Efficacy of Proveblue (Methylene Blue) in an Experimental Cerebral Malaria Murine Model

Dormoi, Jérôme; Briolant, Sébastien; Desgrouas, Camille; Pradines, Bruno

doi:10.1128/aac.02381-12

Cited by 23 publications

(24 citation statements)

References 22 publications

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“…In the mice treated with 10 mg/kg Proveblue for 5 days, one mouse (10%) died at D14 (10.5% parasitemia) with specific signs of CM and another died at D20 (85.9% parasitemia) with no specific signs of CM. Similar results were obtained for 10 mg/kg Proveblue for 5 days, with 78% of mice surviving after treatment (3,4). In the mice treated with 3 mg/kg for 5 days, three mice (30%) died between D23 and D26 (parasitemia between 81.3 and 93.1%) with no specific signs of CM.…”

supporting

confidence: 72%

“…Proveblue exhibited noticeable synergistic effects in combination with mefloquine and quinine and high synergistic effects in combination with dihydroartemisinin, the active metabolite of artemisinin derivatives (2). Treatment with 10 mg/kg of body weight of Proveblue for 5 days significantly reduced or prevented cerebral malaria (CM) in mice (3,4). However, this dose was too high to show synergistic effects in combination with dihydroartemisinin or atorvastatin in malaria cerebral prevention.…”

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confidence: 99%

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Dose Responses of Proveblue Methylene Blue in an Experimental Murine Cerebral Malaria Model

Dormoi

Pradines

2013

Antimicrob Agents Chemother

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Proveblue, which is a methylene blue preparation that complies with the European Pharmacopoeia and contains limited organic impurities and heavy metals of recognized toxicity, has previously been demonstrated to possess in vitro antimalarial activity (1). Proveblue exhibited noticeable synergistic effects in combination with mefloquine and quinine and high synergistic effects in combination with dihydroartemisinin, the active metabolite of artemisinin derivatives (2). Treatment with 10 mg/kg of body weight of Proveblue for 5 days significantly reduced or prevented cerebral malaria (CM) in mice (3, 4). However, this dose was too high to show synergistic effects in combination with dihydroartemisinin or atorvastatin in malaria cerebral prevention.The objective of the present work was to evaluate the in vivo efficacy of Proveblue at several doses in a murine model of experimental CM and determine doses for future in vivo combination evaluation.Fifty-six female C57Bl6/N mice (Charles Rivers, France) were infected on day 0 (D0) with Plasmodium berghei ANKA parasites by intraperitoneal inoculation with 10 5 parasitized erythrocytes. All experiments adhered to French guidelines for animal research and were approved by the ethical committee of the Institut de Recherche Biomédicale des Armées (number 2012-04). The mice were treated when the parasitemia reached 0.1% by daily intraperitoneal (i.p.) injection with a normal saline solution (control) or Proveblue dissolved in a saline solution (3 and 10 mg/kg for 3 days; 1, 3, and 10 mg/kg for 5 days). The parasitemia, clinical signs, neurological symptoms, and weight were supervised as previously described (4).In the control group, all the mice died between D10 and D14, with specific signs of CM and parasitemia ranging from 3.4 to 7.2% (Fig. 1). The observed symptoms for CM were consistent with those of previous publications (3-7). There was a significant difference between the control and treated mouse groups (0.00002 Ͻ P Ͻ 0.0028). In the mice treated with 10 mg/kg Proveblue for 5 days, one mouse (10%) died at D14 (10.5% parasitemia) with specific signs of CM and another died at D20 (85.9% parasitemia) with no specific signs of CM. Similar results were obtained for 10 mg/kg Proveblue for 5 days, with 78% of mice surviving after treatment (3, 4). In the mice treated with 3 mg/kg for 5 days, three mice (30%) died between D23 and D26 (parasitemia between 81.3 and 93.1%) with no specific signs of CM. In the mice treated with 1 mg/kg Proveblue for 5 days, two mice (20%) died at D8 (4.7% parasitemia) and D12 (1.8% parasitemia) with specific signs of CM and two others (20%) died at D20 (88.0% parasitemia) and D25 (93.1% parasitemia) with no specific signs of CM. In the mice treated with 10 mg/kg for 3 days, one mouse (11%) died at D11 (4.2% parasitemia) with specific signs of CM and six mice (66%) died between D26 and D35 (Ͼ86.9% parasitemia) with no specific signs of CM. In the mice treated with 3 mg/kg for 3 days, six mice

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supporting

confidence: 72%

mentioning

confidence: 99%

Dose Responses of Proveblue Methylene Blue in an Experimental Murine Cerebral Malaria Model

