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 the neurotoxicity induced by cytarabine in batches produced by Shanghai Hualian Pharmaceutical Factory to facilitate the improvement of drug production and management. Methods: Macaca mulatta, cynomolgus monkeys and Beagle dogs were used as experimental animals. The drugs tested were cytarabine related to nerve damage events (referred to as cytarabine for short), cytarabine unrelated to nerve damage events (hereinafter referred to as event-independent cytarabine), vincristine and saline . The route of administration is intrathecal (intraspinal) injection. 16 macaques were divided into 4 groups (4 in each group): saline 0.5 ml group, event-free cytarabine 20 mg group, event-related cytarabine 10 mg group, event-related cytarabine 20 mg group. Fifteen cynomolgus monkeys were divided into 5 groups (3 in each group): event-independent cytarabine 20 mg group, event-related cytarabine 20 mg group, event-unrelated cytarabine 20 mg plus vincristine 8 μg group , Event-related cytarabine 20 mg plus vincristine 80 μg group, vincristine 200 μg group. 22 Beagle dogs were divided into 7 groups (event related to cytarabine 40 mg group of 4, the remaining group of 3): saline 2 ml group, the event-related cytarabine 40 mg group, the incident related to sugar Cytidine 40 mg group, event-free cytarabine 40 mg plus vincristine 16 μg group, event-free cytarabine 40 mg plus vincristine 160 μg group, vincristine 16 μg group, vincristine 160 μg group. Results: Macaca fascicularis experiments showed that the two lower limbs of the two monkeys in the event-related cytarabine 10 mg group and the event-related cytarabine 20 mg group had poor coordination and bradykinesia. The events related to cytarabine 10 mg group One monkey was dying on day 42 after dosing; two monkeys in the event-related cytarabine 20 mg group were dying at 23 and 42 d after dosing, respectively. Cynomolgus monkey experiments showed that one monkey in the event-related cytarabine 20 mg group was dying on day 12 after dosing and two monkeys 41 days after dosing; event-unrelated cytarabine 20 mg plus vincristine One monkey in the group of 8μg was dying on the 21st day after administration; the two monkeys who had nothing to do with cytarabine 20mg and vincristine 80μg were dying at the age of 10 and 21 d respectively; the group with 200μg of vincristine All 3 monkeys died after 12-15 days. Beagle dog experiments show that the event related to cytarabine 40 mg group of dogs and non-event-related cytarabine 40 mg plus vincristine 16 μg group of 2 dogs in the 9 ~ 13 d after the application of walking difficulties; the event is not related to sugar Cytosine 40 mg plus vincristine 160 μg group were dying 6 to 7 days after treatment; 3 dogs in vincristine 160 μg group were dying from 4 to 12 days after dosing. Nerve damage was not observed in the saline group and the event-free cytarabine group. Conclusion: Intravenous (intraspinal) injection of Cytarabine containing vincristine can cause nerve damage.