Efficacy of Extended (Six Weeks) Treatment with Miltefosine for Mucosal Leishmaniasis in Bolivia

Soto, Jaime; Rea, Jaime; Valderrama, Margarita; Toledo, Julia; Valda, L.; Ardiles, J Herrera; Berman, Jonathan

doi:10.4269/ajtmh.2009.81.387

Cited by 57 publications

(43 citation statements)

References 7 publications

(9 reference statements)

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“…14,15 Other drugs of lower efficacy are miltefosine and paromomycin. 16,17 Recently, an intravenous liposomal formulation of amphotericin B (AmBisome ® ; Astellas Pharma, Tokyo, Japan) was shown to be effective and better tolerated than sodium stibogluconate for treatment of CL due to L. braziliensis. 18 Although AmBisome is claimed to be more cost effective than sodium stibogluconate treatment, the massive use of AmBisome is prohibitive for low-income people in South America.…”

Section: Introductionmentioning

confidence: 99%

Enhanced photodynamic leishmanicidal activity of hydrophobic zinc phthalocyanine within archaeolipids containing liposomes

Perez

Casasco

Schilrreff

et al. 2014

IJN

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In this work, the in vitro anti-Leishmania activity of photodynamic liposomes made of soybean phosphatidylcholine, sodium cholate, total polar archaeolipids (TPAs) extracted from the hyperhalophile archaea Halorubrum tebenquichense and the photosensitizer zinc phthalocyanine (ZnPcAL) was compared to that of ultradeformable photodynamic liposomes lacking TPAs (ZnPcUDLs). We found that while ZnPcUDLs and ZnPcALs (130 nm mean diameter and −35 mV zeta potential) were innocuous against promastigotes, a low concentration (0.01 µM ZnPc and 7.6 µM phospholipids) of ZnPcALs irradiated at a very low-energy density (0.2 J/cm 2 ) eliminated L. braziliensis amastigotes from J774 macrophages, without reducing the viability of the host cells. In such conditions, ZnPcALs were harmless for J774 macrophages, HaCaT keratinocytes, and bone marrow-derived dendritic cells. Therefore, topical photodynamic treatment would not likely affect skin-associated lymphoid tissue. ZnPcALs were extensively captured by macrophages, but ZnPcUDLs were not, leading to 2.5-fold increased intracellular delivery of ZnPc than with ZnPcUDLs. Despite mediating low levels of reactive oxygen species, the higher delivery of ZnPc and the multiple (caveolin-and clathrin-dependent plus phagocytic) intracellular pathway followed by ZnPc would have been the reason for the higher antiamastigote activity of ZnPcALs. The leishmanicidal activity of photodynamic liposomal ZnPc was improved by TPA-containing liposomes.

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Section: Introductionmentioning

confidence: 99%

Enhanced photodynamic leishmanicidal activity of hydrophobic zinc phthalocyanine within archaeolipids containing liposomes

Perez

Casasco

Schilrreff

et al. 2014

IJN

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“…It has achieved relatively high cure rates in the treatment of visceral (8,26,41,52,54), New World cutaneous (11,44,48,50,57), Old World cutaneous (30,56) and even difficult-to-treat mucocutaneous (49,51) leishmaniasis.…”

