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Jean-claude Dujardin – One of the best experts on this subject based on the ideXlab platform.

  • American Tegumentary Leishmaniasis: Is Antimonial Treatment Outcome
    , 2016
    Co-Authors: Jean-claude Dujardin

    Abstract:

    Background. Antimonials are the firs drug of choice for the treatment of American tegumentary leishmaniasis (ATL); however, their efficac is not predictable, and this may be linked to parasite drug resistance. We aimed to characterize the in vitro antimony susceptibility of clinical isolates of Peruvian patients with ATL who were treated with sodium stibogluconate and to correlate this in vitro phenotype with different treatment outcomes. Methods. Thirty-seven clinical isolates were obtained from patients with known disease and treatment histories. These isolates were typed, and the susceptibility of intracellular amastigotes to pentavalent (SbV) and trivalent (SbIII) Antimonials was determined. Results. We observed 29 SbV-resistant isolates among 4 species of subgenus Viannia, most of which exhibited primary resistance; isolates resistant only to SbIII; and 3 combinations of in vitro phenotypes: (1) parasites sensitive to both drugs, (2) parasites resistant to both drugs, and (3) parasites resistant to SbV only (the majority of isolates fell into this category). There was no correlation between in vitro susceptibility to both Antimonials and the clinical outcome of therapy. Conclusion. Antimony insensitivity might occur in a stepwise fashion (firs to SbV and then to SbIII). Our data question the definitio of true parasite resistance to Antimonials. Further studies of treatment efficac should apply standardized protocols and definition and should also consider host factors

  • relapse after treatment with miltefosine for visceral leishmaniasis is associated with increased infectivity of the infecting leishmania donovani strain
    Mbio, 2013
    Co-Authors: Bart Cuypers, Suman Rijal, Jean-claude Dujardin, Narayan Raj Bhattarai, Surendra Uranw, Maya Berg, Bart Ostyn, Manu Vanaerschot

    Abstract:

    ABSTRACT Leishmania donovani is an intracellular protozoan parasite that causes leishmaniasis, which can range from a self-healing cutaneous disease to a fatal visceral disease depending on the infecting species. Miltefosine is currently the latest and only oral antileishmanial that came out of drug discovery pipelines in the past few decades, but recent reports indicate a significant decline in its efficacy against visceral leishmaniasis (also known as kala-azar) in the Indian subcontinent. This relapse rate of up to 20% within 12 months after treatment was shown not to be related to reinfection, drug quality, drug exposure, or drug-resistant parasites. We therefore aimed to assess other phenotypes of the parasite that may affect treatment outcome and found a significant association between the number of metacyclic parasites, parasite infectivity, and patient treatment outcome in the Indian subcontinent. Together with previous studies on resistance of L. donovani against pentavalent Antimonials, these data suggest that the infectivity of the parasite, or related phenotypes, might be a more determinant factor for treatment failure in visceral leishmaniasis than drug susceptibility, warranting a reassessment of our current view on treatment failure and drug resistance in leishmaniasis and beyond. IMPORTANCE The high miltefosine relapse rate poses a major challenge for the current Kala-Azar Elimination Program in the Indian subcontinent and other leishmaniasis control programs worldwide. This relapse rate could not be related to reinfection, drug-resistant parasites, or reduced treatment quality. Here we report that an increased infectivity of the parasite is associated with miltefosine relapse of visceral leishmaniasis (VL) patients. These results supplement those obtained with Antimonial-resistant L. donovani where an increased infectivity was also observed. This challenges the current view of Leishmania drug susceptibility being the biggest parasitic factor that contributes to treatment failure in leishmaniasis. These selected more infectious parasites may pose an additional burden to leishmaniasis control programs, highlighting the importance of multifaceted control measures to achieve leishmaniasis elimination in the Indian subcontinent and other regions where leishmaniasis is endemic.

