Efficacy and safety of methylene blue in the treatment of malaria: a systematic review

Abstract

BackgroundMethylene blue (MB) was the first synthetic antimalarial to be discovered and was used during the late 19th and early 20th centuries against all types of malaria. MB has been shown to be effective in inhibiting Plasmodium falciparum in culture, in the mouse model and in rhesus monkeys. MB was also shown to have a potent ex vivo activity against drug-resistant isolates of P. falciparum and P. vivax. In preclinical studies, MB acted synergistically with artemisinin derivates and demonstrated a strong effect on gametocyte reduction in P. falciparum. MB has, thus, been considered a potentially useful partner drug for artemisinin-based combination therapy (ACT), particularly when elimination is the final goal. The aim of this study was to review the scientific literature published until early 2017 to summarise existing knowledge on the efficacy and safety of MB in the treatment of malaria.MethodsThis systematic review followed PRISMA guidelines. Studies reporting on the efficacy and safety of MB were systematically searched for in relevant electronic databases according to a pre-designed search strategy. The search (without language restrictions) was limited to studies of humans published until February 2017.ResultsOut of 474 studies retrieved, a total of 22 articles reporting on 21 studies were eligible for analysis. The 21 included studies that reported data on 1504 malaria patients (2/3 were children). Older studies were case series and reports on MB monotherapy while recent studies were mainly controlled trials of combination regimens. MB was consistently shown to be highly effective in all endemic areas and demonstrated a strong effect on P. falciparum gametocyte reduction and synergy with ACT. MB treatment was associated with mild urogenital and gastrointestinal symptoms as well as blue coloration of urine. In G6PD-deficient African individuals, MB caused a slight but clinically non-significant haemoglobin reduction.ConclusionsMore studies are needed to define the effects of MB in P. falciparum malaria in areas outside Africa and against P. vivax malaria. Adding MB to ACT could be a valuable approach for the prevention of resistance development and for transmission reduction in control and elimination programs.Systematic review registrationThis study is registered at PROSPERO (registration number CRD42017062349).Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1045-3) contains supplementary material, which is available to authorized users.

Reversible cholinesterase inhibitors as pretreatment for exposure to organophosphates. A review

“…Both states together form a reversible oxidationreduction system, which reduces oxygen radical generation; this may be one of the mechanisms of its neuroprotective effect (Oz, Lorke, Hasan, & Petroianu, 2011). It is employed clinically for a wide range of indications,e.g., anatomical visualization of various tissues during surgery and treatment of methemoglobinemia, malaria and ifosfamide-induced encephalopathy; its potential to improve cognitive performance in Alzheimer's disease is currently under investigation (for review, see Lu et al, 2018;Oz, Lorke & Petroianu, 2009;Oz et al, 2011). Methylene blue readily passes the blood-brain barrier and has been shown to inhibit AChE in its reduced state, but not in its oxidized form (Augustinsson, 1950;Oz, Lorke, & Petroianu, 2009;Pfaffendorf, Bruning, Batnik, & van Zwieten, 1997).…”

Comparative Study Regarding the Properties of Methylene Blue and Proflavine and Their Optimal Concentrations for In Vitro and In Vivo Applications

“…Dose of 36-72 mg/kg MB over 3 days is the most effective scheme of treatment [20][21][22][23][24]28] Methemoglobinemia MB acts by reacting within red blood cells (RBCs) to form leucomethylene blue, which is a reducing agent of oxidized hemoglobin converting the ferric ion (Fe 3+ ) back to its oxygen carrying ferrous state (Fe 2+ ).…”

“…This treatment was administrated for 3-90 days, as daily or interrupted (e.g., a two-day pause after several days of treatment) oral monotherapy, with largely varying follow-up periods. In a more recent study, the administration of MB to adults at a unique dose of 500 mg per day for 14 days in combination with isopentaquine (IQ) or in combination with IQ and quinine (Q) was reported [20,21]. Another strategy is to administrate MB to children in various combination regimens (MB-amodiaquine, MB-artesunate) in doses ranging from 4 mg/kg per day to 24 mg/kg per day, initially as 2-4 divided doses per day, but no more than 3 days [22,23].…”

In Vitro Activity of Methylene Blue on Mycobacterium Tuberculosis Complex Isolates

“…Regarding infectious diseases, MB has been reported to show activity against Plasmodium falciparum strains and to have the potential to be used as an antimalarial agent in combination with other drugs [18] . In the literature, there are promising studies reporting positive effects of MB on several pathogens causing infections such as candidiasis, choromoblastomycosis, onychomycosis, malaria, acne vulgaris, Acinetobacter infections and wound-associated bacterial infections due to Staphylococci and E. coli [19][20][21][22][23][24] . Also, it has been claimed to be effective in a topical form for the treatment of chronic dermatologic diseases including lichen planus and psoriasis [25,26] .…”