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Jean-claude Dujardin - One of the best experts on this subject based on the ideXlab platform.
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American Tegumentary Leishmaniasis: Is Antimonial Treatment Outcome
2016Co-Authors: Jean-claude DujardinAbstract: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
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relapse after treatment with miltefosine for visceral leishmaniasis is associated with increased infectivity of the infecting leishmania donovani strain
Mbio, 2013Co-Authors: Bart Cuypers, Suman Rijal, Jean-claude Dujardin, Narayan Raj Bhattarai, Surendra Uranw, Maya Berg, Bart Ostyn, Manu VanaerschotAbstract: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.
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Antimonial treatment of visceral leishmaniasis: are current in vitro susceptibility assays adequate for prognosis of in vivo therapy outcome?
Microbes and infection, 2007Co-Authors: Suman Rijal, Marleen Boelaert, Vanessa Yardley, François Chappuis, Saskia Decuypere, Basudha Khanal, Rupa Singh, Simonne De Doncker, Simon L. Croft, Jean-claude DujardinAbstract: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.
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gene expression analysis of the mechanism of natural sb v resistance in leishmania donovani isolates from nepal
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Suman Rijal, Vanessa Yardley, Saskia Decuypere, Basudha Khanal, Simonne De Doncker, Thierry Laurent, Francois Chappuis, Jean-claude DujardinAbstract:Control of visceral leishmaniasis (VL) is being challenged by the emergence of natural resistance against the first line of treatment, pentavalent Antimonials [Sb(V)]. An insight into the mechanism of natural Sb(V) resistance is required for the development of efficient strategies to monitor the emergence and spreading of Sb(V) resistance in countries where VL is endemic. In this work, we have focused on the mechanism of natural Sb(V) resistance emerging in Nepal, a site where anthroponotic VL is endemic. Based on the current knowledge of Sb(V) metabolism and of the in vitro trivalent Antimonial [Sb(III)] models of resistance to Leishmania spp., we selected nine genes for a comparative transcriptomic study on natural Sb(V)-resistant and -sensitive Leishmania donovani isolates. Differential gene expression patterns were observed for the genes coding for 2-thiol biosynthetic enzymes, gamma-glutamylcysteine synthetase (GCS) and ornithine decarboxylase (ODC), and for the Sb(III) transport protein aquaglyceroporin 1 (AQP1). The results indicate that the mechanism for natural Sb(V) resistance partially differs from the mechanism reported for in vitro Sb(III) resistance. More specifically, we hypothesize that natural Sb(V) resistance results from (i) a changed thiol metabolism, possibly resulting in inhibition of Sb(V) activation in amastigotes, and (ii) decreased uptake of the active drug Sb(III) by amastigotes.
Shyam Sundar - One of the best experts on this subject based on the ideXlab platform.
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The overexpression of genes of thiol metabolism contribute to drug resistance in clinical isolates of visceral leishmaniasis (kala azar) in India
Parasites & Vectors, 2014Co-Authors: Neeloo Singh, Mitali Chatterjee, Shyam SundarAbstract: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.
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Visceral Leishmaniasis and Arsenic: An Ancient Poison Contributing to Antimonial Treatment Failure in the Indian Subcontinent?
PLoS neglected tropical diseases, 2011Co-Authors: Meghan R. Perry, Shyam Sundar, Susan Wyllie, Vijay Kumar Prajapati, Joerg Feldmann, Marleen Boelaert, Alan H. FairlambAbstract: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.
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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, 2007Co-Authors: Baptiste Vergnes, Shyam Sundar, Benjamin Gourbal, Isabelle Girard, Jolyne Drummelsmith, Marc OuelletteAbstract:: 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.
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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, 2013Co-Authors: Meghan R. Perry, Susan Wyllie, Joerg Feldmann, Andrea Raab, Alan H. FairlambAbstract: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.
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Visceral Leishmaniasis and Arsenic: An Ancient Poison Contributing to Antimonial Treatment Failure in the Indian Subcontinent?
PLoS neglected tropical diseases, 2011Co-Authors: Meghan R. Perry, Shyam Sundar, Susan Wyllie, Vijay Kumar Prajapati, Joerg Feldmann, Marleen Boelaert, Alan H. FairlambAbstract: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.
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Differential toxicity of Antimonial compounds and their effects on glutathione homeostasis in a human leukaemia monocyte cell line.
Biochemical pharmacology, 2005Co-Authors: Susan Wyllie, Alan H. FairlambAbstract: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.
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dual action of Antimonial drugs on thiol redox metabolism in the human pathogen leishmania donovani
Journal of Biological Chemistry, 2004Co-Authors: Susan Wyllie, Mark Cunningham, Alan H. FairlambAbstract:Abstract Despite extensive use of Antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (SbIII) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, SbIII decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, SbIII inhibits trypanothione reductase in intact cells resulting in accumulation of the disulfide forms of trypanothione and glutathione. These two mechanisms combine to profoundly compromise the thiol redox potential in both amastigote and promastigote stages of the life cycle. Furthermore, we demonstrate that sodium stibogluconate, a pentavalent Antimonial used clinically for the treatment for leishmaniasis, induces similar effects on thiol redox metabolism in axenically cultured amastigotes. These observations suggest ways in which current antimony therapies could be improved, overcoming the growing problem of antimony resistance.
