Portal de investigação
Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double-blind, randomized, placebo-controlled study in healthy subjects
Autores da FMUP
Participantes de fora da FMUP
- Fonseca, M
- Ribeiro, C
- Castilla-Fernández, G
- Gama, H
- Magalhaes, L
- Henriques, SC
- Silva, N
- Pinto, F
- Almeida, L
Unidades de investigação
Abstract
AimsDopamine beta-hydroxylase (D beta H) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS).MethodsA single-centre, prospective, double-blind, randomized, placebo-controlled, crossover study evaluated the effect of 400 mg zamicastat in 22 healthy male subjects. Cold pressor test (CPT) was performed at screening and each treatment period on Days -1 and 10. Plasma and 24 h-urine levels of dopamine (DA), epinephrine (EPI) and norepinephrine (NE), and plasma D beta H activity, were measured.ResultsCompared to placebo, zamicastat showed a - 4.62 mmHg decrease in systolic blood pressure during the cold stimulus vs. rest phases on Day 10 of CPT (P = .020). Zamicastat decreased mean arterial pressure response to cold stimulus during CPT (-2.62 mmHg; P = .025). At Day 10, zamicastat significantly increased plasma DA, before CPT (12.63 ng/L; P = .040) and after CPT (19.22 ng/L; P = .001) as well as the estimated plasma EPI change from baseline after CPT (P = .040). Inhibition of plasma D beta H activity ranged from 19.8% to 25.0%. At Day 10, significant reductions in 24-h urinary excretion of EPI (P = .002) and NE (P = .001) were observed. Zamicastat C tau geometric mean +/- GSD ranged from 45.86 +/- 1.46 ng/mL on Day 3 to 58.64 +/- 1.52 ng/mL on Day 10, with moderate inter-individual variability (CV: 32.6%-36.6%). Steady state was already achieved on Day 6.ConclusionsOur results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.
© 2024 British Pharmacological Society.
Dados da publicação
- ISSN/ISSNe:
- 1365-2125, 0306-5251
- Tipo:
- Article
- Páginas:
- 2781-2792
- DOI:
- 10.1111/bcp.16167
- Link para outro recurso:
- www.scopus.com
British Journal of Clinical Pharmacology Wiley-Blackwell Publishing Ltd
Citações Recebidas na Web of Science: 1
Citações Recebidas na Scopus: 1
Documentos
- Não há documentos
Filiações
Keywords
- blood pressure; catecholamines; cold pressor test; heart rate; zamicastat
Financiamento
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Citar a publicação
Fonseca M,Ribeiro C,Castilla G,Gama H,Magalhaes L,Henriques SC,Silva N,Pinto F,Almeida L,Soares P. Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double-blind, randomized, placebo-controlled study in healthy subjects. Br J Clin Pharmacol. 2024. 90. (11):p. 2781-2792. IF:3,400. (2).