Dormoi

Pradines

2013

Antimicrob Agents Chemother

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“…Interestingly, maprotiline, a tetracyclic antidepressant similar to the tricyclic antidepressant methylene blue, demonstrated nanomolar inhibition of both gametocyte and asexual stages of P. falciparum , but showed greater efficacy against gametocytes. Methylene blue has reported efficacy against gametocytes in vitro and also showed in vivo efficacy against asexual parasites in multiple murine models of cerebral malaria, protecting 75% of mice at 10 mg/kg for five days post-infection [9], [23]–[26]. Our observations suggest further exploration of tetracyclic and tricyclic antidepressants for gametocytocidal activity.…”

Section: Discussionsupporting

confidence: 51%

Gametocytocidal Screen Identifies Novel Chemical Classes with Plasmodium falciparum Transmission Blocking Activity

et al. 2014

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Discovery of transmission blocking compounds is an important intervention strategy necessary to eliminate and eradicate malaria. To date only a small number of drugs that inhibit gametocyte development and thereby transmission from the mosquito to the human host exist. This limitation is largely due to a lack of screening assays easily adaptable to high throughput because of multiple incubation steps or the requirement for high gametocytemia. Here we report the discovery of new compounds with gametocytocidal activity using a simple and robust SYBR Green I- based DNA assay. Our assay utilizes the exflagellation step in male gametocytes and a background suppressor, which masks the staining of dead cells to achieve healthy signal to noise ratio by increasing signal of viable parasites and subtracting signal from dead parasites. By determining the contribution of exflagellation to fluorescent signal and using appropriate cutoff values, we were able to screen for gametocytocidal compounds. After assay validation and optimization, we screened an FDA approved drug library of approximately 1500 compounds, as well as the 400 compound MMV malaria box and identified 44 gametocytocidal compounds with sub to low micromolar IC50s. Major classes of compounds with gametocytocidal activity included quaternary ammonium compounds with structural similarity to choline, acridine-like compounds similar to quinacrine and pyronaridine, as well as antidepressant, antineoplastic, and anthelminthic compounds. Top drug candidates showed near complete transmission blocking in membrane feeding assays. This assay is simple, reproducible and demonstrated robust Z-factor values at low gametocytemia levels, making it amenable to HTS for identification of novel and potent gametocytocidal compounds.

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“…It is conceivable that MB can be considered for application in treatment of both uncomplicated and complicated malaria as well as for its potential for use in LM-and PYR-resistant malaria regions. This therapeutic potential is further highlighted in MB's capacity to efficiently manage cerebral malaria, a complication of untreated malaria [21].…”

Section: Discussionmentioning

confidence: 99%

“…Other studies demonstrated that MB is effective, with 50% inhibitory concentration at 3.62-3.90 nM, on 23 P. falciparum strains resistant to several standard antimalarials, including chloroquine (CQ) [20]. Dormoi et al [21] went on to further demonstrate significant efficacy of MB in the treatment and survival of cerebral malaria in mice infected with non-resistant P. berghei (p = 0.0011).…”

Section: Introductionmentioning

confidence: 99%

Methylene blue inhibits lumefantrine-resistant Plasmodium berghei

Mwangi

Mumo

Kiboi

et al. 2016

J Infect Dev Ctries

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Introduction: Chemotherapy still is the most effective way to control malaria, a major public health problem in sub-Saharan Africa. The largescale use of the combination therapy artemether-lumefantrine for malaria treatment in Africa predisposes lumefantrine to emergence of resistance. There is need to identify drugs that can be used as substitutes to lumefantrine for use in combination therapy. Methylene blue, a synthetic anti-methemoglobinemia drug, has been shown to contain antimalarial properties, making it a candidate for drug repurposing. The present study sought to determine antiplasmodial effects of methylene blue against lumefantrine-and pyrimethamine-resistant strains of P. berghei. Methodology: Activity of methylene blue was assessed using the classical four-day test on mice infected with lumefantrine-resistant and pyrimethamine-resistant P. berghei. A dose of 45 mg/kg/day was effective for testing ED90. Parasitemia and mice survival was determined. Results: At 45 mg/kg/day, methylene blue sustained significant parasite inhibition, over 99%, for at least 6 days post-treatment against lumefantrine-resistant and pyrimethamine-resistant P. berghei (p = 0.0086 and p = 0.0191, respectively). No serious adverse effects were observed. Conclusions: Our results indicate that methylene blue at a concentration of 45 mg/kg/day confers over 99% inhibition against lumefantrineand pyrimethamine-resistant P. berghei for six days. This shows the potential use methylene blue in the development of antimalarials against lumefantrine-and pyrimethamine-resistant parasites.

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Efficacy of Proveblue (Methylene Blue) in an Experimental Cerebral Malaria Murine Model

Cited by 23 publications

References 22 publications

Dose Responses of Proveblue Methylene Blue in an Experimental Murine Cerebral Malaria Model

Dose Responses of Proveblue Methylene Blue in an Experimental Murine Cerebral Malaria Model

Gametocytocidal Screen Identifies Novel Chemical Classes with Plasmodium falciparum Transmission Blocking Activity

Methylene blue inhibits lumefantrine-resistant Plasmodium berghei

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