Influence of sub-chronic selective 11ß-hydroxysteroid dehydrogenase 1 inhibition on the hypothalamic-pituitary-adrenal axis in female cynomolgus monkeys.
Eur J Pharmacol
; 789: 68-74, 2016 Oct 15.
Article
en En
| MEDLINE
| ID: mdl-27393460
Inhibition of local cortisol regeneration from circulating cortisone by blocking 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. Chronic modulation of glucocorticoid homeostasis may result in hypothalamic-pituitary-adrenal (HPA) axis stimulation. HPA axis over-activation leading androgen excess would be undesirable in a therapeutic intervention designed to treat a chronic condition such as the metabolic syndrome. To address whether 11ß-HSD1 inhibition would lead to excess androgens, we treated female cynomolgus monkeys with a selective inhibitor, BI 135558, for 4 weeks. Continual action of the compound over the dosing period was confirmed by constant plasma exposure, and a maintained change in urinary glucocorticoid metabolites consistent with 11ß-HSD1 inhibition. No significant changes in adrenal function, as evidenced by an adrenocorticotropic hormone (ATCH) challenge, were observed. An examination of androgenic hormones revealed a slight increase in dehydroepiandrosterone sulfate (DHEA-S), while other hormones such as testosterone remained within reference values. Overall, treatment with BI 135558 in monkeys did not result in obvious over-activation of the HPA axis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oxazinas
/
Sistema Hipófiso-Suprarrenal
/
Piridonas
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1
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Inhibidores Enzimáticos
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Sistema Hipotálamo-Hipofisario
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Eur J Pharmacol
Año:
2016
Tipo del documento:
Article
Pais de publicación:
Países Bajos