Efficacy of Miltefosine in the Treatment of Visceral Leishmaniasis in India After a Decade of Use

Sundar, Shyam; Singh, Anup; Rai, Madhukar; Prajapati, Vijay Kumar; Singh, Avinash; Ostyn, Bart; Boelaert, Marleen; Dujardin, Jean‐Claude; Chakravarty, Jaya

doi:10.1093/cid/cis474

Cited by 266 publications

(222 citation statements)

References 19 publications

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“…This is even more concerning, when one is reminded that both Sb and miltefosine exploit the same efflux pump (40). Further work is required to understand if the increasing treatment failure rate of miltefosine in the Indian subcontinent is the consequence of the heritage of the antimonials (41). Our study provides molecular insights as to how Sb R LD differentially scrutinizes the innate immune machinery of the host, thereby up-regulating IL-10 and subsequently overexpressing MDR1, giving rise to distinct treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

Antimony-resistant but not antimony-sensitiveLeishmania donovaniup-regulates host IL-10 to overexpress multidrug-resistant protein 1

Mukherjee

Mukhopadhyay

Bannerjee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The molecular mechanism of antimony-resistant Leishmania donovani (Sb R LD)-driven up-regulation of IL-10 and multidrug-resistant protein 1 (MDR1) in infected macrophages (Mϕs) has been investigated. This study showed that both promastigote and amastigote forms of Sb R LD, but not the antimony-sensitive form of LD, express a unique glycan with N-acetylgalactosamine as a terminal sugar. Removal of it either by enzyme treatment or by knocking down the relevant enzyme, galactosyltransferase in Sb R LD (KD Sb R LD), compromises the ability to induce the above effects. Infection of Mϕs with KD Sb R LD enhanced the sensitivity toward antimonials compared with infection with Sb R LD, and infection of BALB/c mice with KD Sb R LD caused significantly less organ parasite burden compared with infection induced by Sb R LD. The innate immune receptor, Toll-like receptor 2/6 heterodimer, is exploited by Sb R LD to activate ERK and nuclear translocation of NF-κB involving p50/c-Rel leading to IL-10 induction, whereas MDR1 up-regulation is mediated by PI3K/Akt and the JNK pathway. Interestingly both recombinant IL-10 and Sb R LD up-regulate MDR1 in Mϕ with different time kinetics, where phosphorylation of PI3K was noted at 12 h and 48 h, respectively, but Mϕs derived from IL-10 −/− mice are unable to show MDR1 up-regulation on infection with Sb R LD. Thus, it is very likely that an IL-10 surge is a prerequisite for MDR1 up-regulation. The transcription factor important for IL-10-driven MDR1 up-regulation is c-Fos/c-Jun and not NF-κB, as evident from studies with pharmacological inhibitors and promoter mapping with deletion constructs.visceral leishmaniasis | antimony resistance | glycoconjugate | antimony efflux K ala-azar or visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani (LD), is (re)emerging and spreading worldwide, essentially because of humanmade and environmental changes, immunosuppression, and drug resistance (1, 2). To combat the disease, organic pentavalent antimonials were introduced in the Indian subcontinent almost 9 decades ago (3) with dramatic clinical success. However, the toxicity, together with the high treatment failure rate (up to 65%) and the emergence of resistance in Bihar State, India, made the drug obsolete in the Indian subcontinent (4, 5). Nevertheless, it is still used as a first-line treatment in Africa and Latin America (6). Interestingly, 78% of the recent clinical isolates from the hyperendemic zone of Bihar State still showed in vitro resistance to antimonials (7), which might be explained by an increased fitness of the corresponding parasites (8).Recently, we have demonstrated three unique characteristics of antimony-resistant LD (Sb R LD). First, it shows a higher concentration of terminal glycoconjugates (N-acetylgalactosamine residues) on its surface than antimony-sensitive LD (Sb S LD) (7).Second, on infection of macrophages (Mϕs), Sb R LD induces a surge of IL-10 (7, 9). Third, we also observed that Sb R LD modulates host cells to overexpress the ATP-b...

