A novel use for an old drug: resistance reversal in Candida albicans by combining dihydroartemisinin with fluconazole.

Aim: To investigate the effects of dihydroartemisinin combined with fluconazole against C. albicans in vitro and to explore the underlying mechanisms. Materials & methods: Checkerboard microdilution assay and time-kill curve method were employed to evaluate the static and dynamic antifungal effects against C. albicans. Reactive oxygen species (ROS) was measured by a fluorescent probe. Results: Combination of dihydroartemisinin and fluconazole exerted potent synergy against planktonic cells and biofilms of fluconazole-resistant C. albicans, with the fractional inhibitory concentration index values less than 0.07. A potent fungistatic activity of this drug combination could still be observed after 18 h. The accumulation of ROS induced by the drug combination might contribute to the synergy. Conclusion: Dihydroartemisinin reversed the resistance of C. albicans to fluconazole.

Lay abstract Patients with weakened immune system often suffer from C. albicans infections. C. albicans is a common fungus. Fluconazole is a widely used antifungal drug owing to its low price and few side effects. Unfortunately, fluconazole is gradually losing its effect against C. albicans due to the constantly emerging resistance in C. albicans. Interestingly, in this study a combined use of fluconazole and an old antimalarial agent restored the effect of fluconazole against resistant C. albicans. The antimalarial drug we used is dihydroartemisinin, with low price, high safety and multiple biological activities, which originates from a traditional Chinese medicine. Our study also presented that this drug combination generated abundant reactive oxygen, which might account for the effect. The drug combination would be expected to be used for treating C. albicans infections.

Studies on pharmacokinetics and tissue distribution of oridonin nanosuspensions.

The purpose of the present study was to investigate the effects of particle size on the pharmacokinetics and tissue distribution of oridonin nanosuspensions after intravenous administration. Two oridonin nanosuspensions with markedly different size were prepared by high pressure homogenization method. The particle size of nanosuspension A is 103.3+/-1.5nm, while B is 897.2+/-14.2nm. Dissolution studies showed that complete dissolution could be obtained within 10min for nanosuspension A, however, nanosuspension B showed a slower dissolution, only 85.2% dissolved by 2h. The pharmacokinetics and tissue distribution of oridonin nanosuspensions A and B were studied after intravenous administration using New Zealand rabbits and Kunming mice as experimental animals, respectively. An Oridonin control solution was studied parallelly. The results showed that oridonin nanosuspension A exhibited pharmacokinetic and biodistribution properties similar to solution due to its rapid dissolution in blood circulation. Oridonin nanosuspension B, however, showed a high uptake in RES organs, meanwhile exhibited a markedly different pharmacokinetic property compared to nanosuspension A. These differences could be attributed to the different particle size of the two nanosuspensions considering their zeta potential had no significant difference. In conclusion, particle size showed obvious effects on pharmacokinetics and tissue distribution of nanosuspensions.