  • Antimonial treatment of visceral leishmaniasis: are current in vitro susceptibility assays adequate for prognosis of in vivo therapy outcome?
    Microbes and infection, 2007
    Co-Authors: Suman Rijal, Marleen Boelaert, Vanessa Yardley, François Chappuis, Saskia Decuypere, Basudha Khanal, Rupa Singh, Simonne De Doncker, Simon L. Croft, Jean-claude Dujardin

    Abstract:

    In most of the Indian subcontinent, the first line treatment for visceral leishmaniasis (VL) is sodium stibogluconate (SSG), an Antimonial drug, but the efficacy of the drug varies according to region. We aimed to characterize the in vitro antimony susceptibility of clinical isolates of Nepalese VL patients, and to correlate this in vitro parasite phenotype to clinical therapy outcome. Thirty-three clinical isolates of L. donovani were taken from patients with known disease history. These isolates were typed and the susceptibility of intracellular amastigotes to pentavalent (SbV) and trivalent (SbIII) Antimonials was determined. We observed (i) 22 SbV-resistant isolates out of 33 tested and (ii) 3 SbIII-resistant isolates out of 12 tested. Amongst the latter, there were three combinations of in vitro phenotypes: (i) parasites sensitive (n=4) or (ii) resistant to both drugs (n=3) and (iii) resistant to SbV only (n=5). There was no geographical clustering in terms of in vitro susceptibility. The relation between the in vitro susceptibility to Antimonials and the corresponding in vivo treatment outcome was ambiguous. Our results highlight the need to adjust the currently used Leishmania drug susceptibility assays if they are to be used for prognosis of in vivo SSG treatment outcome.

Shyam Sundar – One of the best experts on this subject based on the ideXlab platform.

  • The overexpression of genes of thiol metabolism contribute to drug resistance in clinical isolates of visceral leishmaniasis (kala azar) in India
    Parasites & Vectors, 2014
    Co-Authors: Neeloo Singh, Mitali Chatterjee, Shyam Sundar

    Abstract:

    Background Visceral leishmaniasis (VL), also called Kala Azar (KA) or black fever in India, claims around 20,000 lives every year. Chemotherapy remains one of the most important tools in the control of VL. Current chemotherapy for Kala Azar in India relies on a rather limited arsenal of drugs including sodium antimony gluconate and amphotericin B in addition to the very expensive drug miltefosine. Pentavalent Antimonials have been used for more than half a century in the therapy of leishmaniasis as it is relatively safe and inexpensive, however, the spread of resistance to this drug is forcing clinicians in India to abandon this treatment. Consequently, improvement of Antimonial chemotherapy has become a major challenging area of study by leishmaniacs worldwide. The alarming emergence of resistance to the commonly used antleishmanial drug, sodium antimony gluconate, in India, has led us to elucidate the resistance mechanism(s) in clinical isolates. Studies on laboratory mutants have shown that resistance to Antimonials is highly dependent on thiol levels. The parasite evades cytotoxic effects of Antimonial therapy by enhanced efflux of drug upon conjugation with thiols, through overexpressed membrane proteins belonging to the superfamily of ABC transporters. Methods We have carried out functional studies to determine the activity of the efflux pumps in Antimonial resistant clinical isolates collected from disease endemic areas in India and also carried out molecular characterization of thiol levels in these parasites. Results Overexpression of the gene coding for γ glutamylcysteine synthetase was observed in these resistant clinical isolates thereby establishing that thiols represent the key determinants of Antimonial resistance. The SbIII/thiol conjugates can be sequestered by ABC transporter multidrug resistance protein A (MRPA) into intracellular organelles or can be directly pumped out by an uncharacterized transporter. Conclusions Our studies investigating Antimonial resistance in different L. donovani clinical isolates suggest that over functioning of MRP plays a role in generation of antimony resistance phenotype in some L. donovani clinical isolates.

  • Visceral Leishmaniasis and Arsenic: An Ancient Poison Contributing to Antimonial Treatment Failure in the Indian Subcontinent?
    PLoS neglected tropical diseases, 2011
    Co-Authors: Meghan R. Perry, Shyam Sundar, Susan Wyllie, Vijay Kumar Prajapati, Joerg Feldmann, Marleen Boelaert, Alan H. Fairlamb

    Abstract:

    Antimony and arsenic are elements that have a long history of use as poisons, therapeutic agents, or cosmetics. For over a century, compounds containing pentavalent antimony (Antimonials) have formed the basis of treatment of the leishmaniases worldwide. Antimonial preparations remain first-line drugs for visceral leishmaniasis in Sub-Saharan Africa and Brazil [1], but in the hyperendemic state of Bihar, India, the cure rate of Antimonial compounds has declined over the past 30 years from over 85% to less than 50% (Figure 1) [2] and resistance in parasites has been demonstrated [3]. This marked decrease in efficacy has been attributed to long-term, widespread misuse of Antimonials, with patients undergoing inappropriate treatment courses often administered by the largely unregulated Indian private health care system [4], [5]. Here we propose an additional hypothesis to explain the substantially lower efficacy of antimony in Bihar compared to other regions in the world.

