Fontan surgery is a widely used palliative procedure that significantly improves the survival period of patients with complex congenital heart disease(CHD).However,it does not decrease postoperative complication rate....Fontan surgery is a widely used palliative procedure that significantly improves the survival period of patients with complex congenital heart disease(CHD).However,it does not decrease postoperative complication rate.Previous studies suggested that elevated mean pulmonary artery pressure(m PAP)and vascular resistance lead to decreased exercise tolerance and myocardial dysfunction.Therapy with endothelial receptor antagonists(Bosentan)has been demonstrated to improve the patients'prognosis.A double-blind,randomized controlled trial was performed to explore the efficacy of Bosentan in treating patients who underwent the Fontan procedure.Eligible participants were randomly divided into Bosentan group and control group.Liver function was tested at a local hospital and the results were reported to the phone inspector every month.If the results suggested abnormal liver function,treatment would be adjusted or terminated.All the participants finished the follow-up study,with no patients lost to follow-up.Unblinding after 2-year follow-up,no mortality was observed in either group.However,secondary end-points were found to be significantly different in the comparable groups.The cardiac function and 6-min walking distance in the Bosentan group were significantly superior to those in the control group(P=0.018 and P=0.027).Bosentan could improve New York Heart Association(NYHA)functional status and improve the results of the 6-min walking test(6MWT)in Fontan patients post-surgery,and no other benefits were observed.Furthermore,a primary meta-analysis study systematically reviewed all the similar clinical trails worldwide and concluded an overall NYHA class improvement in Fontan patients who received Bosentan treatments.展开更多
Sildenafil and bosentan are often co-administered for pulmonary arterial hypertension (PAH) treatment. The plasma concentration of sildenafil can be decreased by half if co-administered with bosentan. Many patients ta...Sildenafil and bosentan are often co-administered for pulmonary arterial hypertension (PAH) treatment. The plasma concentration of sildenafil can be decreased by half if co-administered with bosentan. Many patients take these agents simultaneously in the morning and the evening. The aim of this study was to examine the pharmacokinetics of sildenafil which was interfered with bosentan administration to ascertain whether these agents should be given concomitantly or separately. A two-way crossover study was conducted in 6 PAH patients with combination therapy of sildenafil and bosentan. Participants underwent the sequence of treatment phases: phase S (sildenafil administered 3 h before bosen-tan);phase B (bosentan administered 3 h before sildenafil);and phase C (administered concomitantly). Blood samples were collected on the last day of each phase. There was no significant difference in maximum plasma concentration or area under the plasma concentration-time curve (AUC0-8) between phase C and phase S (95.5 ± 24.8 vs. 72.9 ± 40.9 (p = 0.07), 209.7 ± 81.8 vs. 180.2 ± 126.4 (p = 0.24), respectively) or between phases C and B (87.8 ± 42.0 vs. 99.6 ± 33.9 (p = 0.59), 197.2 ± 88.2 vs. 240.7 ± 121.8 (p = 0.19), respectively) (ng/mL, mean ± standard deviation). Large intra-and inter-individual variability in sildenafil concentration was noted. The timing of administration of sildenafil and bosentan does not significantly influence the plasma concentration of sildenafil. Physicians do not need to be overly concerned about the timing of administration of these drugs to maximize the sildenafil concentration.展开更多
A simple, precise, and accurate method is developed and validated for the analysis of Bosentan tablet formulation. The method has shown adequate separation of the ingredients from Tablets. Separation was achieved on a...A simple, precise, and accurate method is developed and validated for the analysis of Bosentan tablet formulation. The method has shown adequate separation of the ingredients from Tablets. Separation was achieved on a C18 column using a mobile phase consisting of acetonitrile: 10 Mm ammonium acetate (pH 4.5) buffer (70:30, v/v) at a flow rate of 1.0 ml/min and UV detection at 265 nm. This new method is validated as per the ICH, which includes accuracy, precision, selectivity, linearity and range, robustness and ruggedness. The current method demonstrates good linearity over the range of 5 - 70 ng/ml of bosentan with r2 of 0.999. The average recovery of the method is 98.6%. The degree of reproducibility of the results obtained as an outcome of small deliberate variations in the method parameters and by changing analytical operator has proven that this method is robust and rugged.展开更多
