Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double-blind, randomized, placebo-controlled study in healthy subjects

被引:2
作者
Fonseca, Marlene [1 ]
Ribeiro, Cheila [2 ]
Castilla-Fernandez, Guillermo [2 ,3 ]
Gama, Helena [2 ]
Magalhaes, Luis [2 ]
Henriques, Sara Carolina [1 ,4 ]
Silva, Nuno [1 ,4 ]
Pinto, Filipe [1 ]
Almeida, Luis [1 ,5 ,6 ]
Soares-da-Silva, Patricio [5 ,6 ]
机构
[1] BlueClin Phase I, Porto, Portugal
[2] S Romao & S Mamede, Res & Dev, BIAL Portela & Ca SA Coronado, Mamede, Portugal
[3] Bial R&D Investments SA, Trofa, Portugal
[4] Univ Lisbon, Res Inst Med iMed ULisboa, Fac Pharm, Lisbon, Portugal
[5] Univ Porto, Fac Med, Dept Biomed, Unit Pharmacol & Therapeut, Porto, Portugal
[6] Univ Porto, MedInUP Ctr Drug Discovery & Innovat Med, Porto, Portugal
关键词
blood pressure; catecholamines; cold pressor test; heart rate; zamicastat; CARDIAC AUTONOMIC CONTROL; SYMPATHETIC ACTIVATION; PLASMA;
D O I
10.1111/bcp.16167
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:2781 / 2792
页数:12
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