Comparison of miltefosine and meglumine antimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran

؉ and CD8 ؉ T cells was observed upon stimulation with miltefosine-treated, infected DC. In addition, miltefosine application in vivo did not lead to maturation/emigration of skin DC. DC NO ؊ production, a mechanism used by phagocytes to rid themselves of intracellular parasites, was also unaltered upon miltefosine treatment. Our data confirm prior studies indicating that in contrast to, e.g., pentavalent antimonials, miltefosine functions independently of the immune system, mostly through direct toxicity against the Leishmania parasite.

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confidence: 99%

Miltefosine Efficiently Eliminates Leishmania major Amastigotes from Infected Murine Dendritic Cells without Altering Their Immune Functions

Griewank

Gazeau

Eichhorn

et al. 2010

“…Only a little information has recently become available on miltefosine for treatment of Old World cutaneous leishmaniasis (17,24). In vitro data showed that not all subspecies of the Leishmania parasite have the same sensitivity to miltefosine; L. major parasites were the least sensitive to miltefosine (10).…”

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confidence: 99%

Pharmacokinetics of Miltefosine in Old World Cutaneous Leishmaniasis Patients

Dorlo

Thiel

Huitema

et al. 2008

145

101

The pharmacokinetics of miltefosine in leishmaniasis patients are, to a great extent, unknown. We examined and characterized the pharmacokinetics of miltefosine in a group of patients with Old World (Leishmania major) cutaneous leishmaniasis. Miltefosine plasma concentrations were determined in samples taken during and up to 5 months after the end of treatment from 31 Dutch military personnel who contracted cutaneous leishmaniasis in Afghanistan and were treated with 150 mg miltefosine/day for 28 days. Samples were analyzed with a validated liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 4 ng/ml. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling, using NONMEM. The pharmacokinetics of miltefosine could best be described by an open two-compartment disposition model, with a first elimination half-life of 7.05 days and a terminal elimination half-life of 30.9 days. The median concentration in the last week of treatment (days 22 to 28) was 30,800 ng/ml. The maximum duration of follow-up was 202 days after the start of treatment. All analyzed samples contained a concentration above the LLOQ. Miltefosine is eliminated from the body much slower than previously thought and is therefore still detectable in human plasma samples taken 5 to 6 months after the end of treatment. The presence of subtherapeutic miltefosine concentrations in the blood beyond 5 months after treatment might contribute to the selection of resistant parasites, and moreover, the measures for preventing the teratogenic risks of miltefosine treatment should be reconsidered.

“…The amplification efficiency of each was measured using the PCR program LinReg. Tissue samples were weighted and lysed with 500 ml of lysis buffer (100 mM NaCl, 10 mM Tris-HCl, 25 mM EDTA, and 0.5% SDS [pH 8.0] and 0.1 mg/ml proteinase K) by incubation in a water bath for 4 h at 56°C. Then, DNA was extracted with 1 ml of phenol-chloroform-isoamyl alcohol (25:24:1).…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, their use is contraindicated in pregnant women, in patients with cardiovascular, renal, or hepatic disease, and in children with low body weight (6). Overall, the efficacy of these drugs varies between 55 and 98% depending on the compound and on the Leishmania species causing the clinical manifestation (7,8). However, their elevated toxicity encourages abandonment of treatment and consequently a decrease in the efficacy (9).…”

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confidence: 99%

See 1 more Smart Citation

Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

Montoya

Daza

Muñoz

et al. 2015

An evaluation of the leishmanicidal activity in vitro and in vivo of hypericin, an expanded-spectrum photosensitizer found in Hypericum perforatum, is presented. Hypericin was evaluated against intracellular amastigotes in vitro of Leishmania (Viannia) panamensis. A topical formulation containing 0.5% hypericin was developed and assayed in vivo in a hamster model of cutaneous leishmaniasis. Results demonstrate that hypericin induces a significant antiamastigote effect in vitro against L. panamensis by decreasing the number of parasites inside infected cells. The topical formulation of 0.5% hypericin allows healing of L. panamensis-induced lesions upon a topical application of 40 mg/day plus visible-light irradiation (5 J/cm 2 , 15 min), twice a week for 3 weeks. Cutaneous leishmaniasis (CL) is a parasitic disease caused by protozoa of the genus Leishmania, which manifests as a chronic infection affecting mainly mononuclear phagocytes of the skin (1). The disease affects the poorest populations in 99 countries in tropical and subtropical regions of the world (2, 3). It is estimated that 14 million people are infected, 350 million are at risk, and there are about 1.5 million new cases per year (3, 4). The parasite is transmitted by the bite of an insect vector belonging to the genus Lutzomyia (in America) or Phlebotomus (in Europe, Asia, and Africa) in the subfamily Phlebotominae (5).Only three types of drugs are available to treat CL. They are the pentavalent antimonials (meglumine antimoniate and sodium stibogluconate), pentamidine isethionate, and miltefosine. Miltefosine is the only one available for oral administration (4). These medications are delivered at high doses and for long periods, thus leading to high toxicity. Therefore, their use is contraindicated in pregnant women, in patients with cardiovascular, renal, or hepatic disease, and in children with low body weight (6). Overall, the efficacy of these drugs varies between 55 and 98% depending on the compound and on the Leishmania species causing the clinical manifestation (7,8). However, their elevated toxicity encourages abandonment of treatment and consequently a decrease in the efficacy (9).More recently, photodynamic therapy (PDT) has emerged as an alternative to treat CL (10). This therapy is based on the application of a photosensitizing agent (PA) that, when excited by light of a certain wavelength, induces the production of reactive oxygen species (ROS) that can destroy the microorganism or the target cell (11). In spite of its potential, only a few PAs have been tested against CL in animal models, and only one in humans. Topical application of 5-aminolevulinic acid (ALA) and light in a murine model of CL caused by L. major showed a significant reduction of the parasitic load and the size of lesions (12). Intralesional administration of ALA (one to three PDT sessions) in a patient with CL by L. major produced a 10 to 20% cure, although it is probable that clinical outcome resulted from nonspecific destruction of infected macrophages instead of...