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Thomas P. C. Dorlo - One of the best experts on this subject based on the ideXlab platform.

  • Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation.
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: Semra Palić, Patrick A. Bhairosing, Jos H. Beijnen, Thomas P. C. Dorlo
    Abstract:

    Host immune responses are pivotal for the successful treatment of the leishmaniases, a spectrum of infections caused by Leishmania parasites. Previous studies speculated that augmenting cytokines associated with a type 1 T-helper cell (Th1) response is necessary to combat severe forms of leishmaniasis, and it has been hypothesized that the antileishmanial drug Miltefosine is capable of immunomodulation and induction of Th1 cytokines. A better understanding of the immunomodulatory effects of Miltefosine is central to providing a rationale regarding synergistic mechanisms of activity to combine Miltefosine optimally with other conventional and future antileishmanials that are currently under development. Therefore, a systematic literature search was performed to evaluate to what extent and how Miltefosine influences the host Th1 response. Miltefosine's effects observed in both a preclinical and a clinical context associated with immunomodulation in the treatment of leishmaniasis are evaluated in this review. A total of 27 studies were included in the analysis. Based on the current evidence, Miltefosine is not only capable of inducing direct parasite killing but also of modulating the host immunity. Our findings suggest that Miltefosine-induced activation of Th1 cytokines, particularly represented by increased gamma interferon (IFN-γ) and interleukin 12 (IL-12), is essential to prevail over the Leishmania-driven Th2 response. Differences in Miltefosine-induced host-mediated effects between in vitro, ex vivo, animal model, and human studies are further discussed. All things considered, an effective treatment with Miltefosine is acquired by enhanced functional Th1 cytokine responses and may further be enhanced in combination with immunostimulatory agents.

  • simultaneous population pharmacokinetic modelling of plasma and intracellular pbmc Miltefosine concentrations in new world cutaneous leishmaniasis and exploration of exposure response relationships
    Journal of Antimicrobial Chemotherapy, 2018
    Co-Authors: Anke E Kip, Jos H. Beijnen, Maria Del Mar Castro, Maria Adelaida Gomez, Jan H M Schellens, Alexandra Cossio, Nancy G Saravia, Thomas P. C. Dorlo
    Abstract:

    Objectives: Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC Miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens. Patients and methods: A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC Miltefosine concentrations from Colombian cutaneous leishmaniasis patients [29 children (2-12 years old) and 22 adults] receiving 1.8-2.5 mg/kg/day Miltefosine for 28 days. Results: A three-compartment model with Miltefosine distribution into an intracellular PBMC effect compartment best fitted the data. Intracellular PBMC distribution was described with an intracellular-to-plasma concentration ratio of 2.17 [relative standard error (RSE) 4.9%] and intracellular distribution rate constant of 1.23 day-1 (RSE 14%). In exploring exposure-response relationships, both plasma and intracellular model-based exposure estimates significantly influenced probability of cure. A proposed PK target for the area under the plasma concentration-time curve (day 0-28) of >535 mg·day/L corresponded to >95% probability of cure. In linear dosing simulations, 18.3% of children compared with 2.8% of adults failed to reach 535 mg·day/L. In children, this decreased to 1.8% after allometric dosing simulation. Conclusions: The developed population PK model described the rate and extent of Miltefosine distribution from plasma into PBMCs. Miltefosine exposure was significantly related to probability of cure in this cutaneous leishmaniasis patient population. We propose an exploratory PK target, which should be validated in a larger cohort study.

  • Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis
    Antimicrobial Agents and Chemotherapy, 2016
    Co-Authors: Maria Del Mar Castro, Thomas P. C. Dorlo, Anke E Kip, Maria Adelaida Gomez, Alexandra Cossio, Eduardo Ortiz, Adriana Navas, Nancy G Saravia
    Abstract:

    ABSTRACT An open-label pharmacokinetics (PK) clinical trial was conducted to comparatively assess the PK and explore the pharmacodynamics (PD) of Miltefosine in children and adults with cutaneous leishmaniasis (CL) in Colombia. Sixty patients, 30 children aged 2 to 12 years and 30 adults aged 18 to 60 years, were enrolled. Participants received Miltefosine (Impavido) at a nominal dose of 2.5 mg/kg/day for 28 days. Miltefosine concentrations were measured in plasma and peripheral blood mononuclear cells by liquid chromatography-tandem mass spectrometry of samples obtained during treatment and up to 6 months following completion of treatment, when therapeutic outcome was determined. Fifty-two patients were cured, 5 pediatric patients failed treatment, and 3 participants were lost to follow-up. Leishmania (Viannia) panamensis predominated among the strains isolated (42/46; 91%). Noncompartmental analysis demonstrated that plasma and intracellular Miltefosine concentrations were, overall, lower in children than in adults. Exposure to Miltefosine, estimated by area under the concentration-time curve and maximum concentration, was significantly lower in children in both the central and intracellular compartments ( P In vitro Miltefosine susceptibility was similar for Leishmania strains from adults and children. Our results document PK differences for Miltefosine in children and adults with cutaneous leishmaniasis that affect drug exposure and could influence the outcome of treatment, and they provide bases for optimizing therapeutic regimens for CL in pediatric populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01462500.)

  • Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial
    PLOS Neglected Tropical Diseases, 2016
    Co-Authors: Monique Wasunna, Thomas P. C. Dorlo, Simon Njenga, Manica Balasegaram, Neal Alexander, Raymond Omollo, Tansy Edwards, Brima Musa, Mohammed Hassan Sharaf Ali, Mohammed Yasein Elamin
    Abstract:

    Background: SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and Miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa. Methods: A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of Miltefosine (2.5mg/kg/day) and Miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (Miltefosine) and pharmacodynamic assessments. Results: In sequential analyses with 49–51 patients per arm, initial cure was 85% (95% CI: 73–92) in all arms. At D210, definitive cure was 87% (95% CI: 77–97) for AmBisome + SSG, 77% (95% CI 64–90) for AmBisome + Miltefosine and 72% (95% CI 60–85) for Miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults. Conclusion: No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of Miltefosine in children needs to be evaluated. Trial Registration: The study was registered with ClinicalTrials.gov, number NCT01067443

  • validation and clinical evaluation of a novel method to measure Miltefosine in leishmaniasis patients using dried blood spot sample collection
    Antimicrobial Agents and Chemotherapy, 2016
    Co-Authors: Anke E Kip, Jos H. Beijnen, Hilde Rosing, Michel J X Hillebrand, Jan H M Schellens, Severine Blesson, Bewketu Mengesha, Ermias Diro, Asrat Hailu, Thomas P. C. Dorlo
    Abstract:

    To facilitate future pharmacokinetic studies of combination treatments against leishmaniasis in remote regions in which the disease is endemic, a simple cheap sampling method is required for Miltefosine quantification. The aims of this study were to validate a liquid chromatography-tandem mass spectrometry method to quantify Miltefosine in dried blood spot (DBS) samples and to validate its use with Ethiopian patients with visceral leishmaniasis (VL). Since hematocrit (Ht) levels are typically severely decreased in VL patients, returning to normal during treatment, the method was evaluated over a range of clinically relevant Ht values. Miltefosine was extracted from DBS samples using a simple method of pretreatment with methanol, resulting in >97% recovery. The method was validated over a calibration range of 10 to 2,000 ng/ml, and accuracy and precision were within ±11.2% and ≤7.0% (≤19.1% at the lower limit of quantification), respectively. The method was accurate and precise for blood spot volumes between 10 and 30 μl and for Ht levels of 20 to 35%, although a linear effect of Ht levels on Miltefosine quantification was observed in the bioanalytical validation. DBS samples were stable for at least 162 days at 37°C. Clinical validation of the method using paired DBS and plasma samples from 16 VL patients showed a median observed DBS/plasma Miltefosine concentration ratio of 0.99, with good correlation (Pearson'sr= 0.946). Correcting for patient-specific Ht levels did not further improve the concordance between the sampling methods. This successfully validated method to quantify Miltefosine in DBS samples was demonstrated to be a valid and practical alternative to venous blood sampling that can be applied in future Miltefosine pharmacokinetic studies with leishmaniasis patients, without Ht correction.

Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.

  • Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation.
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: Semra Palić, Patrick A. Bhairosing, Jos H. Beijnen, Thomas P. C. Dorlo
    Abstract:

    Host immune responses are pivotal for the successful treatment of the leishmaniases, a spectrum of infections caused by Leishmania parasites. Previous studies speculated that augmenting cytokines associated with a type 1 T-helper cell (Th1) response is necessary to combat severe forms of leishmaniasis, and it has been hypothesized that the antileishmanial drug Miltefosine is capable of immunomodulation and induction of Th1 cytokines. A better understanding of the immunomodulatory effects of Miltefosine is central to providing a rationale regarding synergistic mechanisms of activity to combine Miltefosine optimally with other conventional and future antileishmanials that are currently under development. Therefore, a systematic literature search was performed to evaluate to what extent and how Miltefosine influences the host Th1 response. Miltefosine's effects observed in both a preclinical and a clinical context associated with immunomodulation in the treatment of leishmaniasis are evaluated in this review. A total of 27 studies were included in the analysis. Based on the current evidence, Miltefosine is not only capable of inducing direct parasite killing but also of modulating the host immunity. Our findings suggest that Miltefosine-induced activation of Th1 cytokines, particularly represented by increased gamma interferon (IFN-γ) and interleukin 12 (IL-12), is essential to prevail over the Leishmania-driven Th2 response. Differences in Miltefosine-induced host-mediated effects between in vitro, ex vivo, animal model, and human studies are further discussed. All things considered, an effective treatment with Miltefosine is acquired by enhanced functional Th1 cytokine responses and may further be enhanced in combination with immunostimulatory agents.

  • simultaneous population pharmacokinetic modelling of plasma and intracellular pbmc Miltefosine concentrations in new world cutaneous leishmaniasis and exploration of exposure response relationships
    Journal of Antimicrobial Chemotherapy, 2018
    Co-Authors: Anke E Kip, Jos H. Beijnen, Maria Del Mar Castro, Maria Adelaida Gomez, Jan H M Schellens, Alexandra Cossio, Nancy G Saravia, Thomas P. C. Dorlo
    Abstract:

    Objectives: Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC Miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens. Patients and methods: A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC Miltefosine concentrations from Colombian cutaneous leishmaniasis patients [29 children (2-12 years old) and 22 adults] receiving 1.8-2.5 mg/kg/day Miltefosine for 28 days. Results: A three-compartment model with Miltefosine distribution into an intracellular PBMC effect compartment best fitted the data. Intracellular PBMC distribution was described with an intracellular-to-plasma concentration ratio of 2.17 [relative standard error (RSE) 4.9%] and intracellular distribution rate constant of 1.23 day-1 (RSE 14%). In exploring exposure-response relationships, both plasma and intracellular model-based exposure estimates significantly influenced probability of cure. A proposed PK target for the area under the plasma concentration-time curve (day 0-28) of >535 mg·day/L corresponded to >95% probability of cure. In linear dosing simulations, 18.3% of children compared with 2.8% of adults failed to reach 535 mg·day/L. In children, this decreased to 1.8% after allometric dosing simulation. Conclusions: The developed population PK model described the rate and extent of Miltefosine distribution from plasma into PBMCs. Miltefosine exposure was significantly related to probability of cure in this cutaneous leishmaniasis patient population. We propose an exploratory PK target, which should be validated in a larger cohort study.

