Methylene blue as an antimalarial agent

Abstract

Methylene blue has intrinsic antimalarial activity and it can act as a chloroquine sensitizer. In addition, methylene blue must be considered for preventing methemoglobinemia, a serious complication of malarial anemia. As an antiparasitic agent, methylene blue is pleiotropic: it interferes with hemoglobin and heme metabolism in digestive organelles, and it is a selective inhibitor of Plasmodium falciparum glutathione reductase. The latter effect results in glutathione depletion which sensitizes the parasite for chloroquine action. At the Centre de Recherche en Santé de Nouna in Burkina Faso, we study the combination of chloroquine with methylene blue (BlueCQ) as a possible medication for malaria in endemic regions. A pilot study with glucose-6-phosphate dehydrogenase-sufficient adult patients has been conducted recently.

Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue

“…The hypothesis that this highly selective, redox-cycling agent interfered with glutathione reductase was recently refuted by the demonstration that MB was equally active against P. falciparum parasites lacking this antioxidant enzyme (38). Other evidence suggests that MB can interfere with hemozoin formation, which occurs in the Plasmodium digestive vacuole and permits the detoxification of reactive iron heme moieties formed during hemoglobin degradation (37). Of note, MB is a weak base that could concentrate in this highly acidic organelle (with a pH of 5.2-5.5) (39).…”

“…The reduced form of MB, which acts as an electron donor, can reverse this oxidation. Against Plasmodium, the mode of action remains enigmatic (36,37). The hypothesis that this highly selective, redox-cycling agent interfered with glutathione reductase was recently refuted by the demonstration that MB was equally active against P. falciparum parasites lacking this antioxidant enzyme (38).…”

Effects of Acridine Derivatives on Ca2+ Uptake by Candida albicans

“…On the other hand, these findings open the frequent possibility used in therapeutics of combining any of the more effective agents found with another agent, perhaps an antifungal, as already explored by Gamarra et al [26][27][28] Out of the three more effective, quinacrine may be a good therapeutic candidate, since it showed a small toxicity and few lateral effects during its use against malaria for many years. On the other hand, nonyl acridine orange, although not knowing its toxicity, might be tried as a local agent against candidiasis.…”

“…Gamarra et al [26] have proposed use of amiodarone, which stimulates Ca 2+ uptake, combined with fluconazole as a possible antifungal treatment against Candida albicans, even for a strain resistant to the antifungal. A similar therapeutic approach was also suggested for methylene blue by Schirmer et al [27,28]. According to a general mechanism proposal, it was decided to evaluate a group of acridine derivatives, to verify whether it can or cannot be applied.…”

Cerebral protection in experimental cardiopulmonary resuscitation (with special reference to the effects of methylene blue)

“…The staining activity of methylene blue, developed by Paul Ehrlich in 1891, provided the foundation of modern chemotherapy [81]. In the late 19 th and early 20 th centuries it was used in humans to treat malaria [82], but then ceased to be used as an anti-malarial due to its two inevitable side effects: green urine and blue sclera. Interest in its use has recently been revived, especially because it is very cheap.…”