gms | German Medical Science

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.