Sun Wei, Doctor B P, Saxena Ashima
Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA.
Chem Biol Interact. 2005 Dec 15;157-158:428-9. doi: 10.1016/j.cbi.2005.10.090.
Human serum butyrylcholinesterase (Hu BChE) has been demonstrated to be a highly effective detoxifying enzyme for counteracting the acute toxicity of organophosphorus (OP) nerve agents. In order to initiate an investigational new drug (IND) application for human use, the safety and pharmacokinetic properties of the enzyme were assessed in guinea pigs. Sixty milligrams per kilogram of Hu BChE was administered to guinea pigs by either i.p. or i.m. injection. Blood was drawn at various time points for up to 2 weeks following enzyme injection for the measurement of blood BChE activity. Hu BChE displayed a mean residence time of 110 h, regardless of the route of administration and the enzyme activity remained almost 10-fold above baseline level even after 2 weeks post enzyme injection. Fourteen days post Hu BChE administration, all animals were subjected to 20 panel serum chemistry, hematology, and complete gross/histopathology examination. Results showed no toxic effects as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. In conclusion, Hu BChE displays a long-lasting stability in the circulation of guinea pigs, and is devoid of any toxic side effects. These results provide convincing data for the safe and effective use of Hu BChE as a bioscavenger to protect humans against all OP nerve agents.
人血清丁酰胆碱酯酶（Hu BChE）已被证明是一种高效解毒酶，可对抗有机磷（OP）神经毒剂的急性毒性。为了启动用于人类的研究性新药（IND）申请，在豚鼠中评估了该酶的安全性和药代动力学特性。通过腹腔注射或肌肉注射给豚鼠施用每千克60毫克的Hu BChE。在酶注射后的长达2周的不同时间点采集血液，用于测量血液中BChE活性。无论给药途径如何，Hu BChE的平均驻留时间为110小时，即使在酶注射后2周，酶活性仍比基线水平高近10倍。在施用Hu BChE 14天后，对所有动物进行20项血清化学、血液学以及完整的大体/组织病理学检查。结果显示，通过一般观察、血清化学、血液学以及大体和组织学组织变化测量，均未发现毒性作用。总之，Hu BChE在豚鼠循环中显示出持久的稳定性，并且没有任何毒副作用。这些结果为安全有效地使用Hu BChE作为生物清除剂来保护人类免受所有OP神经毒剂侵害提供了令人信服的数据。
