微囊化肝细胞移植治疗大鼠急性肝功能衰竭的研究

目的探讨应用生物微胶囊包裹肝细胞(microencapsulatedhepatocyte)腹腔移植治疗急性肝功能衰竭的机制与可行性,评价生物膜功能。方法D-氨基半乳糖(D-gal)诱发急性肝功能衰竭大鼠模型,造模动物随机分成5组:Ⅰ组生理盐水组;Ⅱ组空微胶囊对照组;Ⅲ组促肝细胞生长素(hepatocytegrowthfactor,HGF)组;Ⅳ组裸肝细胞组;Ⅴ组微囊化肝细胞组,观察造模动物的2周存活率及死亡时间、肝功生化指标的变化,2周后收集腹腔内微胶囊,观察其形态与功能。结果Ⅴ组动物的存活率较Ⅳ、Ⅲ、Ⅱ、Ⅰ组有明显提高(分别为66.7%、33.3%、20%、13.3%、20%,P<0.05),其它组间存活率无显著性差异;Ⅴ、Ⅳ、Ⅲ组动物的存活时间明显长于Ⅱ组与Ⅰ组(分别为86.0±7.0、84.0±6.0、83.0±6.0、72.0±5.0、65.0±4.0小时,P<0.05);Ⅴ组移植后24小时起白蛋白(ALB)、总胆红素(TBIL)、凝血酶原时间(PT)较其它组有明显提高(P<0.05)。2周后腹腔收集的空微胶囊形态完整,微囊内肝细胞部分保持存活,Ⅳ组腹腔中大部分游离肝细胞被大网膜包裹破坏。结论微囊化肝细胞移植可以明显提高肝功能衰竭大鼠的存活率,延长生存时间,显著改善肝生化功能。生物微胶囊可以有效阻断免疫排斥反应,保护移植肝细胞,有利于其发挥生物功能。     

APA微囊化BCCs移植逆转神经性疼痛大鼠背根神经节Nav1．8mRNA表达下调

目的观察APA微囊化牛肾上腺嗜铬细胞(BCCs)移植对坐骨神经慢性挤压伤(CCI)大鼠背根神经节(DRG)Nav1.8 mRNA表达的影响.方法 SD大鼠分为4组,每组5只,即对照组(C组),正常大鼠;CCI组,右侧坐骨神经结扎;APA组,CCI模型后7 d,蛛网膜下腔移植500～600个APA空囊;APA-BCCs组,CCI模型后7 d蛛网膜下腔移植5×106个APA微囊化BCCs.测定各组移植前和移植后7d的触诱发痛阈值(g)和CO2激光刺激痛阈值(ms).移植后7 d行为学测定后取DRG冰冻切片,按照原位杂交法检测各组DRG中Nav1.8 mRNA表达的变化.结果 CCI组和APA组大鼠L4和L5 DRG Nav1.8杂交信号较C组明显降低(P＜0.01),两组间差异无显著性(P＞0.05).APA-BCCs组扎侧触诱发痛阈值和CO2痛阈值高于CCI组和APA组结扎侧(P＜0.01),同时DRG中Nav1.8杂交信号较CCI组和APA组明显升高(P＜0.01),于C组差异无显著性(P＞0.05).结论 APA微囊化BCCs蛛网膜下腔移植可使CCI大鼠DRG中表达量下降的Nav1.8 mRNA恢复正常表达,APA微囊化BCCs蛛网膜下腔移植的镇痛作用和促进DRG中Nav1.8 mRNA表达恢复有关.     

