Cation exchange resins as pharmaceutical carriers for methylene blue: binding and release.

Methylene blue is a competitive inhibitor of the glutathione reductase of Plasmodium falciparum and is used in combination with other antimalarial drugs leading to a renaissance of methylene blue in malaria therapy. Its bitter flavour and tissue colouring property impair compliance, especially in children. These problems may be solved by binding the cationic methylene blue to cation exchange materials as pharmaceutical carriers in order to mask the undesirable properties. However, such carriers are only useful if the antimalarial is released under physiological conditions. The binding to seven cation exchange resins was studied. Ion exchangers on acrylic or methacrylic acid basis bound between 1.54 and 2.16 g methylene blue chloride trihydrate per gram ion exchanger. Polymers on divinylbenzene or styrene basis with sulphonic acid groups bound 306 and 384 mg of methylene blue chloride trihydrate per gram ion exchanger. In aqueous solution at pH of 1.5, nearly all bound methylene blue was released. The release of methylene blue from (meth)acrylic acid polymers in the presence of proteins and fat was not affected. From these data ion exchangers present a promising group of pharmaceutical carrier for the safe and compliant drug administration of methylene blue to children.

Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine.

The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa.

Diagnosis of red cell G6PD deficiency in rural Burkina Faso: comparison of a rapid fluorescent enzyme test on filter paper with polymerase chain reaction based genotyping.

Glucose-6-phosphate dehydrogenase (G6PD) deficient individuals are at increased risk of developing haemolysis following treatment with various antimalarial drugs. Reliable field tests for G6PD deficiency are thus needed in chemotherapy studies and their validity has to be assessed. In two phase II clinical trials on methylene blue (MB) antimalarial therapy in rural Burkina Faso, paediatric and adult participants were tested for G6PD deficiency. The results of a haemoglobin-adjusted nicotinamide adenine dinucleotide phosphate (NADPH) fluorescence test on paper (NFP test) were compared with polymerase chain reaction (PCR)-based G6PD genotyping also using blood samples on filter papers. This is the first study comparing sensitivity and specificity of the two methods. There was good agreement between the NFP test results and the PCR findings. The estimate of the sensitivity of the NFP test was 98.2% (95.8-99.6%) and the specificity was 97.1% (94.2-99.2%). In conclusion, the NFP assay is a reliable and inexpensive method for large-scale G6PD deficiency screening in rural West Africa.

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

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. OBJECTIVES: The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa. METHODS: In this hospital-based randomized controlled trial, 226 children (6-59 months) with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days) or CQ (n = 45; 25 mg/kg over three days) respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs). Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14. RESULTS: No differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency) compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%]) in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%]) in the CQ-MB group. CONCLUSION: MB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs.

Safety of the combination of chloroquine and methylene blue in healthy adult men with G6PD deficiency from rural Burkina Faso.

New drug combinations against falciparum malaria which are both effective and affordable for Sub-Saharan African populations are urgently needed. The combination of the well-known drugs chloroquine (CQ) and methylene blue (MB) is such a promising new regimen. However, there is some concern that MB could cause development of haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition which is prevalent in malaria-endemic regions. Against this background, 74 G6PD-deficient but otherwise healthy adult men were given a 3-day oral regimen of a total of 1500 mg CQ and 780 mg MB in the District Hospital of Nouna in north-western Burkina Faso. Haemolysis did not occur, haemoglobin levels remained stable or even rose in the study participants, and the drug regimen was well tolerated. Therefore, standard dosages of MB appear to be safe in G6PD-deficient African populations with predominantly class III G6PD deficiency.

Methylene blue as an antimalarial agent.

Methylene blue has intrinsic antimalarial activity and it can act as a chloroquine sensitizer. In addition, methylene blue must be considered for preventing methemoglobinemia, a serious complication of malarial anemia. As an antiparasitic agent, methylene blue is pleiotropic: it interferes with hemoglobin and heme metabolism in digestive organelles, and it is a selective inhibitor of Plasmodium falciparum glutathione reductase. The latter effect results in glutathione depletion which sensitizes the parasite for chloroquine action. At the Centre de Recherche en Santé de Nouna in Burkina Faso, we study the combination of chloroquine with methylene blue (BlueCQ) as a possible medication for malaria in endemic regions. A pilot study with glucose-6-phosphate dehydrogenase-sufficient adult patients has been conducted recently.

Structural variation in transition-metal bispidine compounds.

The experimentally determined molecular structures of 40 transition metal complexes with the tetradentate bispyridine-substituted bispidone ligand, 2,4-bis(2-pyridine)-3,7-diazabicyclo[3.3.1]nonane-9-one [M(bisp)XYZ]n+; M = CrIII, MnII, FeII, CoII, CuII, CuI, ZnII; X, Y, Z = mono- or bidentate co-ligands; penta-, hexa- or heptacoordinate complexes) are characterized in detail, supported by force-field and DFT calculations. While the bispidine ligand is very rigid (N3...N7 distance = 2.933 +/- 0.025 A), it tolerates a large range of metal-donor bond lengths (2.07 A < sigma(M-N)/4 < 2.35 A). Of particular interest is the ratio of the bond lengths between the metal center and the two tertiary amine donors (0.84 A < M-N3/M-N7 < 1.05 A) and the fact that, in terms of this ratio there seem to be two clusters with M-N3 < M-N7 and M-N3 > or = M-N7. Calculations indicate that the two structural types are close to degenerate, and the structural form therefore depends on the metal ion, the number and type of co-ligands, as well as structural variations of the bispidine ligand backbone. Tuning of the structures is of importance since the structurally differing complexes have very different stabilities and reactivities.

A Very Rigid Bis-bispidine Tetraazamacrocycle and Its Unusual Copper(II) Complex.

The absorption maximum of the orange-colored copper(II) complex of the cyclam derivative L, which has two 3,7-diazabicyclo[3.3.1]nonane units, occurs at 390 nm. This is the lowest value for a copper(II) tetraamine known so far, and indicates an extremely strong ligand field. This maximum is shifted by 110 nm (5740 cm-1 , 68 kJ mol-1 ) to lower wavelengths than that of the parent compound [Cu(cyclam)]2+ ; cyclam=1,4,8,11-tetraazacyclotetradecane.