Treatment of Leishmania donovani-infected hamsters with miltefosine: analysis of cytokine mRNA expression by real-time PCR, lymphoproliferation, nitrite production and antibody responses

Gupta, Reema; Kushawaha, Pramod Kumar; Samant, Mukesh; Jaiswal, Anil K.; Baharia, Rajendra Kumar; Dube, Anuradha

doi:10.1093/jac/dkr485

Cited by 33 publications

(45 citation statements)

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“…Oral administration of edelfosine (26 mg/kg body weight) on a daily basis for 4 weeks (28 days) induced a remarkable decrease in both nasal swelling and parasitic load at the site of infection (Figure 5). This dose is lower than the miltefosine dose (40 mg/kg/day) used in a recent study with L. donovani -infected hamsters [71]. Here, we found no appreciable adverse effects on the general condition of the animals following a daily oral administration of 26 mg/kg edelfosine.…”

Section: Resultscontrasting

confidence: 69%

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

et al. 2012

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BackgroundThe leishmaniases are a complex of neglected tropical diseases caused by more than 20 Leishmania parasite species, for which available therapeutic arsenal is scarce and unsatisfactory. Pentavalent antimonials (SbV) are currently the first-line pharmacologic therapy for leishmaniasis worldwide, but resistance to these compounds is increasingly reported. Alkyl-lysophospoholipid analogs (ALPs) constitute a family of compounds with antileishmanial activity, and one of its members, miltefosine, has been approved as the first oral treatment for visceral and cutaneous leishmaniasis. However, its clinical use can be challenged by less impressive efficiency in patients infected with some Leishmania species, including L. braziliensis and L. mexicana, and by proneness to develop drug resistance in vitro.Methodology/Principal FindingsWe found that ALPs ranked edelfosine>perifosine>miltefosine>erucylphosphocholine for their antileishmanial activity and capacity to promote apoptosis-like parasitic cell death in promastigote and amastigote forms of distinct Leishmania spp., as assessed by proliferation and flow cytometry assays. Effective antileishmanial ALP concentrations were dependent on both the parasite species and their development stage. Edelfosine accumulated in and killed intracellular Leishmania parasites within macrophages. In vivo antileishmanial activity was demonstrated following oral treatment with edelfosine of mice and hamsters infected with L. major, L. panamensis or L. braziliensis, without any significant side-effect. Edelfosine also killed SbV-resistant Leishmania parasites in in vitro and in vivo assays, and required longer incubation times than miltefosine to generate drug resistance.Conclusions/SignificanceOur data reveal that edelfosine is the most potent ALP in killing different Leishmania spp., and it is less prone to lead to drug resistance development than miltefosine. Edelfosine is effective in killing Leishmania in culture and within macrophages, as well as in animal models infected with different Leishmania spp. and SbV-resistant parasites. Our results indicate that edelfosine is a promising orally administered antileishmanial drug for clinical evaluation.

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Section: Resultscontrasting

confidence: 69%

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

et al. 2012

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“…We evaluated the impact of parasite load in two compartments (spleen and liver) after infection by L. infantum strains. The development of molecular approaches to quantify the parasite load in the spleen and liver from experimentally infected hamsters is extremely relevant because this animal model has been used to evaluated potential drugs and candidate vaccines against VL [30], [31], [32], [33], [34], [35], [36], [37], [38]. The LDU index, as described by Stauber [19], has the disadvantage of low sensitivity for detecting amastigotes by optical microscopy.…”

Section: Discussionmentioning

confidence: 99%

Parasite Burden in Hamsters Infected with Two Different Strains of Leishmania (Leishmania) infantum: “Leishman Donovan Units” versus Real-Time PCR

et al. 2012

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To develop and test new therapeutics and immune prophylaxis strategies for visceral leishmaniasis (VL), understanding tissue parasitism evolution after experimental infection with Leishmania infantum is important. Experimental infection in a hamster model (Mesocricetus auratus) reproduces several typical aspects of canine and human VL that are closely related to the inoculum’s route. We quantified the parasitism in the liver and spleen of hamsters experimentally infected by various routes (intradermal, intraperitoneal, and intracardiac [IC]) and different strains of L. infantum (MHOM/BR/74/PP75 and Wild) and compared two different methodologies to evaluate tissue parasitism (Leishman Donovan units [LDU] and real-time qPCR). In addition, the quantification of specific total-IgG in the serum of uninfected and infected hamsters was determined by ELISA. The animals were followed for 1, 3, 6 and 9 months post-infection for survival analysis. We found that infection with the Wild strain by the IC route resulted in higher mortality. Positive antibody (IgG) responses were detected with higher peaks at 6 and 9 months in the IC group inoculated with PP75 strain. However, in animals infected with the Wild strain the IgG levels were elevated in all infected groups during all the time evaluated. We also observed by LDU analysis that the IC route lead to higher parasitism in the liver and spleen with both strains. Furthermore, qPCR showed higher sensitivity for identifying animals with low parasitic burden. In conclusion, qPCR can be useful for assessing parasitism in the spleen and liver of a hamster model infected with L. infantum independent of the route of infection, and this technique may become an essential tool for assessing parasite density in the hamster model after experimental treatment or immunization with potential vaccine candidates.

