Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters

Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CL_h) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CL_h involving OATP1B-mediated hepatic uptake. CL_h can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CL_h and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction.     

顺铂聚乳酸微球的药物释放特性及肝动脉栓塞研究

对顺铂聚乳酸微球进行了体外药物释放和家犬肝动脉栓塞研究。该微球粒径范围为50～200μm,平均粒径为115.76±35.94μm,顺铂含量为37.16%(W/W);体外药物释放机制符合Higuchi方程;肝动脉栓塞后8h,肝组织顺铂浓度高达21.55±12.18μg/g,明显高于肝动脉灌注顺铂组:3.16±0.09μg/g(P<0.05);肝动脉栓塞组的顺铂血浓峰值、各取血点浓度及曲线下面积AUC皆低于肝动脉灌注顺铂组。可望达到提高栓塞部位的药物疗效,降低全身毒副反应的作用。     

继发性肝癌的外科治疗

目的探讨继发性肝癌的手术适应证和方法。方法对52例继发性肝癌的临床病例资料进行回顾性分析。结果分别采用了左半肝切除、右半肝切除、左外叶切除、右前叶切除、右后叶切除和肝楔形切除术。术后1、3、5年的生存率分别为28.3%、19.4%和11.9%。结论对适合手术的继发性肝癌,行肝切除术可以获得满意的效果。     

腹腔镜肝右后叶囊肿开窗引流术35例报告

目的：探讨肝右后叶肝囊肿的腹腔镜处理方法。方法：1998年1月～2005年12月对35例有症状的肝右后叶囊肿（21例主要位于Ⅵ段，14例主要位于第Ⅶ段）采用四孔法行囊肿开窗引流术。囊肿位于肝右后叶上段者采用肝上入路，胆囊牵引钳或三叶钳推压肝脏使其向前向下，暴露肝后囊肿，囊肿开窗，修剪带蒂大网膜放入囊肿。囊肿位于肝右后叶下段者采用肝下入路，超声刀切开肝结肠韧带，右三角韧带及肝肾间疏松组织，胆囊牵引钳抬起肝脏，囊肿开窗，大网膜放入囊腔引流。结果：35例肝右后叶肝囊肿均在腹腔镜下完成肝囊肿开窗引流术，无中转开腹手术。15例采用肝上入路，20例采用肝下入路。手术时间30～95min，平均46min。无手术并发症。35例病理检查结果均为先天性肝囊肿。术后症状均消失。术后住院2～5d，平均3．8d。35例随访6～36个月，平均34个月，33例无复发，2例（为肝上入路病例）囊肿未完全消失，但较术前明显缩小，无明显症状，观察半年未见增大。结论：肝下及肝上入路囊肿开窗引流是腹腔镜下处理肝右叶肝囊肿的有效方法。     

Treatment strategy for synchronous metastases of colorectal cancer: is hepatic resection after an observation interval appropriate?

Background In cases of synchronous colorectal hepatic metastases, the primary colorectal cancer strongly influences on the metastases. Our treatment policy has been to conduct hepatic resection for the metastases at an interval of 3 months after colorectal resection. We examined the appropriateness of interval hepatic resection for synchronous hepatic metastasis. Materials and methods The subjects were 164 patients who underwent resection of hepatic metastasis of colorectal cancer (synchronous, 70 patients; metachronous, 94 patients). Background factors for hepatic metastasis and postoperative results were compared for synchronous and metachronous cases. Results The cumulative survival rate for 164 patients at 3, 5, and 10 years postoperatively was 71.9%, 51.8%, and 36.6%, and the post-resection recurrence rate in remnant livers was 26.8%. Interval resection for synchronous hepatic metastases was conducted in 49 cases after a mean interval of 131 days. No difference was seen in postoperative outcome between synchronous and metachronous cases. Conclusion The outcome was similarly favorable in cases of synchronous hepatic metastasis and in cases of metachronous metastasis. Delaying resection allows accurate understanding of the number and location of hepatic metastases, and is beneficial in determining candidates for surgery and in selecting surgical procedure.     

