高迁移率族蛋白1(high mobility group box 1,HMGB1)是一种高度保守的DNA结合蛋白,与核小体结构的修复及基因转录调控密切相关。HMGB1由坏死细胞或活化的单核/巨噬细胞被动或主动释放至细胞外,并发挥促炎和修复作用。脓毒症是一种全身...高迁移率族蛋白1(high mobility group box 1,HMGB1)是一种高度保守的DNA结合蛋白,与核小体结构的修复及基因转录调控密切相关。HMGB1由坏死细胞或活化的单核/巨噬细胞被动或主动释放至细胞外,并发挥促炎和修复作用。脓毒症是一种全身炎症反应综合征。发生脓毒症时,血清和组织中HMGB1浓度上升,HMGB1在其发生过程中扮演晚期促炎细胞因子的角色。在脓毒症和内毒素血症动物模型中,靶向给予HMGB1抗体或特异性拮抗剂可以改善预后。本文就HMGB1的结构、在细胞核内发挥的作用、释放过程和其在炎症反应及脓毒症中发挥的作用研究进展作一综述。展开更多
Background &Aims: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine pro tease in vitro. Preclinical toxicology data and studies ...Background &Aims: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine pro tease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection. Methods: The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, doubleblind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6). Results: Viral RNA reductions of 2-3 log10 copies/mL were achi eved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction ≥3 log10 copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or comp ensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies. Conclusions: BILN 2061 is a well-tolerated a nd very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity is sues.展开更多
文摘高迁移率族蛋白1(high mobility group box 1,HMGB1)是一种高度保守的DNA结合蛋白,与核小体结构的修复及基因转录调控密切相关。HMGB1由坏死细胞或活化的单核/巨噬细胞被动或主动释放至细胞外,并发挥促炎和修复作用。脓毒症是一种全身炎症反应综合征。发生脓毒症时,血清和组织中HMGB1浓度上升,HMGB1在其发生过程中扮演晚期促炎细胞因子的角色。在脓毒症和内毒素血症动物模型中,靶向给予HMGB1抗体或特异性拮抗剂可以改善预后。本文就HMGB1的结构、在细胞核内发挥的作用、释放过程和其在炎症反应及脓毒症中发挥的作用研究进展作一综述。
文摘Background &Aims: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine pro tease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection. Methods: The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, doubleblind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6). Results: Viral RNA reductions of 2-3 log10 copies/mL were achi eved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction ≥3 log10 copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or comp ensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies. Conclusions: BILN 2061 is a well-tolerated a nd very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity is sues.
