Preclinical Safety Evaluations Of Ginsenoside C-K Intravenous Emulsions

Ginsenoside compound K(20-O-β-D-glucopyranosyl-20-(S)-protopanaxadiol, C-K) isthe main metabolite of protopanaxadiol type ginseng saponins in intestine after oraladministration and also is the major form of protopanaxadiol saponins absorbed to the boby.It has killer and cytotoxic effects to a variety of entities and fluid tumor cell, and it’s a newtype of anti-cancer drugs. Ginsenoside C-K has high lipid-solubility and low water-soluble.It be made emulsions by soybean phospholipid as the emulsifier, makes full use of it’scharacteristic of solubility. According to the need of Provisions for Drug Registration, weevaluate acute toxicity, chronic toxicity, haemolyticus, irritation, hypersensibility, observethe character, degree of the toxic reaction, quantity-effect relationship and time-effectrelationship and reversibility, presume the toxic target organ or target tissue, the safety doserange on clinic and refer the main monitoring indicator. Main research results are as follows:In this acute study, doses of C-K at120mg/kg(2.4mg/ml,50ml/kg) in mice and60mg/kg (2.4mg/ml,25ml/kg) in rats were administered,2times a day. No adverse effectswere observed. Maximum doses is240,120mg/kg in mice and rats respectively.New Zealand rabbits were administered ginsenoside C-K intravenous emulsions at dosesof72,24and8mg/kg (equal to the rabbit equivalent doses of20,6.5,2.2times respectively)for3months and then stopped adiministration for4weeks. Chronic toxicity studies of C-K inNew Zealand rabbits suggested that animals of all dosed groups the outer appearance andbehavior, body weights, organ indexes, the parameters of hemotology, marrow in rabbitshad no significant difference about drug toxicity comparing with control group; Other notablefindings were as follows: an increase in Cholesterol and Triglyceride at group of72mg/kg on month1.5and3, and recovery were observed after stopped administered4weeks. The damages ofliver and renal were observed in some animals at groups of72mg/kg and24mg/kg, and norecovery were observed after stopped administered4weeks at group of72mg/kg.Beagle dogs were administered ginsenoside C-K intravenous emulsions at doses of60,20and6.7mg/kg (equal to the dog equivalent doses of30,10,3.3times respectively) for3months and then stopped adiministration for4weeks. Chronic toxicity studies of C-K inBeagle dogs suggested that animals of all dosed groups the outer appearance and behavior,body weights, organ indexes, the parameters of hemotology, marrow in dogs had no significant difference about drug toxicity comparing with control group; Other notablefindings were as follows: an increase in GPT、ALP and γ-GT at group of60mg/kg on month1.5and3, and recovery were observed after stopped administered4weeks. The damages ofliver were observed in some animals at groups of60mg/kg and20mg/kg, and no recoverywere observed after stopped administered4weeks at group of60mg/kg.The results of haemolyticus, stimulation and hypersensitiveness studies showed that nohemolysis was found in vitro on2.4mg/ml (equal to the clinical drug concentration of3timesrespectively), no stimulation actions were found in musculus quadriceps femoris and vicinaltissue of rabbits treated with C-K2.4mg/ml, and there was no active anaphylaxis in Guineapigs at doses of12mg/kg and6.4mg/kg, moreover there was no passive cutaneousanaphylaxis reaction in rats at doses of24mg/kg and7.2mg/kg.In conclusion, NOAEL is8mg/kg and6.7mg/kg on New Zealand rabbits and Beagledogs respectively, pay attention to change of index liver, kidney related when Clinical trials.