Non-clinical Safety Studies Of Shenmai Injection

The adverse reactions of traditional Chinese medicine injection become more frequent in recent years, and its safety question has received the society’s wide attention. Promoted by the special operation of re-evaluation the safety of traditional Chinese medicine, this study was designed to conduct the non-clinical safety re-evaluation of Shenmai injection. It was comprised of acute toxicity study via intravenous dripping in Beagle dogs, fertility and early embryonic developmental toxicity in SD rats, effects on embryo and fetal development in SD rats. The purpose of this study is to evaluate the potential toxic reaction of Shenmai injection in Beagle dogs, with the emphasis of determining its maternal, embryo and fetal developement exposure, then to provide references for increase of clinical applicable people and rational drug use. The study was consisted of following three tests:1. Acute Toxicity Study in Beagle DogsBeagle dogs were assigned to 3 groups of negative control (5% glucose injection), vehicle control (the major components is 0.5% Tween-80) and Shenmai injection (5 g/kg) with 2 animals/sex per group, and the maximum dosage method was used for administration. Animals in each group were intravenously dripped with a single maximum administrable volume at 50 mL/kg. Results indicated that, about 5 min post-dose, animals in vehicle control and Shenmai injection (5 g/kg) groups were successively noted with slight to moderate anaphylactoid symptoms including face swelling, ear redness, rapid respiration and vomit etc. These signs were gradually back to normal at about 3 hrs post-dose. No other abnormalities were found in body weight, hematology, clinical chemistry and ECG of Shenmai injection-treated animals. No abnormality was detected in pathological exam of Shenmai injection-treated animals at the end of observation phase. In conclusion, Beagle dogs received single maximum intravenous dripping of Shenmai injection (5 g/kg), no abnormality was noted except a transit anaphylactoid symptom, which was related to the Tween 80 contained in vehicle control article.2. Fertility and Early Embryonic Development Evaluation in SD RatsIn the study, totally 176 SD rats were randomly assigned to 4 groups of control (5% glucose injection), Shenmai injection low dose (0.3 g/kg/d), middle dose (0.6 g/kg/d) and high dose (1.2 g/kg/d) groups, with 22 rats/sex per group. Animals in each dose group were intravenously injected with Shenmai injection or 5% glucose injection using a volume of 12 mL/kg. Males were dosed once daily for consecutive 4 weeks before the first mating and through the cohabitation period and until the final necropsy. Females were dosed once daily for consecutive 2 weeks before mating and through the cohabitation period until gestation day (GD) 7. On GD 15, all surviving pregnant females were euthanized followed by exsanguination. The number of corpora lutea, implantation sites, live and dead fetuses, and the number of resorptions were counted and recorded the findings. The weight of uterus and ovary were weighed and the ratios were calculated. No test article-related abnormality was found in clinical signs, body weight and body weight gain, food consumption, reproductive function and early embryonic development in Shenmai injection-treated animals. In conclusion, the reproductive functions and early embryonic development were not affected by Shenmai injection at 0.3,0.6 and 1.2 g/kg, and the NOAEL was established at 1.2 g/kg.3. Embryo and Fetal Development in SD RatsTotally 112 mated females were randomly divided into 4 groups of control(5% glucose injection), Shenmai injection low dose (0.3 g/kg/d), middle dose (0.6 g/kg/d) and high dose (1.2 g/kg/d) groups. The animals were dosed once daily by intravenous injection with Shenmai injection or 5% glucose injection from GD 6 to GD 15 at a dose volume of 12 mL/kg. On GD 20, all surviving F0 females were euthanized followed by exsanguination. The number of corpora lutea, implantation sites, viable and dead fetuses, and the number of resorptions were examined. Findings were recorded. The weight of uterus and ovary were also weighed, and the ratios of them were reported. The body weights, body length, tail length of the fetuses were recorded and the appearance, skeleton and visceral form were examined. There were no test article-related abnormalities in clinical signs, body weight, body weight gain, food consumption, the reproductive function of the gravid female, embryonic development and fetal examinations. In conclusion, the maternal, embryo and fetal development were not affected by Shenmai injection at 0.3,0.6 and 1.2 g/kg, and the NO AEL was established at 1.2 g crud drug/kg.