inhibitor of neutral endopeptidase and ACE being developed by Pfizer. Roberts Pharmaceuticals has acquired an exclusive licensing rights from Pfizer to develop and market sampatrilat. Sampatrilat may have potential for the treatment of hypertension and congestive heart failure. Phase II clinical studies are underway in the UK.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;SCH 42495 is the orally active prodrug of the neutral endopeptidase (NEP) inhibitor SCH 42354. It is being developed as a cardiovascular agent, and is currently undergoing phase II clinical trials in Japan with Schering-Plough for the treatment of hypertension and heart failure.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS