Über die Wirkung des Methylenblau bei Malaria

Guttmann, P.; Ehrlich, P.

doi:10.1016/b978-0-08-009056-6.50006-3

Cited by 102 publications

(103 citation statements)

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“…The antimicrobial activity of phenothiazines has been known since the time of Ehrlich (1891) [7]; nevertheless, enhancement of the activity of conventional antibiotics by these and other compounds has only recently been a subject of interest. To the best of our knowledge, phenothiazines such as thiethylperazine have not previously been evaluated for their antibiotic resistancemodifying activity.…”

Section: Discussionmentioning

confidence: 99%

Synergy between phenothiazines and oxacillin against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i>

Hadji-nejad¹,

Rahbar²,

Mehrgan³

2010

Trop. J. Pharm Res

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Purpose: To evaluate the antimicrobial and resistance-reversal activities of seven phenothiazine derivatives against one standard methicillin-sensitive and ten methicillin-resistant Staphylococcus aureus (MRSA) strains originating from human infections. Methods: Minimum inhibitory concentrations (MIC) of the compounds were determined by agar dilution method, and synergy between phenothiazines and oxacillin was investigated using Checkerboard (microbroth dilution) technique. Results: We found that all S. aureus strains, regardless of their susceptibility to oxacillin, were inhibited by phenothiazines at a concentration of 8 -256 µg/mL, with thioridazine being the most potent inhibitory agent. Phenothiazines at sub-inhibitory concentrations lowered the MIC of oxacillin from 256 to 2 µg/mL, which is a clinically significant level. The highest number of synergistic combinations, i.e., fractional inhibitory concentration (FIC) index less than 0.5, was seen with chlorpromazine and perphenazine. However, thioridazine reversed antibiotic resistance at a concentration as low as 4 µg/mL. Conclusion: Although synergy was observed at concentrations higher than those that phenothiazines usually attain in vivo, the potential offered by non-antibiotics justifies further animal experiments as well as clinical trials to establish their clinical relevance.

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Section: Discussionmentioning

confidence: 99%

Synergy between phenothiazines and oxacillin against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i>

Hadji-nejad¹,

Rahbar²,

Mehrgan³

2010

Trop. J. Pharm Res

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“…Our data reveal highly potent gametocytocidal and transmission-blocking properties of the thiazine dye MB. Characterized by a short plasma half-life and a high bioavailability (18 h and 72%, respectively) (30), this compound was the first synthetic compound ever used in clinical therapy, dating back to the 1891 report of its antimalarial properties by the renowned chemist Paul Ehrlich (31,32). Recently, there has been renewed interest in this affordable and already clinically registered compound, with a series of studies that have assessed the benefit of adding MB to antimalarial combinations (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue

Adjalley

Johnston

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

291

348

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Clinical studies and mathematical models predict that, to achieve malaria elimination, combination therapies will need to incorporate drugs that block the transmission of Plasmodium falciparum sexual stage parasites to mosquito vectors. Efforts to measure the activity of existing antimalarials on intraerythrocytic sexual stage gametocytes and identify transmission-blocking agents have, until now, been hindered by a lack of quantitative assays. Here, we report an experimental system using P. falciparum lines that stably express gametocyte-specific GFP-luciferase reporters, which enable the assessment of dose-and time-dependent drug action on gametocyte maturation and transmission. These studies reveal activity of the first-line antimalarial dihydroartemisinin and the partner drugs lumefantrine and pyronaridine against early gametocyte stages, along with moderate inhibition of mature gametocyte transmission to Anopheles mosquitoes. The other partner agents monodesethyl-amodiaquine and piperaquine showed activity only against immature gametocytes. Our data also identify methylene blue as a potent inhibitor of gametocyte development across all stages. This thiazine dye almost fully abolishes P. falciparum transmission to mosquitoes at concentrations readily achievable in humans, highlighting the potential of this chemical class to reduce the spread of malaria.artemisinin-based combination therapies | transfection

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“…Phenothiazinium redox dyes have diverse applications as biological redox indicators, vital stains and diagnostic dyes [17], modulators of mitochondrial respiration [18], infusional antidotes against cyanide poisoning and methemoglobinemia [19], antiinfective agents [20,21], and photosensitizers [22][23][24], but their therapeutic potential and mechanism of action as anti-cancer redox chemotherapeutics are largely unexplored [23,25]. Compounds containing the 3,7-diaminophenothiazinium redox pharmacophore including thionine (T, 3,7-diamino-phenothiazinium acetate), methylene blue (MB, 3,7-bis (dimethylamino)-phenothiazinium chloride), and toluidine blue O (TB, 2-methyl-3-amino-7-dimethylamino-phenothiazinium chloride) are two-electron redox systems with standard reduction potentials [e.g.…”

Section: Introductionmentioning

confidence: 99%

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

Wondrak

2007

Free Radical Biology and Medicine

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Altered redox signaling and regulation in cancer cells represent a chemical vulnerability that can be targeted by selective chemotherapeutic intervention. Here, we demonstrate that 3,7-diaminophenothiazinium-based redoxcyclers (PRC) induce selective cancer cell apoptosis by NAD (P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Using PRC lead compounds including toluidine blue against human metastatic G361 melanoma cells, apoptosis occurred with phosphatidylserine-externalization, loss of mitochondrial transmembrane potential, cytochrome C release, caspase-3 activation, and massive ROS production. Consistent with reductive activation and subsequent redoxcycling as the mechanism of PRC cytotoxicity, co-incubation with catalase achieved cell protection, whereas reductive antioxidants enhanced PRC-cytotoxicity. Unexpectedly, human A375 melanoma cells were resistant to PRCinduced apoptosis, and PRC-sensitive G361 cells were protected by preincubation with the NQO1-inhibitor dicoumarol. Indeed, NQO1 specific enzymatic activity was nine fold higher in G361 than in A375 cells. The critical role of NQO1 in PRC-bioactivation and cytotoxicity was confirmed, when NQO1-transfected breast cancer cells (MCF7-DT15) stably overexpressing active NQO1 displayed strongly enhanced PRC-sensitivity as compared to vector-control transfected cells with base line NQO1 activity. Based on the known overexpression of NQO1 in various tumors these findings suggest the feasibility of developing PRC lead compounds into tumor-selective bioreductive chemotherapeutics.

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Über die Wirkung des Methylenblau bei Malaria

Cited by 102 publications

References 0 publications

Synergy between phenothiazines and oxacillin against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i>

Synergy between phenothiazines and oxacillin against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i>

Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

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