Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841]

Meißner, Peter; Mandi, Germain; Witte, Steffen; Coulibaly, Boubacar; Mansmann, Ulrich; Rengelshausen, Jens; Schiek, W; Jahn, Albrecht; Sanon, Mamadou; Tapsoba, Théophile; Walter‐Sack, Ingeborg; Mikus, Gerd; Burhenne, Jürgen; Riedel, K.; Schirmer, Heiner; Kouyaté, Bocar; Müller, Olaf

doi:10.1186/1475-2875-4-45

Cited by 58 publications

(33 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This approach has recently been tested in clinical trials in the Nouna District of Burkina Faso (6,22). In this study, cases of MB toxicity or intolerance were not reported; however, a clear advantage over CQ monotherapy could not be observed either (24). Several reasons were proposed to be responsible for this clinical failure.…”

mentioning

confidence: 79%

“…A mechanism of reverting chloroquine resistance by MB as a glutathione reductase inhibitor has been proposed (10,15,32), and clinical trials assessing the safety and effectiveness of MB are already under way (6,24). In order to facilitate the design of future field studies and the interpretation of respective results, we have characterized the effects of the drug in cell cultures in detail.…”

Section: Discussionmentioning

confidence: 99%

“…Several reasons were proposed to be responsible for this clinical failure. They include (i) the possibility that the dosage of the highly watersoluble MB was not high enough (24), (ii) the possibility that MB and CQ do act antagonistically, and (iii) the possible formation of stable blue pigments in blood cells by MB leading to false-positive counts of persistent parasitemia. As summarized by Wainwright and Amaral (37), the latter cause can be largely excluded.…”

mentioning

confidence: 99%

See 2 more Smart Citations

In Vitro Assessment of Methylene Blue on Chloroquine-Sensitive and -Resistant Plasmodium falciparum Strains Reveals Synergistic Action with Artemisinins

Akoachere

Buchholz

Fischer

et al. 2005

Antimicrob Agents Chemother

101

View full text Add to dashboard Cite

Methylene blue (MB) represents a promising antimalarial drug candidate for combination therapies against drug-resistant parasite strains. To support and facilitate the application of MB in future field trials, we studied its antiparasitic effects in vitro. MB is active against all blood stages of both chloroquine (CQ)-sensitive and CQ-resistant P. falciparum strains with 50% inhibitory concentration (IC 50 ) values in the lower nanomolar range. Ring stages showed the highest susceptibility. As demonstrated by high-performance liquid chromatography-tandem mass spectrometry on different cell culture compartments, MB is accumulated in malarial parasites. In drug combination assays, MB was found to be antagonistic with CQ and other quinoline antimalarials like piperaquine and amodiaquine; with mefloquine and quinine, MB showed additive effects. In contrast, we observed synergistic effects of MB with artemisinin, artesunate, and artemether for all tested parasite strains. Artemisinin/MB combination concentration ratios of 3:1 were found to be advantageous, demonstrating that the combination of artemisinin with a smaller amount of MB can be recommended for reaching maximal therapeutic effects. Our in vitro data indicate that combinations of MB with artemisinin and related endoperoxides might be a promising option for treating drug-resistant malaria and should be studied in future field trials. Resistance development under this drug combination is unlikely to occur.Methylene blue (MB)-a drug clinically applied in methemoglobinopathies-has also been shown to have antimalarial effects and was identified as a specific inhibitor of Plasmodium falciparum glutathione reductase (GR). Thus, MB was recently reconsidered as a useful antimalarial drug (12,22,32). Advantages of MB include its intrinsic inhibition of heme polymerization within the food vacuole (2), its prevention of methemoglobinemia-a serious complication of malaria anemia (1)-and its relatively low price. Furthermore, MB shows high selectivity indices with respect to the viability of the human monocytic leukemia-derived cell line J-111 (2, 36), indicating that its cytotoxicity for mammalian cells is low. Considerable side effects of MB have been reported (16, 27), but they are likely to be restricted to persons with certain forms of inherited glucose-6-phosphate dehydrogenase (G6PD) deficiency.Due to increasing drug resistance, the development of chloroquine (CQ) sensitizers in combination with CQ is given high priority in antimalarial drug research (35). CQ-resistant parasites were shown to possess significantly increased concentrations of reduced glutathione (GSH) when compared with sensitive parasites. Thus, the reduction of glutathione disulfide by the flavoenzyme glutathione reductase and/or the de novo synthesis of GSH seems to be more efficient in resistant parasites (10,15,23). In Plasmodium, GSH is likely to be involved in buffering the reducing milieu, in antioxidant defense, redox signaling, DNA synthesis, and heme degradation, and in detoxification re...

show abstract

mentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

In Vitro Assessment of Methylene Blue on Chloroquine-Sensitive and -Resistant Plasmodium falciparum Strains Reveals Synergistic Action with Artemisinins

Akoachere

Buchholz

Fischer

et al. 2005

Antimicrob Agents Chemother

101

View full text Add to dashboard Cite

show abstract

“…[55] In light of these results, it is not surprising that a clinical trial showed no advantage in using a combination of methylene blue and CQ over CQ monotherapy in an area with a high probability of chloroquine resistance. [56] …”

Section: Chloroquine Resistancementioning

confidence: 97%

“…[251] However, there is some degree of cross-resistance in the group of sulfonamides. The combination of dapsone and chlorproguanil (56) was evaluated in different clinical studies, [252][253][254] and was recently introduced as LapDap to the market. LapDap is active against strains carrying the triple mutant DHFR which are predominant in Africa, but it is inactive against strains harboring the quadruple mutant, abundant in Asia and South America.…”

Section: Chlorproguanil/dapsone (Lapdap)mentioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

View full text Add to dashboard Cite

Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

show abstract

The Reducing Milieu of Parasitized Cells as a Target of Antimalarial Agents: Methylene Blue as an Ethical Drug

Meißner

Adler

Kasozi

et al. 2011

Apicomplexan Parasites

View full text Add to dashboard Cite

Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841]

Abstract: Background: Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen.

Cited by 58 publications

References 32 publications

In Vitro Assessment of Methylene Blue on Chloroquine-Sensitive and -Resistant Plasmodium falciparum Strains Reveals Synergistic Action with Artemisinins

In Vitro Assessment of Methylene Blue on Chloroquine-Sensitive and -Resistant Plasmodium falciparum Strains Reveals Synergistic Action with Artemisinins

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

The Reducing Milieu of Parasitized Cells as a Target of Antimalarial Agents: Methylene Blue as an Ethical Drug

Contact Info

Product

Resources

About