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

AIMS: Dopamine beta-hydroxylase (DßH) 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). METHODS: A 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 DßH activity, were measured. RESULTS: Compared 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 DßH 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 Cτ 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. CONCLUSIONS: Our results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.

The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first-in-class ACKR3/CXCR7 antagonist, ACT-1004-1239.

Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug-drug interactions (DDIs). ACT-1004-1239 is a potent and selective, first-in-class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT-1004-1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single-dose ACT-1004-1239 in healthy male subjects. In the open-label, fixed-sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT-1004-1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT-1004-1239 in the second period. We report a median of difference in tmax (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of Cmax and AUC0-∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of t1/2 was 1.46 (1.26, 1.70). Both treatments were well-tolerated with an identical incidence in subjects reporting treatment-emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT-1004-1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2- to <5-fold), and this should be considered in further clinical studies if CYP3A4 inhibitors are concomitantly administered.

Drug-Drug Interaction between Oral Zamicastat and Continuous Epoprostenol Infusion at Steady-State Conditions in Healthy Subjects.

This study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single-center, open-label, two-period study. In period 1, epoprostenol 8 ng/kg/min was administered alone. In period 2, epoprostenol 8 ng/kg/min was administered following an 8-day treatment with zamicastat. Since the initial dose of epoprostenol showed to be insufficiently tolerated, it was decreased to 6 ng/kg/min. Blood samples were collected to determine the metabolites of epoprostenol and concentrations of zamicastat and its metabolites. A total of 54 subjects were enrolled and data from 28 subjects were available for pharmacokinetic analysis. The epoprostenol plus zamicastat-to-epoprostenol geometric means ratio (GMR) and corresponding 90% confidence interval (CI) for Cav,ss and area under the plasma concentration-time curve from time 0 up to 16 h at steady state (AUC0-16,ss) of the metabolites of epoprostenol were within the acceptance bioequivalence range (80.00%-125.00%). The intrasubject coefficient of variation (ISCV) was below 10% for both parameters, on both metabolites. For zamicastat AUC0-τ,ss, the zamicastat plus epoprostenol-to-zamicastat GMR and corresponding 90% CI were within the bioequivalence acceptance range, while for zamicastat Cmax,ss, the lower limit of the 90% CI was slightly below the acceptance range. For zamicastat metabolites, Cmax,ss and AUC0-τ,ss and the zamicastat plus epoprostenol-to-zamicastat GMR were below the acceptance bioequivalence range. ISCV was between 30% and 41% for Cmax,ss and between 21% and 41% for AUC0-τ,ss, for zamicastat and both metabolites. This study showed that the administration of zamicastat did not significantly modify the cardiovascular effects of epoprostenol and that the interactions between zamicastat and epoprostenol are not expected to be clinically relevant.

Consumption of ultra-processed foods and associated factors in children from Barbacena (MG), Brazil / Consumo de alimentos ultraprocessados e fatores associados em crianças de Barbacena (MG), Brasil

Abstract Objective: To evaluate the prevalence of ultra-processed food consumption and associated factors among children enrolled in the public school system of the city of Barbacena, Minas Gerais, Brazil. Methods: This is a cross-sectional study conducted with schoolchildren aged 7-9 years, of both sexes, enrolled in state public schools. Food intake was assessed using the Previous Day Food Questionnaire and the level of physical activity by the Previous Day Physical Activity Questionnaire. The listed foods were classified according to the extent and purpose of industrial processing, using the NOVA classification. Pearson's χ2 test, Fisher's exact test, χ2 with Yates correction, and Poisson regression were used in the statistical analysis, estimating the crude and adjusted prevalence ratio, with 95% confidence intervals. Results: The prevalence of daily ultra-processed food consumption was 69.6%. After adjusted analyses, the consumption of ultra-processed food was associated with the omission of breakfast, mid-afternoon snack, supper, low physical activity, and consumption of risk foods. On the other hand, consumption of in natura or minimally processed foods was associated with older age, the consumption of lunch, mid-afternoon snack, dinner, and protective foods. Conclusions: There is a high prevalence of ultra-processed foods consumption, associated with unhealthy dietary habits among schoolchildren. This highlights the need for nutritional counseling and educational actions, favoring healthy eating in childhood.

