Potency variation of small-molecule chymase inhibitors across species

Chymases (EC 3.4.21.39) are mast cell serine proteinases that are variably expressed in different species and, in most cases, display either chymotryptic or elastolytic substrate specificity. Given that chymase inhibitors have emerged as potential therapeutic agents for treating various inflammatory, allergic, and cardiovascular disorders, it is important to understand interspecies differences of the enzymes as well as the behavior of inhibitors with them. We have expressed chymases from humans, macaques, dogs, sheep (MCP2 and MCP3), guinea pigs, and hamsters (HAM1 and HAM2) in baculovirus-infected insect cells. The enzymes were purified and characterized with kinetic constants by using chromogenic substrates. We evaluated in vitro the potency of five nonpeptide inhibitors, originally targeted against human chymase. The inhibitors exhibited remarkable cross-species variation of sensitivity, with the greatest potency observed against human and macaque chymases, with K_i values ranging from ∼0.4 to 72 nM. Compounds were 10-300-fold less potent, and in some instances ineffective, against chymases from the other species. The X-ray structure of one of the potent phosphinate inhibitors, JNJ-18054478, complexed with human chymase was solved at 1.8 Å resolution to further understand the binding mode. Subtle variations in the residues in the active site that are already known to influence chymase substrate specificity can also strongly affect the compound potency. The results are discussed in the context of selecting a suitable animal model to study compounds ultimately targeted for human chymase.     

癌痛从痰论治探讨

癌痛是晚期癌症患者的主要症状之一,属于中医痛证范畴。痰是产生癌痛的重要中医病机,消痰法是治疗癌痛的重要方法。     

Graves甲亢多种治疗方法对Graves眼病影响的系统评价

目的 通过榆索、分析文献系统评价131I、手术、抗甲状腺药物(ATD)治疗Graves病(GD)对Graves眼病(GO)的影响.方法 检索了MEDIJNE(1966年-2006年3月)、EMBASE(1984-2005年)、The Cochrane Library(2006年第1期)、中国生物医学文献光盘数据库(EBMdisc,1978年1月-2006年4月)和中国学术期刊全文数据库(CNKI,1994-2006年)所收录的有关不同GD治疗方法对GO影响的文献,同时从参考文献中追溯文献.对纳入研究的方法学质量进行评价,根据是否采取预防甲状腺功能低下(简称甲低)发生的措施对纳入研究进行亚组分析,结果采用RevMan4.2软件进行统计学分析.结果 最终纳入随机对照研究5项,非随机对照研究2项,病例对照研究1项,共1625例患者.Meta分析显示:如GD治疗后早期未采取措施预防甲低,131I与手术治疗、131I与ATD治疗GD在诱发或加重GO以及减轻GO症状方面莘异有统计学意义[检验值分别为2.31,5.97,3.70,5.55;P均＜0.05];如GD治疗后早期采取措施预防甲低,手术与ATD治疗GD在诱发或加重GO以及减轻GO症状方面差异无统计学意义(检验值分别为0.27,0.99;P均＞0.05),尚无研究涉及131I治疗GD后早期采取甲低预防措施时131I对GO的影响.结论 若未及时采取甲低预防措施,131I较ATD、手术治疗GD更容易诱发或加重GO,减轻GO的症状却不如后两者,对于治疗前已有活动性GO的患者,应慎用131I.     

狭叶五味子中化合物扁枝杉香豆素和(-)-表儿茶酸体外抗乙型肝炎病毒活性研究

目的 研究从狭叶五味子Schisandra lancifolia中分离化合物扁枝杉香豆素(phyllocoumarin)和(-)-表儿茶酸[(-)-epicatechin]的体外抗乙型肝炎病毒(HBV)活性.方法 为了筛选和确认扁枝杉香豆素和(-)-表儿茶酸体外抗HBV活性,以HepG2.2.15细胞为体外研究HBV模型,分别用RPMI 1640完全培养基稀释不同质量浓度的药物作用于细胞,培养3 d后收集上清,采用MTT法检测药物对HepG2.2.15细胞的生长影响和ELISA法检测培养上清中HBsAg和HBeAg的水平,评价扁枝杉香豆素和(-)-表儿茶酸对HBsAg和HBeAg的影响.结果 扁枝杉香豆素和(-)-表儿茶酸具有一定的体外抗HBV活性,其细胞毒性非常小,CC_(50)均大于200μg/mL.扁枝杉香豆素具有较强的抑制HBsAg和HBeAg分泌作用.阳性对照药物阿德福韦酯也抑制HBVHBsAg和HBeAg分泌,但在相同质量浓度(1.6μg/mL)下其抑制作用较扁枝杉香豆素弱.结论 狭叶五味子中化合物扁枝杉香豆素和(-)-表儿茶酸具有一定体外抑制HBV HBsAg和HBeAg分泌的作用,从而起到抗HBV作用.     

