摘要

Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants. Please see later in the article for the Editors' Summary.

译文

15 名临床试验参与者中有 7 名接受了核苷类似物 (fialuridine [FIAU]) 治疗,出现了急性肝衰竭。五名接受治疗的参与者死亡,两名需要肝移植。对小鼠、大鼠、狗和灵长类动物进行的临床前毒理学研究没有提供任何迹象表明 FIAU 对人类具有肝毒性。因此,我们研究了是否可以在具有人源化肝脏的嵌合 TK-NOG 小鼠中检测到 FIAU 诱导的肝脏毒性。用 400 、 100 、 25 或 2.5 毫克/千克/天口服 FIAU 治疗对照组和嵌合 TK-NOG 小鼠。通过测量血浆乳酸和肝酶、评估肝组织学和电子显微镜来评估药物治疗的反应。用 FIAU 400 毫克/千克/天治疗 4 天后,嵌合小鼠出现了肝功能衰竭和乳酸酸中毒的临床和血清学证据。肝组织的分析揭示了在人类而不是小鼠肝细胞区域的脂肪变性。电子显微照片显示在 FIAU 处理的嵌合小鼠的人肝细胞中的脂质和线粒体异常。在用 FIAU 100 、 25 或 2.5 毫克/千克/天治疗 14 天的嵌合小鼠中检测到剂量依赖性肝脏毒性。在用相同的 FIAU 剂量治疗 14 天的对照小鼠中,肝脏毒性没有出现。相比之下,用另一种核苷酸类似物 (sofosbuvir 440 或 44 毫克/千克/天 po) 治疗 14 天,在人类试验参与者中没有引起肝脏毒性,在具有人源化肝脏的小鼠中没有引起肝脏毒性。使用带有人源化肝脏的嵌合 TK-NOG 小鼠,可以很容易地检测到 FIAU 诱导的肝脏毒性, 即使用 FIAU 剂量治疗小鼠,该剂量仅比人类参与者的剂量高 10 倍。在 FIAU 处理的嵌合小鼠中观察到的临床特征、实验室异常、肝脏组织学和超微结构变化反映了 FIAU 处理的人类参与者的情况。在临床前毒理学研究中使用嵌合小鼠可以提高在人类参与者中进行测试的候选药物的安全性。请参见文章后面的编辑总结。

Acute hepatic failure

重症 肝衰竭 疾病
概述  :  

急性肝衰竭是由由病毒、细菌感染以及药物、酒精中毒等各种不同病因引起的严重肝损伤,导致肝脏的合成、解毒、排泄和生物转化功能发生严重障碍或失代偿,出现以凝血机制障碍、黄疸、肝性脑病和腹水等为主要表现的一组临床症候群。在中国,HBV是导致肝衰竭最常见的病因。 病理机制急性肝衰竭病理学基础为:一次性打击的一致性的大块性(>2/3肝小叶)或亚大块性坏死(1/3~2/3肝小叶),网状支架不塌陷或少量不完全性塌陷。坏死区肝窦扩张、充血、出血,炎症细胞浸润,可有胆汁淤积。病程数天后坏死灶周围出现胆

acute 英 [əˈkju:t] 美 [əˈkju:t]

释义   adj. 严重的,[医] 急性的;敏锐的;激烈的;尖声的

例句   He is an acute observer.他是一个敏锐的观察者。

 

hepatic 英 [hɪˈpætɪk] 美 [hɪˈpætɪk]

释义   adj. 肝的;肝脏色的;治肝病的

例句   AIM: To investigate the role of resistin in hepatic insulin resistance and its mechanism.目的:探讨抵抗素在肝脏胰岛素抵抗中的作用及其机制。

 

failure 英 [ˈfeɪljə(r)] 美 [ˈfeɪljər]

释义   n. 失败;故障;失败者;破产

例句   You have to have success and failure.你必须经受成功和失败。


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