APA微囊化BCCs移植逆转神经性疼痛大鼠背根神经节Navl.8 mRNA表达下调

目的观察APA微囊化牛肾上腺嗜铬细胞(BCCs)移植对坐骨神经慢性挤压伤(CCI)大鼠背根神经节(DRG)Nav1.8 mRNA表达的影响.方法 SD大鼠分为4组,每组5只,即对照组(C组),正常大鼠;CCI组,右侧坐骨神经结扎;APA组,CCI模型后7 d,蛛网膜下腔移植500～600个APA空囊;APA-BCCs组,CCI模型后7 d蛛网膜下腔移植5×106个APA微囊化BCCs.测定各组移植前和移植后7d的触诱发痛阈值(g)和CO2激光刺激痛阈值(ms).移植后7 d行为学测定后取DRG冰冻切片,按照原位杂交法检测各组DRG中Nav1.8 mRNA表达的变化.结果 CCI组和APA组大鼠L4和L5 DRG Nav1.8杂交信号较C组明显降低(P＜0.01),两组间差异无显著性(P＞0.05).APA-BCCs组扎侧触诱发痛阈值和CO2痛阈值高于CCI组和APA组结扎侧(P＜0.01),同时DRG中Nav1.8杂交信号较CCI组和APA组明显升高(P＜0.01),于C组差异无显著性(P＞0.05).结论 APA微囊化BCCs蛛网膜下腔移植可使CCI大鼠DRG中表达量下降的Nav1.8 mRNA恢复正常表达,APA微囊化BCCs蛛网膜下腔移植的镇痛作用和促进DRG中Nav1.8 mRNA表达恢复有关.     

瘦素水平与巨大胎儿的关系

为探讨瘦素与巨大胎儿发生的关系。应用酶联免疫法 (ELIST)检测 2 0例巨大儿 (巨大儿组 )及 2 0例正常体重儿 (对照组 )孕母血清、脐血瘦素水平。结果 ,巨大儿组孕母血清瘦素为 ( 2 5 6±8 2 ) μg/L ,显著高于对照组 ( 1 8 8± 7 8) μg/L( P <0 0 5)。巨大儿组脐血瘦素水平为 ( 1 6 8± 7 0 ) μg/L显著高于对照组 ( 7 7± 4 6) μg/L( P <0 0 0 1 )。两组孕母血清瘦素与胎儿出生重量无相关性 ,而脐血瘦素水平与胎儿出生体重呈正相关 (r =0 65,P <0 .0 1 )。结果提示 ,巨大儿的发生与脐血瘦素水平相关。     

抗前列腺干细胞抗原单克隆抗体治疗鼠前列腺癌移植瘤

目的　探索鼠源性抗前列腺干细胞抗原单克隆抗体 (Anti PSCAmAb)对裸鼠实体性前列腺癌移植瘤的治疗效果。方法　 (1 )BALB/c裸小鼠皮下注射激素非依赖性前列腺癌细胞株PC 3细胞 ,细胞数为 2× 1 0 6/只 ,建立前列腺癌实体性移植瘤的动物模型。 (2 )选择肿瘤体积大小相近的1 0只荷瘤鼠 ,随机分成治疗组 (N1 =5 )和对照组 (N2 =5 )。治疗组荷瘤鼠腹腔注射Anti PSCAmAb2 0 0 μg ,3天一次 ,连续三次 ;对照组使用等量PBS。 (3)观察 5周 ,记录实验鼠存活情况 ,检测血清前列腺特异抗原 (PSA) ,处死存活的裸鼠 ,测量残存肿瘤的重量、体积并计算肿瘤体积抑制率。取肿瘤组织进行光镜及透射电镜检查。结果　治疗组和对照组的裸鼠均存活 ,血清PSA平均值分别为 :(3 2 8± 0 5 5 )ng/ml和 (7 2 6± 0 4 3)ng/ml;平均瘤重分别为 (0 95± 0 1 7) g和 (3 0 8± 0 1 8)g ;肿瘤体积分别为 (1 6 4 5 9± 1 4 0 8)mm3 和 (5 4 8 4 9± 1 9 79)mm3 ,P <0 0 5 ,治疗组与对照组间均有显著性差异。治疗组肿瘤体积抑制率为 6 9 98%。光镜显示治疗组肿瘤组织内出现大片组织坏死性改变 ,并可见大量炎症细胞浸润 ,透射电镜显示肿瘤细胞的凋亡现象。结论　Anti PSCAmAb对裸鼠前列腺癌实体性移植瘤有显著的治疗     

