<i>Leishmania</i>Resistance to Miltefosine Associated with Genetic Marker

Cojean, Sandrine; Houzé, Sandrine; Haouchine, Djamel; Huteau, Françoise; Lariven, Sylvie; Hubert, Véronique; Michard, F.; Bories, Christian; Pratlong, Francine; Bras, J. Le; Loiseau, Philippe M.; Matheron, Sophie

doi:10.3201/eid1804.110841

Cited by 89 publications

(75 citation statements)

References 8 publications

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“…Strains of L. donovani isolated from visceral leishmaniasis and PKDL patients who relapsed following milte- fosine treatment were significantly more tolerant to miltefosine than the corresponding pretreatment strains (19). The selective potential of miltefosine treatment in visceral leishmaniasis was also substantiated by the incremental increase in tolerance of sequential isolates of Leishmania infantum obtained at relapse from an HIV-coinfected patient who received maintenance treatment with miltefosine for several years (22). The emergence of tolerant/ resistant Leishmania populations in different clinical, epidemiological, and geographic circumstances underscores the need for measures to protect the effective life of this drug.…”

Section: Discussionmentioning

confidence: 68%

Treatment Failure and Miltefosine Susceptibility in Dermal Leishmaniasis Caused by Leishmania Subgenus Viannia Species

Obonaga

Fernández

Valderrama

et al. 2014

Antimicrob Agents Chemother

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Treatment failure and parasite drug susceptibility in dermal leishmaniasis caused by Leishmania (Viannia) species are poorly understood. Prospective evaluation of drug susceptibility of strains isolated from individual patients before drug exposure and at clinical failure allows intrinsic and acquired differences in susceptibility to be discerned and analyzed. To determine whether intrinsic susceptibility or loss of susceptibility to miltefosine contributed to treatment failure, we evaluated the miltefosine susceptibility of intracellular amastigotes and promastigotes of six Leishmania (Viannia) braziliensis and six Leishmania (Viannia) panamensis strains isolated sequentially, at diagnosis and treatment failure, from two children and four adults >55 years old with concurrent conditions. Four patients presented only cutaneous lesions, one had mucosal disease, and one had disseminated mucocutaneous disease. Expression of the Leishmania drug transporter genes abca2, abca3, abcc2, abcc3, abcg4, abcg6,

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Section: Discussionmentioning

confidence: 68%

Treatment Failure and Miltefosine Susceptibility in Dermal Leishmaniasis Caused by Leishmania Subgenus Viannia Species

Obonaga

Fernández

Valderrama

et al. 2014

Antimicrob Agents Chemother

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“…These two pentavalent antimonials remained the first-line treatments in numerous countries. Miltefosine and new formulations of amphotericin B represented a breakthrough for leishmaniasis treatment; however, the risk of emergence of resistant strains and the high cost of these new alternatives raised concerns regarding their widespread use in developing countries (30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Cunha-Júnior

Martins

Canto‐Cavalheiro

et al. 2016

Antimicrob Agents Chemother

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e Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and antileukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis.

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“…Quite recently the first case of miltefosine resistance in a clinical field isolate of L. infantum was documented. 30 The potential differential properties of the liposomes compared with the aqueous form of OlPC await proper pharmacokinetic evaluation and/or longer treatment duration. In terms of efficacy, further studies are needed to assess the clinical performance in a chronic infection model using a late curative therapeutic approach and adopting a longer post-treatment evaluation period to assess the potential of full parasitological cure, particularly after single dosing.…”

Section: Fortin Et Almentioning

confidence: 99%

Efficacy and tolerability of oleylphosphocholine (OlPC) in a laboratory model of visceral leishmaniasis

Fortin

Hendrickx

Yardley

et al. 2012

Journal of Antimicrobial Chemotherapy

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Objectives: The alkylphospholipid oleylphosphocholine (OlPC) is a structural analogue of miltefosine and may represent a potential therapeutic backup for the treatment of visceral leishmaniasis (VL). This laboratory study compared the in vitro and in vivo activity profile of both OlPC and miltefosine. Methods:The in vitro potency of OlPC was compared with that of miltefosine, amphotericin B, paromomycin and pentavalent antimony (Sb V ) using the intracellular amastigote assay on different Old World and New World Leishmania species. The in vivo efficacy was dose titrated in the Leishmania infantum hamster model after infection with 2×10 7 amastigotes (day 0) and oral treatment at day 21 using an aqueous (OlPC/H 2 O) and liposomal formulation of OlPC in single and repeated (5 day) oral dosing regimens. The amastigote reductions in the liver, spleen and bone marrow were assessed (day 35).Results: The in vitro activity of OlPC against Leishmania donovani, L. infantum, Leishmania tropica, Leishmania mexicana and Leishmania panamensis showed mean IC 50 values ,5 mM, while the IC 50 values for Leishmania major and Leishmania braziliensis were 7.7 and 13.5 mM, respectively. These results are fairly similar to those obtained for miltefosine. In the hamster model, treatment with 20 and 40 mg/kg for 5 days proved that both OlPC formulations were equipotent and showed a markedly higher efficacy compared with miltefosine. A single dosing of 100 mg/kg of OlPC/H 2 O or OlPC liposomes reduced the parasite burdens by 96. 2% and 99.3% in liver, 99.8% and 99.9% in spleen, and 87.6% and 96.9% in bone marrow, respectively. No signs of toxicity or adverse drug-related effects were noted.Conclusions: These data suggest that OlPC may become a promising candidate to improve and simplify current case management of VL. Additional pharmacological and pharmacokinetic studies are ongoing to assess the full potential of OlPC as a 'drug candidate'.

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LeishmaniaResistance to Miltefosine Associated with Genetic Marker

Cited by 89 publications

References 8 publications

Treatment Failure and Miltefosine Susceptibility in Dermal Leishmaniasis Caused by Leishmania Subgenus Viannia Species

Treatment Failure and Miltefosine Susceptibility in Dermal Leishmaniasis Caused by Leishmania Subgenus Viannia Species

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Efficacy and tolerability of oleylphosphocholine (OlPC) in a laboratory model of visceral leishmaniasis

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