    Figure 1

    Results of consecutive clinical studies of Antimonials at 20 mg/kg dosing in Bihar, India.

    Since the 1970s, millions of inhabitants of Asia have been chronically exposed to naturally occurring arsenic on a daily basis through the large-scale insertion of multiple shallow tubewells which were originally installed for provision of clean and safe drinking water [6]. Antimony and arsenic are metalloids belonging to Group 15 of the periodic table that share many structural and chemical properties [7]. Antimony resistance in Leishmania parasites can be induced experimentally by exposure to stepwise increasing concentrations of sublethal concentrations of trivalent arsenite in culture [8]. If an individual who is chronically exposed to arsenic is infected with Leishmania, the parasites would be exposed to arsenic due to its presence within organs of the lymphoreticular system [9]. This could lead to the development of an arsenic-resistant Leishmania strain that would be cross-resistant to Antimonial therapy. This viewpoint article will expand on, and discuss the evidence for, the possible contribution of arsenic to decreased Antimonial efficacy in Bihar.

  • a proteomics screen implicates hsp83 and a small kinetoplastid calpain related protein in drug resistance in leishmania donovani clinical field isolates by modulating drug induced programmed cell death
    Molecular & Cellular Proteomics, 2007
    Co-Authors: Baptiste Vergnes, Shyam Sundar, Benjamin Gourbal, Isabelle Girard, Jolyne Drummelsmith, Marc Ouellette

    Abstract:

    : The therapeutic mainstay against the protozoan parasite Leishmania is still based on the antiquated pentavalent Antimonials (Sb(V)), but resistance is increasing in several parts of the world. Resistance is now partly understood in laboratory isolates, but our understanding of resistance in field isolates is lagging behind. We describe here a comparative analysis of a genetically related pair of Sb(V)-sensitive and -resistant Leishmania donovani strains isolated from kala-azar patients. The resistant isolate exhibited cross-resistance to other unrelated Leishmania drugs including miltefosine and amphotericin B. A comparative proteomics screen has highlighted a number of proteins differentially expressed suggesting that programmed cell death (PCD) is modified in the resistant parasite. Indeed drug-induced PCD progression was altered in the Sb(V)-resistant strain as determined using early and late markers of apoptosis. Two proteins, the heat shock protein HSP83 and the small kinetoplastid calpain-related protein (SKCRP14.1) were shown to be intimately implicated in the drug-induced PCD phenotype. HSP83 increased drug resistance and reduced drug-mediated PCD activation by interfering with the mitochondrial membrane potential, whereas SKCRP14.1 promoted Antimonial-induced PCD but protected against miltefosine-induced PCD. This study highlights the important role of PCD in drug susceptibility/resistance in the protozoan parasite Leishmania.

Alan H. Fairlamb – One of the best experts on this subject based on the ideXlab platform.

  • Chronic exposure to arsenic in drinking water can lead to resistance to Antimonial drugs in a mouse model of visceral leishmaniasis
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Meghan R. Perry, Susan Wyllie, Joerg Feldmann, Andrea Raab, Alan H. Fairlamb

    Abstract:

    The Indian subcontinent is the only region where arsenic contamination of drinking water coexists with widespread resistance to Antimonial drugs that are used to treat the parasitic disease visceral leishmaniasis. We have previously proposed that selection for parasite resistance within visceral leishmaniasis patients who have been exposed to trivalent arsenic results in cross-resistance to the related metalloid antimony, present in the pentavalent state as a complex in drugs such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). To test this hypothesis, Leishmania donovani was serially passaged in mice exposed to arsenic in drinking water at environmentally relevant levels (10 or 100 ppm). Arsenic accumulation in organs and other tissues was proportional to the level of exposure and similar to that previously reported in human liver biopsies. After five monthly passages in mice exposed to arsenic, isolated parasites were found to be completely refractory to 500 μg⋅mL−1 Pentostam compared with the control passage group (38.5 μg⋅mL−1) cultured in vitro in mouse peritoneal macrophages. Reassessment of resistant parasites following further passage for 4 mo in mice without arsenic exposure showed that resistance was stable. Treatment of infected mice with Pentostam confirmed that resistance observed in vitro also occurred in vivo. We conclude that arsenic contamination may have played a significant role in the development of Leishmania Antimonial resistance in Bihar because inadequate treatment with Antimonial drugs is not exclusive to India, whereas widespread Antimonial resistance is.