Suman Rijal - One of the best experts on this subject based on the ideXlab platform.
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Metabolomics to Unveil and Understand Phenotypic Diversity between Pathogen Populations
2016Co-Authors: Richard A. Scheltema, Andris Jankevics, Kirstyn Brunker, Suman RijalAbstract:Leishmaniasis is a debilitating disease caused by the parasite Leishmania. There is extensive clinical polymorphism, including variable responsiveness to treatment. We study Leishmania donovani parasites isolated from visceral leishmaniasis patients in Nepal that responded differently to Antimonial treatment due to differing intrinsic drug sensitivity of the parasites. Here, we present a proof-of-principle study in which we applied a metabolomics pipeline specifically developed for L. donovani to characterize the global metabolic differences between Antimonial-sensitive and Antimonial-resistant L. donovani isolates. Clones of drug-sensitive and drug-resistant parasite isolates from clinical samples were cultured in vitro and harvested for metabolomics analysis. The relative abundance of 340 metabolites was determined by ZIC-HILIC chromatography coupled to LTQ-Orbitrap mass spectrometry. Our measurements cover approximately 20 % of the predicted core metabolome of Leishmania and additionally detected a large number of lipids. Drug-sensitive and drug-resistant parasites showed distinct metabolic profiles, and unsupervised clustering and principal component analysis clearly distinguished the two phenotypes. For 100 metabolites, the detected intensity differed more than three-fold between the 2 phenotypes. Many of these were in specific areas of lipid metabolism, suggesting that the membrane composition of the drug-resistant parasites is extensively modified. Untargeted metabolomics has been applied on clinical Leishmania isolates to uncover major metaboli
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relapse after treatment with miltefosine for visceral leishmaniasis is associated with increased infectivity of the infecting leishmania donovani strain
Mbio, 2013Co-Authors: Bart Cuypers, Suman Rijal, Jean-claude Dujardin, Narayan Raj Bhattarai, Surendra Uranw, Maya Berg, Bart Ostyn, Manu VanaerschotAbstract: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.
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Antimonial treatment of visceral leishmaniasis: are current in vitro susceptibility assays adequate for prognosis of in vivo therapy outcome?
Microbes and infection, 2007Co-Authors: Suman Rijal, Marleen Boelaert, Vanessa Yardley, François Chappuis, Saskia Decuypere, Basudha Khanal, Rupa Singh, Simonne De Doncker, Simon L. Croft, Jean-claude DujardinAbstract: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.
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Epidemiological dynamics of Antimonial resistance in Leishmania donovani: Genotyping reveals a polyclonal population structure among naturally-resistant clinical isolates from Nepal
Infection genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2006Co-Authors: Thierry Laurent, Suman Rijal, Vanessa Yardley, Saskia Decuypere, Basudha Khanal, Rupa Singh, Simonne De Doncker, Simon L. Croft, Gabriele Schönian, Katrin KuhlsAbstract:Pentavalent Antimonials (SbV) are the first line drug against leishmaniasis worldwide, but drug resistance is increasingly reported, particularly in the Indian sub-continent, where it represents a major threat for the control of anthroponotic visceral leishmaniasis (VL). In order to understand the epidemiological dynamics of Antimonial resistance in anthroponotic VL, we analysed here the population structure of 24 Leishmania donovani stocks isolated from anthroponotic VL-patients from Eastern Nepal: 13 SbV-naturally resistant and 11 SbV-sensitive, as demonstrated by in vitro drug susceptibility assays. The parasites were genotyped by PCR-RFLP analysis of kDNA minicircles and by microsatellite analysis and the encountered polymorphism revealed a polyclonal structure among resistant isolates. Furthermore, analysis of paired samples obtained from the same patients before treatment and after failure revealed primary as well as acquired resistance. The hypothesis of independent events of drug resistance emergence is proposed and confronted to alternative explanations. Our results show the dynamics of drug resistance epidemiology and highlight the importance of surveillance networks.
