阿糖胞苷神经损害事件原因的动物实验研究

Experimental animal studies on cytarabine-induced causes of neurological damage event

目的:研究上海华联制药厂生产的有关批次阿糖胞苷所致神经损害事件的原因,以利于改进药品的生产和管理。方法:实验动物采用猕猴、食蟹猴和Beagle犬。供试药物为与神经损害事件有关的阿糖胞苷(简称事件有关阿糖胞苷)、与神经损害事件无关的阿糖胞苷(简称事件无关阿糖胞苷),长春新碱及生理盐水。给药途径为鞘内(椎管内)注射。猕猴16只分为4组(每组4只):生理盐水0.5 ml组,事件无关阿糖胞苷20 mg组,事件有关阿糖胞苷10 mg组,事件有关阿糖胞苷20 mg组。食蟹猴15只分为5组(每组3只):事件无关阿糖胞苷20 mg组,事件有关阿糖胞苷20 mg组,事件无关阿糖胞苷20 mg加长春新碱8μg组,事件无关阿糖胞苷20 mg加长春新碱80μg组,长春新碱200μg组。Beagle犬22只分为7组(事件有关阿糖胞苷40 mg组为4只,其余组各为3只):生理盐水2 ml组,事件无关阿糖胞苷40 mg组,事件有关阿糖胞苷40 mg组,事件无关阿糖胞苷40 mg加长春新碱16μg组,事件无关阿糖胞苷40 mg加长春新碱160μg组,长春新碱16μg组,长春新碱160μg组。结果:猕猴实验显示,事件有关阿糖胞苷10 mg组2只猴和事件有关阿糖胞苷20 mg组3只猴出现双下肢协调不佳和运动迟缓;事件有关阿糖胞苷10 mg组1只猴于给药后42 d处于濒死;事件有关阿糖胞苷20 mg组2只猴分别于给药后23和42 d处于濒死。食蟹猴实验显示,事件有关阿糖胞苷20 mg组1只猴于给药后12 d和2只猴于给药后41 d处于濒死;事件无关阿糖胞苷20 mg加长春新碱8μg组1只猴于给药后21 d处于濒死;事件无关阿糖胞苷20 mg加长春新碱80μg组2只猴分别于给药后10和21 d处于濒死;长春新碱200μg组3只猴均于给药后12～15 d死亡。Beagle犬实验显示,事件有关阿糖胞苷40 mg组4只犬和事件无关阿糖胞苷40 mg加长春新碱16μg组2只犬于用药后9～13 d出现行走困难;事件无关阿糖胞苷40 mg加长春新碱160μg组2只犬在用药后6～7 d处于濒死;长春新碱160μg组3只犬于给药后4～12 d处于濒死。生理盐水组和事件无关阿糖胞苷组均未出现神经损害症状。结论:含长春新碱的阿糖胞苷制品鞘内(椎管内)注射能致神经损害。

Objective： To study the causes of neurological damage event related to some cytarabine preparations manufactured by Shanghai Hualian Pharmaceutical Factory in order to improve the manufacture and administration of medicinal products. Methods ：The animals for the experiment were cynomologus monkeys, rhesus monkeys, and Beagle dogs. The drugs for testing include neurological damage event-related eytarabine （or event-related cytarabine for short ）, non-neurological damage event-related cytarabine （or non-event-related cytarabine for short）, vincristine, and normal saline. The route of administration was intratheeal （lumbar） injection. Sixteen cynomolgus monkeys were divided into four groups （4 monkeys in each group） ： the normal saline 0.5 ml group, the non-eventrelated cytarabine 20 mg group, the event-related eytarabine 10 mg group, and the event-related eytarabine 20 mg group. Fifteen rhesus monkeys were divided into five groups （3 monkeys in each group ）： the non-event-related cytarabine 20 mg group, the event-related cybarabine 20 mg group, the non-event-related cytarabine 20 mg plus vincristine 8 μg group, the non-event-related cytarabine 20 mg plus vineristine 80 μg group, and the vincristine 200 μg group. Twenty-two Beagle dogs were divided into seven groups （4 dogs in the event-related eytarabin 40 mg group and 3 dogs in each other groups） ： the normal saline 2 ml group, the non-event-related cytarabine 40 mg group, event-related cytarabine 40 mg group, non-event-related eytarabine 40 mg plus vincristine 16μg group, non-event-related cytarabine 40 mg plus vincristine 160 μg group, the vineristine 16 μg group, and the vincristine 160μg group. Results： In the cynomologus monkey experiments： 2 monkeys in the event-related cytarabine 10 mg group and 3 monkeys in the event-related cytarabine 20 mg group developed poor coordination in lower limbs and bradykinesia; one monkey in the event-related cytarabine 10 mg group was moribund 42 days after drug administration and 2 monkeys in the event-related cytarabine 20 mg group were moribund 23 days and 42 days after drug administration, respectively. In the rhesus monkey experiments： one monkey 12 days after drug administration and two monkeys 41 days after drug administration were moribund in the event-cytarabine 20 mg group; one monkey in the non-event-related cytarabine 20 mg plus vincristine 8 μg group was moribund 21 days after drug administration; two monkeys in the non-event-related eytarabine 20 mg plus vindristine 80 μg group were moribund 10 days and 21 days after drug administration, respectively; three monkeys in the vincristine 200μg group died 12-15 days after drug administration. In Beagle dog experiments： four dogs in the event-related cytarabine 40 mg group and two dogs in the non-event-related cytarahine 40 mg plus vincristine 16μg developed difficulty walking 9-13 days after drug administration; two dogs in the non-event-related cytarabine 40 mg plus vincristine 160μg group were moribund 6-7 days after drug administration; three dogs in the vineristine 160 μg group were moribund 4-12 days after drug administration. No neurological damage symptoms were observed in the normal saline and non-event-related cytarabine groups. Conclusion： Intrathecal （lumbar） injection of a vincristine-eontaining cytarabine preparation can cause neurological damage.