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confidence: 99%

Optimal Dosing of Miltefosine in Children and Adults with Visceral Leishmaniasis

Dorlo

Huitema

Beijnen

et al. 2012

Antimicrob Agents Chemother

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bOnly anecdotal data are available on the pharmacokinetics (PK) of miltefosine in children suffering from visceral leishmaniasis (VL). While failure rates were higher in children with VL, steady-state concentrations appeared lower than those seen with adults. We hypothesized that the current linear dosage (in milligrams per kilogram of body weight) is too low for children and that a new dosing algorithm based on an appropriate body size model would result in an optimal exposure. A population PK analysis was performed on three historic pooled data sets, including Indian children, Indian adults, and European adults. Linear and allometric scaling of PK parameters by either body weight or fat-free mass (FFM) was evaluated for body size models. Based on the developed PK model, a dosing algorithm for miltefosine in children and adults was proposed and evaluated in silico. The population PK model employing allometric scaling fitted best to the pooled miltefosine data. Allometric scaling by FFM reduced between-subject variability, e.g., for drug clearance, from 49.6% to 32.1%. A new allometric miltefosine dosing algorithm was proposed. Exposure to miltefosine was lower in children than adults receiving 2.5 mg/kg/day: a C max of 18.8 g/ml was reached by 90% of adults and 66.7% of children. The allometric daily dose resulted in similar levels of exposure to miltefosine for adults and children. The use of a new allometric dosing algorithm for miltefosine in VL patients results in optimal exposure to miltefosine in both adults and children and might improve clinical outcome in children.V isceral leishmaniasis (VL) or kala-azar (Hindi for "black fever") has been classified as one of the world's "most neglected diseases" (62), and of all the parasitic diseases, it ranks third in terms of morbidity and mortality after only malaria and lymphatic filariasis (38). The World Health Organization (WHO) reported in 2004 that leishmaniasis is responsible for around 50,000 deaths and almost 2 million disability-adjusted life-years per year, approximately half of which can be attributed to children from lowincome countries (38, 60), but in reality the burden of leishmaniasis is probably much larger due to massive underreporting of both cases and deaths in the often remote areas where leishmaniasis is prevalent (47).Miltefosine (hexadecylphosphocholine; marketed by Paladin Laboratories Inc. as Impavido) is the newest addition to the small repertory of antileishmanial drugs and to date is the only drug that can be administered orally. It has achieved relatively high cure rates in the treatment of visceral (8, 26, 41, 52, 54), New World cutaneous (11,44,48,50,57), Old World cutaneous (30, 56) and even difficult-to-treat mucocutaneous (49, 51) leishmaniasis.During the development of miltefosine, two clinical trials were designed to investigate the efficacy and safety of miltefosine in children (Ͻ12 years of age) in which a total of 119 pediatric patients were enrolled, employing dosages linearly extrapolated from the daily adult dosage (in ...

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“…120 Increasing the duration of treatment to 6 weeks increased the cure rates from 71% to 75%. 121 All these studies suggest that miltefosine could be an alternative option for the treatment of CL and ML in these region however treatment of diffuse cutaneous leishmaniasis has not been encouraging. 122-124 …”

Section: Review Of Antileishmanial Agentsmentioning

confidence: 99%

An update on pharmacotherapy for leishmaniasis

Sundar

Chakravarty

2014

Expert Opinion on Pharmacotherapy

246

191

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Introduction Leishmaniasis broadly manifests as visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). The treatment of leishmaniasis is challenging and the armamentarium of drugs is small, duration of treatment is long, and most drugs are toxic. Areas covered A literature search on treatment of leishmaniasis was done on PubMed. Single dose of liposomal amphotericin B (L-AmB) and multidrug therapy (L-AmB + miltefosine, L-AmB + paromomycin (PM), or miltefosine + PM) are the treatment of choice for VL in the Indian subcontinent. A 17-day combination therapy of pentavalent antimonials (Sbv) and paromomycin remains the treatment of choice for East African VL. L-AmB is the recommended regimen for VL in the Mediterranean region and South America. Treatment of CL should be decided by the severity of clinical lesions, etiological species and its potential to develop into mucosal leishmaniasis. Expert opinion There is an urgent need to implement a single dose L-AmB or combination therapy in the Indian subcontinent. Combination therapy with newer drugs needs to be tested in Africa. Due to the toxicity of systemic therapy, a trend towards local treatment for New World CL (NWCL) is preferred in patients without risk of mucosal disease.

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Efficacy of Extended (Six Weeks) Treatment with Miltefosine for Mucosal Leishmaniasis in Bolivia

Cited by 57 publications

References 7 publications

Enhanced photodynamic leishmanicidal activity of hydrophobic zinc phthalocyanine within archaeolipids containing liposomes

Enhanced photodynamic leishmanicidal activity of hydrophobic zinc phthalocyanine within archaeolipids containing liposomes

Optimal Dosing of Miltefosine in Children and Adults with Visceral Leishmaniasis

An update on pharmacotherapy for leishmaniasis

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