Failure of Pentavalent Antimony in Visceral Leishmaniasis in India: Report from the Center of the Indian Epidemic

Sundar, Shyam; More, Deepak K.; Singh, Manoj Kumar; Singh, Vijay Pratap; Sharma, Swati; Makharia, Anand; Kumar, Puneet; Murray, Henry W.

doi:10.1086/318121

Cited by 559 publications

(420 citation statements)

References 17 publications

(35 reference statements)

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“…2 Until recently, first-line therapy for VL in all these countries was pentavalent antimonials (Sb v ). 3 However, since the 1990 s a sustained and progressive decline in cure rates with Sb v has been reported from the Bihar state of India, 4,5 and indications of similar trends were also observed in Nepal. 6 In contrast, Sb v therapy continues to be effective in HIV-negative kala-azar patients in Bangladesh and East Africa.…”

Section: Introductionmentioning

confidence: 74%

Clinical risk factors for therapeutic failure in kala-azar patients treated with pentavalent antimonials in Nepal

Rijal

Bhandari

Koirala

et al. 2010

Transactions of the Royal Society of Tropical Medicine and Hygi

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a b s t r a c tDrug-related factors and parasite resistance have been implicated in the failure of pentavalent antimonials (Sb v ) in the Indian subcontinent; however, little information is available on host-related factors. Parasitologically confirmed kala-azar patients, treatment naïve to Sb v , were prospectively recruited at a referral hospital in Nepal and were treated under supervision with 30 doses of quality-assured sodium stibogluconate (SSG) 20 mg/kg/day and followed for 12 months to assess cure. Analysis of risk factors for treatment failure was assessed in those receiving ≥25 doses and completing 12 months of follow-up. One hundred and ninety-eight cases were treated with SSG and the overall cure rate was 77.3% (153/198). Of the 181 cases who received ≥25 doses, 12-month follow-up data were obtained in 169, comprising 153 patients (90.5%) with definite cure and 16 (9.5%) treatment failures. In the final logistic regression model, increased failure to SSG was significantly associated with fever for ≥12 weeks [odds ratio (OR) = 7.4], living in districts bordering the high SSG resistance zone in Bihar (OR = 6.1), interruption of treatment (OR = 4.3) and ambulatory treatment (OR = 10.2). Early diagnosis and supervised treatment is of paramount importance to prevent treatment failures within the control programme.

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Section: Introductionmentioning

confidence: 74%

Clinical risk factors for therapeutic failure in kala-azar patients treated with pentavalent antimonials in Nepal

Rijal

Bhandari

Koirala

et al. 2010

Transactions of the Royal Society of Tropical Medicine and Hygi

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“…This was relevant because of the failure of conventional chemotherapeutic agents due to the emergence of resistance to pentavalent antimonials (5,66). Mice were immunized with pUMVC3-UB-ORFF DNA vaccine and challenged with antimony-sensitive AG83 or -resistant GE1F8R promastigotes of L. donovani and checked for the parasite burden in spleen and liver of infected mice.…”

Section: Discussionmentioning

confidence: 99%

“…However, current chemotherapeutic agents are unsuitable, in part because of their high toxicity and the emergence of drug resistance (4,5). Thus, identification of novel immunological targets that can be effective against both antimony-susceptible and -resistant strains of Leishmania is of tremendous economic and medical importance (6).…”

Section: Ubiquitin Conjugation Of Open Reading Frame F Dna Vaccine Lementioning

confidence: 99%

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

Sharma

Madhubala

2009

The Journal of Immunology

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Resistance of Leishmania donovani to sodium antimony gluconate has become a critical issue in the current, prolonged epidemic in India. Hence, there is an urgent need for a vaccine that is protective against both antimony-susceptible and -resistant strains of L. donovani. The multigene LD1 locus located on chromosome 35 of Leishmania is amplified in ∼15% of the isolates examined. The open reading frame F (ORFF), a potential vaccine candidate against visceral leishmaniasis, is part of the multigene LD1 locus. ORFF was expressed as a chimeric conjugate of ubiquitin to elicit an Ag-specific cell-mediated immune response. Analysis of the cellular immune responses of ubiquitin-conjugated ORFF (UBQ-ORFF) DNA-immunized, uninfected BALB/c mice demonstrated that the vaccine induced enhanced IFN-γ-producing CD4+ and CD8+ T cells compared with nonubiquitinated ORFF DNA vaccine. Higher levels of IL-12 and IFN-γ and the low levels of IL-4 and IL-10 further indicated that the immune responses with UBQ-ORFF were mediated toward the Th1 rather than Th2 type. Infection of immunized mice with either the antimony-susceptible (AG83) or -resistant (GE1F8R) L. donovani strain showed that UBQ-ORFF DNA vaccine induced higher protection when compared with ORFF DNA. UBQ-ORFF DNA-immunized and -infected mice showed a significant increase in IL-12 and IFN-γ and significant down-regulation of IL-10. High levels of production of nitrite and superoxide, two macrophage-derived oxidants that are critical in controlling Leishmania infection, were observed in protected mice. The feasibility of using ubiquitinated-conjugated ORFF DNA vaccine as a promising immune enhancer for vaccination against both antimony-susceptible and -resistant strains of L. donovani is reported.

