【作者】 张敏；

【导师】 谢靳；

【作者基本信息】 湖北中医学院 ， 中西医结合妇产科， 2009， 硕士

【摘要】 目的:为了系统地研究复方感冒合剂的安全性,指导孕妇临床合理用药,本实验在SD孕鼠胚胎器官形成期给药,探讨复方感冒合剂对孕鼠的胚胎发育毒性。方法:将健康未交配的SD大鼠75只,雌性50只,雄性25只,于每天晚上18:00按照雌雄2:1的比例进行合笼交配,次日对雌鼠进行阴栓检查,对同笼未发现阴栓的雌鼠作阴道分泌物涂片,检查有无精子细胞,凡查见精子提示已交配成功。怀孕当天记为孕0天。将孕鼠随机分为5组,即复方感冒合剂高、中、低剂量组、阴性对照组和阳性对照组,（以下依次称为A、B、C、D、E组）。A、B、C组分别于大鼠受孕第7-16d连续灌胃给予复方感冒合剂相当于生药剂量13.0g/kg、6.5g/kg、3.3g/kg;同期D组给予等剂量的生理盐水;阳性对照组给予等剂量复方盐酸伪麻黄碱缓释胶囊,即新康泰克（按300mg伪麻黄碱/kg孕鼠体重算）,给药体积均为10ml/kg。于妊娠第0天开始,每3天称一次孕鼠的体重,观察药物对孕鼠体重的影响,并跟据体重变化调整给药剂量。所有孕鼠在受孕第20天处死,进行胚胎毒性效应研究。记录每只孕鼠子宫胎盘重量,子宫胎鼠胎盘总重。仔细检查并记录活胎数、死胎数和吸收胎数。逐一测量活胎鼠的体重、身长、尾长,并检查活胎外观有无异常。每窝50%的活胎鼠经茜素红和阿利新蓝骨骼双染后检查全身骨骼发育情况。50%活胎鼠用Bouin液浸泡后做内脏检查。结果:1.复方感冒合剂对孕鼠一般情况的影响A、B、C组孕鼠给药后外观体征、行为活动、粪便性状没有观察到明显异常变化,三组孕鼠增重与D组比较,F=0.035,F_{0.05（3,36）}=2.77,F<F_{0.05（3,36）},P>0.05,差异无统计学意义。E组孕鼠给药后第2天开始出现活动和饮食减少,大便干燥等变化,停药2天后开始恢复,与D组比较孕鼠体重增加明显减慢,t=3.763,t_0.05（18）=2.101,t_0.01（18）=2.878,t>t_0.01（18）,P<0.01,差异有显著性意义。2.复方感冒合剂对孕鼠生殖能力的影响A、B、C各组孕鼠子宫胎盘重量与D组比较,F=0.026,F_{0.05（3,36）}=2.77,F<F_{0.05（3,36）},P>0.05,差异无统计学意义。A、B、C各组孕鼠子宫胎鼠胎盘总重与D组比较,F=0.00054,P>0.05,差异无统计学意义。A、B、C各组孕鼠吸收胎数、活胎数、死胎数与D组比较,X²=3.9,X_0.05²（6）=12.95,X²<X_0.05²（6）,P>0.05,差异无统计学意义。E组孕鼠子宫胎盘重量、子宫胎鼠胎盘总重明显降低,与D组比较,t值分别为3.27、2.945,均大于t_0.01（18）=2.878,P<0.01,差异有显著性意义。E组活胎数减少,吸收胎和死胎数增多,与D组比较,X²=11.9,X_0.05²（2）=5.99,X_0.01²（2）=9.21,X²>X_0.01²（2）,P<0.01,差异有显著性意义。3.复方感冒合剂对胎鼠生长发育的影响A、B、C组胎鼠的体重与D组比较t值分别为:1.588、-1.716、1.094,体长与D组比较t值分别为:0.883、0、0.413,尾长与D组比较,t值分别为:1.626、1.186、1.140,以上结果所对应的P值均大于0.05,差异无统计学意义。E组与D组比较胎鼠的体重明显降低,体长和尾长明显缩短,与D组比较,t值分别为3.20、3.491、3.123,所对应的P值均小于0.01,差异有显著性意义。4.复方感冒合剂对胎鼠外观的影响身体外形异常表现为露脑、额裂、脐疝、腹裂、畸形足、短尾、无尾等。A、B、C、D、E各组胎鼠均未见露脑、额裂、腹裂、畸形足、无尾等外观变化。脐疝、短尾等变化的总发生率分别为:A组:2.44%;B组:2.30%;C组:1.16%;D组:2.22%;E组:14.86%。A、B、C组与D组比较,X²=2.27,X_0.05²（3）=7.81,X²<X_0.05²（3）,P>0.05,差异无统计学意义。E组与D组比较,X²=-5.73,X_0.05²（1）=3.84,X²>X_0.05²（1）,P<0.05,差异有统计学意义。5.复方感冒合剂对胎鼠骨骼的影响A、B、C组胎鼠骨骼总变异及畸形率与D组比较,X²=0.34,X_0.05²（3）=7.81,X²<X_0.05²（3）,P>0.05,差异无统计学意义。E组胎鼠除有波状肋和骨骼发育迟缓外,还发现较多骨骼畸形,表现为椎体分离、椎体分裂（椎骨椎体中心软骨分裂）、肋缺失、颈肋、腰肋等。其总变异及畸形率与D组比较,X²=7.27,X_0.05²（1）=3.84,X_0.01²（1）=6.63,X²>X_0.01²（1）,P<0.01,差异有显著性意义。6.复方感冒合剂对胎鼠内脏的影响A、B、C组胎鼠散在出现胸腺颈部残留、肾盂积水等内脏畸形,三组总畸形率与D组比较,X²=1.22,X_0.05²（3）=7.81,X²<X_0.05²（3）,P>0.05,差异无统计学意义。E组胎鼠出现较多内脏畸形,如胸腺颈部残留、突眼、肾盂积水、脑室扩张等,总畸形率与D组比较,X²=6.97,X_0.05²（1）=3.84,X_0.01²（1）=6.63,X²>X_0.01²（1）,P<0.01,差异有显著性意义。结论:综合以上结果发现:在本实验室条件下,复方感冒合剂高、中、低剂量在孕鼠致畸敏感期灌胃给药,各剂量均无明显母体毒性、胚胎毒性和致畸作用,且在实验剂量范围内,复方感冒合剂未呈现剂量反应关系。通过阴性对照组的结果可以发现在无任何外因干预的情况下胎鼠也有出现一定比例变异和畸形的可能。阳性对照组出现明显的母体毒性、胚胎毒性和致畸作用。因此,为避免对胚胎发育产生毒性作用,建议妊娠期间慎重选择感冒药,严格掌握用药剂量并遵循配伍原则。更多还原

【Abstract】 Objective:In order to study systematically the security of compound prescription cold mixture, and to guide clinical rational drug use in pregnant women, SD pregnant rats were administered during their embryos organ formation period in this experiment to explore the compound prescription cold mixture’ s toxicity for embryonic developmental of pregnant rats.Method:Healthy SD rats 75 which did not mate female 50, male 25, at 18: 00 every night in accordance with the ratio of 2: 1 for male and female cage mate together, the next day to carry out female vaginal suppository for inspection, on the same cage did not find the female vaginal suppository for vaginal secretion smear to check for sperm cells, where the investigation has been prompted to see the mating success of sperm. the day of Pregnancy was recorded as 0 days of pregnant. The pregnant rats were randomly divided into 5 groups, namely, a compound prescription cold mixture high, medium and low dose, negative control group and positive control group, （respectively referred to as A, B, C, D, E group）. A, B, C group respectively in the pregnancy in 7-16 days gavage forcompound prescription cold mixtureto give the pregnant rats 13.0g/kg、6. 