New Treatment Approach in Indian Visceral Leishmaniasis: Single‐Dose Liposomal Amphotericin B Followed by Short‐Course Oral Miltefosine

Sundar, Shyam; Rai, Madhukar; Chakravarty, Jaya; Agarwal, Dipti; Agrawal, Neha; Vaillant, Michel; Olliaro, Piero; Murray, Henry W.

doi:10.1086/591972

Cited by 177 publications

(99 citation statements)

References 18 publications

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“…Benaim et al (47) demonstrated the specific antiparasitic effects of amiodarone and the synergistic effects of combinations with posaconazole against Trypanosoma cruzi, in vitro and in vivo; similar effects were more recently reported for Leishmania mexicana and miltefosine (48). There is a growing recognition of the relevance of combination therapies to address several limitations of currently available antiLeishmania drugs, including toxicity as well as natural and acquired drug resistance (1,3,(49)(50)(51)(52). Indeed, several studies have reported the superior efficacies of combination therapies against leishmaniasis, and some of them demonstrated the synergic effects of combinations of amphotericin B with other available drugs, such as miltefosine, paromomycin, meglumine antimoniate, or azythromycin (49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 74%

Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

Macedo-Silva

Visbal

Urbina

et al. 2015

Antimicrob Agents Chemother

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e Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14␣-demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis.

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Section: Discussionmentioning

confidence: 74%

Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

Macedo-Silva

Visbal

Urbina

et al. 2015

Antimicrob Agents Chemother

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“…Amphotericin B, particularly in liposomal formulation (68), has become the drug of choice in developed countries and where antimony resistance is problematic, but issues of cost and toxicity remain (69). Oral miltefosine, recently shown to be effective in VL (70), has also more recently been shown to be compatible for use in combination therapy with Amphotericin B (71). Of note, it has been long recognized from studies in experimental VL that the efficacy of the antimonial drugs is exquisitely dependent upon host immune function, being modulated by a number of key T cell-derived cytokines (11,14,44).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

Dalton¹,

Maroof²,

Owens³

et al. 2010

J. Clin. Invest.

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Receptor tyrosine kinases are involved in multiple cellular processes, and drugs that inhibit their action are used in the clinic to treat several types of cancer. However, the value of receptor tyrosine kinase inhibitors (RTKIs) for treating infectious disease has yet to be explored. Here, we have shown in mice that administration of the broad-spectrum RTKI sunitinib maleate (Sm) blocked the vascular remodeling and progressive splenomegaly associated with experimental visceral leishmaniasis. Furthermore, Sm treatment restored the integrity of the splenic microarchitecture. Although restoration of splenic architecture was accompanied by an increase in the frequency of IFN-γ + CD4 + T cells, Sm treatment alone was insufficient to cause a reduction in tissue parasite burden. However, preconditioning by short-term Sm treatment proved to be successful as an adjunct therapy, increasing the frequency of IFN-γ + and IFN-γ + TNF + CD4 + T cells, enhancing NO production by splenic macrophages, and providing dose-sparing effects when combined with a first-line immune-dependent anti-leishmanial drug. We propose, therefore, that RTKIs may prove clinically useful as agents to restore immune competence before the administration of chemo-or immunotherapeutic drugs in the treatment of visceral leishmaniasis or other diseases involving lymphoid tissue remodeling, including cancer.

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“…Strict control of drug delivery and prevention of drug resistance would also be facilitated by the use of short combined treatments such as those currently being studied in India. 29 Increased risk of treatment failure in patients coming from Nepalese districts close to the areas of Bihar where 4,6,12 The intense cross-border migration of populations between Nepal and Bihar, considered an important risk factor for the spread of VL in this region, 27 would also suggest a spread of resistant strains of L. donovani from Bihar to Nepal. 30 …”

Section: Discussionmentioning

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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New Treatment Approach in Indian Visceral Leishmaniasis: Single‐Dose Liposomal Amphotericin B Followed by Short‐Course Oral Miltefosine

Abstract: ClinicalTrials.gov identifier: NCT00370825 .

Cited by 177 publications

References 18 publications

Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

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

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