Toxicology Reliability Evaluation Of Compound Bisoprolol And Isosorbide Dinitrate Patch

Objective: To assess the toxicology reliability of compound bisoprolol and isosorbide dinitrate patch in its acute toxicity, long-term toxicity, heredity toxicity and reproduction toxicity.Methods:①Acute toxicity test. Forty healthy Wistar rats were divided randomly into four groups(10 in each group, 5 male and 5 female) which respectively present intact skin control group, intact skin test group, damaged skin control group and damaged skin test group. Intact skin test group and damaged skin test group were treated with compound bisoprolol and isosorbide dinitrate patch in 200mg/kg bw; intact skin control group and damaged skin control group was treated with blank patch. Patches were removed after 24h and results were observed.②Long-term toxicity test. Forty healthy Wistar rats were divided randomly into two groups(20 in each group, 10 male and 10 female) which respectively present test group and control group. Test group was treated with compound bisoprolol and isosorbide dinitrate patch in 150mg/kg bw; control group was treated with blank patch. Rats were treated with patches for continuous three days and then for a day interval, thus four days is a cycle. Ten rats in each group were sacrificed 10 weeks after this treatment and indexes were determined. The rest 10 rats in each group were observed for 2 more weeks of stop treatment and then were sacrificed and determined in the same method.③Heredity toxicity test, including Ames test and mouse micronucleus test. In Ames test, five different concentrations of the test matter were tested that were 5000, 500, 50, 5, 0.5μg per dish; no treatment control group, solvent control group(dimethyl sulfoxide) and positive control group were also set up. Standard plate process was used in which every disposal repeats three times with or without S9 and then 37℃cultivation for 48h is made and repeat the whole above procedure one more time. In mouse micronucleus test, fifty healthy Kunming mice were divided randomly into three groups(10 in each group, 5 male and 5 female). There are three test matter groups with different dosage of 100mg/kg, 20mg/kg, 4mg/kg, a positive group(cyclophosphamide) and a negative group(dimethyl sulfoxide). Three test matter groups and negative group were treated per cutem once a day for continuous 4 days and sacrificed in fifth day. Positive group was treated by intraperitoneal injection only once and then sacrificed in 24h. The femoral bone marrow smear was made and results were observed.④Reproduction toxicity test. Rat teratology study was selected. Eighty healthy sexual mature Wistar female rats were divided randomly into four groups: three different dosage groups of compound bisoprolol and isosorbide dinitrate patch(150mg/kg bw, 30mg/kg bw, 6mg/kg bw) and a negative control group. After pregnancy, the rats in different groups were treated with patches during 6~15th day of pregnancy. All pregnant rats were put to death at 20th day of pregnancy. Results were observed.