Objective Endothelin is a key role in the pathogenic of pulmonary arterial hypertension. High concentrations of endothelin 1 have been recorded in plasma and lungs of patients with pulmonary artery hypertension associ...Objective Endothelin is a key role in the pathogenic of pulmonary arterial hypertension. High concentrations of endothelin 1 have been recorded in plasma and lungs of patients with pulmonary artery hypertension associated with congenital heart disease,and the concentrations of endothelin-1 was correlated with severity degree展开更多
Background:Lung hypoplasia,pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia(CDH).This study was undertaken to investigate if anten...Background:Lung hypoplasia,pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia(CDH).This study was undertaken to investigate if antenatal use of sildenafil and/or bosentan attenuates vascular remodeling,promotes branching,and improves alveolarization in experimental nitrofeninduced CDH.Methods:Nitrofen(100 mg)was gavage-fed to pregnant rats at post conception day(PCD)9 to induce CDH.The rats were randomized to 5 groups:1)control;2)nitrofen;3)nitrofen+sildenafil 100 mg/kg per day at PCD 16-20;4)nitrofen+bosentan 30 mg/kg per day,at PCD 16-20,and 5)nitrofen+bosentan+sildenafil,same doses and administration days.After cesarean delivery,the offsprings were sacrifi ced.The diaphragmatic defect and pulmonary hypoplasia were identified,and the lungs were dissected.Arterial wall thickness,bronchiolar density and alveolarization were assessed.Results:The offsprings with CDH were characterized by severe pulmonary hypoplasia(lung weight-to-body weight ratio:0.0263[95%confidence interval(CI)0.0242-0.0278)]in the nitrofen group versus 0.0385(95%CI 0.0355-0.0424)in the control group(P=0.0001).Pulmonary arterial wall thickness was decreased to 3.0(95%CI 2.8-3.7)μm in the nitrofen+sildenafil group versus 5.0(95%CI 4.1-4.9)μm in the nitrofen group(P=0.02).Terminal bronchioles increased to 13.7(95%CI 10.7-15.2)μm in the nitrofen+bosentan group in contrast to 8.7(95%CI 7.2-9.4)μm in the nitrofen group(P=0.002).More significant differences(P=0.0001)were seen in terminal bronchioles in the nitrofen+sildenafil+bosentan group than in the nitrofen group[14.0(95%CI 12.5-15.4)μm versus 8.5(95%CI 7.1-9.3)μm].Pulmonary arterial wall thickness was also decreased in the former group.Conclusions:In this rat model,antenatal treatment with sildenafil attenuates vascular remodeling.Bosentan promotes the development of terminal bronchioles in nitrofen-induced CDH.展开更多
基金supported by the National Natural Science Foundation of China(No.31330029)
文摘Fontan surgery is a widely used palliative procedure that significantly improves the survival period of patients with complex congenital heart disease(CHD).However,it does not decrease postoperative complication rate.Previous studies suggested that elevated mean pulmonary artery pressure(m PAP)and vascular resistance lead to decreased exercise tolerance and myocardial dysfunction.Therapy with endothelial receptor antagonists(Bosentan)has been demonstrated to improve the patients'prognosis.A double-blind,randomized controlled trial was performed to explore the efficacy of Bosentan in treating patients who underwent the Fontan procedure.Eligible participants were randomly divided into Bosentan group and control group.Liver function was tested at a local hospital and the results were reported to the phone inspector every month.If the results suggested abnormal liver function,treatment would be adjusted or terminated.All the participants finished the follow-up study,with no patients lost to follow-up.Unblinding after 2-year follow-up,no mortality was observed in either group.However,secondary end-points were found to be significantly different in the comparable groups.The cardiac function and 6-min walking distance in the Bosentan group were significantly superior to those in the control group(P=0.018 and P=0.027).Bosentan could improve New York Heart Association(NYHA)functional status and improve the results of the 6-min walking test(6MWT)in Fontan patients post-surgery,and no other benefits were observed.Furthermore,a primary meta-analysis study systematically reviewed all the similar clinical trails worldwide and concluded an overall NYHA class improvement in Fontan patients who received Bosentan treatments.