5g/kg、3. 3g/kg. D group, in the same period gaven the same doses of normal saline. And the positive control group were gaven same dose of compound pseudoephedrine hydrochloride sustained-release capsules, that is, the new Kangtaike （at 300mg pseudoephedrine / kg body weight count）.The medicine volume was 10ml/kg. In the pregnancy 0th day start, every 3 days to check one time the pregnant rats body weight, observe the influence of the medicine for the pregnant rats body weight, and according to the body weight to adjust the medicament dose . All pregnant rats be killed in the pregnancy 20th day , to conduct the embryo poisonous effect research. And to record each pregnant rat uterus placental weight, and the total weight of the uterus and placenta and fetal rat.To inspect and record the live embryo number, the dead embryo number, and the absorption embryo number carefully. To measure live weight、body length and tail length of fetal rat, and to check whether there were abnormal appearance of live births. Each nest 50% live embryo rats double dye after the sodium alizarinsulfonate and the Aly new blue skeleton to inspect the whole body skeleton growth situation. 50% live embryo rats to were given the internal organs inspection after the Bouin fluid immersion.Result:1. the effects of compound prescription cold mixture to pregnant rats reproductive capacityThe appearance of signs, behavior activity, stool traits of A, B, C group pregnant rats after were administered not observed in apparent anomalies, three groups of pregnant rats weight gain compared with the D group,F=0. 035, F_{0.05（3,36）} =2. 77, F<F_{0.05（3,36）}, P>0. 05, there was no significant difference. E group of pregnant rats arise activities and diet began to decrease、feces become dry after the second days of administration , such as changes in 2 days after discontinuation of treatment began to recover, compared with the D group pregnant rats’ weight gain significantly slower , t=3. 763, t_0.05（18）=2. 101, t_0.01（18）=2. 878, t>t_0.01（18）, P < 0. 01,The difference was significant.2. the effects of compound prescription cold mixture to pregnant rats reproductive capacityThe utero placental weight of A, B, C pregnant rats compared with D group , F=0. 026, F_{0.05（3, 36）}=2. 77, F<F_{0.05（3, 36）}, P>0. 05, there was no significant difference. the placenta in fetal rat uterine total weight of A, B, C pregnant rats in each group compared with D group, F=0. 00054, P>0. 05, there was no significant difference. the live embryo number, the dead embryo number, and the absorpted embryo number of A, B, C pregnant rats in each group compared with D group, X²=3. 9, X_0.05²（6）=12. 9, 5 X²<X_0.05²（6）, P>0. 05, there was no significant difference. the weight of placenta and uterine of pregnant rats、total weight of the uterine placenta in fetal rats of E group significantly decreased compared with D group, t numeric were 3.27,2.945, were greater than t_0.01（18）=2. 878 , t>t_0.01（18）,P <0.01 , the difference was significant.the live embryo number, the dead embryo number, and the absorpted embryo number of E group compared with D group,X²=11. 9, X_0.05²（2） =5.99, X_0.01²（2） =9.21, X²>X_0.01²（2） , P <0. 01, The difference was significant.3. the effects of compound prescription cold mixture to fetal rats growth and developmentThe body weight of fetal rats of A, B, C group compared with the D group , t numeric were as follows: 1. 