鲑鱼降钙素口腔喷剂的急性毒理与口腔黏膜吸收最大耐受量实验

Experimental Study on Acute Toxicology of Salcalcitonin Buccal Spray in Mice

目的考察鲑鱼降钙素口腔喷剂经肌内注射以及经舌下黏膜给药对小鼠的急性毒性反应,为长期毒理学实验提供剂量设计依据。方法清洁级昆明种小鼠90只,其中50只(雌雄各半)肌内注射给予鲑鱼降钙素口腔喷剂37 715,44 370,52 200,61 413,72 250 U.kg-1,共5个剂量组;20只雄性小鼠肌内注射给予鲑鱼降钙素口腔喷剂58 432,55 650,53 000,52 200 U.kg-1,共4个剂量组。20只小鼠(雌雄各半)经舌下黏膜4次涂抹给药(10 000 U.kg-1)。观察小鼠症状体征、死亡率等相应指标的变化。结果鲑鱼降钙素口腔喷剂对小鼠肌内单次注射半数致死量(LD50值)为55 780.24 U.kg-1,95%的可置信区间是50 660.56～61 417.36 U.kg-1。雌性小鼠致死率呈现良好剂量效应关系,其LD50值为50 428.21 U.kg-1,95%的可置信区间是43 257.21～58 788.00 U.kg-1;对雄性小鼠LD50值为68 173.75 U.kg-1,95%的可置信区间是52 372.73～88 742.05 U.kg-1。在注射后的24 h内所有小鼠均出现左右下肢站立不稳、行动姿势改变、耸毛、不安、发抖、共济失调等临床症状;给药后24～96 h内出现左右下肢站立不稳、行动姿势改变等临床症状;96 h后存活动物均恢复正常的运动与呼吸。鲑鱼降钙素口腔喷剂10 000 U.kg-1经舌下1 d内分4次涂抹给药后昆明种小鼠没有出现明显的异常反应,舌下黏膜给药最大耐受量为10 000 U.kg-1。结论鲑鱼降钙素口腔喷剂肌内注射具有一定的急性毒性作用,舌下黏膜吸收急性毒性较低,相对于肌内注射更为安全。鲑鱼降钙素口腔喷剂对实验小鼠的急性毒理作用具有明显的性别选择性。

Objective To investigate the acute toxicology of salcalcitonin administered via muscle and sublingually for further chronic toxicity study. Methods 90 cleaning KM mice were given with salcalcitonin buccal spray by muscle injection and tongue mucous with different doses, respectively. The acute reaction and the main viscera pathological morphology were evaluated by observing the fur, symptoms of central nervous system and mortality. Results LD50 in cleaning mice（♂ ＋ ♀ ）of salcalcitonin by muscle injection was 55 780.24 U ·kg^-1（50 660.56 -61 417.36 U · kg^-1）. But LD50 in cleaning KM mice （ ♂ ） by muscle injection was 68 173.75 U ·kg^-1 （ 52 372.73 - 88 742.05 U · kg^-1）. Within 24 h of injection, all mice appeared astasia, abnormal action, restless, shivering and ataxia. The symptoms lasted till 96 h. No unexpected reaction was found in mice by of salcalcitonin buccal spray given via tongue mucous for four times, and the MTD of which was 10 000 U · kg^-1. Conclusion It shows that salcalcitonin i.m. presents certain acute toxicity, but via tongue mucous is more safe. The sexuality of mice impacts acute toxicity of salcalcitonin buccal spray.