scholarly journals Use of Antimony in the Treatment of Leishmaniasis: Current Status and Future Directions

2011 ◽  
Vol 2011 ◽  
pp. 1-23 ◽  
Author(s):  
Arun Kumar Haldar ◽  
Pradip Sen ◽  
Syamal Roy
Keyword(s):  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Current Status ◽  
Vanadium Compounds ◽  
Future Directions ◽  
Kala Azar ◽  
Efflux Mechanism ◽  
Transplantation Antigens ◽  
Antigen Presenting

In the recent past the standard treatment of kala-azar involved the use of pentavalent antimonials Sb(V). Because of progressive rise in treatment failure to Sb(V) was limited its use in the treatment program in the Indian subcontinent. Until now the mechanism of action of Sb(V) is not very clear. Recent studies indicated that both parasite and hosts contribute to the antimony efflux mechanism. Interestingly, antimonials show strong immunostimulatory abilities as evident from the upregulation of transplantation antigens and enhanced T cell stimulating ability of normal antigen presenting cells when treated with Sb(V) in vitro. Recently, it has been shown that some of the peroxovanadium compounds have Sb(V)-resistance modifying ability in experimental infection with Sb(V) resistant Leishmania donovani isolates in murine model. Thus, vanadium compounds may be used in combination with Sb(V) in the treatment of Sb(V) resistance cases of kala-azar.

scholarly journals Inhibition of ABC Transporters Abolishes Antimony Resistance in Leishmania Infection

2007 ◽  
Vol 52 (3) ◽  
pp. 1080-1093 ◽  
Author(s):  
Jayati Mookerjee Basu ◽  
Ananda Mookerjee ◽  
Rajdeep Banerjee ◽  
Manik Saha ◽  
Subhankar Singh ◽  
...  
Keyword(s):  
Abc Transporters ◽  
Leishmania Donovani ◽  
Host Cells ◽  
Leishmania Infection ◽  
Blood Monocytes ◽  
Glycoprotein P ◽  
Kala Azar ◽  
Antimony Resistance ◽  
Parasite Replication

ABSTRACT The emergence of antimony (Sb) resistance has jeopardized the treatment of visceral leishmaniasis in various countries. Previous studies have considered the part played by leishmanial parasites in antimony resistance, but the involvement of host factors in the clinical scenario remained to be investigated. Here we show that unlike infection with Sb-sensitive (Sbs) Leishmania donovani, infection with Sb-resistant (Sbr) L. donovani induces the upregulation of multidrug resistance-associated protein 1 (MRP1) and permeability glycoprotein (P-gp) in host cells, resulting in a nonaccumulation of intracellular Sb following treatment with sodium antimony gluconate (SAG) favoring parasite replication. The inhibition of MRP1 and P-gp with resistance-modifying agents such as lovastatin allows Sb accumulation and parasite killing within macrophages and offers protection in an animal model in which infection with Sbr L. donovani is otherwise lethal. The occurrence of a similar scenario in clinical cases is supported by the findings that unlike monocytes from SAG-sensitive kala-azar (KA) patients, monocytes from SAG-unresponsive KA patients overexpress P-gp and MRP1 and fail to accumulate Sb following in vitro SAG treatment unless pretreated with inhibitors of ABC transporters. Thus, the expression status of MRP1 and P-gp in blood monocytes may be used as a diagnostic marker for Sb resistance and the treatment strategy can be designed accordingly. Our results also indicate that lovastatin, which can inhibit both P-gp and MRP1, might be beneficial for reverting Sb resistance in leishmaniasis as well as drug resistance in other clinical situations, including cancer.

scholarly journals In VivoSelection of Paromomycin and Miltefosine Resistance in Leishmania donovani and L. infantum in a Syrian Hamster Model

2015 ◽  
Vol 59 (8) ◽  
pp. 4714-4718 ◽  
Author(s):  
S. Hendrickx ◽  
A. Mondelaers ◽  
E. Eberhardt ◽  
P. Delputte ◽  
P. Cos ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Primary Resistance ◽  
Hamster Model ◽  
Content Type ◽  
Resistance Selection ◽  
Syrian Golden Hamsters ◽  
Resistant Strains ◽  
Selection Of