  • validation and clinical evaluation of a novel method to measure Miltefosine in leishmaniasis patients using dried blood spot sample collection
    Antimicrobial Agents and Chemotherapy, 2016
    Co-Authors: Anke E Kip, Jos H. Beijnen, Hilde Rosing, Michel J X Hillebrand, Jan H M Schellens, Severine Blesson, Bewketu Mengesha, Ermias Diro, Asrat Hailu, Thomas P. C. Dorlo
    Abstract:

    To facilitate future pharmacokinetic studies of combination treatments against leishmaniasis in remote regions in which the disease is endemic, a simple cheap sampling method is required for Miltefosine quantification. The aims of this study were to validate a liquid chromatography-tandem mass spectrometry method to quantify Miltefosine in dried blood spot (DBS) samples and to validate its use with Ethiopian patients with visceral leishmaniasis (VL). Since hematocrit (Ht) levels are typically severely decreased in VL patients, returning to normal during treatment, the method was evaluated over a range of clinically relevant Ht values. Miltefosine was extracted from DBS samples using a simple method of pretreatment with methanol, resulting in >97% recovery. The method was validated over a calibration range of 10 to 2,000 ng/ml, and accuracy and precision were within ±11.2% and ≤7.0% (≤19.1% at the lower limit of quantification), respectively. The method was accurate and precise for blood spot volumes between 10 and 30 μl and for Ht levels of 20 to 35%, although a linear effect of Ht levels on Miltefosine quantification was observed in the bioanalytical validation. DBS samples were stable for at least 162 days at 37°C. Clinical validation of the method using paired DBS and plasma samples from 16 VL patients showed a median observed DBS/plasma Miltefosine concentration ratio of 0.99, with good correlation (Pearson'sr= 0.946). Correcting for patient-specific Ht levels did not further improve the concordance between the sampling methods. This successfully validated method to quantify Miltefosine in DBS samples was demonstrated to be a valid and practical alternative to venous blood sampling that can be applied in future Miltefosine pharmacokinetic studies with leishmaniasis patients, without Ht correction.

  • quantification of Miltefosine in peripheral blood mononuclear cells by high performance liquid chromatography tandem mass spectrometry
    Journal of Chromatography B, 2015
    Co-Authors: Anke E Kip, Jos H. Beijnen, Hilde Rosing, Michel J X Hillebrand, Maria Del Mar Castro, Maria Adelaida Gomez, Jan H M Schellens, Thomas P. C. Dorlo
    Abstract:

    Phagocytes, the physiological compartment in which Leishmania parasites reside, are the main site of action of the drug Miltefosine, but the intracellular pharmacokinetics of Miltefosine remain unexplored. We developed a bioanalytical method to quantify Miltefosine in human peripheral blood mononuclear cells (PBMCs), expanding from an existing high performance liquid chromatography-tandem mass spectrometry method for the quantification of Miltefosine in plasma. The method introduced deuterated Miltefosine as an internal standard. Miltefosine was extracted from PBMC pellets by addition of 62.5% methanol. Supernatant was collected, evaporated and reconstituted in plasma. Chromatographic separation was performed on a reversed phase C18 column and detection with a triple-quadrupole mass spectrometer. Miltefosine was quantified using plasma calibration standards ranging from 4 to 1000 ng/mL. This method was validated with respect to its PBMC matrix effect, selectivity, recovery and stability. No matrix effect could be observed from the PBMC content (ranging from 0.17 to 26.3 × 106 PBMCs) reconstituted in plasma, as quality control samples were within 3.0% of the nominal concentration (precision less than 7.7%). At the lower limit of quantitation of 4 ng/mL plasma, corresponding to 0.12 ng/106 PBMCs in a typical clinical sample, measured concentrations were within 8.6% of the nominal value. Recovery showed to be reproducible as adding additional pre-treatment steps did not increase the recovery with more than 9%. This method was successfully applied to measure intracellular Miltefosine concentrations in PBMC samples from six cutaneous leishmaniasis patients up to one month post-treatment.

