Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.This study was supported by the National Health and Medical Research Council of Australia.     

男性肝硬化患者血清睾丸酮、雌二醇水平

本文观察了80例男性肝炎后肝硬化患者。检测了血清睾丸酮（T），雌二醇（E2）水平及E2／T比值的变化。与正常对照组及脑血管意外对照组进行了统计比较，发现E2及E2／T比值升高，T值降低2与对照组间比较均有显著差异，但肝硬化各组间无明显差异。文中分析了检测结果并探讨了与性功能变化的关系。认为性功能降低可能是由于血清睾丸酮水平降低所致。     

Report of a Case of Pericardial Mesothelioma with Liver Metastases Responding Well to Pemetrexed and Platinum-Based Chemotherapy

Pericardial mesothelioma remains a disease with a bleak prognosis. We report the case of a patient with metastases to liver and good response to pemetrexed and carboplatin-based combination chemotherapy and consequent prolonged progression-free survival.     

乙型肝炎与肝硬化和肝细胞癌的关系

近年来,应用免疫组织化学技术观察肝组织内乙型肝炎表面抗原(HBsAg)的研究屡有报导。大多数作者认为乙型肝炎在肝硬化、肝癌的发病中起重要作用;但有的流行病学研究则认为在某些地区,肝炎不是肝癌的病因。我省是肝癌高发区之一,关于这方面尚未见有报道。本文应用免疫酶法标记定位观察肝硬化、肝癌病人肝组织中HBsAg,以探讨本地区肝炎与肝硬化和肝细胞癌的关系。     

缺血预处理对缺血-再灌注硬化肝脏P-选择素表达的影响及保护作用

目的 :探讨缺血预处理 (IPC)对肝硬化肝脏缺血再灌注 (I R)损伤的保护作用以及 IPC对 P 选择素表达的影响和作用。方法 :2 4只雄性肝硬化 SD大鼠 ,随机分为 3组 ,每组 8只 :假手术组 (SO组 ) ,缺血再灌注组 (I R组 ) ,缺血预处理组 (IPC组 )。用高效液相色谱法测定肝组织三磷酸腺苷 (ATP)、二磷酸腺苷(ADP)、一磷酸腺苷 (AMP)并计算能荷 (EC) ,用全自动生化仪测定血清丙氨酸转氨酶 (AL T)、天冬氨酸转氨酶 (AST)、乳酸脱氢酶 (L DH) ,记录肝脏胆汁分泌量 ,用链霉菌抗生物素蛋白过氧化酶 (SP)法免疫组织化学染色检测肝组织 P 选择素蛋白表达 ,并计算肝组织中性粒细胞浸润数和丙二醛含量 (TBA法 )。结果 :再灌注12 0分钟后 ,IPC组 ATP含量和 EC水平明显高于 I R组 ,AL T、AST、L DH释放受到明显抑制 (P均 <0 .0 0 1) ,肝组织胆汁分泌量明显多于 I R组 (P<0 .0 1) ,肝组织中性粒细胞浸润数受到抑制 (P<0 .0 5 ) ,丙二醛产生明显减少 (P<0 .0 0 1)。与 I R组比较 ,IPC组肝细胞 P选择素蛋白表达受到明显抑制 (P<0 .0 5 )。结论 :缺血预处理通过抑制肝组织 P选择素的表达 ,减少中性粒细胞黏附浸润 ,从而减轻肝脏缺血再灌注损伤程度 ,保护肝功能     

肝硬化门静脉高压症内毒素血症的治疗

目的　研究肝硬化门静脉高压症 (PHC)病人内毒素血症治疗方法及其对预后的影响。方法　选 3 6例 PHC择期手术病人 ,随机分为治疗组 (n=18)和对照组 (n=18) ;治疗组入院后除保肝、纠正低蛋白血症及贫血等术前一般准备外 ,另行每日服用中药茵陈小承气汤和稀生理盐水碘伏液灌肠术等 ,对照组行 PHC的常规术前准备。观察两组病人术前血浆内毒素(PE)水平变化和术后全身炎症反应综合症 (SIRS)、多脏器障碍综合症 (MODS)的发生率等。结果　入院时所有 PHC病人均存在不同程度的内毒素血症。经过术前准备 ,治疗组术前 PE水平由 0 .13 9± 0 .0 2 2 Eu/ m l降至 0 .12 2± 0 .0 2 4 Eu/ m l(P<0 .0 5 ) ,对照组则下降不明显 (P>0 .0 5 )。术后治疗组的 SIRS、MODS的发生率和死亡率分别为 :11.1%、5 .6%、0 % ;对照组则分别为 :4 4 .4 %、2 7.8%、5 .6%。术后胃肠功能的恢复时间 :治疗组 (78.3± 2 1.2 h)比对照组 (13 8.4± 4 2 .5 h)显著缩短 (P<0 .0 0 1)。结论　应用茵陈小承气汤结合稀生理盐水碘状液清洁胃肠道 ,可以降低 PHC病人由于细菌易位所致的内毒素血症以及其对机体的损害 ,从而减少 PHC病人术后 SIRS、MODS的发生率及死亡率     

