Pharmacodynamic Studies And Preclinical Safety Evaluations Of Dehydrocavidine

Objective: To investigate the preventive and curative effects of dehydrocavidine (YHL-DC) on carbon tetrachloride (CCl₄) induced liver injury in rodents and to evaluate the preclinical safty of YHL-DC. Methods: In pharmacodynamic studiesof YHL-DC, CCl₄ was used to induce various liver injurys, such as acute liver injury in mice and liver fibrosis in rats. The following pharmacodynamic studies were carried out: Preventive effects of YHL-DC at doses of 0.125, 0.250, 0.500 mg/kg on CCl₄ induced acute liver injury in mice. Curative effects of YHL-DC at doses of 0.125, 0.250, 0.500 mg/kg on CCl₄ induced acute liver injury in mice. Curative effect of YHL-DC at doses of 0.125, 0.250, 0.500 mg/kg on carbon tetrachloride induced liver fibrosis in rats. The following preclinical safety evaluations of YHL-DC were carried out: Safety pharmacology sudies, acute toxicity sudies, chronic toxicity studies andother toxicity studies. Results: Pharmacodynamic studies of YHL-DC showed thatwhen mice were pre-treated with YHL-DC, the elevated level of ALT, AST and T-BIL induced by CCl₄ could be dose-dependently decreased. Pathological scores of the liver in pre-treated mice were lower than acute liver injury mice without YHL-DC treatment. When mice were post-treated with YHL-DC at doses of 0.125,0.250,0.500 mg/kg, the elevated level of ALT, AST and T-BIL induced by CCl₄ could also be dose-dependently decreased. Pathological scores of the liver in post-treated mice were lower than acute liver injury mice without YHL-DC treatment. Serum ALT, AST and TBIL levels were found to be elevated in rats with liver fibrosis. However, treatment with YHL-DC at doses of 0.125, 0.250, 0.500 mg/kg resulted in reversing the elevated serum enzymes induced by CCl₄. Serum Alb levels were elevated in YHL-DC group when compared to liver fibrosis rats without YHL-DC treatment. In addition, treatment with YHL-DC also significantly prevented the formation of hydroxidepraline in rats with liver fibrosis. The results of preclinical safety evaluation showed that there were no adverse effects of YHL-DC on respiratory, circulatory systems of Beagle dogs or nervous systerm of mice. The iv MTD of YHL-DC were above 40, 20 and 10 mg/kg in mice, rats and Beagle dogs, respectively. The ip MTD were above 50 and 30 mg/kg in mice and rats, respectively. All the MTDs are much higher than recommended clinical dose. Possible toxic target was alimentary systerm, in long term YHL-DC treated rats, the safty dose is 1.5 mg/kg. Possible target organs were alimentary and endocrine systems in long term YHL-DC treated dogs, with the safty dose of 0.75 mg/kg. All the toxic effects were reversible. No abvious irritant actions were found in blood vesseles or musculus quadriceps femoris and vicinal tissue of rabbits treated with YHL-DC. No hemolysis was found in vitro. Guinea pigs showed no active anaphylaxis when treated with YHL-DC. Moreover, there was no passive cutaneous anaphylaxis reaction in YHL-DC treated rats.Conclusion: YHL-DC showed significant preventive and curative effects on CCl₄induced acute liver injury in mice. In CCl₄ induced liver fibrosis rats, YHL-DC could partly ameliorate the damage. In long term toxicity studies of YHL-DC, the target organs may be the alimentary and endocrine systems, and the toxic effects of YHL-DC are reversible.