588、-1. 716、1. 094, body Length compared with the D group, t numeric were as follows: 0.883、0、0.413, Tail length compared with the D group, t numeric were as follows: 1.626、1.186、1.140，These results corresponding to P numeric greater than 0.05, the difference was not statistically significant. E group compared with D group body weight of fetal rats reduced significantly , body length and tail length was significantly shorter , t numeric were 3.20、3.491、3.123, Corresponding to P <0. 01,The difference was significant.4. the effects of compound prescription cold mixture to fetal rats appearancePhysical appearance differences usually are exposed brain, forehead split, umbilical hernia, abdominal dehiscence, foot deformities, a short tail, no tail and so on . A, B, C, D, E in each group were not exposed brain, forehead split, abdominal dehiscence, foot deformities, a short tail, no tail changes in appearance. umbilical hernia, a short tail, such as changes in the overall incidence rates were: A: 2.44%; B: 2.30%; C: 1.16%; D: 2.22%; E: 14.86%. Comparison of A, B, C group and D group, X²=2.27 , X_0.05²（3） =7. 81, X²<X_0.05²（3）, P>0. 05, there was no significant difference. E group compared with the D group, X²=-5. 73 , X_0.05²（1） =3. 84, X²>X_0.05²（1）, P<0. 05, the difference was statistically significant.5. the effects of compound prescription cold mixture to fetal rats boneThe total variation and malformation rate of fetal rat bone of A, B, C group compared with D group, X²=0. 34, X_0.05²（3）=7.81, X²<X_0.05²（3）, P>0. 05, there was no significant difference. The fetal rats of E group in addition to have wavy ribs and skeletal growth retardation, but also found that there were more skeletal deformities, showed vertebral separation, split vertebral body （Split vertebrae vertebral cartilage center）, missing rib, cervical rib, lumbar costatum. The total variation and malformation rate compared with D group, X²=7. 27, X_0.05²（1）=3. 84, X_0.01²（1）=6. 63, X²>X_0.01²（1）,P<0. 01,The difference was significant.6. the effects of compound prescription cold mixture to fetal rats organsA, B, C group scattered emerged residual visceral malformation , such as thymus residues in the sneck, hydronephrosis, the rate of the total malformation of three groups compared with D group, X²=1.22 , X_0.05²（3）=7.81, X²<X_0.05²（3）, P>0. 05, there was no significant difference. E group occurred more frequently visceral malformations of fetal rats , such as thymus in the neck ,exophthalmos, hydronephrosis, ventricular expansion, etc. the total malformation rate compared with the D group, X²=6. 97, X_0.05²（1）=3. 84, X_0.01²（1）=6. 63, X²>X_0.01²（1）, P<0. 05, The difference was significant.Conclusion:The results above showed that : in the laboratory conditions, the compound prescription cold mixture of high, medium and low doses have been gavaged to pregnant rats in teratogenic sensitive period, the dose had no significant maternal toxicity, embryo toxicity and teratogenic effects, and in experimental dose range, compound prescription cold mixture haven’t appeared in a dose-response relationship . But positive control group have appeared significant maternal toxicity , embryo toxicity and teratogenic effect. Thus, in order to avoid the effects of embryo development toxicity ,it is recommended to choose cold medicine carefully during pregnancy , strictly dose of drugs and adhere to the principle of compatibility.更多还原