Acute toxicity of Dichroa alkali salt and efficacy enhancement and toxicity alleviation in combination with artemisinin and its derivatives北大核心CSCD

OBJECTIVE: To explore the possibility that Dichroa alkali salt (DAS) can enhance efficacy and reduce toxicity when combined with artemisinin and its derivatives. METHODS: Kunming mice were used in acute toxicity test of DAS. Diarrhea rate, mortality, 50% lethal dose (LD50), LD90, 50% diarrhea dose (DD50) and DD90 were determined, and the safe dose of DAS was defined. An animal model of malaria was established by inoculating strains of the parasite in an antimalarial in vivo experiment. The model mice were ig given drugs, once a day, for 4 d. The titer was compared between alone use and combined use of DAS with artemisinin and its derivatives. Blood of the caudal vein was dynamically collected for blood smear. Gemsa dying assay was used to observe whether the change of the parasite and its revival under a microscope in each group. Finally, negative conversion ratio, anti-revival ratio, 50% effective dose(ED50) and ED90 were calculated. RESULTS: The safe dose of DAS was 0.5 mg·kg-1 in acute toxicity test. While a low dose of DAS (0.25 and 0.5 mg·kg-1) was alone used, negative conversion ratio was relatively low and anti-revival effect was not obvious. In vivo experiments of anti-mouse malaria indicated that compared with alone use of DAS 0.5 mg·kg-1 or artemisinin with its derivatives [artemisinin, dihydroartemisinin(Dih), artemether and artesunate], negative conversion ratio and anti-revival ratio were increased significantly (P< 0.01, P<0.05) when DAS 0.5 mg·kg-1 and artemisinin (134, 192, 274, 392 and 560 mg·kg-1), Din(52,80 and 123 mg·kg-1), artemether (10,20, 40 and 80 mg·kg-1) and artesunate (32.5,65.0 and 130.0 mg·kg-1) were used in combination. When DAS 0.5 mg · kg-1 and artemisinin with its four derivatives were in combination used, the titer was increased 1.8, 1.2, 2.0 and 1.6 times compared with alone use of artemisinin and its derivatives, respectively. In addition, diarrhea or death didn't occur in combined groups. CONCLUSION: DAS has a narrow safe dose window. DAS in combination with artemisinin and its derivatives can possibly reduce toxicity while enhancing efficacy.