The effect of LCZ696 (sacubitril/valsartan) on amyloid-ß concentrations in cerebrospinal fluid in healthy subjects.
Br J Clin Pharmacol
; 81(5): 878-90, 2016 May.
Article
em En
| MEDLINE
| ID: mdl-26663387
ABSTRACT
AIMS:
LCZ696 (angiotensin receptor neprilysin inhibitor) is a novel drug developed for the treatment of heart failure with reduced ejection fraction. Neprilysin is one of multiple enzymes degrading amyloid-ß (Aß). Its inhibition may increase Aß levels. The potential exists that treatment of LCZ696, through the inhibition of neprilysin by LBQ657 (an LCZ696 metabolite), may result in accumulation of Aß. The aim of this study was to assess the blood-brain-barrier penetration of LBQ657 and the potential effects of LCZ696 on cerebrospinal fluid (CSF) concentrations of Aß isoforms in healthy human volunteers.METHODS:
In a double-blind, randomized, parallel group, placebo-controlled study, healthy subjects received once daily LCZ696 (400 mg, n = 21) or placebo (n = 22) for 14 days.RESULTS:
LCZ696 had no significant effect on CSF AUEC(0,36 h) of the aggregable Aß species 1-42 or 1-40 compared with placebo (estimated treatment ratios 0.98 [95% CI 0.73, 1.34; P = 0.919] and 1.05 [95% CI 0.82, 1.34; P = 0.702], respectively). A 42% increase in CSF AUEC(0,36 h) of soluble Aß 1-38 was observed (estimated treatment ratio 1.42 [95% CI 1.05, 1.91; P = 0.023]). CSF levels of LBQ657 and CSF Aß 1-42, 1-40, and 1-38 concentrations were not related (r(2) values 0.022, 0.010, and 0.008, respectively).CONCLUSIONS:
LCZ696 did not cause changes in CSF levels of aggregable Aß isoforms (1-42 and 1-40) compared with placebo, despite achieving CSF concentrations of LBQ657 sufficient to inhibit neprilysin. The clinical relevance of the increase in soluble CSF Aß 1-38 is currently unknown.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Tetrazóis
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Compostos de Bifenilo
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Barreira Hematoencefálica
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Neprilisina
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Peptídeos beta-Amiloides
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Antagonistas de Receptores de Angiotensina
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Aminobutiratos
Tipo de estudo:
Clinical_trials
Limite:
Adolescent
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Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article