利用无创遥测技术开展伴随重复给药毒性试验的食蟹猴安全药理学研究

目的 应用食蟹猴重复给药毒性伴随安全药理学研究的实例，探究利用无创遥测技术进行伴随于重复给药毒性试验的心血管、呼吸系统安全药理学研究的可行性。方法 重复给药毒性试验取食蟹猴40只（雌雄各半，其中32只进行安全药理学研究），分为4组，即空白对照组、佐剂对照组和四价重组诺如病毒疫苗（毕赤酵母）低、高剂量组，分别为不给任何受试物，每次im佐剂对照品1 mL（2人份）/猴、四价重组诺如病毒疫苗（毕赤酵母）0.5 mL（1人份）/猴和1 mL（2人份）/猴，每4周给药1次，共给药4次。食蟹猴经穿脱马甲和猴椅固定的适应性训练后开始正式试验；安全药理学试验数据的采集安排在首次与第3次给药时，使用马甲式遥测系统采集给药后0~24 h的呼吸、心电、体温等相关参数，并增加采集给药后0~2、5~6、23~24 h时间段的血压数据（将猴保定在猴椅上）。结果 单次及3次给予四价重组诺如病毒疫苗（毕赤酵母）低、高剂量以及佐剂对照品对食蟹猴呼吸、心电、血压、体温等各项指标均未见明显影响。部分时段的指标波动均属猴正常的应激（受束缚状态下）变化或昼夜生理节律性变化。结论 在本试验剂量条件下，单次及多次im四价重组诺如病毒疫苗（毕赤酵母），对食蟹猴呼吸系统、心血管系统均未见明显影响；利用马甲式无创遥测系统结合重复给药毒性试验进行安全药理学研究（心血管、呼吸系统）具有良好的可行性，符合动物福利3R原则，尤其适合于重复给药后的安全药理学研究。

Safety pharmacology study in cynomolgus monkeys combined with repeat-dose toxicity test using non-invasive telemetry technique

Objective The feasibility of the study of cardiovascular and respiratory safety pharmacology using non-invasive telemetry technology combined with repeated toxicity test was explored by the example of safety pharmacology study in cynomolgus monkeys. Methods As a case, this study observed the effects of quadrivalent recombinant norovirus vaccine (pichia pastoris), on the respiratory and cardiovascular systems in conscious cynomolgus monkeys combining with the repeat-dose toxicity test of quadrivalent recombinant norovirus vaccine (pichia pastoris). A total of 40 cynomolgus monkeys were used for repeat-dose toxicity test, 32 of them were subjected to safety pharmacology study. Animals were divided into four groups, namely blank control group, adjuvant control group, low dose group and high dose group of quadrivalent recombinant norovirus vaccine (pichia pastoris). Animals in blank control group did not administrate any article, and those in other three groups were intramuscularly injected with adjuvant 1 mL (2 human dose)/monkey, quadrivalent recombinant norovirus vaccine (pichia pastoris) 0.5 mL (1 human dose)/monkey, 1 mL (2 human dose)/monkey, once every 4 weeks, a total of 4 times for repeat-dose toxicity test. The cynomolgus monkeys began formal testing after the adaptive training of wearing the vest and fixed in the monkey chair. The data of safety pharmacology test were collected on the first and third administration, and the parameters of respiration, electrocardiogram, body temperature from 0 to 24 hours after administration were collected using the telemetry system, and the data of blood pressure in period of 0-2, 5-6, 23-24 hours after administration were collected for the monkey fixed on the monkey chair. Results The first and third administration of quadrivalent recombinant norovirus vaccine (pichia pastoris), in low or high dose, or adjuvant control all had no significant effect on the respiratory, electrocardiogram, blood pressure and body temperature in cynomolgus monkeys. The fluctuation of the few indexes in some periods was related to the normal stress in the state of restraint or the circadian rhythm of the monkey. Conclusion Under the conditions of this test, single or multiple intramuscular injections of preventive biologics quadrivalent recombinant norovirus vaccine (pichia pastoris) had no significant effect on the respiratory and cardiovascular system in cynomolgus monkeys. It is feasible to perform a safety pharmacology study combined with a repeat-dose toxicity test using a noninvasive telemetry system, which would be following animal welfare 3R principle, especially be suitable for safety pharmacology studies after multiple administration.