Clinical and hormonal effects of the new angiotensin II receptor antagonist LRB081.

Détails

ID Serval
serval:BIB_4E7794C0EAC3
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Clinical and hormonal effects of the new angiotensin II receptor antagonist LRB081.
Périodique
Journal of Cardiovascular Pharmacology
Auteur⸱e⸱s
Noël B., Del Re G., Capone P., Brunner H.R., Nussberger J.
ISSN
0160-2446 (Print)
ISSN-L
0160-2446
Statut éditorial
Publié
Date de publication
1996
Peer-reviewed
Oui
Volume
28
Numéro
2
Pages
252-258
Langue
anglais
Notes
Publication types: Clinical Trial ; Journal Article ; Randomized Controlled Trial
Résumé
The renin-angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. Antagonizing angiotensin (Ang) II at the receptor site may produce fewer side effects than inhibition of the promiscuous converting enzyme. The present study was designed to assess in healthy human subjects the effect of LRB081, a new orally active AT1-receptor antagonist, on the pressor action of exogenous Ang II. At the same time, plasma hormones and drug levels were monitored. At 1-week intervals and in a double-blind randomized fashion, 8 male volunteers received three doses of LRB081 (10, 40, and 80 mg) and placebo. Blood pressure (BP) was measured at a finger by photoplethysmograph. The peak BP response to intravenous injection of a standard dose of Ang II was determined before and for < or = 24 h after administration of an oral dose of LRB081 or placebo. After drug administration, the blood BP response to Ang II was expressed in percent of the response before drug administration. At the same time, plasma renin activity (PRA), Ang II, aldosterone, catecholamine (radioassays), and drug levels (by high-performance liquid chromatography) were monitored. After LRB081 administration, a dose dependent inhibition of the BP response to Ang II was observed. Maximal inhibition of the systolic BP response was 54 +/- 3 (mean +/- SEM), 63 +/- 2, and 93 +/- 1% with 10, 40, and 80 mg LRB081, respectively. The time to peak was 3 h for 6 subjects and 4 and 6 h for 2 others. Preliminary plasma half-life (t1/2) was calculated at 2 h. With the highest dose, the inhibition remained significant for 24 h (31 +/- 5%, p < 0.05). Maximal BP-blocking effect and maximal plasma drug level coincided, suggesting that the unmetabolized LRB081 is responsible for the antagonistic effect. PRA and Ang II increased dose dependently after LRB081 intake. Aldosterone, epinephrine, and norepinephrine concentrations remained unchanged. No clinically significant adverse reaction was observed during the study. LRB081 is a well-tolerated, orally active, potent, and long-acting Ang II receptor antagonist. Unlike in the case of losartan, no active metabolite of LRB081 has been shown to be responsible for the main effects.
Mots-clé
Adult, Aldosterone/blood, Angiotensin II/blood, Angiotensin II/metabolism, Angiotensin Receptor Antagonists, Blood Pressure/drug effects, Catecholamines/blood, Double-Blind Method, Hormones/blood, Humans, Male, Pyrimidinones/adverse effects, Pyrimidinones/pharmacokinetics, Regional Blood Flow/drug effects, Renin/blood, Thiophenes/adverse effects, Thiophenes/pharmacokinetics
Pubmed
Web of science
Création de la notice
05/03/2008 16:40
Dernière modification de la notice
20/08/2019 14:04
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