  • Failure of Miltefosine in visceral leishmaniasis is associated with low drug exposure
    Journal of Infectious Diseases, 2014
    Co-Authors: Thomas P. C. Dorlo, Suman Rijal, Bart Ostyn, Peter J. De Vries, Rupa Singh, Narayan Raj Bhattarai, Surendra Uranw, Jean-claude Dujardin, Marleen Boelaert, Jos H. Beijnen
    Abstract:

    BACKGROUND: Recent reports indicated high Miltefosine treatment failure rates for visceral leishmaniasis (VL) on the Indian subcontinent. To further explore the pharmacological factors associated with these treatment failures, a population pharmacokinetic-pharmacodynamic study was performed to examine the relationship between Miltefosine drug exposure and treatment failure in a cohort of Nepalese patients with VL. METHODS: Miltefosine steady-state blood concentrations at the end of treatment were analyzed using liquid chromatography tandem mass spectrometry. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed-effects modeling and a logistic regression model. Individual estimates of Miltefosine exposure were explored for their relationship with treatment failure. RESULTS: The overall probability of treatment failure was 21%. The time that the blood concentration was >10 times the half maximal effective concentration of Miltefosine (median, 30.2 days) was significantly associated with treatment failure: each 1-day decrease in Miltefosine exposure was associated with a 1.08-fold (95% confidence interval, 1.01-1.17) increased odds of treatment failure. CONCLUSIONS: Achieving a sufficient exposure to Miltefosine is a significant and critical factor for VL treatment success, suggesting an urgent need to evaluate the recently proposed optimal allometric Miltefosine dosing regimen. This study establishes the first evidence for a drug exposure-effect relationship for Miltefosine in the treatment of VL.

Govinda S Visvesvara - One of the best experts on this subject based on the ideXlab platform.

  • Assessment of blood–brain barrier penetration of Miltefosine used to treat a fatal case of granulomatous amebic encephalitis possibly caused by an unusual Balamuthia mandrillaris strain
    Parasitology Research, 2015
    Co-Authors: Jane T. Atkins, Thomas P. C. Dorlo, Rosemaria Gennuso, Danny Kofos, Rama R. Sriram, Teresa Hayes, Yvonne Qvarnstrom, Zuzana Kucerova, B. Joseph Guglielmo, Govinda S Visvesvara
    Abstract:

    Balamuthia mandrillaris , a free-living ameba, causes rare but frequently fatal granulomatous amebic encephalitis (GAE). Few patients have survived after receiving experimental drug combinations, with or without brain lesion excisions. Some GAE survivors have been treated with a multi-drug regimen including Miltefosine, an investigational anti-leishmanial agent with in vitro amebacidal activity. Miltefosine dosing for GAE has been based on leishmaniasis dosing because no data exist in humans concerning its pharmacologic distribution in the central nervous system. We describe results of limited cerebrospinal fluid (CSF) and serum drug level testing performed during clinical management of a child with fatal GAE who was treated with a multiple drug regimen including Miltefosine. Brain biopsy specimens, CSF, and sera were tested for B. mandrillaris using multiple techniques, including culture, real-time polymerase chain reaction, immunohistochemical techniques, and serology. CSF and serum Miltefosine levels were determined using a liquid chromatography method coupled to tandem mass spectrometry. The CSF Miltefosine concentration on hospital admission day 12 was 0.4 μg/mL. The serum Miltefosine concentration on day 37, about 80 h post-Miltefosine treatment, was 15.3 μg/mL. These are the first results confirming some blood–brain barrier penetration by Miltefosine in a human, although with low-level CSF accumulation. Further evaluation of brain parenchyma penetration is required to determine optimal Miltefosine dosing for Balamuthia GAE, balanced with the drug’s toxicity profile. Additionally, the Balamuthia isolate was evaluated by real-time polymerase chain reaction (PCR), demonstrating genetic variability in 18S ribosomal RNA (18S rRNA) sequences and possibly signaling the first identification of multiple Balamuthia strains with varying pathogenicities.

