Safety Evaluation Of Midkine Antisense Oligonnucleotide Nano-liposomes

According to the principle of drug safety evaluation and research guidance of CFDA,the new anti-hepatoma drug MK-ASODNs was studied about safety.Study on toxicity of MK-ASODNs in Beagle dogs after single intravenous administration:8 Beagle dogs(4(?),4(?))were divided into treatment group(2(?),2(?))and negative control group(2(?),2(?))by cumulative dose method.During the experiment,the death and near death observation,clinical observation,weight,food intake record,electrocardiogram,body temperature,eye examination,clinical pathology and histopathological examination were detected.Results:Beagle dogs did not die at the maximum dose of 11.12 mg/kg,and there was an obvious toxic reaction when the dose was 11.12 mg/kg.Therefore,MTD>11.12 mg/kg of MK-ASODNs in the single dose toxicity test of Beagle dogs.Study on toxicity of MK-ASODNs in Beagle dogs after 4-week continuous intravenous administration:Beagle 40 dogs(20(?),20(?))were divided into low,medium and high dose group and saline control group,each group of 5 males and 5 females.During the experiment,the death and near death observation,clinical observation,weight,food intake record,electrocardiogram,body temperature,eye examination,clinical pathology,histopathology and immune index were detected.Results:histopathological examination found the lesions in the stomach,intestine,kidney,lung,liver,thymus and bone marrow organs of the 4 mg/kg high dose group occurred during the administration,but the lesions were obviously alleviated at the end of the recovery period.Therefore,the main target organs of intravenous injection of MK-ASODNs were stomach,intestine,kidney,lung,liver,thymus and bone marrow,and HNSTD was 4 mg/kg.Safety pharmacology experiment of MK-ASODNs:24 Beagle dogs(12(?),12(?))divided into low,medium and high dose group and saline control group,each group of 3 males and 3 females.Blood pressure?electrocardiogram and respiratory indexes were measured during the experiment.A total of 150 ICR mice(75(?),75(?))were divided into 3 groups,which were used in mice spontaneous activity test,mouse rotating bar test and pentobarbital sodium hypnotic effect experiment.Each batch was divided into low,medium and high dose group and saline control group,each group of male 25,female 25.The central nervous indexes were detected during the experiment.Results:in the Beagles dog safety pharmacology experiment,the QRS interval data of the 8 mg/kg high dose group was significantly decreased compared with the control group(P<0.05)in the 6 hour electrocardiogram.There was no significant difference in ECG,blood pressure and respiratory index between the 2 mg/kg low-dose group and the 4 mg/kg medium-dose group(P>0.05).In ICR mice safety pharmacological experiment,no change in rod drop time was observed in mouse rotating stick test.The spontaneous walking distance and average speed of mice in 50 mg/kg high dose group were significantly lower than those in the solvent control group(P<0.05).In the experiment of hypnotic effect of pentobarbital sodium,the sleep latency,sleep latency and duration of sleep in the 50 mg/kg high-dose group were significantly higher than those in the solvent control group(P<0.01).However,there was no significant difference between the 12.5 mg/kg low-dose group,the 25 mg/kg medium-dose group and the solvent control group in the central nervous index(P>0.05).Therefore,the NOAEL observed in the cardiovascular system and respiratory system in Beagle dogs was 4mg/kg.The NOAEL of MK-ASODNs injected into the central nervous system in ICR mice was 25 mg/kg.