RESUMO
Objective: To assess the safety and efficacy of the endothelin receptor antagonist ambrisentan in pediatric pulmonary arterial hypertension (PAH). Study design: In this open-label, phase IIb study, patients with PAH aged 8 to <18 years were randomized to low- or high-dose ambrisentan for 24 weeks. Most patients were receiving other PAH medication(s) that could not be changed during the trial. The primary outcome was safety (treatment-emergent adverse events [TEAEs]); secondary outcome was efficacy (including change from baseline to week 24 in 6-minute walking distance and World Health Organization functional class). Study staff were blinded to treatment. No statistical testing was performed. Results: Most of the 41 patients randomized (80%) experienced ≥1 TEAE; most were mild (22%) or moderate (49%) in severity (no difference between dose groups). Most common TEAEs were headache (24%), nausea (17%), abdominal pain (12%), and nasopharyngitis (12%). Eight patients had serious TEAEs; 2 were fatal (unrelated to study treatment). Improved 6-minute walking distance was observed from baseline to week 24: total mean (SD) change, +40.69 (84.58) meters; World Health Organization functional class was maintained or improved in 70% and 27% patients, respectively. Conclusions: Ambrisentan was well tolerated; TEAEs were consistent with the adult safety profile. Efficacy was similar to previous findings in adult PAH; however, interpretation is limited by small sample size. Findings support a potentially similar benefit:risk profile in pediatric (8 to <18 years) and adult patients with PAH. Trial registration: ClinicalTrials.gov: NCT01332331.
RESUMO
OBJECTIVE: To evaluate the efficacy, safety, and pharmacokinetics of the endothelin receptor antagonist bosentan as adjunctive therapy for neonates with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: This was a phase 3, multicenter, randomized, placebo-controlled exploratory trial (FUTURE-4). Eligible patients were >34 weeks gestation, <7 days old, receiving inhaled nitric oxide (iNO) treatment (≥4 hours), and had persistent respiratory failure (oxygenation index [OI] ≥12). After 2:1 randomization, bosentan 2 mg/kg or placebo was given by nasogastric tube twice daily for ≥48 hours and up to 1 day after iNO weaning. RESULTS: Twenty-one neonates received a study drug (13 bosentan, 8 placebo). Compared with the placebo group, the group treated with bosentan had a higher median baseline OI and greater need for vasoactive agents. One treatment failure (need for extracorporeal membrane oxygenation) occurred in the group treated with bosentan. The time to weaning from iNO or mechanical ventilation was not different between the groups. Bosentan was well tolerated and did not adversely affect systemic blood pressure or hepatic transaminase levels. Anemia and edema were more frequent in patients receiving bosentan. Blood concentrations of bosentan were low and variable on day 1, and achieved steady state on day 5. CONCLUSION: Adjunctive bosentan was well tolerated, but did not improve oxygenation or other outcomes in our patients with PPHN. This effect may be related to delayed absorption of bosentan on treatment initiation in critically ill neonates or to more severe illness of the neonates who received bosentan. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01389856.
Assuntos
Antagonistas dos Receptores de Endotelina/uso terapêutico , Síndrome da Persistência do Padrão de Circulação Fetal/tratamento farmacológico , Sulfonamidas/uso terapêutico , Bosentana , Método Duplo-Cego , Antagonistas dos Receptores de Endotelina/efeitos adversos , Feminino , Humanos , Recém-Nascido , Masculino , Óxido Nítrico/administração & dosagem , Respiração Artificial , Sulfonamidas/efeitos adversos , Falha de Tratamento , Resultado do TratamentoRESUMO
OBJECTIVES: To assess the level of serum resistin in obese and lean children and to establish a relationship with circulating inflammatory and vascular markers. STUDY DESIGN: This is a cross-sectional study including 67 obese and 62 lean children (mean age 10.9 ± 2.8 years, age range 5.4-16.6 years). We assessed circulating hormones (insulin, leptin, insulin-like growth factor 1), markers of inflammation (resistin, high sensitivity C-reactive protein, interleukin-6, chemokine ligand 2), and endothelial cell activation (vascular and intercellular adhesion molecules: vascular cell adhesion molecule 1 and intercellular adhesion molecule; E-selectin; P-selectin; endothelin 1). RESULTS: Body weight, body mass index (BMI), insulin, leptin, high-sensitivity C-reactive protein, vascular adhesion molecule 1, and E-selectin levels were significantly higher in obese than in lean subjects. Resistin was similar among the groups in the prepubertal period, but increased significantly in the obese adolescents (18.6 ± 24.9) compared with lean subjects (7.9 ± 10.7 ng/mL; P = .038). Resistin was not associated with BMI z score (P > .05). Subjects with resistin levels above 9 (ng/mL) had higher concentration of interleukin-6, chemokine ligand 2, endothelin-1, and insulin-like growth factor 1 but not of leptin, insulin, or BMI. CONCLUSION: Resistin was increased in obese adolescents independently of the quantity of the adipose tissue. In this population, increased resistin levels were related to inflammation and endothelial activation. We may hypothesize that interventions aiming to diminish resistin expression may slow down atherogenesis in adolescents.