Disposition of antipyrine in patients with extensive metastatic liver disease

Summary In the present study the effect of metastatic liver disease on hepatic drug metabolism has been examined by studying the pharmacokinetics of antipyrine and the urinary excretion of antipyrine and its three major metabolites (4-hydroxyantipyrine, norantipyrine, and 3-hydroxymethylantipyrine) in 12 patients with extensive metastatic liver disease, and in 12 matched healthy controls.In the patients total liver volume, the volume of the liver parenchyma, and the volume of the liver metastases were determined by computed tomography. The volume of liver metastases always exceeded 35% of the total liver volume.There were no significant differences between the patients and controls in plasma half-life, plasma clearance, or apparent volume of distribution of antipyrine.The cumulative urinary excretion of antipyrine and its three major metabolites was significantly lower in patients [44 (18)%] than in controls [71 (8)%]. The excretion of antipyrine itself was unchanged and the decrease in cumulative excretion was due to reduced excretion of the three metabolites.The results show that the activity of the hepatic mixed function oxidases was not impaired even in patients with extensive metastatic liver disease. This may be because liver metastases do not cause a corresponding reduction in the volume of normal hepatic parenchyma. The decreased urinary excretion of the three major metabolites of antipyrine, which are mainly glucuronidated, may have been due to an alteration in the process of conjugation.     

Detection of liver fibrosis with magnetic cross-relaxation

The utility of MRI using magnetization transfer (MT) enhanced pulse sequences to diagnose hepatic cirrhosis in a rat model was investigated. Hepatic T₁ was measured with and without MT off-resonance RF pulses in 17 treated and six control rats. The livers were evaluated histologically, and the hydroxyproline content quantitatively measured. We did not find a statistically significant linear correlation between the MR relaxation times and the degree of tissue injury. However, the MR measurements performed with MT were superior to those without differentiating the treated and control groups. Specifically, the T₁ times were 695 ±76 ms for the treated group, versus 748 ± 61 ms in the controls; P= 0.095. The T_1sat times were also lower in the treated group, with statistical significance: 367 ± 51 ms versus 421 ± 38 ms, P = 0.016. Finally, the change in the relaxation rates (the inverse of the relaxation times) with and without saturation were 1.31 ± 0.22 s^?1 (treated group) versus 1.05 ± 0.12 s^?1 (controls), which differed significantly, P= 0.001.     

Apoptosis of bile duct epithelial cells in hepatic allograft rejection

Liver biopsy remains the 'gold standard' for monitoring rejection in liver transplant patients. Portal inflammation, bile duct damage and endothelialitis are recognized features of hepatic allograft rejection. The pathogenesis of the bile duct injury during rejection, however, remains unclear. To define the mechanism of bile duct damage, we studied the light- and electronmicroscopic appearance of hepatic tissue from selected patients in whom allograft failure was solely due to rejection. Of the 25 orthotopic liver transplant rejection cases examined, 17 were mild, seven were moderate and one was severe rejection. Light microscopy examination of the damaged bile duct epithelium revealed evidence of apoptosis which was confirmed by electronmicroscopy. Furthermore, there appeared to be a positive correlation between the grade of rejection and the number of apoptotic cells. Also included in the study were 13 cases of chronic active hepatitis and 10 normal livers which showed the least apoptotic cells. We conclude that the identification of apoptotic cells in damaged bile ducts in allograft biopsies might be helpful in the diagnosis of rejection and in assessment of the severity of rejection.     

Gln与rhGh对肝硬化病人肠黏膜屏障的影响

目的观察Gln与rhGh各单独应用及联合应用对肝硬化病人小肠黏膜屏障形态学和功能学的影响。方法20个肝硬化病人随机分成四组,给予等氮等热量营养支持7d,Gln+rhGh组口服Gln[0.3g/(Kg·d)]和皮下注射rhGh(10U/d);Gln组口服Gln;rhGh组应用皮下注射rhGh;CONT对照组应用相应安慰剂。观察治疗前后患者小肠黏膜通透性和十二指肠黏膜绒毛高度和隐窝深度的变化,分别比较。结果Gln+rhGh组治疗后小肠黏膜通透性有显著性的降低(P<0.05),且显著低于其他三组(P<0.05);十二指肠黏膜绒毛高度和隐窝深度有显著性的增高(P<0.05),且显著高于其他三组(P<0.05)。结论Gln与rhGh联合应用能减低肠道黏膜的通透性和维持其形态学的完整。