Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria

Rengelshausen, Jens; Burhenne, Jürgen; Fröhlich, Margit; Tayrouz, Yorki; Singh, Shio Kumar; Riedel, K.; Müller, Olaf; Hoppe-Tichy, Torsten; Haefeli, Walter E.; Mikus, Gerd; Walter‐Sack, Ingeborg

doi:10.1007/s00228-004-0818-0

Cited by 76 publications

(70 citation statements)

References 23 publications

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“…CQ remains one of the cheapest antimalarial easily accessible in developing countries. Rengelshausen et al (2004) showed that oral co-administration of MB and CQ did not show major pharmacokinetic interactions confirming the feasibility of this combination. Nevertheless, in a trial conducted in Burkina Faso, where high resistance of Plasmodium to CQ was reported, Meissner et al (2006) found that the CQ-MB combination was not sufficently effective in the treatment of uncomplicated malaria in young children.…”

Section: Discussionmentioning

confidence: 71%

Blood schizontocidal activity of methylene blue in combination with antimalarials againstPlasmodium falciparum

et al. 2007

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Summary :Methylene blue (MB) is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodium strains. We showed that around 5 nM of MB were able to inhibit 50 % of the parasite growth in vitro and that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC) method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy. Résumé

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Section: Discussionmentioning

confidence: 71%

Blood schizontocidal activity of methylene blue in combination with antimalarials againstPlasmodium falciparum

et al. 2007

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“…MB is readily absorbed and quickly distributed to various organs including the brain [134]. One of the most common uses of MB is the chronic treatment of congenital methemoglobinemia, which is due to methemoglobin reductase deficiency.…”

Section: Clinical Uses Of Methylene Bluementioning

confidence: 99%

Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

Atamna

Kumar

2010

JAD

120

100

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Abstract. The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of toxic species of amyloid-β (Aβ) peptides. This review discusses two potential approaches to delay the onset of AD. The first approach is use of diaminophenothiazines (e.g., methylene blue; MB) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. We have shown that MB increases heme synthesis, cytochrome c oxidase (complex IV), and mitochondrial respiration, which are impaired in AD brains. Consistently, MB is one of the most effective agents to delay senescence in normal human cells. A key action of MB appears to be enhancing mitochondrial function, which is achieved at nM concentrations. We propose that the cycling of MB between the reduced leucomethylene blue (MBH2) and the oxidized (MB) forms may explain, in part, the mitochondria-protecting activities of MB. The second approach is use of naturally occurring osmolytes to prevent the formation of toxic forms of Aβ. Osmolytes (e.g., taurine, carnosine) are brain metabolites typically accumulated in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation, without perturbing other cellular processes. Experimental evidence suggests that the level of carnosine is significantly lower in AD patients. Osmolytes may inhibit the formation of Aβ species in vivo, thus preventing the formation of soluble oligomers. Osmolytes are efficient antioxidants that may also increase neural resistance to Aβ. The potential significance of combining MB and osmolytes to treat AD are discussed.

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“…Paul Ehrlich, who introduced the concept of modern target-based chemotherapy using MB as an example, and Paul Guttmann described the compound as being an effective antimalarial agent (28). Despite its beneficial antimalarial activity, the drug disappeared from the scene because up-and-coming compounds such as chloroquine were more effective; in addition, soldiers resented taking MB because of inevitable but harmless side effects: green or blue urine and bluish sclerae (47,55).…”

Section: Methylene Blue (Mb or Mbmentioning

confidence: 99%

“…This means that the predominant species in cytosolic spaces is uncolored leucoMB. In urine that is stained blue or green by MB, a mixture of MB and leucoMB is excreted (47).…”

mentioning

confidence: 99%

Interactions of Methylene Blue with Human Disulfide Reductases and Their Orthologues fromPlasmodium falciparum

Buchholz

Schirmer

Eubel

et al. 2008

Antimicrob Agents Chemother

150

122

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Methylene blue (MB) has experienced a renaissance mainly as a component of drug combinations against Plasmodium falciparum malaria. Here, we report biochemically relevant pharmacological data on MB such as rate constants for the uncatalyzed reaction of MB at pH 7.4 with cellular reductants like NAD(P)H (k ‫؍‬ 4 M ؊1 s ؊1 ), thioredoxins (k ‫؍‬ 8.5 to 26 M ؊1 s ؊1 ), dihydrolipoamide (k ‫؍‬ 53 M ؊1 s ؊1 ), and slowly reacting glutathione. As the disulfide reductases are prominent targets of MB, optical tests for enzymes reducing MB at the expense of NAD(P)H under aerobic conditions were developed. The product leucomethylene blue (leucoMB) is auto-oxidized back to MB at pH 7 but can be stabilized by enzymes at pH 5.0, which makes this colorless compound an interesting drug candidate. MB was found to be an inhibitor and/or a redox-cycling substrate of mammalian and P. falciparum disulfide reductases, with the k cat values ranging from 0.03 s ؊1 to 10 s ؊1 at 25°C. Kinetic spectroscopy of mutagenized glutathione reductase indicates that MB reduction is conducted by enzyme-bound reduced flavin rather than by the active-site dithiol Cys 58 /Cys 63 . The enzyme-catalyzed reduction of MB and subsequent auto-oxidation of the product leucoMB mean that MB is a redox-cycling agent which produces H 2 O 2 at the expense of O 2 and of NAD(P)H in each cycle, turning the antioxidant disulfide reductases into pro-oxidant enzymes. This explains the terms subversive substrate or turncoat inhibitor for MB. The results are discussed in cellpathological and clinical contexts. Methylene blue (MB or MBϩ ) [also known as methylthionine hydrochloride or 3,7-bis(dimethylamino)phenothiazin-5-ium chloride] was the very first synthetic compound to be used as a drug. Paul Ehrlich, who introduced the concept of modern target-based chemotherapy using MB as an example, and Paul Guttmann described the compound as being an effective antimalarial agent (28). Despite its beneficial antimalarial activity, the drug disappeared from the scene because up-and-coming compounds such as chloroquine were more effective; in addition, soldiers resented taking MB because of inevitable but harmless side effects: green or blue urine and bluish sclerae (47, 55).After MB was revisited as an antimalarial agent (6, 53) and found to be an inhibitor of Plasmodium falciparum glutathione (GSH) reductase (GR) (23), it was studied as a partner drug in antimalarial drug combinations (2,39,48,51).Compared with other antiparasitic agents, MB is affordable and registered in most countries (as the treatment of choice for acute and chronic methemoglobinemia [16,17,36]), and it can be made internationally available in sufficient dosages (51). The price for treating a malaria episode in a child with an MB-containing drug combination would be less than €0.50 (40). Drug resistance has not been reported for MB and could not be provoked in rodent malaria models (52, 53).Because of its favorable properties, including the differential staining of cell biological structures and protein cr...

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Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria

Abstract: Oral co-administration of methylene blue appears to result in a small reduction of chloroquine exposure which is not expected to be clinically relevant and thus represents no concern for further development as an anti-malarial combination.

Cited by 76 publications

References 23 publications

Blood schizontocidal activity of methylene blue in combination with antimalarials againstPlasmodium falciparum

Blood schizontocidal activity of methylene blue in combination with antimalarials againstPlasmodium falciparum

Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

Interactions of Methylene Blue with Human Disulfide Reductases and Their Orthologues fromPlasmodium falciparum

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