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gene expression analysis of the mechanism of natural sb v resistance in leishmania donovani isolates from nepal
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Suman Rijal, Vanessa Yardley, Saskia Decuypere, Basudha Khanal, Simonne De Doncker, Thierry Laurent, Francois Chappuis, Jean-claude DujardinAbstract:Control of visceral leishmaniasis (VL) is being challenged by the emergence of natural resistance against the first line of treatment, pentavalent Antimonials [Sb(V)]. An insight into the mechanism of natural Sb(V) resistance is required for the development of efficient strategies to monitor the emergence and spreading of Sb(V) resistance in countries where VL is endemic. In this work, we have focused on the mechanism of natural Sb(V) resistance emerging in Nepal, a site where anthroponotic VL is endemic. Based on the current knowledge of Sb(V) metabolism and of the in vitro trivalent Antimonial [Sb(III)] models of resistance to Leishmania spp., we selected nine genes for a comparative transcriptomic study on natural Sb(V)-resistant and -sensitive Leishmania donovani isolates. Differential gene expression patterns were observed for the genes coding for 2-thiol biosynthetic enzymes, gamma-glutamylcysteine synthetase (GCS) and ornithine decarboxylase (ODC), and for the Sb(III) transport protein aquaglyceroporin 1 (AQP1). The results indicate that the mechanism for natural Sb(V) resistance partially differs from the mechanism reported for in vitro Sb(III) resistance. More specifically, we hypothesize that natural Sb(V) resistance results from (i) a changed thiol metabolism, possibly resulting in inhibition of Sb(V) activation in amastigotes, and (ii) decreased uptake of the active drug Sb(III) by amastigotes.
Piero Olliaro - One of the best experts on this subject based on the ideXlab platform.
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treatment of cutaneous leishmaniasis with aminosidine paromomycin ointment double blind randomized trial in the islamic republic of iran
Bulletin of The World Health Organization, 2003Co-Authors: Ali Asilian, T Jalayer, M Nilforooshzadeh, R L Ghassemi, Richard Peto, S Wayling, Piero Olliaro, Farrokh ModabberAbstract:Objective: To compare the parasitological and clinical efficacy of four weeks versus two weeks of treatment with aminosidine (paromomycin) ointment in patients with cutaneous leishmaniasis caused by Leishmania major in the Islamic Republic of Iran. Methods: Double-blind, randomized trial of four weeks of aminosidine ointment (n = 108) vs two weeks of aminosidine ointment and two weeks of placebo (n = 108). Patients were assessed on days 15, 29, 45, and 105 for clinical cures and clinical and parasitological cures. Findings: Four weeks' treatment gave significantly better cure rates than two weeks' treatment: on day 29, there were 80/108 (74%) vs 64/108 (59%) clinical cures (P = 0.05) and 47 (44%) vs 26 (24%) clinical and parasitological cures (P = 0.005). By day 45, fewer patients who received four weeks' treatment had required rescue treatment with Antimonials than those who received two weeks' treatment: 20 (19%) vs 36 (33%) (P = 0.02). On day 105, the results still favoured those who had been allocated four weeks of active treatment, but the differences were no longer as clearly significant. No side-effects were observed or reported. Conclusion: Approximately two-thirds of patients given ointment for four weeks were cured clinically. Although about half of those cured might have recovered spontaneously even without treatment, four weeks of aminosidine ointment could become the first-line treatment for uncomplicated cutaneous leishmaniasis due to L. major, with Antimonials needed in only the one-third of patients not cured by the end of treatment with aminosidine. This would considerably reduce the costs and side-effects associated with Antimonial drugs.
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treatment of visceral leishmaniasis kala azar with aminosidine paromomycin Antimonial combinations a pilot study in bihar india
Transactions of The Royal Society of Tropical Medicine and Hygiene, 1992Co-Authors: C P Thakur, Piero Olliaro, S Gothoskar, S Bhowmick, B K Choudhury, S Prasad, Manoj Kumar, B B VermaAbstract:A 20 d drug regimen of aminosidine (= paromomycin) at 12 mg/kg/d in combination with sodium stibogluconate at 20 mg/kg/d proved efficacious and well-tolerated in patients with visceral leishmaniasis in the State of Bihar, India. Eighteen of 22 evaluable patients achieved an ultimate cure. The remaining 4 patients, although not cleared of parasites, had their parasite grade reduced and also improved clinically. This confirms prior findings in Kenyan patients with kala-azar, and indicates that this regimen is a valid alternative to Antimonial compounds alone in the State of Bihar, where cases of kala-azar not responding to Antimonial drugs and intolerant of pentamidine are increasingly recorded.
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Treatment of visceral leishmaniasis (kala-azar) with aminosidine (= paromomycin)-Antimonial combinations, a pilot study in Bihar, India.
Transactions of the Royal Society of Tropical Medicine and Hygiene, 1992Co-Authors: Piero Olliaro, S Gothoskar, S Bhowmick, B K Choudhury, S Prasad, Manoj Kumar, B B VermaAbstract:A 20 d drug regimen of aminosidine (= paromomycin) at 12 mg/kg/d in combination with sodium stibogluconate at 20 mg/kg/d proved efficacious and well-tolerated in patients with visceral leishmaniasis in the State of Bihar, India. Eighteen of 22 evaluable patients achieved an ultimate cure. The remaining 4 patients, although not cleared of parasites, had their parasite grade reduced and also improved clinically. This confirms prior findings in Kenyan patients with kala-azar, and indicates that this regimen is a valid alternative to Antimonial compounds alone in the State of Bihar, where cases of kala-azar not responding to Antimonial drugs and intolerant of pentamidine are increasingly recorded.