用血清药理学方法观察羊蓝合剂对体外培养成骨细胞的影响

目的观察老年大鼠含羊蓝合剂 (YLM)血清对体外培养成骨细胞的作用。方法用血清药理学方法 ,在新生大鼠头骨成骨细胞培养液中 ,分别加入不同浓度 (72g kg、36g kg、18g kg)的老年大鼠含YLM血清 ,观察成骨细胞的增殖功能和分化功能。结果成骨细胞增殖率 ,YLM H、M、L组分别为 15 3、12 3、115 %,与对照组比较 ,P <0 0 0 1、P <0 0 5 ;成骨细胞ALP活性 ,YLM -H、M、L组分别为1 34 6 0± 0 186 7、1 0 42 0± 0 1495、0 96 0 0± 0 135 4,其中YLM H、M组与对照组 (0 8410± 0 10 49)比较 ,P<0 0 0 1、P <0 0 1;成骨细胞BGP分泌 ,YLM H、M、L组分别为 86 5 0± 2 2 13、74 2 0± 17 4 2、6 2 2 0±15 95 ,其中YLM H、M组与对照组 (5 3 80± 16 5 6 )比较 ,P <0 0 1、P <0 0 5。结论老年大鼠含YLM血清对成骨细胞的增殖和分化功能具有增强作用。     

黄芪注射液对大鼠肝损伤的保护作用

目的 :探讨黄芪注射液 (HQI)对大鼠实验性肝损伤的保护作用。方法 :采用硫代乙酰胺所致肝损伤模型 ,并测定肝功能 ,肝组织学检查及肝组织血浆和血清脂质过氧化测定。结果 :硫代乙酰胺模型组 2 4 h后大鼠血清 GPT为(1110 .0± 15 2 .5 ) U/10 0 m L,显著高于正常对照组 (P<0 .0 1)。HQI低、中、高剂量组大鼠血清 GPT分别为 (788.3±75 .3) U/10 0 m L、(76 0 .7± 6 7.7) U/10 0 m L、(5 17.1± 6 2 .2 ) U/10 0 m L,均显著低于模型组 (P<0 .0 1)。HQI治疗组肝组织和血清 MDA浓度显著低于模型组 ;病理学改变显著。结论 :HQI0 .5 g/kg～ 4 g/kg可对抗硫代乙酰胺引起的大鼠肝脏损伤 ;本实验结果提示 ,HQI具有减少脂质过氧化物产生的作用     

肝硬化病人血液学改变影响因素探讨

目的探讨肝硬化时外周血象的变化及其主要影响因素。方法用自动血细胞分析仪测定 130例肝硬化病人的血红蛋白 (Hb)、白细胞 (WBC)、血小板 (PLT)数值。观察脾肿大程度与血象变化的关系及并发感染时白细胞及分类的变化。结果 10 5例 (80 8% )有两种或两种以上血细胞减少 ,减少程度与脾肿大有关。脾正常组 (A组 )、脾轻度肿大组 (B组 )、脾中度及重度肿大组 (C组 )的Hb值分别为 94 6± 2 8 2g/L、82 6± 2 6 1g/L、70 1± 2 2 0g/L(P <0 0 5 ) ;PLT分别为 79 2± 2 6 1× 10 9/L、6 0 6± 19 9× 10 9/L、5 5 9± 15 4× 10 9/L ,A组与B组及A组与C组比较P <0 0 1,B组与C组比较P>0 0 5 ;WBC分别为 3 96± 1 2× 10 9/L、3 16± 1 1× 10 9/L、2 47± 1 0× 10 9/L(P <0 0 5 ) ;伴有感染时 ,WBC >10× 10 9/L者 16例 (2 4 2 % )。WBC≤ 4 0× 10 9/L的人数 ,无感染组 (6 4例 )占 82 8% ,感染组 (6 6例 )占 16 7% (P <0 0 0 1)。白细胞不增高的病人 ,中性粒细胞≥ 0 75者 ,无感染组 17 1% ,感染组80 % (P <0 0 1)。结论 80 %以上肝硬化病人有两种或两种以上血细胞减少 ,减少程度主要与脾肿大有关。合并感染时 ,白细胞增高者仅 2 4 2 %。凡肝硬化病人WBC≥ 4 0× 10 9/L且中性粒细胞≥ 0     