ABSTRACTIn 2002 and 2006, respectively, miltefosine (MIL) and paromomycin (PMM) were licensed in the Indian subcontinent for treatment of visceral leishmaniasis; however, their future routine use might become jeopardized by the development of drug resistance. Although experimental selection of resistant strainsin vitrohas repeatedly been reported using the less relevant promastigote vector stage, the outcome of resistance selection on intracellular amastigotes was reported to be protocol and species dependent. To corroborate thesein vitrofindings, selection of resistance inLeishmania donovaniandLeishmania infantumwas achieved by successive treatment/relapse cycles in infected Syrian golden hamsters. For PMM, resistant amastigotes were already obtained within 3 treatment/relapse cycles, while their promastigotes retained full susceptibility, thereby sharing the same phenotypic characteristics asin vitro-generated PMM-resistant strains. For MIL, even five treatment/relapse cycles failed to induce significant susceptibility changes in either species, which also corresponds with thein vitroobservations where selection of an MIL-resistant phenotype proved to be quite challenging. In conclusion, these results argue for cautious use of PMM in the field to avoid rapid emergence of primary resistance and highlight the need for additional research on the mechanisms and dynamics of MIL resistance selection.

scholarly journals In Vitro Low Responsiveness of Leishmania donovani Towards Sodium Antimony Gluconate

2016 ◽  
Vol 2 (1) ◽  
pp. 8-12
Author(s):  
Murshed Alam ◽  
AKM Shamsuzzaman ◽  
AKM Musa ◽  
Abul Hossain Khan ◽  
Md Chand Mahmud ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Leishmania Donovani ◽  
Standard Dose ◽  
Kala Azar ◽  
History Of ◽  
Resistant Strains ◽  
Drug Responsiveness ◽  
Drug Resistant Strains ◽  
Sodium Antimony Gluconate

Kala-azar has been uprising concomitantly with drug-resistant strains of the causatinve agent, particularly in the neighbouring India. The actual perspective of drug resistance in Leishmania donovani in Bangladesh is yet to be explored. So, this prospective study, as a preliminary one, was done to observe in vitro drug responsiveness against Sodium Antimony Gluconate (SAG) and Amphotericin B of 41 strains of L. donovani isolated from Kala-azar cases. The cases (n=41) were selected from 45 clinically suspected febrile patients those who were positive for Kala-azar by immunochromatographic test (ICT). The selected cases were subsequently confirmed as Kala-azar by detection of Leishmania Donovan (LD) bodies from bone marrow aspirates (n=38) by microscopy and/or showing promastigotes in modified McNeal, Nicole and Novy (NNN) media (n=41). Minimum Inhibitory Concentrations (MICs) of SAG and Amphotericin B were seen in relation with history of previous SAG therapy of the patients. Among 08 strains with previous SAG therapy, MICs of SAG were 500 µg in 05 (62.5%) and 250 µg in 03 (37.5%) cases. In remaining 33 strains with no previous SAG therapy, MIC of the drug was 250 µg. In all 41 strains, MIC of Amphotericin B was 05 µg irrespective of the history of previous SAG therapy. The study revealed that strains of L. donovani with low responsiveness to standard dose of pentavalent antimonials have been started to appear in our community that needs further study at community level in a larger population.Bangladesh J Med Microbiol 2008; 02 (01): 8-12DOI: http://dx.doi.org/10.3329/bjmm.v2i1.21782

scholarly journals Spatial analysis ofLeishmania donovaniexposure in humans and domestic animals in a recent kala azar focus in Nepal

Parasitology ◽  
2010 ◽  
Vol 137 (11) ◽  
pp. 1597-1603 ◽  
Author(s):  
BASUDHA KHANAL ◽  
ALBERT PICADO ◽  
NARAYAN RAJ BHATTARAI ◽  
GERT VAN DER AUWERA ◽  
MURARI LAL DAS ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Public Health Problem ◽  
Domestic Animals ◽  
Major Public Health Problem ◽  
Scan Statistic ◽  
Transmission Cycle ◽  
Kala Azar ◽  
Information System Technology