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“…The isolation of parasites and infection to naïve hamsters were carried out as described earlier (Gupta et al, 2011). Infected animals (n = 5) harbouring 38-40 amastigotes/100 macrophage nuclei were then distributed with six animals in each group for drug treatment in the following manner: (i) infected controls (no therapy was given): (ii) Free DOX; (iii) NE-DOX; (iv) SA-NCs-DOX; (v) control (no DOX) NE; and (vi) control SA-NCs.…”

Section: Measurement Of No Production In Infected Macrophagesmentioning

confidence: 99%

“…Eighteen hours prior to termination of the experiment, XTT (50 μL) was added to 100 μL of the supernatant of each well and absorbance was measured at 480 nm with 650 nm as the reference wavelength. To estimate NO production, nitrite accumulation in culture supernatants of hamster peritoneal macrophages was determined by the Griess reagent, as described elsewhere (Gupta et al, 2011).…”

Section: Measurement Of Lymphoproliferative Responses (Ltt) and No Prmentioning

confidence: 99%

Coating doxorubicin‐loaded nanocapsules with alginate enhances therapeutic efficacy against Leishmania in hamsters by inducing Th1‐type immune responses

Kansal

Tandon

Verma

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe aim of the present study was to evaluate the immunomodulatory and chemotherapeutic potential of alginate-(SA) coated nanocapsule (NCs) loaded with doxorubicin (SA-NCs-DOX) against visceral leishmaniasis in comparison with nano-emulsions containing doxorubicin (NE-DOX). EXPERIMENTAL APPROACHNE-DOX was prepared using low-energy emulsification methods. Stepwise addition of protamine sulphate and SA in a layer-by-layer manner was used to form SA-NCs-DOX. SA-NCs-DOX, NE-DOX and Free DOX were compared for their cytotoxicity against Leishmania donovani-infected macrophages in vitro and generation of T-cell responses in infected hamsters in vivo. KEY RESULTSSize and ζ potential of the NE-DOX and SA-NCs-DOX formulations were 310 ± 2.1 nm and (−)32.6 ± 2.1 mV, 342 ± 4.1 nm and (−)29.3 ± 1.2 mV respectively. SA-NCs-DOX was better (1.5 times) taken up by J774A.1 macrophages compared with NE-DOX. SA-NCs -DOX showed greater efficacy than NE-DOX against intramacrophagic amastigotes. SA-NCs-DOX treatment exhibited enhanced apoptotic efficiency than NE-DOX and free DOX as evident by cell cycle analysis, decrease in mitochondrial membrane potential, ROS and NO production. T-cell responses, when assessed through lymphoproliferative responses, NO production along with enhanced levels of iNOS, TNF-α, IFN-γ and IL-12 were found to be up-regulated after SA-NCs-DOX, compared with responses to NE-DOX in vivo. Parasitic burden was decreased in Leishmania-infected hamsters treated with SA-NCs-DOX, compared with NE-DOX. CONCLUSIONS AND IMPLICATIONSOur results provide insights into the development of an alternative approach to improved management of leishmaniasis through a combination of chemotherapy with stimulation of the innate immune system.

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Treatment of Leishmania donovani-infected hamsters with miltefosine: analysis of cytokine mRNA expression by real-time PCR, lymphoproliferation, nitrite production and antibody responses

Abstract: Treatment of Leishmania-infected hamsters with miltefosine reverses the Th2-type response into a strong Th1-type immune response.

Cited by 33 publications

References 9 publications

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Parasite Burden in Hamsters Infected with Two Different Strains of Leishmania (Leishmania) infantum: “Leishman Donovan Units” versus Real-Time PCR

Coating doxorubicin‐loaded nanocapsules with alginate enhances therapeutic efficacy against Leishmania in hamsters by inducing Th1‐type immune responses

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