血管紧张素Ⅱ受体拮抗剂与血管紧张素Ⅱ转化酶抑制剂联合应用治疗以肾病综合征表现的糖尿病肾病32例

目的　观察血管紧张素Ⅱ受体拮抗剂 (ARB)与血管紧张素Ⅱ转化酶抑制剂 (ACEI)联合应用和单用ACEI治疗以肾病综合征为临床表现的 2型糖尿病肾病 (DN)的疗效比较。方法　 5 2例临床确诊的 2型糖尿病肾病分为两组 ,A组单用ACEI治疗 2 0例 ,B组ARB联合ACEI治疗 32例。结果　治疗 2个月后A组 2 4小时尿蛋白平均 3 0 2± 1 10g ,B组 2 4小时尿蛋白平均 2 6 6± 1 32g (P <0 0 1)。血浆白蛋白A组 2 4 6 0± 1 80g/L ,B组 2 6 80± 1 2 0g/L (P <0 0 5 ) ,6个月后 2 4小时尿蛋白A组 2 5 4± 0 89g/L ,B组 2 14± 1 0 3g/L (P <0 0 1) ,血浆白蛋白A组 2 8 80± 2 10g/L ,B组 31 10± 1 80g/L (P <0 0 1)。经过一年治疗 ,A组肌酐清除率平均下降速率为 3 5ml/min·y ,B组为 2 8ml/min·y。结论　ARB与ACEI联合应用对以肾病综合征为临床表现的 2型糖尿病肾病的治疗效果更优于单用ACEI组 ,并具有更好的肾脏保护作用。     

抑制NF-κB活性对糖尿病大鼠肾脏TGF-β1 mRNA表达影响

目的　研究抑制核因子 κB(NF κB)活性对糖尿病大鼠肾脏TGF β1mRNA表达影响。 方法　纯种♂Wistar大鼠分为 3组 :A组为正常对照组 (11只 ) ,B组为糖尿病大鼠未干预组 (11只 ) ,C组为糖尿病大鼠PDTC(NF κB活性抑制剂 )干预组 (9只 )。饲养 18wk后取出肾脏 :以电泳迁移率变动分析技术检测肾组织NF κB活性 ,透射电镜检测肾小球基底膜厚度及系膜基质密度 (系膜基质面积 /系膜面积 ) ,RT PCR检测TGF β1mRNA表达。酶免疫分析法检测 2 4h尿白蛋白排泄 (UAE)。结果　肾组织NF κB活性在B组大鼠肾组织 (1 85± 0 5 4× 10 6)显著高于A组 (0 0 7± 0 11×10 6,P <0 0 1) ,C组 (0 2 5± 0 2 5× 10 6)显著低于B组 (P <0 0 1)。B组与A组比较 ,UAE (2 18± 1 98mgvs 0 4 1± 0 4 7mg,P <0 0 1)、肾小球基底膜厚度 (5 31 6± 10 7 6nmvs 312 4±2 5 4nm ,P <0 0 1)及系膜基质密度 (5 6 4 1± 6 78vs 33 95±5 2 2 ,P <0 0 1)均显著增高 ;C组大鼠UAE(0 5 6± 0 72 )mg、肾小球基底膜厚度 (315 8± 2 1 4 )nm及系膜基质密度 (37 97±7 37)均显著低于B组 (均P <0 0 1)。肾组织TGF β1mR NA表达在B组大鼠 (0 5 3± 0 2 0 )显著高于A组 (0 2 6±0 13,P <0 0 1) ,C组 (0 2 9± 0 10 )显?     

