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首页> 外文期刊>Archives of Toxicology >Safety assessment of intraportal liver cell application in New Zealand white rabbits under GLP conditions
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Safety assessment of intraportal liver cell application in New Zealand white rabbits under GLP conditions

机译：在GLP条件下在新西兰白兔中应用门静脉内肝细胞的安全性评估

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Liver cell transplantation (LCT) is considered a new therapeutic strategy for the treatment of acute liver failure and inborn metabolic defects of the liver. Although minimally invasive, known safety risks of the method include portal vein thrombosis and pulmonary embolism. Since no systematic data on these potential side effects exist, we investigated the toxicological profile of repeated intraportal infusion of allogeneic liver cells in 30 rabbits under GLP conditions. Rabbit liver cells were administered once daily for 6 consecutive days at 3 different dose levels, followed by a 2-week recovery period. No test item-related mortality was observed. During cell infusion, clinical findings such as signs of apathy and hyperventilation, moderate elevations of liver enzymes ALT and AST and a slight decrease in AP were observed, all fully reversible. Cell therapy-related macroscopic and histological findings, especially in liver and lungs, were observed in animals of all dose groups. In conclusion, the liver and lungs were identified as potential toxicological target organs of intraportal allogeneic liver cell infusion. A NOAEL (no observed adverse effect level) was not defined because of findings observed also in the low-dose group. No unexpected reactions became apparent in this GLP study. Overall, LCT at total doses up to 12 % (2 % daily over 6 days) of the total liver cell count were tolerated in rabbits. Observed adverse effects are not considered critical for treatment in the intended patient populations provided that a thorough monitoring of safety relevant parameters is in place during the application procedure.
机译：肝细胞移植（LCT）被认为是治疗急性肝衰竭和肝脏先天性代谢缺陷的新治疗策略。尽管该方法具有微创性，但该方法的已知安全风险包括门静脉血栓形成和肺栓塞。由于没有关于这些潜在副作用的系统数据，我们研究了在GLP条件下重复门静脉输注同种异体肝细胞在30只兔子中的毒理学特征。每天以3种不同的剂量水平连续6天每天给药一次兔肝细胞，然后进行2周的恢复期。没有观察到与测试项目有关的死亡率。在细胞输注过程中，观察到临床表现，如冷漠和过度换气的征兆，肝酶ALT和AST的中度升高以及AP的轻微降低，全部完全可逆。在所有剂量组的动物中均观察到细胞疗法相关的宏观和组织学发现，尤其是在肝和肺中。总之，肝和肺被确定为门静脉内同种异体肝细胞输注的潜在毒理学靶器官。由于在低剂量组中也观察到发现，因此未定义NOAEL（未观察到不良反应水平）。在这项GLP研究中，没有意外反应变得明显。总体而言，兔的总剂量不超过总肝细胞计数的12％（6天每天2％）的LCT是可以耐受的。如果在应用过程中已对安全相关参数进行了全面监控，则观察到的不良反应对于预期的患者人群的治疗并不重要。

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