Liposomal amphotericin B for the treatment of visceral leishmaniasis

Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Clinical Infectious Diseases (Impact Factor: 9.42). 11/2006; 43(7):917-24. DOI: 10.1086/507530
Source: PubMed

ABSTRACT During the past decade, liposomal amphotericin B has been used with increasing frequency to treat visceral leishmaniasis (VL). The World Health Organization convened a workshop to review current knowledge and to develop guidelines for liposomal amphotericin B use for VL. In Europe, liposomal amphotericin B is widely used to treat VL. In Africa and Asia, the VL disease burden is high and drug access is poor; liposomal amphotericin B is available only through preferential pricing for nonprofit groups in East Africa. Clinical trials and experience demonstrate high efficacy and low toxicity for liposomal amphotericin B (total dose, 20 mg/kg) in immunocompetent patients with VL. Combination trials in areas with antileishmanial drug resistance, and treatment and secondary prophylaxis trials in VL-human immunodeficiency virus-coinfected patients, are important to safeguard the current armamentarium and to optimize regimens. The public health community should work to broaden access to preferential liposomal amphotericin B pricing by public sector VL treatment programs.

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Available from: Luigi Gradoni, Jul 17, 2015
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    • "Lipid formulations of the polyene antibiotic AmB are now the mainstay for the treatment of Leishmania in the epidemic region of Bihar in India where nearly 65% of the cases are refractory to the first line antimonial drugs (Bern et al., 2006; Chappuis et al., 2007). Although some sporadic unusual cases have been reported recently (Srivastava et al., 2011; Purkait et al., 2012), clinical resistance has not yet threatened the efficacy of AmB, even when used through many courses as for treating HIV co-infected patients (Lachaud et al., 2009). "
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    ABSTRACT: Amphotericin B (AmB) in its liposomal form is now considered as either first- or second-line treatment against Leishmania infections in different part of the world. Few cases of AmB resistance have been reported and resistance mechanisms toward AmB are still poorly understood. This paper reports a large-scale comparative proteomic study in the context of AmB resistance. Quantitative proteomics using stable isotope labeling of amino acids in cell culture (SILAC) was used to better characterize cytoplasmic and membrane-enriched (ME) proteomes of the in vitro generated Leishmania infantum AmB resistant mutant AmB1000.1. In total, 97 individual proteins were found as differentially expressed between the mutant and its parental sensitive strain (WT). More than half of these proteins were either metabolic enzymes or involved in transcription or translation processes. Key energetic pathways such as glycolysis and TCA cycle were up-regulated in the mutant. Interestingly, many proteins involved in reactive oxygen species (ROS) scavenging and heat-shock proteins were also up-regulated in the resistant mutant. This work provides a basis for further investigations to understand the roles of proteins differentially expressed in relation with AmB resistance.
    08/2014; 4(2):126–132. DOI:10.1016/j.ijpddr.2014.05.002
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    • "Whilst these drugs are effective, they are characterised by high rates of toxicity and mortality, particularly for complicated cases (Collin et al. 2004), the need for long hospital stays and growing resistance in some areas like India (Chappuis et al. 2007). Liposomal amphotericin B (AmBisome) – a relatively new drug that combines high efficacy with low toxicity – is currently the preferential treatment in high-income countries (Bern et al. 2006). This drug has also been included for first-line VL treatment in East Africa in the 2010 revised World Health Organization (WHO) recommendations (WHO 2010). "
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    ABSTRACT: The aim of this study was to report the patient profile and treatment outcomes, including relapses, of patients with visceral leishmaniasis (VL) treated with liposomal amphotericin B (AmBisome) in Gedaref, Sudan. AmBisome was offered to two groups of patients: primary VL patients with specific criteria (age ≤2 or ≥45 years, advanced clinical disease, pregnancy, HIV co-infection and contraindications for antimonials) and VL relapses. AmBisome was given at a total dose of 30 mg/kg, over 10 days. Slow responders received up to 50 mg/kg. Treatment failure was confirmed parasitologically. Standardised treatment outcomes were assessed. Between March 2010 and June 2012, a total of 281 (74%) patients with primary VL and 98 (26%) patients with VL relapses received AmBisome (54% male, median age = 11 years, interquartile range 2-30). End-of-treatment outcomes for primary VL were 260 (92%) initial cure including three (1%) slow responders, three (1%) treatment failures, 14 (5%) deaths and four (1%) unknown outcomes. Outcomes for VL relapses were 92 (94%) initial cure with five (5%) slow responders, four (4%) treatment failures, one (1%) death and one (1%) unknown outcome. At 6 months, there were 19 (7%) relapses amongst primary VL and 10 (10%) VL relapses had a new relapse. Loss to follow-up in both groups was 38%. None of the deaths that occurred during the study period was attributed to AmBisome. AmBisome appears to be effective for initial cure of VL and the drug seems safe, but is expensive (400 USD/treatment). Sustained mechanisms to allow improved access of this expensive drug particularly in East Africa are urgently needed. Relapses and losses to follow-up require specific investigation.
    Tropical Medicine & International Health 01/2014; 19(2). DOI:10.1111/tmi.12238 · 2.30 Impact Factor
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    • "Thus, there is limited oral bioavailability , which contributes to the low in vivo efficacy of BPQ. Liposomes have been widely used as safe and effective vehicles for drug delivery systems (Frézard and Demicheli, 2010), and liposomal amphotericin B has been used to treat leishmaniasis with fewer toxic effects (Bern et al., 2006; Sundar et al., 2011). The presence of phosphatidylserine (PS) in the membrane of liposomes has been shown to support the targeting delivery of drugs to intracellular amastigotes as a result of the interaction with macrophage scavenger receptors (Tempone et al., 2004, 2010). "
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    ABSTRACT: The objective of this study was to develop a novel liposomal formulation, containing phosphatidylserine (PS), of buparvaquone (BPQ) and to evaluate its in vivo effectiveness in Leishmania (L.) infantum chagasi-infected hamsters. The activity of BPQ was evaluated against both the promastigote forms of different Leishmania species and the intracellular amastigotes of L. (L.) infantum chagasi. Buparvaquone was entrapped in PS-liposomes (BPQ-PS-LP), and the drug was quantified by ultra-high-performance liquid chromatography. The treatment was quantified by detecting the RNA of the living amastigotes in the spleen and the liver by real-time PCR. In vitro assays with L. (L.) infantum chagasi intracellular amastigotes were performed in peritoneal macrophages for the evaluation of the 50% inhibitory concentration (IC(50)). BPQ-PS-LP at 0.33 mg/kg/day for eight consecutive days reduced the number of amastigotes by 89.4% (P<0.05) in the spleen and by 67.2% (P>0.05) in the liver, compared to 84.3% (P<0.05) and 99.7% (P<0.05), respectively, following Glucantime® treatment at 50 mg/kg/day. Free BPQ at 20 mg/kg/day failed to treat the hamsters when compared to the untreated group. BPQ was significantly (P<0.05) selective against L. (L.) infantum chagasi intracellular amastigotes, with an IC(50) value of 1.5 μM; no in vitro mammalian cytotoxicity could be detected. Other cutaneous species were also susceptible to BPQ, with IC(50) values in the range 1-4 μM. BPQ-PS-LP caused a significant reduction in the parasite burden at a 60-fold lower dose than did the free BPQ. These results show the potential of PS-liposome formulations for the successful targeted delivery of BPQ in visceral leishmaniasis.
    Experimental Parasitology 03/2012; 130(3):195-9. DOI:10.1016/j.exppara.2012.01.010 · 1.86 Impact Factor
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