Research performed at:
1. Institute for Clinical Infectious Diseases, Central Military Hospital 108, Hanoi, Vietnam.
2. Australian Defence Force Malaria and Infectious Disease Institute, Brisbane, Australia.
3. Queensland Institute of Medical Research Berghofer, Brisbane, Australia.
The authors:
Chu Xuan Anh, Marina Chavchich, Geoffrey W. Birrell, Karin Van Breda, Thomas Travers, Kerryn Rowcliffe, Anton R. Lord, G. Dennis Shanks, Michael D. Edstein.
High rates of artemisinin-based combination therapy (ACT) failures in the treatment of Plasmodium falciparum malaria in Southeast Asia have led to triple drug strategies to extend the useful life of ACTs.
In this study, we determined whether methylene blue [MB; 3,7-bis(dimethylamino)phenothiazin-5-ium chloride hydrate] alters the pharmacokinetics of artesunate-amodiaquine (ASAQ) and enhances the ex vivo antimalarial activity of ASAQ. In an open-label, randomized crossover design, a single oral dose of ASAQ (200 mg AS/540 mg AQ) alone or with MB (325 mg) was administered to 15 healthy Vietnamese volunteers. Serial blood samples were collected up to 28 days after dosing.
Pharmacokinetic properties of the drugs were determined by noncompartmental analysis. After drug administration, plasma samples from seven participants were assessed for ex vivo antimalarial activity against the artemisinin sensitive MRA1239 and the artemisinin-resistant MRA1240 P. falciparum lines, in vitro.
MB significantly increased the mean area under the curve of the active metabolite of AS, dihydroartemisinin (1,246 473 versus 917 405 ng·h/ml, P — 0.009) but did not alter the pharmacokinetics of AQ, AS, or desethylamodiaquine. Comparing the antimalarial activities of the plasma samples from the participants collected up to 48 h after ASAQ plus MB (ASAQ — MB) and ASAQ dosing against the MRA1239 and MRA1240 lines, MB significantly enhanced the blood schizontocidal activity of ASAQ by 2.0-fold and 1.9-fold, respectively.
The ring-stage survival assay also confirmed that MB enhanced the ex vivo antimalarial activity of ASAQ against MRA1240 by 2.9-fold to 3.8-fold, suggesting that the triple-drug combination has the potential to treat artemisinin-resistant malaria and for malaria elimination.