The emergence of partial artemisinin resistance in Plasmodium falciparum on the Cambodia-Thai border and more recently on the Myanmar-Thai border jeopardizes the renewed global efforts of control and elimination of malaria. Containment of this severe threat requires reduction of transmission of the resistant phenotype by adding gametocytocidal drugs to the treatment of falciparum malaria. Mathematical models also predict that transmission blocking will be required if the goal of malaria elimination is to be achieved. The only drug currently available with strong gametocytocidal properties against the more mature gametocytes is primaquine. However, the oxidative properties of primaquine readily causes acute haemolysis in glucose 6 phosphate dehydrogenase (G6PD) deficiency, the degree of which appears to be inversely related to G6PD enzyme activity. Because of these safety concerns, primaquine is not widely deployed in treatment regimens for falciparum malaria, even in areas with documented artemisinin resistance. Methylene blue, which does not exert its action through an oxidative mechanism, is a promising alternative as a gametocytocidal adjuvant to artemisinin combination therapies (ACTs). Paul Ehrlich discovered methylene blue as the first synthetic drug ever to treat malaria. In contrast with primaquine, the thiazine dye methylene blue asserts its properties as an oxidizing agent only at very high doses, whereas at pharmacologic doses it has reducing agent properties and is for this reason used as a medication for the treatment of methemoglobinemia. A recent laboratory study identified methylene blue as a potent inhibitor of gametocyte development across all stages, almost fully abolishing P. falciparum transmission to mosquitoes at concentrations readily achievable in humans. In addition, a recent clinical study in 180 children with uncomplicated falciparum malaria in Burkina Faso showed that, compared to artesunate-amodiaquine alone, addition of the cheap drug methylene blue to either artesunate or amodiaquine importantly reduced gametocyte carrier rates measured at days 3, 7, and 14 of follow-up. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline. The current series of studies will investigate further methylene blue as a potential gametocytocidal drug in the treatment of uncomplicated falciparum malaria.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Primaquine 45 mg single dose Or Methylene Blue 600 mg single dose followed by Methylene Blue 600 mg single dose or Primaquine 45 mg single dose.
Hospital for Tropical Diseases
Bangkok, Thailand
Pharmacokinetic profile of Primaquine
Maximum concentration (Cmax), Area under the concentration curve (AUC 0-24), Elimination rate constant (PRQ-λz), and Elimination half life (t1/2) for primaquine when given standard dose in G6PD normal and G6PD deficiency
Time frame: 7 days
Pharmacokinetic profile of Carboxyprimaquine
Maximum concentration (Cmax), area under the concentration curve (AUC 0-24), elimination rate constant (PRQ-λz), and elimination half life (t1/2) for carboxyprimaquine (primaquine metabolite) when given standard dose in G6PD normal and G6PD deficiency
Time frame: 7 days
Pharmacokinetic profile of Methylene blue
Maximum concentration(Cmax), area under the concentration curve (AUC 0-24) elimination rate constant (MB-λz), and elimination half life (t1/2) for methylene blue when given standard dose in G6PD normal and G6PD deficiency
Time frame: 7 days
Oocysts production in mosquitoes
Reduction of oocysts production in mosquitoes fed with gametocytes which were exposed to methylene blue and primaquine
Time frame: 7 days
Methaemoglobin, Hematocrit and Hemoglobin levels
Methaemoglobin, hematocrit and hemoglobin level when given primaquine and methylene blue in G6PD normal and G6PD deficiency
Time frame: 7 days
Safety of Primaquine and Methylene Blue
Safety and tolerability parameters, including adverse events, clinical laboratory, and vital signs assessments
Time frame: 1 month
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