RESUMO Objetivo Avaliar a prevalência de consumo de alimentos ultraprocessados e fatores associados em crianças matriculadas na rede pública do município de Barbacena, Minas Gerais, Brasil. Métodos Trata-se de um estudo transversal realizado com escolares de 7 a 9 anos de ambos os sexos, matriculados na rede pública estadual de ensino. O consumo alimentar foi avaliado utilizando o Questionário Alimentar do Dia Anterior e o nível de atividade física pelo Questionário de Atividade Física do Dia Anterior. Os alimentos listados foram classificados segundo a extensão e propósito do processamento industrial, conforme proposto pela classificação NOVA. Na análise estatística foram utilizados os testes χ2 de Pearson, Exato de Fisher, χ2 com correção de Yates e regressão de Poisson, estimando-se a razão de prevalência bruta e ajustada, com intervalos de confiança de 95%. Resultados A prevalência de consumo de alimentos ultraprocessados foi de 69,6%. Após análises ajustadas, o consumo de alimentos ultraprocessados foi associado à omissão do café da manhã, lanche da tarde e ceia, baixo nível de atividade física e ao consumo de alimentos de risco. Por outro lado, o consumo de alimentos in natura ou minimamente processados foi associado à maior idade, consumo de almoço, lanche da tarde, jantar e alimentos protetivos. Conclusões Verificamos uma alta prevalência no consumo de alimentos ultraprocessados, associada a hábitos alimentares não saudáveis, em crianças escolares. Isso destaca a necessidade de ações de educação alimentar e nutricional, favorecendo o consumo alimentar saudável na infância.

Abdominal obesity-related risk factors in children from public schools of Barbacena, Minas Gerais, Brazil / Fatores associados à obesidade abdominal em crianças matriculadas na rede pública de ensino, Barbacena, Minas Gerais

ABSTRACT Objective: To evaluate the sociodemographic and lifestyle factors associated with abdominal obesity in children from public schools in Barbacena, state of Minas Gerais, Brazil. Methods: This is a cross-sectional study conducted on 326 students aged 7 to 9 years from public schools in the urban area of the city. Anthropometric data included body weight, height, body mass index according to age, waist circumference, and waist-to-height ratio. Food consumption was evaluated using the Previous Day Food Questionnaire. Abdominal obesity was assessed based on waist circumference and waist-to-height ratio. The bivariate and multivariate analyses were performed by logistic regression, estimating the crude and adjusted odds ratio (OR), with 95% confidence interval. Results: The prevalence of overweight was 30.7%; whereas the prevalence of abdominal obesity was 9.2 and 12.6% according to waist circumference and waist-to-height ratio, respectively. Boys (OR 2.76; 95%CI 1.22-6.25) and children from central schools (OR 2.73; 95%CI 1.08-6.80) presented an increased chance of abdominal obesity according to waist circumference. Abdominal obesity according to waist-to-height ratio was associated with the central location of the schools (OR 2.18; 95%CI 1.02-4.63) and the habit of skipping supper (OR 2.01; 95%CI 1.00-4.09). Conclusions: The findings showed that being a boy, studying in a central school, and skipping supper were the main risk factors associated with abdominal obesity.

RESUMO Objetivo: Avaliar os fatores sociodemográficos e de estilo de vida associados à obesidade abdominal em crianças de escolas públicas de Barbacena, Minas Gerais. Métodos: Trata-se de estudo transversal realizado com 326 escolares de sete a nove anos, matriculados em escolas da zona urbana da cidade. As variáveis antropométricas avaliadas foram peso, estatura, índice de massa corpórea por idade, circunferência da cintura e relação cintura-estatura. O consumo alimentar foi registrado pelo Questionário Alimentar do Dia Anterior. A obesidade abdominal foi avaliada com base na circunferência da cintura e relação cintura-estatura. As análises bivariada e multivariada foram realizadas por meio de regressão logística, estimando-se a Odds Ratio (OR) bruta e ajustada, com os intervalos de confiança de 95% (IC95%). Resultados: A prevalência de excesso de peso foi de 30,7%, enquanto a prevalência de obesidade abdominal foi de 9,2 e 12,6%, de acordo com circunferência da cintura e relação cintura-estatura, respectivamente. Crianças do sexo masculino (OR 2,76; IC95% 1,22-6,25) e de escolas centrais (OR 2,73; IC95% 1,08-6,80) tiveram maior chance de apresentar obesidade abdominal segundo a circunferência da cintura. A obesidade abdominal, de acordo com a relação cintura-estatura, associou-se à localização central das escolas (OR 2,18; IC95% 1,02-4,63) e à omissão da ceia (OR 2,01; IC95% 1,00-4,09). Conclusões: Os achados mostraram que ser do sexo masculino, estudar em escola central e omitir a ceia foram os principais fatores de risco associados à obesidade abdominal.