  • Visceral Leishmaniasis and Arsenic: An Ancient Poison Contributing to Antimonial Treatment Failure in the Indian Subcontinent?
    PLoS neglected tropical diseases, 2011
    Co-Authors: Meghan R. Perry, Shyam Sundar, Susan Wyllie, Vijay Kumar Prajapati, Joerg Feldmann, Marleen Boelaert, Alan H. Fairlamb

    Abstract:

    Antimony and arsenic are elements that have a long history of use as poisons, therapeutic agents, or cosmetics. For over a century, compounds containing pentavalent antimony (Antimonials) have formed the basis of treatment of the leishmaniases worldwide. Antimonial preparations remain first-line drugs for visceral leishmaniasis in Sub-Saharan Africa and Brazil [1], but in the hyperendemic state of Bihar, India, the cure rate of Antimonial compounds has declined over the past 30 years from over 85% to less than 50% (Figure 1) [2] and resistance in parasites has been demonstrated [3]. This marked decrease in efficacy has been attributed to long-term, widespread misuse of Antimonials, with patients undergoing inappropriate treatment courses often administered by the largely unregulated Indian private health care system [4], [5]. Here we propose an additional hypothesis to explain the substantially lower efficacy of antimony in Bihar compared to other regions in the world.

    Figure 1

    Results of consecutive clinical studies of Antimonials at 20 mg/kg dosing in Bihar, India.

    Since the 1970s, millions of inhabitants of Asia have been chronically exposed to naturally occurring arsenic on a daily basis through the large-scale insertion of multiple shallow tubewells which were originally installed for provision of clean and safe drinking water [6]. Antimony and arsenic are metalloids belonging to Group 15 of the periodic table that share many structural and chemical properties [7]. Antimony resistance in Leishmania parasites can be induced experimentally by exposure to stepwise increasing concentrations of sublethal concentrations of trivalent arsenite in culture [8]. If an individual who is chronically exposed to arsenic is infected with Leishmania, the parasites would be exposed to arsenic due to its presence within organs of the lymphoreticular system [9]. This could lead to the development of an arsenic-resistant Leishmania strain that would be cross-resistant to Antimonial therapy. This viewpoint article will expand on, and discuss the evidence for, the possible contribution of arsenic to decreased Antimonial efficacy in Bihar.

  • Differential toxicity of Antimonial compounds and their effects on glutathione homeostasis in a human leukaemia monocyte cell line.
    Biochemical pharmacology, 2005
    Co-Authors: Susan Wyllie, Alan H. Fairlamb

    Abstract:

    Trivalent Antimonial compounds (Sb(III)), originally used in the treatment of leishmaniasis, are now being proposed as a novel therapy for acute promyelocytic leukaemia (APL). Here, we examine the effects of Sb(III) and pentavalent Antimonial drugs (Sb(V)) on glutathione homeostasis, oxidative stress and apoptosis in the human leukaemia monocyte cell line, THP-1. Although growth of THP-1 macrophages is unaffected by Sb(V), macrophages are extremely sensitive to Sb(III). On exposure to Sb(III), intracellular free glutathione (GSH) levels in macrophages decrease linearly by 50% over 4h, associated with efflux of both GSH and accumulation of intracellular glutathione disulphide (GSSG). Together these effects increase the redox potential of the GSSG/GSH couple from -282 to -225mV. Sb(III)-induced GSH efflux from THP-1 macrophages is accompanied by the concomitant efflux of Sb(III) at a constant molar ratio of 3 (GSH) to 1 (Sb(III)), respectively. Sb(III) directly inhibits glutathione reductase activity in macrophages, significantly retarding the regeneration of GSH from GSSG, following diamide oxidation. Sb(III)-treated THP-1 macrophages go on to exhibit elevated levels of reactive oxygen species and show the early signs of apoptosis. The absence of these effects in Sb(V)-treated THP-1 cells suggests that macrophages do not efficiently reduce Sb(V) to Sb(III). Collectively, these findings suggest that Sb(III) seriously compromises thiol homeostasis in THP-1 macrophages and that this may be an early defining event in the mode of action of Antimonials against leukaemia cells.