合成新药SC001A胺盐的毒性研究

SC1001A is a new sedative, hypnotic and anti-epileptic drug. Screening for possible mutagenicity of the agent consisted of a battery scheme of short-term mutagenic tests with different hereditary detecting end points. Three assays were with in the scheme: Ames test (for detecting gene mutation in vitro), micronucleus test (for detecting chromosomal aberration in vivo) and CHL (Chinese hamster lung cell line) test (for detecting chromosomal aberration in vitro). In addition, a routine teratogenicity study on SC1001A was carried out in mice. They were given daily at 3-dose levels (exposed to up to 33% of the LD50 by gastric incubation from the 6th through the 15th day of gestation. SC1001A gave uniformly negative results in all three mutagenic assay systems. Results of the teratogenic experiment showed that only the pregnant rate in bred mice in the moderate dose group and the mean maternal body weight gain of the dams during gestation in the low dose group were significantly lower than those in the corresponding control group. A clear dose-response relationship was not demonstrated. All dose levels of SC1001A used caused no adverse effects on the number of survival fetuses per litter, growth or development of the fetal mice. No malformations in the external appearance, of the internal organs and of the skeletal systems in fetal mice were observed. The above-mentioned results indicated that SC1001A induced neither gene mutation nor chromosomal damage both in vitro and in vivo. There was no evidence of teratogenesis. Therefore, it is estimated that SC1001A is probably comparatively safe as a pharmaceutical product for human beings in usual dosage.     

SC1001钠盐和胺盐在人体内的药代动力学研究

The pharmacokinetics of SC1001-Sodium and SC1001-Aminum in the human body was studied. After 200 mg SC1001-Sodium or SC1001-Aminum by oral administration, plasma concentration-time data were fitted to curves by means of the nonlinear least-square method, employing the program we ourselves compiled. With F-test, comparing gamma 2(1) -value and AIC-value, the linear one compartment open model was available. The mean pharmacokinetic parameters fitted one by one were as follows with the first value given belonging to SC1001-Sodium and the second to SC1001-Aminum: Ka: 0.7248 and 0.5102 h-1; Ke: 0.0597 and 0.1149 h-1; T1/2, a: 1.1437 and 1.8999 h; T1/2, e: 15.7428 and 6.1497 h; AUC: 600.15 and 28.61 micrograms.h/ml; Tm: 4.4798 and 4.3728h.     

SC1001钠盐和胺盐在人体内的药代动力学研究

健康人口服SC1001钠盐或SC1001胺盐200mg后,血药时间数据用自编程序进行非线性最小二乘法曲线拟合,经F检验、γ_1~2和AIC值比较,符合线性一室模型。其药代动力学参数平均值(前者为SC1001钠盐,后者为SC1001胶盐数据)如下:Ka为0.7248和0.5102h~(-1);Ke为0.0597和0.1149h~(-1);T_(1/2),a为1.1437和1.8999h,T_(1/2),e为15.7428和6.1497h;AUC为600.15和28.61μg·h/ml,T_m为4.4798和4.3728h。     

合成新药SC1001胺盐对抗马桑内酯所致树鼩癫痫和镇静作用的研究

作者用一种哺乳类动物——树鼩为实验对象,观察SC1001胺盐的镇静和抗癫痫作用。结果表明:SC1001胶盐对树鼩有镇静作用,并有明显的抗马桑内酯所致癫痫的作用,表现为发作率降低,小发作和大发作均减少,大发作时间缩短。     

SC1001钠盐对马桑内酯点燃家兔脑神经细胞超微结构的观察

The ultrastructural changes of hippocampus and cerebral cortex neurons were derived from the rabbits kindled by coriaria lactone and from the kindled rabbits after treatment with SC1001 Na. The results of experiment showed that the hippocampus and cerebral cortex neurons in the kindled group had some degenerative changes, such as the swelling mitochondria, dilated rough endoplasmic reticulum and Golgi complexes when the injuries of neurons were not serious, but the seriously injured neurons were subjected to rupture of the cell membrane and solution of most organella, with only a small amount of degenerative organella. In the group treated with SC1001 Na, the ultrastructure of brain neurons demonstrated a tendency of recreation to normal which showed that SC1001 Na had cured many of the degenerative brain cells. This suggested that active treatment is very important for the epileptic patients.     

合成新药SC1001胺盐对抗马桑内酯所致树qu癫痫和镇静作用的研究

In this experiment, the calmative and anti-epileptic effects of SC1001A were observed in fifty-five tupaias (Tupaia belangeri Yunalis), both male and female, were divided into four groups. The animals of the first group were perfused with SC1001A (400mg/kg) into their stomach. The animals of the second group were injected with coriaria lactone (5mg/kg, i.m.) for inducing seizures. The remaining two groups received SC1001A 100 and 400 mg/kg respectively by the same way as that of the first group, and 1 min later, they were injected immediately with coriaria lactone (5 mg/kg, i.m.). After the drug being perfused, the behaviors of all the experimental animals were observed continuously for 2-3 h. The results of the experiment indicated that SC1001A was possessed of a calmative effect which appeared shortly after drug (mean 12.88 min) and did not sustain a long time (mean 98 min). In addition, SC1001A was obviously effective on epilepsy induced by coriaria lactone in tupaias, in reducing the seizure rate, the times of petit mal and grand mal, as well as the duration of grand mal.     