SUMMARYVisceral leishmaniasis (VL) is a major public health problem in the Indian subcontinent where theLeishmania donovanitransmission cycle is described as anthroponotic. However, the role of animals (in particular domestic animals) in the persistence and expansion of VL is still a matter of debate. We combined Direct Agglutination Test (DAT) results in humans and domestic animals with Geographic Information System technology (i.e. extraction maps and scan statistic) to evaluate the exposure toL. donovanion these 2 populations in a recent VL focus in Nepal. A Poisson regression model was used to assess the risk of infection in humans associated with, among other factors, the proportion of DAT-positive animals in the proximities of the household. The serological results showed that both humans and domestic animals were exposed toL. donovani. DAT-positive animals and humans were spatially clustered. The presence of serologically positive goats (IRR=9·71), past VL cases (IRR=2·62) and the proximity to a forest island dividing the study area (IRR=3·67) increased the risk of being DAT-positive in humans. Even if they are not a reservoir, domestic animals, and specially goats, may play a role in the distribution ofL. donovani, in particular in this new VL focus.

scholarly journals Peptides to Tackle Leishmaniasis: Current Status and Future Directions

2021 ◽  
Vol 22 (9) ◽  
pp. 4400
Author(s):  
Alberto A. Robles-Loaiza ◽  
Edgar A. Pinos-Tamayo ◽  
Bruno Mendes ◽  
Cátia Teixeira ◽  
Cláudia Alves ◽  
...  
Keyword(s):  
Structural Characteristics ◽  
Treatment Options ◽  
Peptide Sequence ◽  
Current Status ◽  
In Vitro Assays ◽  
Amino Acid Residues ◽  
Future Directions ◽  
Innovative Therapies ◽  
Antileishmanial Drug

Peptide-based drugs are an attractive class of therapeutic agents, recently recognized by the pharmaceutical industry. These molecules are currently being used in the development of innovative therapies for diverse health conditions, including tropical diseases such as leishmaniasis. Despite its socioeconomic influence on public health, leishmaniasis remains long-neglected and categorized as a poverty-related disease, with limited treatment options. Peptides with antileishmanial effects encountered to date are a structurally heterogeneous group, which can be found in different natural sources—amphibians, reptiles, insects, bacteria, marine organisms, mammals, plants, and others—or inspired by natural toxins or proteins. This review details the biochemical and structural characteristics of over one hundred peptides and their potential use as molecular frameworks for the design of antileishmanial drug leads. Additionally, we detail the main chemical modifications or substitutions of amino acid residues carried out in the peptide sequence, and their implications in the development of antileishmanial candidates for clinical trials. Our bibliographic research highlights that the action of leishmanicidal peptides has been evaluated mainly using in vitro assays, with a special emphasis on the promastigote stage. In light of these findings, and considering the advances in the successful application of peptides in leishmaniasis chemotherapy, possible approaches and future directions are discussed here.

scholarly journals Immunomodulation in Human Dendritic Cells Leads to Induction of Interferon-Gamma Production byLeishmania donovaniDerived KMP-11 Antigen via Activation of NF-κB in Indian Kala-Azar Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Rajesh Chaudhary ◽  
Ajay Amit ◽  
Anupam Yadav ◽  
Anurag Singh ◽  
Vikash Kumar ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Leishmania Donovani ◽  
T Cell Anergy ◽  
Kala Azar ◽  
Human Dendritic Cells ◽  
Antigen Presenting ◽  
And Control ◽  
Stimulation Of

Dendritic cells (DCs) and macrophages (MΦs) are well-known antigen presenting cells with an ability to produce IL-12 which indicates that they have potential of directing acquired immunity toward a Th1-biased response. The aim of this study was to examine the effect ofLeishmaniaspecific KMP-11 antigen through comparison of immune responses after presentation by DCs and MΦs to T cells in Indian patients with VL. Patients with DCS and MΦs were directed against a purifiedLeishmania donovaniantigen (KMP-11) and phytohaemagglutinin (PHA). The cytokines (IL-12, IL-10, and TGF-β) producing abilities of the DCs and MΦs against these antigens were determined by flow cytometry. The transcription factor (NF-κB) and T-cell cytokine support (IFN-γ, IL-10), which could be significant in effector immune function, were also determined. Severe hindrance in the immune protection due toLeishmaniaparasites, as revealed by decreased expression of IL-12 and upregulation of IL-10 and TGF-βexpression in the MΦs compared to DCs, occurred in VL patients. The production of IL-12 in response toL. donovaniKMP-11 antigen was increased in DCs which was reduced in MΦs of VL patients. In contrast, the presentation of KMP-11 antigen by DCs to T-lymphocytes in VL patients significantly increased the IFN-γproduced by these immune cells, whereas the levels of IL-10 were significantly elevated after presentation of KMP-11antigen by MΦs. The VL patients were observed with severely dysfunctional MΦs in terms of NF-κB activity that could be recovered only after stimulation of DCs withL. donovaniKMP-11 antigen. Immunologically the better competitiveness of KMP-11 antigen through a dendritic cell delivery system may be used to revert T-cell anergy, and control strategy can be designed accordingly against kala-azar.

