Pharmacokinetics and immunologic consequences of exposing macaques to purified homologous butyrylcholinesterase.
Pharmacokinetics and immunologic consequences of exposing macaques to purified homologous butyrylcholinesterase.
复制标题
将猕猴暴露于纯化的同源丁酰胆碱酯酶的药代动力学和免疫学后果。
DOI：
10.1016/s0024-3205(02)02203-8
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发表时间：
2002
期刊：
影响因子：
6.1
通讯作者：
Saxena,Ashima
中科院分区：
文献类型：
--
作者：
Rosenberg,Yvonne;Luo,Chunyuan;Ashani,Yacov;Doctor,BhupendraP;Fischer,Randy;Wolfe,Gary;Saxena,Ashima
接触神经毒剂和杀虫剂形式的有机磷化合物构成了日益严重的军事和平民威胁。近年来，人们的注意力集中在使用外源性胆碱酯酶作为有效的预防性治疗，以保护免受OP。显然，任何潜在的生物清除剂的一个关键先决条件是延长循环停留时间，这是由蛋白质的大小，碳水化合物结构的微观异质性，和诱导（如果有的话）的抗酶抗体重复注射酶的影响。以前，它被证明，多次注射马丁酰胆碱酯酶（BChE）到兔子，大鼠，或恒河猴，导致平均停留时间跨越数天，和可变的免疫反应。本研究旨在评估将纯化的猕猴BChE以与预防OP毒性所需的剂量相似的剂量施用到相同物种的猕猴中的药代动力学和免疫学后果。在猴中静脉注射7，000 U同源酶显示出比异源Hu BChE报告的平均血浆停留时间（33.7 ± 2.9 h）长得多的平均血浆停留时间（MRT = 225 ± 19 h）。4周后给予较小的第二次注射3，000 U，达到预期的酶活性峰值血浆水平，但令人惊讶的是，四只猕猴的MRT显示出很大的变化，范围从54到357小时。在注射酶后，在猕猴中未检测到抗体应答。这些结果预示着人类BChE作为人类解毒药物的潜在用途。
Exposure to organophosphorus compounds (OPs), in the form of nerve agents and pesticides poses an ever increasing military and civilian threat. In recent years, attention has focused on the use of exogenously administered cholinesterases as an effective prophylactic treatment for protection against OPs. Clearly, a critical prerequisite for any potential bioscavenger is a prolonged circulatory residence time, which is influenced by the size of protein, the microheterogeneity of carbohydrate structures, and the induction (if any) of anti-enzyme antibodies following repeated injections of the enzyme. Previously, it was demonstrated that multiple injections of equine butyrylcholinesterase (BChE) into rabbits, rats, or rhesus monkeys, resulted in a mean residence time spanning several days, and variable immune responses. The present study sought to assess the pharmacokinetics and immunological consequences of administration of purified macaque BChE into macaques of the same species at a dose similar to that required for preventing OP toxicity. An i.v. injection of 7,000 U of homologous enzyme in monkeys demonstrated much longer mean residence times in plasma (MRT = 225 ± 19 h) compared to those reported for heterologous Hu BChE (33.7 ± 2.9 h). A smaller second injection of 3,000 U given four weeks later, attained predicted peak plasma levels of enzyme activity, but surprisingly, the MRT in the four macaques showed wide variation and ranged from 54 to 357 h. No antibody response was detected in macaques following either injection of enzyme. These results bode well for the potential use of human BChE as a detoxifying drug in humans.