伴肝转移的Ⅳ期胃癌手术方式的合理选择

目的探讨不同手术方式对伴肝转移的Ⅳ期胃癌患者的临床疗效。方法回顾性分析1993-2004年间102例伴肝转移的Ⅳ期胃癌病例的手术方式,评价不同术式对预后的影响。结果肝转移H1的胃癌病例行姑息切除后半年、1年和2年的生存率分别为69%、44%和6%,与改道手术、开腹探查术者的生存率比较,差异有统计学意义(P=0.009)。肝转移H2的胃癌病例姑息切除术后半年、1年和2年的生存率分别为56%、13%和6%,与改道手术、开腹探查术者的生存率比较,差异无统计学意义(P=0.068)。肝转移H3的胃癌病例行姑息切除半年、1年和2年的生存率分别为25%、13%和0,与改道手术、开腹探查术者的生存率比较,差异无统计学意义(P=0.157)。有或无腹膜转移的病例,其术后生存率比较,差异亦无统计学意义(P=0.132)。结论肝转移H1的胃癌患者,无论伴与不伴腹膜转移,均应尽量行姑息性切除手术。肝转移H2、H3的Ⅳ期胃癌患者行切除性手术无益于预后。     

奥曲肽对肝动脉栓塞治疗大鼠肝癌影响的实验研究

目的　观察奥曲肽(octreotide)降低肝动脉栓塞(HAE)促进肿瘤新生血管生长的作用以及抑瘤作用。方法　采用大鼠肝内种植Walker 256瘤株制作肝癌模型,分为对照组、Octreotide组、HAE组和HAE+octreotide组共四组。定期切取肿瘤标本测量肿瘤体积,检测标本中的血管内皮生长因子(VEGF)的表达及微血管密度(MVD)。结果　各干预组肿瘤体积均小于对照组(P<0.01), HAE+octreotide组肿瘤体积也小于 HAE组(P<0.05); HAE+octrotide组 VEGF表达低于HAE组(P<0.05);Octreotide组、HAE+octreotide组 MVD表达低于对照组(P<0.05)。结论　在对大鼠肝癌的治疗中,行肝动脉栓塞时联用奥曲肽,可降低单纯肝动脉栓塞引起的癌组织 VEGF高表达,减少肿瘤新生血管形成,加强其抑瘤作用。     

国人C型肝性脑病发病诱因分析

目的了解国人C型肝性脑病发病诱因及相关因素。方法对国内已经发表的11个研究样本（患者总样本量1131例）进行综合分析。结果在9类纳入统计分析的诱因中：消化道出血占43．8％、各种感染占33．9％、电解质紊乱占29．1％、医源性因素占28．2％、饮食不节占14．2％、肾功能衰竭占13．0％，分居前6位，另外腹泻占2．4％，便秘占1．8％，原因未明／无占2．7％。其中医源性因素按照发生频率依次为：大量利尿和／或放腹水占14．5％、手术／创伤占6．0％，药物占4．5％，输血／输复合氨基酸占3．2％。结论警惕肝性脑病多种诱因的存在，尤其不能忽视医源性因素。按照发病概率积极寻找并消除诱因，对于改善顸后尤为重要。     

第Ⅲ段肝管空肠吻合解除肝门部胆管恶性梗阻

肝门部胆管恶性梗阻的治疗仍然十分困难。若不解除胆道梗阻,病人很快因肝细胞功能衰竭而死亡。由于肿瘤在肝门部侵润性生长,直接经肝门的手术往往不可能实现。1980～1993年间,我们采用第Ⅲ段肝管空肠吻合术姑息治疗28例肝门部胆管恶性梗阻的黄疸病人。24例为肝门部胆管癌,2例为胆囊癌,2例为胃癌肝门部淋巴结转移。术后19例病人恢复顺利;5例发生并发症,4例病人手术后死亡。24例存活病人中,19例黄疸完全消退3月以上,手术有效率为79％。4例黄疸再次出现,2例因胆管炎需要入院治疗。作者认为:第Ⅲ段肝管空肠吻合术能有效解除不能切除的肝门部恶性肿瘤病人的胆道梗阻。     

肝部分切除术治疗肝内胆管结石

目的：总结肝部分切除治疗左肝内胆管结石的经验。方法：对1995年至2002年7月152例肝内胆管结石病人，13例行肝部分切除进行总结。结果：在10例行肝左外叶切除，3例行肝左叶切除经验的基础上，总结出在基层医院医疗设备不完善的情况下，控制肝脏手术中出血，简化手术，以免导致肝功能的恶化。减少了术后结石残留和复发率。结论：治疗肝内胆管结石的最有效的手段是切除病变肝段。