Change of hepatic histamine content during hepatic fibrosis

Hepatic function was studied by measuring the time courses of several variables in blood and liver using a chronic liver-injury model produced by administering CCl4 consecutively for 12 weeks in rats. A marked increase in liver histamine content occurred after 10 weeks of treatment with CCl4. At weeks 10 and 12, liver histamine levels in the CCl4-treated group were 1.95 and 4.61 times higher, respectively, than in the control group. This change in liver histamine content appeared after that in other variables such as glutamic pyruvic transaminase, alkaline phosphatase, and white blood cells, but it corresponded to a change in liver hydroxyproline. Increased mast cells were seen in fibrotic foci around Glisson's sheath by microscopic morphological observation of the liver 12 weeks after treatment with CCl4. The histamine concentration in plasma tended to decrease after CCl4 treatment, and at week 12 the decrease was statistically significant compared with control. The liver activities of histamine-metabolizing enzymes, histamine-N-methyltransferase and histaminase, decreased to 1/3.4 and 1/6.0 times those of the nontreated group, respectively, 12 weeks after treatment with CCl4, whereas blood histaminase increased about 9.2 times. The increase in histamine content in injured liver was presumedly derived from the increase in mast cells in the inflamed area of the liver; also, the deficiency of histamine-metabolizing enzymes in liver might have caused the high histamine content in the liver. On the other hand, the decrease in plasma histamine concentration might have occurred as a consequence of the enzyme leakage from hepatocytes that accompanied the breakdown of hepatocytes by CCl4 and thus, of the histamine metabolism in blood by the leaked enzymes. The same kind of experiment was performed using a dimethylnitrosamine-induced liver injury model in rats. The increase of hydroxyproline in the liver occurred 11 days after that of histamine content in liver. These results suggest the possibility that increased histamine in the liver may participate in the biosynthesis of collagen.     

Ethanol-induced disturbance of hepatic microcirculation and hepatic hypoxia

The hypothesis was tested whether ingestion of ethanol might disturb the hepatic microcirculation with resulting hepatic hypoxia. Infusion of ethanol increased the portal pressure concentration-dependently in rat livers perfused with Krebs-Henseleit buffer at a constant flow rate (Emax = 11.5 cm H2O, EC50 = 90 mM). This increase in portal pressure was due to hepatic vasoconstriction, since it diminished in the presence of sodium nitroprusside, a direct acting vasodilator. The regional hepatic tissue hemoglobin concentration after perfusion with added erythrocyte suspension (hematocrit 1%), measured by tissue-reflectance spectrophotometry, was significantly diminished by the infusion of ethanol, indicating the impairment of the microcirculation of the superficial layer of the liver. When the absorption spectrum of the liver was examined by reflectance spectrophotometry, infusion of ethanol caused a parallel reduction of all the mitochondrial respiratory cytochromes in a concentration-dependent fashion, concomitant with the increase of portal pressure, indicating a marked reduction of oxygen concentration in superficial liver tissue. The reduction of the respiratory cytochromes was also associated with the decrease in oxygen consumption of the liver, indicating that the hepatic hypoxia was due to the reduction of oxygen delivery to hepatocytes rather than the increased oxygen consumption of the liver. The reduction of the respiratory cytochromes was correlated with the increase in portal pressure and was inhibited by sodium nitroprusside. These data indicate that the ethanol-induced hepatic vasoconstriction disturbs hepatic microcirculation, resulting in hepatic hypoxia and reduction of mitochondrial respiratory cytochromes.     

肝脓肿增强动态CT扫描动脉期肝脏短暂强化的诊断价值

目的 探讨肝脓肿增强动态CT扫描时动脉期肝脏实质短暂强化(THPE)的病理基础及其临床意义.方法 回顾性分析行增强动态CT扫描的肝脓肿病例43例,均常规先行平扫,分别于注射对比剂后30 s、65 s和3～5 min行动脉期、门静脉期和延迟扫描,分析THPE发生率、部位、形态和各期强化表现.结果 43例中,动脉期有28例出现THPE,发生率65%.28例共有脓肿36个,出现THPE 36处,表现为动脉期出现肝叶/段形(占31%)、扇形(占50%)、不规则形(占14%)或弥漫形(占5%)强化,门静脉期/延迟扫描与正常肝实质呈等密度.肝脓肿THPE以叶/段形、扇形多见(81%).结论 肝脓肿THPE常以叶/段形、扇形多见,提高对THPE征象的认识,对了解病变的病理基础、病变定性,尤其是化脓性炎症期、脓肿形成初期的不典型肝脓肿的诊断和鉴别诊断具有重要作用.     