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“…All of these drugs have severe limitations including administration diffculties, long treatment regimes, lifethreatening side effects, varied parasitological cure rates for different strains, lack of effcacy against late stage diseases, and increasing incidence of drug resistance. [2][3][4][5] The intracellular reducing environment of trypanosomatids is maintained by a unique thiol redox system where the glutathione/glutathione reductase (GR) couple found in mammalian cells is replaced by the (bis-glutathionyl)spermidine trypanothione/trypanothione reductase (TR) couple. 6 TR is a key enzyme of the parasite antioxidant defence, 7,8 does not occur in the mammalian host and has been found to be essential for all trypanosomatids currently studied.…”

mentioning

confidence: 99%

Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening

Holloway

Baell

Fairlamb

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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A high-throughput screening campaign of a library of 100,000 lead-like compounds identified 2-iminobenzimidazoles as a novel class of trypanothione reductase inhibitors. These 2-iminobenzimidazoles display potent trypanocidal activity against Trypanosoma brucei rhodesiense, do not inhibit closely related human glutathione reductase and have low cytotoxicity against mammalian cells. KeywordsTropical diseases; Trypanosomiasis therapeutics; Trypanothione reductase inhibitors; Highthroughput screening; Medicinal chemistry; Imino benzimidazoles Parasitic protozoa of the family Trypanosomatidae are the causative agent of many significant tropical diseases including African trypanosomiasis, Chagas disease and Leishmaniasis. In the 2004 world health report 1 African trypanosomiasis was reported to cause 48 thousand deaths and a disease burden of 1525 thousand DALYs (disability adjusted life years) annually, Chagas disease 14 thousand deaths and a disease burden of 667 thousand DALYs and Leishmaniasis 51 thousand deaths and a disease burden of 2090 DALYs. There are currently nine key drugs in use for the treatment of these disease states ( Fig. 1): suramin and pentamidine against early stage African trypanosomiasis, and eflornithine and melarsoprol against late stage disease; nifurtimox and benznidazole against early stage Chagas disease; meglumine antimonite and sodium stibogluconate against Leishmaniasis, and amphotericin B against anti-mony-resistant strains. All of these drugs have severe limitations including administration diffculties, long treatment regimes, lifethreatening side effects, varied parasitological cure rates for different strains, lack of effcacy against late stage diseases, and increasing incidence of drug resistance. [2][3][4][5] The intracellular reducing environment of trypanosomatids is maintained by a unique thiol redox system where the glutathione/glutathione reductase (GR) couple found in mammalian cells is replaced by the (bis-glutathionyl)spermidine trypanothione/trypanothione reductase (TR) couple. 6 TR is a key enzyme of the parasite antioxidant defence, 7,8 does not occur in the mammalian host and has been found to be essential for all trypanosomatids currently studied. 9 Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts TR and human GR have similar catalytic mechanisms with 14 of the 19 amino acid residues close to the substrate binding site being conserved. However, they are specific to their respective disulfide substrates (Fig. 2). 11 GR has a hydrophilic, positively charged region in its active site that interacts with the glycine carboxylates of glutathione disulfide, while TR has a larger binding site with a negatively charged region with which the spermidine moiety of trypanothione disulfide binds. 12 The absence of TR from the mammalian host and the sensitivity of trypanosomatids to oxidative stress makes TR an attractive target for trypanosomiasis therapeutics. 13 The objective of this work, therefore, was to identify novel classes of TR inhibit...

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Failure of Pentavalent Antimony in Visceral Leishmaniasis in India: Report from the Center of the Indian Epidemic

Cited by 559 publications

References 17 publications

Clinical risk factors for therapeutic failure in kala-azar patients treated with pentavalent antimonials in Nepal

Clinical risk factors for therapeutic failure in kala-azar patients treated with pentavalent antimonials in Nepal

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening

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