Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects

Autor: Catherine Watson, Dean F. Rigel, Daniel LaSala, Fumin Fu, Michael E. Beil, Sam Rebello, Arco Y. Jeng, Jing Liu, Chii-Whei Hu, William P. Dole, Yiming Zhang, Joël Ménard, Jennifer Leung-Chu, Wei Chen, Guiqing Liang
Přispěvatelé: Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Novartis Pharmaceutical Corporation, Novartis Institutes for BioMedical Research (NIBR), Novartis Pharmaceuticals Corporation, Novartis Institutes for BioMedical Research, Taibi, Nadia
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Aldosterone synthase
Male
Pyridines
Angiotensinogen
Pharmacology
Spironolactone
Kidney
Plasma renin activity
Cortisol
Placebos
Rats
Sprague-Dawley
Translational Research
Biomedical
chemistry.chemical_compound
Cushing ’ s disease
Mineralocorticoid receptor
Renin
Aldosterone
Medicine(all)
biology
Imidazoles
Heart
General Medicine
Haplorhini
Cushing’s disease
3. Good health
Eplerenone
Mineralocorticoid
Rats
Transgenic
medicine.drug
medicine.medical_specialty
medicine.drug_class
General Biochemistry
Genetics and Molecular Biology
Natriuresis
Double-Blind Method
Internal medicine
Renin–angiotensin system
medicine
Animals
Cytochrome P-450 CYP11B2
Humans
Double-transgenic rat
business.industry
Biochemistry
Genetics and Molecular Biology(all)
Research
Translational research
Rats
Disease Models
Animal
Endocrinology
chemistry
[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie
biology.protein
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
business
Zdroj: Journal of Translational Medicine
Journal of Translational Medicine, BioMed Central, 2014, 12 (1), pp.340
ISSN: 1479-5876
Popis: Background Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (Ki = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase. Methods Hormonal effects of orally administered LCI699 were examined in rat and monkey in vivo models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTG rat) model overexpressing human renin and angiotensinogen. Results Rat and monkey in vivo models of stimulated aldosterone release predicted human dose– and exposure–response relationships, but overestimated the selectivity of LCI699 in humans. In the dTG rat model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49 ± 3% and 39 ± 6% respectively (Day 1, mean ± SEM; P
Databáze: OpenAIRE
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