Pharmacological effects of reiousan on experimental hepatic injuries and hepatic functions

Pharmacological effects of Reiousan, a crude drug preparation consisting of bezoar and ginseng, on experimental hepatic injuries and hepatic functions were studied. After administration of Reiousan, carbon tetrachloride, d-galactosamine and alpha-naphthylisothiocyanate-induced experimental hepatic injuries in rats were inhibited. Facilitation of recovery from increased retention rate of sulfobromophthalein in hepatectomized rats, increase in hepatic blood flow, inhibition of superoxide anions, and decrease in blood ethanol concentration in rats administered ethanol were observed after application of Reiousan. Inhibitory effects of Reiousan on experimental hepatic injuries may result from the increase in hepatic blood flow and inhibition of superoxide anions.     

选择性肝动脉栓塞治疗肝海绵状血管瘤(附17例报告)

目的研究经肝动脉栓塞治疗海绵状血管瘤的方法和效果。方法将导管超选择插入17例肝血管瘤的供血动脉,以碘油或超液态碘油、明胶海棉和（或）钢圈栓塞。结果所有病例均成功实施了栓塞治疗。17例中有11例分别于术后1～12个月行CT或B超随访。瘤体缩小〉50％者8例,〉30％者2例,1例缩小不明显。全部患者中临床症状消失者11例,明显减轻者5例,总有效率94％,术后无严重并发症。结论超选择性肝动脉栓塞是治疗肝海绵状血管瘤的安全、有效的首选方法。     

Selective cyclooxygenase inhibition improves hepatic encephalopathy in fulminant hepatic failure of rat

Prostaglandin plays an important role in the pathogenesis of hepatic encephalopathy. This study investigated the therapeutic effects of selective cyclooxygenase (COX) inhibitor on hepatic encephalopathy in thioacetamide-induced fulminant hepatic failure (FHF) rats. The selective COX-1 inhibitor (SC-560), COX-2 inhibitor (NS-398) or distilled water (control) was administered in the normal and FHF rats. The mortality rates were calculated and severity of hepatic encephalopathy was evaluated using Opto-Varimex activity sensors. Besides, the levels of blood ammonia, 6-keto-prostaglandin-F(1α) (PGF(1α), active metabolite of prostacyclin), tumor necrosis factor α (TNF-α) and liver biochemistry tests were measured. The hepatic mRNA expressions of nitric oxide synthase and COX were determined, and the liver histopathological changes were examined. The liver biochemistries and motor activities were similar among COX-1, COX-2 treated and control groups. SC-560 treatment improved the survival of FHF rats (mortality rates: SC-560 group 0%, control 33%; P=0.037). Besides, SC-560 treatment improved hepatic encephalopathy and decrease plasma levels of PGF(1α), but did not change TNF-α levels. There were no significant differences in liver biochemistry and ammonia levels except that the aspartate aminotransferase levels were lower in the NS-398 treated group. Both hepatic COX-1 and COX-2 mRNA expressions were attenuated after SC-560 treatment. The decreased COX-2 and increased constitutive nitric oxide synthase mRNA expressions were found after NS-398 treatment. Besides, the histopathology of liver got improved after selective COX inhibition. In conclusion, COX-1 inhibition by SC-560 decreases the mortalities and improves motor activities, suggesting COX-1, rather than COX-2, plays a major role in hepatic encephalopathy of FHF rats.     

