Intravenous epoprostenol is recommended for World Health Organization functional class(WHO-FC) Ⅳ patients with pulmonary arterial hypertension(PAH) in the latest guidelines. However, in portopulmonary hypertension(Po...Intravenous epoprostenol is recommended for World Health Organization functional class(WHO-FC) Ⅳ patients with pulmonary arterial hypertension(PAH) in the latest guidelines. However, in portopulmonary hypertension(PoP H) patients, advanced liver dysfunction and/or thrombocytopenia often makes the use of intravenous epoprostenol challenging. Here we report the cases of two WHO-FC Ⅳ PoP H patients who were successfully treated with a combination of two oral vasodilators used to treat PAH: ambrisentan and tadalafil. Oral vasodilator therapy using a combination of ambrisentan and tadalafil may be a safe and effective therapeutic option for WHO-FC Ⅳ PoP H patients and should be considered for selected patients with severe and rapidly progressing PoP H.展开更多
AIM: To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model.METHODS: Fatty liver shionogi(FLS) FLS-ob/ob mice(male, 12 wk old...AIM: To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model.METHODS: Fatty liver shionogi(FLS) FLS-ob/ob mice(male, 12 wk old) received ambrisentan(2.5 mg/kg orally per day; n = 8) or water as a control(n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver.RESULTS: In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group(18.0 μg/g ± 6.1 μg/g vs 33.9 μg/g ± 13.5 μg/g liver, respectively, P = 0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, were also significantly lower in the ambrisentan group(0.46% ± 0.18% vs 1.11% ± 0.28%, respectively, P = 0.0003; and 0.12% ± 0.08% vs 0.25% ± 0.11%, respectively, P = 0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1(TIMP-1) were significantly lower by 60% and 45%, respectively, in the ambrisentan group. Inflammation, steatosis, and endothelin-related m RNA expression in the liver were not significantly different between the groups.CONCLUSION: Ambrisentan attenuated the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis.展开更多
The title compound was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. The crystal is of orthorhombic system （C22H22N2O4, Mr = 378.42）, space group P2121 with a = 6.8786（12...The title compound was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. The crystal is of orthorhombic system （C22H22N2O4, Mr = 378.42）, space group P2121 with a = 6.8786（12）, b = 14.259（2）, c = 19.712（3） A, V= 1933.5（6） A3, Z = 4, Dc = 1.300 g/cm3, f（000） = 800, μ= 0.090 mm-1, the final R = 0.0324 and wR = 0.0775 for 2410 observed reflections （I 〉 2σ（I））. The structure, especially the absolute configuration, of the title compound ambrisentan, an important endothelin receptor antagonist, was confirmed by single- crystal X-ray diffraction. The three aromatic rings in the lattice are basically orthogonal to one another. There is an intermolecular hydrogen bond in the crystal, which helps to further stabilize the crystal. One of the two non-classical intramolecular hydrogen bonds can help to stabilize the molecular conformation in the lattice.展开更多
文摘Intravenous epoprostenol is recommended for World Health Organization functional class(WHO-FC) Ⅳ patients with pulmonary arterial hypertension(PAH) in the latest guidelines. However, in portopulmonary hypertension(PoP H) patients, advanced liver dysfunction and/or thrombocytopenia often makes the use of intravenous epoprostenol challenging. Here we report the cases of two WHO-FC Ⅳ PoP H patients who were successfully treated with a combination of two oral vasodilators used to treat PAH: ambrisentan and tadalafil. Oral vasodilator therapy using a combination of ambrisentan and tadalafil may be a safe and effective therapeutic option for WHO-FC Ⅳ PoP H patients and should be considered for selected patients with severe and rapidly progressing PoP H.
文摘AIM: To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model.METHODS: Fatty liver shionogi(FLS) FLS-ob/ob mice(male, 12 wk old) received ambrisentan(2.5 mg/kg orally per day; n = 8) or water as a control(n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver.RESULTS: In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group(18.0 μg/g ± 6.1 μg/g vs 33.9 μg/g ± 13.5 μg/g liver, respectively, P = 0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, were also significantly lower in the ambrisentan group(0.46% ± 0.18% vs 1.11% ± 0.28%, respectively, P = 0.0003; and 0.12% ± 0.08% vs 0.25% ± 0.11%, respectively, P = 0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1(TIMP-1) were significantly lower by 60% and 45%, respectively, in the ambrisentan group. Inflammation, steatosis, and endothelin-related m RNA expression in the liver were not significantly different between the groups.CONCLUSION: Ambrisentan attenuated the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis.
基金Supported by the Key Project of National Innovative Drug of China(2009ZX09301-008-P-05)the Science Foundation of Tianjin (12JCYBJC18800-2012)
文摘The title compound was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. The crystal is of orthorhombic system （C22H22N2O4, Mr = 378.42）, space group P2121 with a = 6.8786（12）, b = 14.259（2）, c = 19.712（3） A, V= 1933.5（6） A3, Z = 4, Dc = 1.300 g/cm3, f（000） = 800, μ= 0.090 mm-1, the final R = 0.0324 and wR = 0.0775 for 2410 observed reflections （I 〉 2σ（I））. The structure, especially the absolute configuration, of the title compound ambrisentan, an important endothelin receptor antagonist, was confirmed by single- crystal X-ray diffraction. The three aromatic rings in the lattice are basically orthogonal to one another. There is an intermolecular hydrogen bond in the crystal, which helps to further stabilize the crystal. One of the two non-classical intramolecular hydrogen bonds can help to stabilize the molecular conformation in the lattice.
文摘目的采用网状Meta分析的方法比较安贝生坦、波生坦、西他生坦和马西替坦四种内皮素受体拮抗剂治疗肺动脉高压的疗效和耐受性。方法计算机检索Pub Med、EMBASE、Cochrane Library和中国生物医学文献数据库、中国知网、万方数据库,检索时间截至2014年1月31日,纳入比较四种内皮素受体拮抗剂治疗肺动脉高压的随机对照试验,主要结局指标为疗效和耐受性,次要结局指标为病死率和临床恶化率。研究筛选、数据提取及方法学质量评价均由两人独立完成。分别使用Rev Man 5.2和GEMTC软件进行直接比较和网状Meta分析。结果纳入12篇文献,包含13个随机对照试验,总计2191例患者。直接Meta分析结果显示,4种内皮素受体拮抗剂疗效均优于安慰剂,在耐受性方面,只有安贝生坦的效果优于安慰剂,其余药物与安慰剂的比较差异无统计学意义。网状Meta分析结果显示:在疗效方面,安贝生坦和波生坦的疗效优于安慰剂,西他生坦及马西替坦与安慰剂比较以及各种药物的互相比较差异均无统计学意义。等级概率图显示:安贝生坦效果最佳,其次为波生坦、西他生坦,马西替坦疗效最差。在耐受性方面,安贝生坦与西他生坦优于安慰剂,其余药物与安慰剂的比较以及各类药物之间的比较差异均无统计学意义。等级概率图显示:耐受性最好的药物为安贝生坦,其余依次为西他生坦、马西替坦,最差为波生坦。结论在治疗肺动脉高压的4种内皮素受体拮抗剂中,安贝生坦在疗效和耐受性方面均优于其他3种药物。在未来的研究中,应该更多关注安贝生坦及其他药物在病死率和临床恶化率方面的效果,此外,应注重探讨不同药物剂量、不同类型肺动脉高压患者的具体疗效。