超声造影在肝癌介入治疗后疗效评价中的应用

目的:探讨实时灰阶超声造影(contrast-enhanced grey-scale ultrasonography,CE-US)在肝癌介入治疗后疗效评价中的应用价值。方法:经肘前浅静脉团注超声对比剂SonoVue,观察各时相病灶的强化特点,并与治疗前CE-US、治疗后CT、MRI图像及随访结果进行比较,综合判断介入治疗效果。结果:CE-US可以清晰地显示病灶内有无局部或整体强化,能准确评价肝癌介入治疗后疗效。结论:CE-US在评价肝癌介入疗效时具有重要的临床价值。     

免疫吸附治疗在肾移植致敏受者中的应用

目的：探讨蛋白A免疫吸附（immunoads Orption，IA）治疗对清除肾移植致敏受者体内特异性抗HLA抗体的疗效和安全性。方法：10例肾移植致敏（PRA〉50％）受者用彤新蛋白A免疫吸附柱行IA治疗，测定治疗前后血免疫球蛋白及PRA水平。结果：10例患者IA治疗次数为4～15次（中位数9）。所有患者IA治疗后血清总IgG水平都明显下降（P〈0．001），IgA和IgM也较治疗前显著降低（P〈0．01）。PRA8例转阴，1例〈30％，1例仍为100％。结论：对于肾移植致敏受者，IA是一种特异性高、安全有效的治疗措施。     

What the structure of angiostatin may tell us about its mechanism of action

Summary.  Originally discovered in 1994 by Folkman and coworkers, angiostatin was identified through its antitumor effects in mice and later shown to be a potent inhibitor of angiogenesis. An internal fragment of plasminogen, angiostatin consists of kringle domains that are known to be lysine-binding. The crystal structure of angiostatin was the first multikringle domain-containing structure to be published. This review will focus on what is known about the structure of angiostatin and its implications in function from the current literature.     

肾动脉狭窄支架植入术的临床疗效观察

目的探讨肾动脉狭窄支架植入术的临床疗效.方法1997年1月～2004年12月,我院行支架介入治疗肾动脉狭窄27例.对27例术前、术后及随访期内血压、肾功能以及生活质量进行评估,并与同期单纯药物治疗肾动脉狭窄27例进行比较.结果介入组27例植入支架40枚,手术成功24例(88.9%,24/27),失败3例(11.1%,3/27),手术并发症5例(18.5%,5/27).术后在血压下降(包括收缩压舒张压)肌酐下降,肾小球滤过率增加方面,介入组获益率明显优于药物组,两组比较差异均有显著性,术后随访6个月～8年6个月,中位数为1年9个月,介入组有19例能比较健康的生活和工作,药物组仅12例能维持生活和工作.结论支架介入治疗较单纯药物治疗肾动脉狭窄疗效显著.     

经皮激光椎间盘减压术治疗颈性眩晕的临床研究

目的探讨经皮激光椎间盘减压术治疗颈性眩晕的疗效及机制。方法对31例颈性眩晕患者36个突出间盘行经皮激光椎间盘减压术，观察术后3个月以上的疗效。结果28例术后眩晕立即消除(90％)，明显改善者2例(7％)，无效者1例(3％)，无神经损害、感染等并发症发生。结论导致颈性眩晕的主要原因是颈椎间盘突出、颈椎失稳，激惹交感神经诱发椎动脉痉挛。钩突关节肥大并非是主要致病因素。经皮激光椎间盘减压术使椎间盘内压骤然降低，加之局部直接热疗，从而可消除椎动脉痉挛，对治疗颈性眩晕有明显疗效。     

CASE OF FASCIOLIASIS: EXTRACTION WITH ENDOSCOPIC RETROGRADE CHOLANGIOGRAPHY

Fascioliasis is a worldwide zoonotic infection with fasciola hepatica and fasciola gigantica. The zoonoses are particularly endemic in sheep‐raising countries and are also endemic in Turkey. Clinical features of fascioliasis relate to the stage and intensity of infection. Fasciola hepatica infection comprises two stages: hepatic and biliary, with different signs and symptoms. Cholestatic symptoms may be sudden, but, in some cases, they may be preceded by a long period of fever, eosinophilia and vague gastrointestinal symptoms. We reported a case with fever and upper‐quadrant abdominal pain since 3 months that comes from an area endemic for fasciola hepatica, with suspected imaging about fasciola hepatica in common bile duct on ultrasonography. After that, fasciola hepatica was extracted with endoscopic retrograde cholangiography.