Article
Methylene Blue as a Prodrug of Azure B
Search Medline for
Authors
Published: | January 8, 2013 |
---|
Outline
Text
MB-based drug combinations against schizonts and gametocytes of Plasmodium falciparum have been tested in clinical trials conducted by Müller, Meissner and Coulibaly in Nouna, Burkina Faso [1], [2], [3]. In vitro and even more so in vivo, methylene blue is readily demethylated to give trimethylthionine (azure B) [4]. This finding could be due to first-pass metabolization in the liver by N-demethylases and/or to enhanced intercellular exchange of demethylated, neutral quinoneimine-forming products of MB [1]. Recently, interest in MB and its metabolites was reinforced by C. Wischik's group because of their possible protective role in Alzheimer's disease (see [5] for a review).
We had already shown that MB is a ligand of different redox flavoenzymes such as glutathione reductases and Plasmodium falciparum lipoamide dehydrogenase [1]. Consequently, we have studied now azure B with the same enzymes. The fact that azure B was a substrate and a better ligand for all tested flavoenzymes was supported by x-ray diffraction analysis of a glutathione reductase/azure B complex, where the phenothiazine was localised to an aromate-binding subsite that is possibly too small for the bulkier MB molecule. If MB is a prodrug and azure B the major active agent, it will be necessary to focus not only on methylene blue but even more so on azure B.
References
- 1.
- Meissner P, Adler H, Kasozi D, Fritz-Wolf K, Schirmer RH. In: Becker K, ed. Apicomplexan Parasites. Molecular Approaches toward Targeted Drug Development. Wiley-VCH Verlag; 2011. p. 115-36.
- 2.
- Coulibaly B, Zoungrana A, Mockenhaupt FP, Schirmer RH, Klose C, et al. Strong Gametocytocidal Effect of Methylene Blue-Based Combination Therapy against Falciparum Malaria: A Randomised Controlled Trial. PLoS ONE. 2009;4(5):e5318. DOI: 10.1371/journal.pone.0005318
- 3.
- Müller O, Sié A, Meissner P, Schirmer RH, Kouyaté B. Artemisinin resistance on the Thai-Cambodian border. Lancet. 2009 Oct 24;374(9699):1419. DOI: 10.1016/S0140-6736(09)61857-2
- 4.
- Warth A, Goeppert B, Bopp C, Schirmacher P, Flechtenmacher C, Burhenne J. Turquoise to dark green organs at autopsy. Virchows Arch. 2009 Mar;454(3):341-4. DOI: 10.1007/s00428-009-0734-x
- 5.
- Schirmer RH, Adler H, Pickhardt M, Mandelkow E. "Lest we forget you--methylene blue...". Neurobiol Aging. 2011 Dec;32(12):2325.e7-16. DOI: 10.1016/j.neurobiolaging.2010.12.012