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Section: Discussionmentioning

confidence: 99%

Antimony-resistant but not antimony-sensitiveLeishmania donovaniup-regulates host IL-10 to overexpress multidrug-resistant protein 1

Mukherjee

Mukhopadhyay

Bannerjee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…36 Those patients who could not be given amphotericin B were treated with capsules of miltefosine for 28 days in the dose of 2.5 mg/kg body weight in two divided doses orally, except females of child-bearing age and pregnant females. 37 Statistical analysis. All data were entered in a computer using Excel (Version MS Office 7).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of rK-39 Strip Test Using Urine for Diagnosis of Visceral Leishmaniasis in an Endemic Region of India

Singh

Pandey

Das

et al. 2013

The American Society of Tropical Medicine and Hygiene

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Abstract. The definitive diagnosis of visceral leishmaniasis (VL) requires invasive procedures for demonstration of parasites in tissue smear or culture. These procedures need expertise and laboratory supports and cannot be performed in the field. The aim of the present study was to evaluate the existing rK-39 immunochromatographic nitrocellulose strips test (ICT) with some modification in human urine for diagnosis of VL. The test was performed on both sera and urine samples on the same 786 subjects (365 confirmed VL and 421 control subjects). The sensitivity of the rK-39 ICT in serum was 100%, whereas the specificity was 93.8%, 100%, and 96.2% in healthy controls from endemic, non-endemic, and other infectious diseases, respectively. However, in urine samples, the test showed 96.1% sensitivity and 100% specificity. Considering sensitivity and feasibility of the test in the field, rK-39 ICT using urine samples can be an alternative to conventional invasive VL diagnosis.

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“…Currently, miltefosine is licensed in India, Colombia, and Germany. It is administered at a dose of 150 mg (in 2e3 doses) for 28 days in adults >50 kg (50 mg/day in adults weighting <50 kg, 2.5 mg/kg/day in children), and 150 mg/day (in 2e3 doses) for 6 weeks in immunodeficient patients [178]. Due to the possible teratogenicity, miltefosine should not be administered to women who may become pregnant within 2 months after drug discontinuation.…”

Section: Miltefosinementioning

confidence: 99%

Leishmaniasis in travelers: A literature review

Mansueto

Seidita

Vitale

et al. 2014

Travel Medicine and Infectious Disease

112

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Summary Leishmaniasis is a vector-borne protozoan infection whose clinical spectrum ranges from asymptomatic infection to fatal visceral leishmaniasis. Over the last decades, an increase in imported leishmaniasis cases in developed, non-endemic countries, have been pointed-out from a review of the international literature. Among the possible causes are increasing international tourism, influx of immigrants from endemic regions and military operations. The main area for the acquisition of cutaneous leishmaniasis, especially for adventure travelers on long-term trips in highly-endemic forested areas, is represented from South America, whereas popular Mediterranean destinations are emerging as the main areas to acquire visceral variant. Leishmaniasis should be considered in the diagnostic assessment of patients presenting with a compatible clinical syndrome and a history of travel to an endemic area, even if this occurred several months or years before. Adventure travelers, researchers, military personnel, and other groups of travelers likely to be exposed to sand flies in endemic areas, should receive counseling regarding leishmaniasis and appropriate protective measures. ª

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Efficacy of Miltefosine in the Treatment of Visceral Leishmaniasis in India After a Decade of Use

Abstract: As compared to the phase III trial that led to registration of the drug a decade ago, there is a substantial increase in the failure rate of oral miltefosine for treatment of VL in India.

Cited by 266 publications

References 19 publications

Antimony-resistant but not antimony-sensitiveLeishmania donovaniup-regulates host IL-10 to overexpress multidrug-resistant protein 1

Antimony-resistant but not antimony-sensitiveLeishmania donovaniup-regulates host IL-10 to overexpress multidrug-resistant protein 1

Evaluation of rK-39 Strip Test Using Urine for Diagnosis of Visceral Leishmaniasis in an Endemic Region of India

Leishmaniasis in travelers: A literature review

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