反相高效液相色谱法测定血浆中SC1001A的含量

作者用反相高效液相色谱法测定人血浆中SC1001A的含量。采用Zorbax-ODS柱,甲醇:水(70:30)为流动相,在266nm波长处检测。检测结果:相关系数为0.9980,变异系数1.00％,回收率84.58％。本法不需经萃取,具有快速、灵敏、准确等优点。可提供临床实验室作SC1001A的血药浓度测定、剂型及药物动力学研究之用。     

合成新药SC1001钠盐对抗马桑内脂所致家兔癫痫的研究

In the present experiment, SC1001Na synthesized by West China University of Medical Sciences was used for studying to resist epilepsy induced by coriaria lactone. Forty-two normal male rabbits weighing 1.7-2.5 kg were randomly divided into four groups. The animals of the control group received coriaria lactone (3 mg/kg, i.m.). The animals in each of the experimental groups were injected separately with SC1001Na (100, 200 and 300 mg/kg, i.p.), but the control animals were not injected with SC1001Na. Thirty minutes later, the animals of the experimental groups were injected with the same dose of coriaria lactone as the control animals. The behavior of all animals before and after injection were observed continuously in 4-5 hours. The ECoG of eight animals of them were observed at the same time with telemetric method. The results of experiments indicated that SC1001Na is effective on epilepsy induced by coriaria lactone, in decreasing seizure rate, lengthening latent period, reducing seizure degree, as well as in decreasing mortality.     

合成新药SC1001钠盐对抗马桑内酯所致家兔癫痫的研究

作者采用遥测记录皮层电图和同时观察行为的方法,观察了SC1001钠盐的抗癫痫作用。实验结果表明,此药对马桑内酯所致的家兔癫痫有降低发生率、延长潜伏期、减轻发作程度和降低死亡率等作用,尤以延长潜伏期更为显著。     

合成新药SC1001钠盐对家兔呼吸频率、心率、直肠温度和皮层电图的影响

作者用SC1001钠盐(200mg/kg)注入家兔腹腔内,观察其对呼吸频率、心率、直肠温度和皮层电图的影响。实验结果表明,对家兔的呼吸频率、直肠温度有轻微的抑制作用,对中枢神经活动有明显的抑制作用,对心率有加快作用。     

中药甘遂注射液的毒性试验研究

本文报道了雌性小鼠腹腔注射中药甘遂注射液,LD_(50)为88mg/kg,相当于人体实际用量的17.6倍;致突变试验为阴性结果,其中包括小鼠骨髓细胞染色体畸变分析和基因突变试验;用甘遂注射液引产后对小鼠再次受孕率无影响;在5mg/kg和1mg/kg剂量下均有明显胚胎毒性,但对存活胎仔无致畸作用。     

SC1001钠盐对马桑内酯所致家兔海马点燃性癫痫发作的影响

作者用点燃效应模型对SC1001钠盐的抗痫作用进行了观察。实验结果表明,此药对马桑内酯所致家兔海马点燃性发作有一定的对抗作用,但肌肉注射SC1001钠盐100mg/kg的疗效不如肌肉注射苯巴比妥钠30mg/kg显著。     

SC1001Na对反复癫痫发作大鼠胸腺、脾及脑中腺苷脱氨酶活性的影响

用SC_(1001)Na对马桑内酯造成的反复癫痫发作大鼠进行治疗,剂量200mg/kg体重。一周后实验组大鼠胸腺、大脑及小脑中腺苷脱氨酶活性均明显低于对照组,胸腺指数也明显下降。由此提示该剂量的SC_(1001)Na不仅对大鼠免疫器官的发育有一定抑制作用,而且其抗痫作用机理可能与腺苷脱氨酶活性下降,脑中腺苷水平升高有关。     

SC1001钠盐对马桑内酯点燃家兔脑神经细胞超微结构的观察

本文报道用马桑内酯阈下剂量反复注入家兔海马造成点燃效应,再用SC1001钠盐治疗,观察其海马及大脑皮层神经细胞超微结构的变化。结果表明:SC1001钠盐能使马桑内酯点燃家兔已出现的神经损害有一定的恢复。     

应用大鼠体外胚胎培养模型研究生草乌对胚胎发育的影响

目的探讨生草乌对胚胎发育的毒性作用及机制。方法应用大鼠着床后体外全胚胎培养模型,将9.5dSD大鼠胚胎与含不同浓度(终浓度分别为:0、0.63、1.25、2.5、5mg生药/mL)生草乌的大鼠即刻离心血清共培养48h,观察其对大鼠胚胎生长发育和组织器官形态分化的影响。结果随着生草乌剂量增加,胚胎生长发育和器官分化的各项指标均呈现下降趋势,有一定的剂量-效应关系。生草乌最大无作用剂量为1.25mg生药/mL,2.5mg生药/mL以上剂量可诱发卵黄囊生长和血管分化不良、生长迟缓及形态分化异常,严重者出现体节紊乱、小头、心脏发育迟滞(心小,停留在心管期)及心脏空泡等。结论较高剂量生草乌对体外培养大鼠胚胎具有一定的毒性作用,建议孕妇妊娠期间(特别是妊娠前3个月)慎用或禁用草乌。