Abstract
BackgroundArtemisinin-based combination therapy (ACT) has been adopted as national policy for the first-line treatment in large number of malaria-endemic regions. However, artemisinin-resistant parasites have emerged and are spreading, with slow-cleaning parasites being reported in patients treated with ACT. It means that more parasites are exposed to the partner drug alone and the risk of developing resistant parasites against the partner drug is increasing. Therefore, the development of a new method to enhance the effect of artemisinin is required. In this study, the potential effect of probucol as a combination drug of dihydroartemisinin (DHA), an artemisinin derivative, was examined.MethodsC57BL/6 J mice infected with Plasmodium yoelii XL-17 were treated with probucol and/or DHA. The mice were fed with a probucol mixed diet from 2 weeks before infection and through infection period. DHA was injected to mice three to 5 days post infection once a day. In addition, 0.5 % (w/w) probucol was mixed with vitamin E supplemented diet (800 mg/kg) and fed to mice infected with P. yoelii XL-17 to examine the mechanisms of probucol on murine malaria. Furthermore, 8-OHdG, a biomarker of oxidized DNA, was detected in infected red blood cells (iRBC) taken from infected mice by immunofluorescent staining.ResultsWith dose-dependent manner, both probucol and DHA decreased parasitaemia and increased survival rate of mice infected with P. yoelii XL-17. A significantly larger amount of 8-OHdG was detected in iRBC taking from probucol-treated mice than control mice. In addition, a large amount of vitamin E supplementation eliminated the effect of probucol against P. yoelii XL-17 infection and lowered the effect of probucol on host plasma vitamin E concentration. The effective doses for probucol and DHA were 0.5 % and 30 mg/kg, respectively, in each single treatment. While the combination treatment of 0.25 % probucol and 7.5 mg/kg DHA was effective in all mice from P. yoelii XL-17 infection.ConclusionThis study demonstrated that probucol has some impact on malaria by oxidative stress through the induction of host plasma vitamin E deficiency. Moreover, the effective dose of DHA on malaria was decreased by prophylactic treatment of probucol. This finding indicates that probucol might be a candidate for a prophylactic treatment drug to enhance the effect of DHA.
Highlights
Artemisinin-based combination therapy (ACT) has been adopted as national policy for the first-line treatment in large number of malaria-endemic regions
The results of this study showed that the effective dosage of probucol and DHA were 0.5 % (w/w) and 30 mg/kg, respectively, when mice were infected with 4 × 104 of P. yoelii XL-17 infected red blood cells (iRBC) (Figs. 1, 5)
These results indicate that probucol prophylactic treatment enhances the effect of DHA on P. yoelii XL-17 infection in mice
Summary
Artemisinin-based combination therapy (ACT) has been adopted as national policy for the first-line treatment in large number of malaria-endemic regions. Artemisinin-resistant parasites have emerged and are spreading, with slow-cleaning parasites being reported in patients treated with ACT. Artemisinin and its derivatives have become essential components of anti-malarial treatment and their rapid clinical and parasitological responses are life saving in severe malaria [3]. These features invoke a potential problem of inadequate treatment because malaria patients who quickly feel better after. Kume et al Malar J (2016) 15:472 taking these drugs tend to stop their treatment before completion of the regime Such cessation provides the risk of emerging artemisinin-resistant parasites [4, 5]. The first artemisinin resistance was reported in western Cambodia [8] and the rate of slow-clearing infections rapidly increased from 0.6 % in 2001 to 20 % in 2010 in western Cambodia [9]
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