scholarly journals Relapse after Treatment with Miltefosine for Visceral Leishmaniasis Is Associated with Increased Infectivity of the Infecting Leishmania donovani Strain

mBio ◽  
2013 ◽  
Vol 4 (5) ◽  
Author(s):  
Keshav Rai ◽  
Bart Cuypers ◽  
Narayan Raj Bhattarai ◽  
Surendra Uranw ◽  
Maya Berg ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Treatment Failure ◽  
Relapse Rate ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Drug Susceptibility ◽  
Current View ◽  
Content Type ◽  
Control Programs ◽  
Kala Azar

ABSTRACTLeishmania donovaniis 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 ofL. donovaniagainst 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.IMPORTANCEThe 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-resistantL. donovaniwhere an increased infectivity was also observed. This challenges the current view ofLeishmaniadrug 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.

Implications of co-infection ofLeptomonasin visceral leishmaniasis in India

Parasitology ◽  
2015 ◽  
Vol 142 (14) ◽  
pp. 1657-1662 ◽  
Author(s):  
ANGAMUTHU SELVAPANDIYAN ◽  
KAVITA AHUJA ◽  
NITI PURI ◽  
ANUJA KRISHNAN
Keyword(s):  
Immune Response ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Vaccine Development ◽  
Indian Subcontinent ◽  
Clinical Isolates ◽  
Protozoan Parasites ◽  
New Paradigm ◽  
Insect Parasite ◽  
Kala Azar

SUMMARYProtozoan parasitesLeishmania donovani(family: Trypanosomatidae) cause fatal visceral leishmaniasis (VL) and the infection relapses in apparently cured population as post kala-azar dermal leishmaniasis (PKDL) in the Indian subcontinent. In recent years co-infection of another Trypanosomatid parasiteLeptomonaswithL. donovaniduring VL/PKDL in this region has become prominent. The observation of clinically lesser-known insect parasite,Leptomonasin leishmaniasis is intriguing to researchers. The presence of Leishmania look alikeLeptomonasin the cultures of clinical isolates ofLeishmaniahas been worrisome to those, who prefer to work with pureLeishmaniacultures for drug and vaccine development or immune response studies. The exact implications of such a co-habitation, which might lead to a delay in the diagnostics of VL and elevate mortality, need a thorough investigation. Also whetherLeptomonasis involved in leishmaniasis manifestation needs to be ascertained. Thus we are currently witnessing a new paradigm of a parasitic co-infection in VL/PKDL cases in India and this review outlines various opportunities for further research in understanding such emerging co-infection.

scholarly journals Impact of sequelae of visceral leishmaniasis and their contribution to ongoing transmission of Leishmania donovani

2019 ◽  
Vol 77 (6) ◽  
Author(s):  
Malcolm S Duthie ◽  
Yasuyuki Goto ◽  
Prakash Ghosh ◽  
Dinesh Mondal
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Positive Impact ◽  
Indian Subcontinent ◽  
Intervention Strategies ◽  
Diagnostic Methods ◽  
Control Programs ◽  
Kala Azar ◽  
New Treatments

ABSTRACT Visceral leishmaniasis (VL) in the Old World is caused by infection with Leishmania donovani. Although the numbers of new reported cases of VL in Africa have been relatively stable for several years, the low numbers currently reported on the Indian subcontinent suggest a positive impact of new treatments and intervention strategies. In both regions, however, VL relapse and post-kala-azar dermal leishmaniasis (PKDL) maintain infectious reservoirs and therefore present a threat to control programs. In this review, we outline the evolving appreciation of PKDL as an impactful disease in its own right and discuss the various diagnostic methods that can be applied for the detection and characterization of PKDL cases. We also highlight the data that indicate the potential, and likely contribution, of PKDL cases to ongoing transmission of L. donovani.

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