Combined suboptimal schedules of topical paromomycin, meglumine antimoniate and miltefosine to treat experimental infection caused byLeishmania(Viannia)braziliensis

Morais-Teixeira, Eliane de; Aguiar, Marta Gontijo; Lima, Bruna Soares de Souza; Ferreira, Lucas Antônio Miranda; Rabello, Ana

doi:10.1093/jac/dkv254

Cited by 6 publications

(7 citation statements)

References 28 publications

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“…Organ parasite burdens expressed as Leishman-Donovan units (LDU) were calculated as the number of parasites per 1,000 nucleated cells × organ weight (mg). To determine whether the spleen and liver contained live parasites, the parasite burden was quantified in these tissues by Limiting Dilution Assay (LDA) as previously described (17–19). Briefly, a weighed small piece of spleen or liver from experimental mice was first homogenized in Schneider's medium supplemented with 10% FCS, and then diluted with the same medium to a final concentration of 1 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

EBI-3 Chain of IL-35 Along With TGF-β Synergistically Regulate Anti-leishmanial Immunity

et al. 2019

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Immunosuppression is a characteristic feature of chronic leishmaniasis. The dynamicity and the functional cross talks of host immune responses during Leishmania infection are still not clearly understood. Here we explored the functional aspects of accumulation of immune suppressive cellular and cytokine milieu during the progression of murine visceral leishmaniasis. In addition to IL-10 and TGF-β, investigation on the responses of different subunit chains of IL-12 family revealed a progressive elevation of EBI-3 and p35 chains of IL-35 with Leishmania donovani infection in BALB/c mice. The expansion of CD25 and FoxP3 positive T cells is associated with loss of IFN-γ and TNF-α response in advanced disease. Ex-vivo and in vivo neutralization of TGF-β and EBI-3 suggests a synergism in suppression of host anti-leishmanial immunity. The down-regulation of EBI-3 and TGF-β is crucial for re-activation of JAK-STAT pathway for induction as well as restoration of protective immunity against L. donovani infection.

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Section: Methodsmentioning

confidence: 99%

EBI-3 Chain of IL-35 Along With TGF-β Synergistically Regulate Anti-leishmanial Immunity

et al. 2019

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“…Miltefosine is an antineoplastic medicine that acts on kinase B protein, an important enzyme related to cell division and is responsible to cause erythrocytes lysis.’ The present results allow to conclude that miltefosine combined with BZTS softened cytotoxic and hemolytic effects concomitantly to increase antileishmania activity, characterizing the ideal for the drug association and confirm the advantages previously described by Chou (2006) . Many researchers explore the possibility to combine miltefosine with other drugs, mainly interested in its proven antileishmania effect by oral route and in its still questionable safety in human’s treatment ( de Morais-Teixeira et al, 2015 ; Trinconi et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Induction of Early Autophagic Process on Leishmania amazonensis by Synergistic Effect of Miltefosine and Innovative Semi-synthetic Thiosemicarbazone

et al. 2017

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Drug combination therapy is a current trend to treat complex diseases. Many benefits are expected from this strategy, such as cytotoxicity decrease, retardation of resistant strains development, and activity increment. This study evaluated in vitro combination between an innovative thiosemicarbazone molecule – BZTS with miltefosine, a drug already consolidated in the leishmaniasis treatment, against Leishmania amazonensis. Cytotoxicity effects were also evaluated on macrophages and erythrocytes. Synergistic antileishmania effect and antagonist cytotoxicity were revealed from this combination therapy. Mechanisms of action assays were performed in order to investigate the main cell pathways induced by this treatment. Mitochondrial dysfunction generated a significant increase of reactive oxygen and nitrogen species production, causing severe cell injuries and promoting intense autophagy process and consequent apoptosis cell death. However, this phenomenon was not strong enough to promote dead in mammalian cell, providing the potential selective effect of the tested combination for the protozoa. Thus, the results confirmed that drugs involved in distinct metabolic routes are promising agents for drug combination therapy, promoting a synergistic effect.

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“…There is an urgent requirement for new treatments that can eliminate the parasite and safely accelerate lesion healing with minimal scarring and are feasible for use in low-resource health care systems (5, 6). In recent years, combination therapy of commercially available drugs has received more attention as an alternative strategy to develop more effective, lower-dose, and shorter treatments for many infectious diseases, including CL (7–11). With the goal of identifying such an improved therapeutic option for Leishmania major and Leishmania mexicana CL, we investigated the potential of the cheap, safe, and orally bioavailable 4-aminoquinoline chloroquine (CQ) to increase the activities of three standard antileishmanial drugs.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Paromomycin-Chloroquine Combination Therapy in Experimental Cutaneous Leishmaniasis

Wijnant

Bocxlaer

Yardley

et al. 2017

Antimicrob Agents Chemother

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The 4-aminoquinoline chloroquine (CQ) is clinically used in combination with doxycycline to cure chronic Q fever, as it enhances the activity of the antibiotic against the causative bacterium Coxiella burnetii residing within macrophage phagolysosomes. As there is a similar cellular host-pathogen biology for Leishmania parasites, this study aimed to determine whether such an approach could also be the basis for a new, improved treatment for cutaneous leishmaniasis (CL). We have evaluated the in vitro and in vivo activities of combinations of CQ with the standard drugs paromomycin (PM), miltefosine, and amphotericin B against Leishmania major and Leishmania mexicana. In 72-h intracellular antileishmanial assays, outcomes were variable for different drugs. Significantly, the addition of 10 μM CQ to PM reduced 50% effective concentrations (EC50s) by over 5-fold against L. major and against normally insensitive L. mexicana parasites. In murine models of L. major and L. mexicana CL, daily coadministration of 50 mg/kg of body weight PM and 25 mg/kg CQ for 10 days resulted in a significant reduction in lesion size but not in parasite load compared to those for mice given the same doses of PM alone. Overall, our data indicate that PM-CQ combination therapy is unlikely to be a potential candidate for further preclinical development.

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Combined suboptimal schedules of topical paromomycin, meglumine antimoniate and miltefosine to treat experimental infection caused byLeishmania(Viannia)braziliensis

Cited by 6 publications

References 28 publications

EBI-3 Chain of IL-35 Along With TGF-β Synergistically Regulate Anti-leishmanial Immunity

EBI-3 Chain of IL-35 Along With TGF-β Synergistically Regulate Anti-leishmanial Immunity

Induction of Early Autophagic Process on Leishmania amazonensis by Synergistic Effect of Miltefosine and Innovative Semi-synthetic Thiosemicarbazone

Efficacy of Paromomycin-Chloroquine Combination Therapy in Experimental Cutaneous Leishmaniasis

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