Assuntos
Células Endoteliais/metabolismo , Inflamação/sangue , Obesidade/sangue , Resistina/sangue , Acelerometria , Adolescente , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Exercício Físico , Feminino , Humanos , Inflamação/etiologia , Masculino , Análise Multivariada , Obesidade/complicações , Análise de RegressãoRESUMO
OBJECTIVES: To measure preclinical noninvasive markers of atherosclerosis in youth with type 1 diabetes (T1DM), and to determine their associations between physical activity level and cardiorespiratory fitness (maximal oxygen consumption [VO2max]). STUDY DESIGN: This was a cross-sectional study including 32 patients with T1DM and 42 healthy subjects aged 6 to 17 years. Main outcome measures included arterial flow-mediated dilation (FMD) and intima-media thickness with high-resolution ultrasonography; physical activity by accelerometer (valid 26 patients with T1DM, 35 healthy subjects) and VO2max. RESULTS: Compared with healthy control subjects, patients with T1DM had higher intima-media thickness (mean 0.50 mm [0.48-0.52, 95% CI] vs 0.48 [0.47-0.49], P=.02) and reduced FMD (4.9% [4.1%-5.7%] vs 7.3 [6.4-8.1], P=.001), VO2max (45.5 mL/kg/min [43.0-48.0] vs 48.7 [46.7-50.6], PAssuntos
Doença da Artéria Coronariana/diagnóstico por imagem
, Doença da Artéria Coronariana/prevenção & controle
, Diabetes Mellitus Tipo 1/epidemiologia
, Atividade Motora
, Nitroglicerina/uso terapêutico
, Vasodilatadores/uso terapêutico
, Adolescente
, Biomarcadores/sangue
, Criança
, Doença da Artéria Coronariana/sangue
, Estudos Transversais
, Endotélio Vascular/diagnóstico por imagem
, Exercício Físico
, Feminino
, Nível de Saúde
, Humanos
, Masculino
, Túnica Íntima/patologia
, Ultrassonografia
Assuntos
Anti-Hipertensivos/uso terapêutico , Epoprostenol/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Algoritmos , Anemia Falciforme/epidemiologia , Criança , Doença Crônica , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Pneumopatias/epidemiologia , Inibidores da Fosfodiesterase 5 , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: To measure resting and ambulatory systemic blood pressure (BP) and left ventricular mass (LVM) in prepubertal obese and lean children and to determine their relationships. STUDY DESIGN: Cross-sectional study including 44 obese and 22 lean prepubertal children (mean age 8.8 +/- 1.5 years). We measured casual and 24-hour ambulatory BP, LVM and LVM index (LVMI) by echocardiography, and whole body lean tissue and fat mass by dual-energy X-ray absorptiometry. RESULTS: Mean 24-hour systolic BP (124.8 +/- 14.2 vs 105.5 +/- 8.8 mm Hg), diastolic BP (72.8 +/- 7.3 vs 62.7 +/- 3.8 mm Hg), and LVMI (36.1 +/- 5.8 vs 30.9 +/- 5.7, g x m(-2.7)) were significantly higher in obese than in lean subjects. Systolic ambulatory hypertension was present in 47.6% of obese children, and casual BP was normal in 55% of those cases. Body fatness, lean tissue mass, and 24-hour BP correlated positively with LVMI. When adjusted for body fatness, LVMI was only associated with 24-hour systolic BP (adjusted R(2) = 15.9%; P = .001). CONCLUSIONS: Ambulatory systemic hypertension and increased LVM are found in obese children. Left ventricular mass is partially determined by systemic BP. We conclude that prevention and treatment of childhood obesity should be initiated as early as possible to prevent the premature development of hypertension and end-stage organ damage.
Assuntos
Pressão Sanguínea , Ventrículos do Coração/anatomia & histologia , Hipertensão/etiologia , Hipertrofia Ventricular Esquerda/etiologia , Obesidade/complicações , Tecido Adiposo , Monitorização Ambulatorial da Pressão Arterial , Constituição Corporal , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Estudos Transversais , Ecocardiografia , Feminino , Ventrículos do Coração/patologia , Humanos , Hipertensão/diagnóstico , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Masculino , Obesidade/patologia , Obesidade/fisiopatologia , Valores de Referência , Análise de RegressãoRESUMO
OBJECTIVES: To characterize correlations between clinical classifications of heart failure and diagnostic workup. STUDY DESIGN: Pre- and postoperative characteristics of 20 children with heart failure secondary to valvular rheumatic disease were studied. RESULTS: Both scoring systems correlated with N-terminal pro-brain natriuretic peptide (N-proBNP) but not with troponin I (TnI). The PHFI correlated with N-proBNP, end-systolic wall stress, left ventricular mass index and left atrium to aorta diameter ratio. No correlation could be established between modified Ross score, or the New York Heart Association (NYHA) grade and echocardiographic measurements. Cardiothoracic and Sokolow indexes were correlated with the PHFI as well as to the NYHA classification. CONCLUSION: In this study, PHFI seems better correlated with radiologic, electrocardiographic, echocardiographic, and biologic assessment of heart failure in children. Clinical severity was correlated with N-proBNP but not with TnI.