Kinetic determinants of hepatic clearance: Plasma protein binding and hepatic uptake

Hepatic clearance prediction, using scaled data obtained from hepatocytes and microsomes, often under-predicts the eventual observed clearance. This occurs commonly where the compound is highly bound and/or a sinusoidal transporter substrate. The authors’ own laboratory observations and those reported in the literature indicate that consideration of transporter effects in vitro is not sufficient to provide a direct, quantitative estimate of hepatic clearance in vivo. The physiology of contributing processes has been reviewed and the processes were compiled into a kinetic model of compound disposition for a hepatocyte compartment. The model has variables describing the kinetic effects of plasma protein binding, sinusoidal uptake, passive permeability, and cellular disposition. Parameters were determined experimentally requiring, in some instances, assays less familiar or routine to Drug metabolism and pharmacokinetics (DMPK) laboratories. The model accurately fitted data for the hepatic disposition of a UCB-proprietary compound that did not undergo metabolism but was a substrate for protein binding and sinusoidal uptake. On addition of bovine serum albumin to the assay, the uptake kinetics approximated neither those for the free fraction nor the total concentration. However, the model accurately predicted the intermediate observed kinetics and illustrated the kinetic effects of plasma protein binding and the complex interplay between various competing and collaborating processes. Through the use of simulations the model illustrated the influence of different combinations and influences of hepatic kinetic processes. Possible causes behind the extraction of highly bound compounds were identified as (1) low compound permeability facilitating active uptake and (2) high permeability facilitating the role of intracellular metabolism. In almost all circumstances k_off is not low enough (<1?s^–1) to limit the extraction of plasma protein bound compounds; however, k_on still exerts an effect through competition with the uptake process. Crucially the model indicated the complex nature of the combined processes, whose broad range of effects on hepatic disposition could only be accurately determined with a kinetic model.     

Kinetic determinants of hepatic clearance: plasma protein binding and hepatic uptake

Hepatic clearance prediction, using scaled data obtained from hepatocytes and microsomes, often under-predicts the eventual observed clearance. This occurs commonly where the compound is highly bound and/or a sinusoidal transporter substrate. The authors' own laboratory observations and those reported in the literature indicate that consideration of transporter effects in vitro is not sufficient to provide a direct, quantitative estimate of hepatic clearance in vivo. The physiology of contributing processes has been reviewed and the processes were compiled into a kinetic model of compound disposition for a hepatocyte compartment. The model has variables describing the kinetic effects of plasma protein binding, sinusoidal uptake, passive permeability, and cellular disposition. Parameters were determined experimentally requiring, in some instances, assays less familiar or routine to Drug metabolism and pharmacokinetics (DMPK) laboratories. The model accurately fitted data for the hepatic disposition of a UCB-proprietary compound that did not undergo metabolism but was a substrate for protein binding and sinusoidal uptake. On addition of bovine serum albumin to the assay, the uptake kinetics approximated neither those for the free fraction nor the total concentration. However, the model accurately predicted the intermediate observed kinetics and illustrated the kinetic effects of plasma protein binding and the complex interplay between various competing and collaborating processes. Through the use of simulations the model illustrated the influence of different combinations and influences of hepatic kinetic processes. Possible causes behind the extraction of highly bound compounds were identified as (1) low compound permeability facilitating active uptake and (2) high permeability facilitating the role of intracellular metabolism. In almost all circumstances k(off) is not low enough (<1 s(-1)) to limit the extraction of plasma protein bound compounds; however, k(on) still exerts an effect through competition with the uptake process. Crucially the model indicated the complex nature of the combined processes, whose broad range of effects on hepatic disposition could only be accurately determined with a kinetic model.     

伊曲康唑致假性肝囊肿

患者女,41岁。因右手无名指甲癣多年,先后外用克霉唑软膏、脚癣一次净、帕特药合、达克宁霜等药治疗,均未显效,故来医院就诊。患者既往身体健康,无任何传染病史及药敏史,体检时发现有胆结石,查体各系统正常,血、尿常规,肝、肾功能均正常。肝、胆、脾、肾彩超提示,胆囊内有1.5cm×1.0cm、1.0cm×1.0cm结石两粒,余正常。确诊为真菌感染所致甲癣,胆石症。治疗:口服伊曲康唑胶囊,采取间歇冲击疗法,即首日300mg顿服,后改为每日200mg,于餐后立即服用,连用7d,停药21d为一个疗程;连续治疗3个疗程。嘱患者3个疗程后来复诊。复诊时,患者甲癣好转。但有…