Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
Pharmaceutical Sciences Department, Unites States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, 21010, USA.
Chem Biol Interact. 2021 Aug 1;344:109499. doi: 10.1016/j.cbi.2021.109499. Epub 2021 May 4.
Exogenously administered human serum butyrylcholinesterase (Hu BChE) affords protection by binding to organophosphorus (OP) nerve agents and pesticides in circulation. The resulting Hu BChE-OP conjugate undergoes 'aging' and the conjugate circulates until cleared from the body. Thus, we evaluated the effects of Hu BChE-OP conjugates on the general health and operant behavior of macaques. Rhesus macaques trained to perform a six-item serial probe recognition (SPR) task were administered 30 mg/kg of Hu BChE-soman conjugate (n = 4) or Hu BChE-VX conjugate (n = 4) by intramuscular injection. Performance on the SPR task was evaluated at 60-90 min after conjugate administration and daily thereafter for the next 4 weeks. Diazepam (3.2 mg/kg), a positive control, was administered 5 weeks after conjugate administration and performance on the SPR task was evaluated as before. Blood collected throughout the study was analyzed for acetylcholinesterase (AChE) and BChE activities. Residual BChE activity of conjugates displayed a similar pharmacokinetic profile as free Hu BChE. Neither of the Hu BChE-OP conjugates produced clear or pronounced degradations in performance on the SPR task. In contrast, diazepam clearly impaired performance on the SPR task on the day of administration in 7 of 8 macaques (and sometimes longer). Taken together, these results suggest that Hu BChE-OP conjugates are safe and provide further support for the development of Hu BChE as a bioscavenger for use in humans.
外源性给予的人血清丁酰胆碱酯酶（Hu BChE）通过与循环中的有机磷（OP）神经毒剂和杀虫剂结合提供保护。由此产生的 Hu BChE-OP 缀合物经历“老化”，并且缀合物循环直到从体内清除。因此，我们评估了 Hu BChE-OP 缀合物对猕猴一般健康和操作性行为的影响。接受过六项序列探针识别（SPR）任务训练的恒河猴通过肌肉注射接受 30mg/kg 的 Hu BChE-梭曼缀合物（n=4）或 Hu BChE-VX 缀合物（n=4）。在缀合物给药后 60-90 分钟评估 SPR 任务的表现，此后每天评估 4 周。地西泮（3.2mg/kg），一种阳性对照，在缀合物给药后 5 周给予，并在之前评估 SPR 任务的表现。整个研究过程中收集的血液用于分析乙酰胆碱酯酶（AChE）和 BChE 活性。缀合物的残留 BChE 活性显示出与游离 Hu BChE 相似的药代动力学特征。两种 Hu BChE-OP 缀合物都没有明显或明显地降低 SPR 任务的表现。相比之下，地西泮在 8 只猕猴中的 7 只（有时更长时间）在给药当天清楚地损害了 SPR 任务的表现。综上所述，这些结果表明 Hu BChE-OP 缀合物是安全的，并进一步支持 Hu BChE 作为生物清除剂在人类中的开发。