文摘Sildenafil and bosentan are often co-administered for pulmonary arterial hypertension (PAH) treatment. The plasma concentration of sildenafil can be decreased by half if co-administered with bosentan. Many patients take these agents simultaneously in the morning and the evening. The aim of this study was to examine the pharmacokinetics of sildenafil which was interfered with bosentan administration to ascertain whether these agents should be given concomitantly or separately. A two-way crossover study was conducted in 6 PAH patients with combination therapy of sildenafil and bosentan. Participants underwent the sequence of treatment phases: phase S (sildenafil administered 3 h before bosen-tan);phase B (bosentan administered 3 h before sildenafil);and phase C (administered concomitantly). Blood samples were collected on the last day of each phase. There was no significant difference in maximum plasma concentration or area under the plasma concentration-time curve (AUC0-8) between phase C and phase S (95.5 ± 24.8 vs. 72.9 ± 40.9 (p = 0.07), 209.7 ± 81.8 vs. 180.2 ± 126.4 (p = 0.24), respectively) or between phases C and B (87.8 ± 42.0 vs. 99.6 ± 33.9 (p = 0.59), 197.2 ± 88.2 vs. 240.7 ± 121.8 (p = 0.19), respectively) (ng/mL, mean ± standard deviation). Large intra-and inter-individual variability in sildenafil concentration was noted. The timing of administration of sildenafil and bosentan does not significantly influence the plasma concentration of sildenafil. Physicians do not need to be overly concerned about the timing of administration of these drugs to maximize the sildenafil concentration.
文摘A simple, precise, and accurate method is developed and validated for the analysis of Bosentan tablet formulation. The method has shown adequate separation of the ingredients from Tablets. Separation was achieved on a C18 column using a mobile phase consisting of acetonitrile: 10 Mm ammonium acetate (pH 4.5) buffer (70:30, v/v) at a flow rate of 1.0 ml/min and UV detection at 265 nm. This new method is validated as per the ICH, which includes accuracy, precision, selectivity, linearity and range, robustness and ruggedness. The current method demonstrates good linearity over the range of 5 - 70 ng/ml of bosentan with r2 of 0.999. The average recovery of the method is 98.6%. The degree of reproducibility of the results obtained as an outcome of small deliberate variations in the method parameters and by changing analytical operator has proven that this method is robust and rugged.
文摘Objective Endothelin is a key role in the pathogenic of pulmonary arterial hypertension. High concentrations of endothelin 1 have been recorded in plasma and lungs of patients with pulmonary artery hypertension associated with congenital heart disease,and the concentrations of endothelin-1 was correlated with severity degree
基金supported by grants from the Fondo de Fomento a la Investigación,Instituto Mexicano del Seguro Social(FOFOI-FIS,IMSS,2006/1A/I/031-FIS/IMSS/PROT/205)by Miami Children's Hospital&Sheridan Health Corporation.
文摘Background:Lung hypoplasia,pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia(CDH).This study was undertaken to investigate if antenatal use of sildenafil and/or bosentan attenuates vascular remodeling,promotes branching,and improves alveolarization in experimental nitrofeninduced CDH.Methods:Nitrofen(100 mg)was gavage-fed to pregnant rats at post conception day(PCD)9 to induce CDH.The rats were randomized to 5 groups:1)control;2)nitrofen;3)nitrofen+sildenafil 100 mg/kg per day at PCD 16-20;4)nitrofen+bosentan 30 mg/kg per day,at PCD 16-20,and 5)nitrofen+bosentan+sildenafil,same doses and administration days.After cesarean delivery,the offsprings were sacrifi ced.The diaphragmatic defect and pulmonary hypoplasia were identified,and the lungs were dissected.Arterial wall thickness,bronchiolar density and alveolarization were assessed.Results:The offsprings with CDH were characterized by severe pulmonary hypoplasia(lung weight-to-body weight ratio:0.0263[95%confidence interval(CI)0.0242-0.0278)]in the nitrofen group versus 0.0385(95%CI 0.0355-0.0424)in the control group(P=0.0001).Pulmonary arterial wall thickness was decreased to 3.0(95%CI 2.8-3.7)μm in the nitrofen+sildenafil group versus 5.0(95%CI 4.1-4.9)μm in the nitrofen group(P=0.02).Terminal bronchioles increased to 13.7(95%CI 10.7-15.2)μm in the nitrofen+bosentan group in contrast to 8.7(95%CI 7.2-9.4)μm in the nitrofen group(P=0.002).More significant differences(P=0.0001)were seen in terminal bronchioles in the nitrofen+sildenafil+bosentan group than in the nitrofen group[14.0(95%CI 12.5-15.4)μm versus 8.5(95%CI 7.1-9.3)μm].Pulmonary arterial wall thickness was also decreased in the former group.Conclusions:In this rat model,antenatal treatment with sildenafil attenuates vascular remodeling.Bosentan promotes the development of terminal bronchioles in nitrofen-induced CDH.
