Oral Miltefosine for Indian Visceral Leishmaniasis

Sundar, Shyam; Jha, T K; Thakur, C.P.; Engel, Juergen; Sindermann, H.; Fischer, Christina; Junge, Klaus; Bryceson, A. D. M.; Berman, Jonathan

doi:10.1056/nejmoa021556

Cited by 662 publications

(484 citation statements)

References 16 publications

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“…16 A significant association with treatment failure was also seen in patients presenting with a large spleen at presentation, reflecting more advanced disease. 17 Recently, new drugs have been proposed as firstline therapy for VL, namely miltefosine 18,19 and paromomycin. 20 Also, the use of combination therapy to protect drugs from emerging resistance has been advocated.…”

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confidence: 99%

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: 99%

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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“…Presently, amphotericin B and the oral anticancer drug miltefosine are considered the best therapeutic solutions for the treatment of VL. 7 Considering the high toxicity and incomplete efficacy of the current clinical drugs, the search for new targets showing antileishmanial activity is very much desirable and would be of great relevance to both synthetic and medicinal chemists.…”

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Molecular Docking and in Vitro Antileishmanial Evaluation of Chromene-2-thione Analogues

Verma

Prajapati

Verma

et al. 2012

ACS Med. Chem. Lett.

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Leishmaniases are an epidemic in various countries, and the parasite is developing resistance against available drugs. Thus, development of new drugs against Leishmania is an open area of investigation for synthetic organic chemists. To meet this challenge, a series of chromene-2-thione derivatives have been synthesized and docked into the active site of trypanothione reductase (TryR) enzyme required for redox balance of the parasite. These were screened on promastigote, axenic amastigote, and intracellular amastigote stages of Leishmania donovani and found to show high levels of antileishmanial activity together with minimal toxicity to human peripheral blood mononuclear cells. Compounds 3b and 3k were found to be the most active among the tested compounds. Although the compounds show moderate antileishmanial activity, they identify a chemical space to design and develop drugs based on these chromene-2-thione derivatives against the Leishmania parasite.

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“…Otros medicamentos potencialmente efectivos son: la pentamidina, la anfotericina B, el alopurinol, la mefloquina y la miltefosina (4,(6)(7)(8); estos medicamentos aunque pueden resultar en eficacias similares a la obtenida con los SbV, varía en función de la forma clínica de la enfermedad y de la especie de Leishmania involucrada. Así, por ejemplo, el alopurinol y la mefloquina, que son medicamentos potencialmente efectivos contra Leishmania mexicana (9), no lo son para el tratamiento de la leishmaniasis cutánea causada por Leishmania panamensis y Leishmania braziliensis en Colombia y Brasil (10)(11)(12).…”

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“…Actualmente, se tiene como candidato a la miltefosina, un medicamento oral que ha presentado tasas de curación superiores al 95% para casos de leishmaniaisis visceral producida por Leishmania donovani en India (8,15), al igual que para casos de leishmaniaisis cutánea por L. panamensis en Colombia donde se ha observado una tasa de curación mayor del 91% a la dosis de 2,5 mg/kg por día (16,17). Sin embargo, la efectividad de la miltefosina para el tratamiento de la leishmaniasis cutánea producida por L. braziliensis o L. mexicana en Guatemala ha sido alrededor del 50% (17).…”

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“…Sin embargo, el valor clínico de la terapia con los SbV se está viendo amenazado por la aparición cada vez más frecuente de fracasos terapéuticos, principalmente en India donde, aproximadamente, falla el 50% de los tratamientos para leishmaniasis visceral con las dosis estándar de SbV (18). Estas fallas terapéuticas pueden deberse a variaciones no sólo en el contenido de SbV en los lotes del medicamento, como se ha evidenciado previamente (19), sino también por la aparición de parásitos resistentes al SbV (8,(20)(21)(22).…”

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Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

et al. 2005

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Actualmente, los parásitos protozoarios son uno de los principales agentes causantes de morbilidad y mortalidad en el mundo, un problema complicado, además, por la aparición de resistencia a medicamentos en estos organismos. La resistencia a medicamentos observada en parásitos protozoarios se debe a diferentes mecanismos como la disminución de la entrada del medicamento a la célula por cambios en el transportador requerido, la pérdida de la activación del medicamento por parte del hospedero, las alteraciones en el blanco del medicamento y la expresión exagerada del transportador múltiple de medicamentos o glicoproteína P (Pgp). En esta revisión, nos centramos en: 1) el papel de las glicoproteínas P (Pgp) de la familia de proteínas ABC (ATP binding cassette) como los transportadores de múltiples medicamentos en la mediación de resistencia en protozoarios, especialmente en Leishmania, y en el desarrollo de resistencia cruzada para medicamentos estructural y funcionalmente no relacionados, y 2) en algunos conceptos relacionados con los mecanismos moduladores que podrían revertir la resistencia a medicamentos por fármacos y productos naturales. Numerosos moduladores o quimiosensibilizadores son conocidos por alterar la capacidad de las glicoproteínas P para mantener concentraciones intracelulares subtóxicas del medicamento; algunos ejemplos incluyen los bloqueadores de los canales de calcio como el verapamilo; sin embargo, se requieren altas concentraciones para una inhibición eficiente y duradera, las cuales producen efectos adversos indeseables. Por tanto, se necesitan más investigaciones relacionadas con los moduladores naturales para Pgp, los cuales podrían presentar menor toxicidad para el hospedero.Palabras clave: Leishmania, protozoos, multirresistencia, glicoproteína P, productos naturales. Leishmania: role of P glycoprotein in drug resistance and reversion strategiesProtozoan parasites are important causative agents of morbidity and mortality throughout the world -a problem further complicated by the emergence of drug resistance in these parasites. Mechanisms of drug resistance include the following: decreased uptake of the drug into the cell, loss of drug activation, alterations in the drug target, and over-expression of a well-known multiple drug transporter proteins. In this review, two critical components of resistance are stressed: (1) the role of ATP binding cassette proteins, such as P-glycoproteins, in mediating drug resistance in Leishmania and other protozoans, followed by development of cross-resistance to many structurally and functionally unrelated drugs, and (2) some concepts concerning the reversal mechanism of multidrug resistance by drugs and natural products. Several modulators or chemosensitizers alter the capacity of P-glycoproteins to maintain subtoxic intracellular drug concentrations. Calcium channel blockers such as verapamil act in this mode; however, high concentrations are required for an efficient and effective inhibition and, in addition, produce undesirable side effects. The di...

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Oral Miltefosine for Indian Visceral Leishmaniasis

Abstract: Oral miltefosine is an effective and safe treatment for Indian visceral leishmaniasis. Miltefosine may be particularly advantageous because it can be administered orally. It may also be helpful in regions where parasites are resistant to current agents.

Cited by 662 publications

References 16 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

Molecular Docking and in Vitro Antileishmanial Evaluation of Chromene-2-thione Analogues

Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

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