  • in vitro activity of Miltefosine and voriconazole on clinical isolates of free living amebas balamuthia mandrillaris acanthamoeba spp and naegleria fowleri
    Journal of Eukaryotic Microbiology, 2006
    Co-Authors: Frederick L Schuster, Joseph B Guglielmo, Govinda S Visvesvara
    Abstract:

    . The anticancer agent Miltefosine and the antifungal drug voriconazole were tested in vitro against Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. All three amebas are etiologic agents of chronic (Balamuthia, Acanthamoeba) or fulminant (Naegleria) encephalitides in humans and animals and, in the case of Acanthamoeba, amebic keratitis. Balamuthia exposed to <40 μm concentrations of Miltefosine survived, while concentrations of ≥40 μM were generally amebacidal, with variation in sensitivity between strains. At amebastatic drug concentrations, recovery from drug effects could take as long as 2 weeks. Acanthamoeba spp. recovered from exposure to 40 μM, but not 80 μM miltefosin. Attempts to define more narrowly the minimal inhibitory (MIC) and minimal amebacidal concentrations (MAC) for Balamuthia and Acanthamoeba were difficult due to persistence of non-proliferating trophic amebas in the medium. For N. fowleri, 40 and 55 μM were the MIC and MAC, respectively, with no trophic amebas seen at the MAC. Voriconazole had little or no inhibitory effect on Balamuthia at concentrations up to 40 μg/ml, but had a strong inhibitory effect upon Acanthamoeba spp. and N. fowleri at all drug concentrations through 40 μg/ml. Following transfer to drug-free medium, Acanthamoeba polyphaga recovered within a period of 2 weeks; N. fowleri amebas recovered from exposure to 1 μg/ml, but not from higher concentrations. All testing was done on trophic amebas; drug sensitivities of cysts were not examined. Miltefosine and voriconazole are potentially useful drugs for treatment of free-living amebic infections, though sensitivities differ between genera, species, and strains.

  • in vitro activity of Miltefosine and voriconazole on clinical isolates of free living amebas balamuthia mandrillaris acanthamoeba spp and naegleria fowleri
    Journal of Eukaryotic Microbiology, 2006
    Co-Authors: Frederick L Schuster, Joseph B Guglielmo, Govinda S Visvesvara
    Abstract:

    The anticancer agent Miltefosine and the antifungal drug voriconazole were tested in vitro against Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. All three amebas are etiologic agents of chronic (Balamuthia, Acanthamoeba) or fulminant (Naegleria) encephalitides in humans and animals and, in the case of Acanthamoeba, amebic keratitis. Balamuthia exposed to or=40 microM were generally amebacidal, with variation in sensitivity between strains. At amebastatic drug concentrations, recovery from drug effects could take as long as 2 weeks. Acanthamoeba spp. recovered from exposure to 40 microM, but not 80 microM miltefosin. Attempts to define more narrowly the minimal inhibitory (MIC) and minimal amebacidal concentrations (MAC) for Balamuthia and Acanthamoeba were difficult due to persistence of non-proliferating trophic amebas in the medium. For N. fowleri, 40 and 55 microM were the MIC and MAC, respectively, with no trophic amebas seen at the MAC. Voriconazole had little or no inhibitory effect on Balamuthia at concentrations up to 40 microg/ml, but had a strong inhibitory effect upon Acanthamoeba spp. and N. fowleri at all drug concentrations through 40 microg/ml. Following transfer to drug-free medium, Acanthamoeba polyphaga recovered within a period of 2 weeks; N. fowleri amebas recovered from exposure to 1 microg/ml, but not from higher concentrations. All testing was done on trophic amebas; drug sensitivities of cysts were not examined. Miltefosine and voriconazole are potentially useful drugs for treatment of free-living amebic infections, though sensitivities differ between genera, species, and strains.

Peter J. De Vries - One of the best experts on this subject based on the ideXlab platform.

  • Failure of Miltefosine in visceral leishmaniasis is associated with low drug exposure
    Journal of Infectious Diseases, 2014
    Co-Authors: Thomas P. C. Dorlo, Suman Rijal, Bart Ostyn, Peter J. De Vries, Rupa Singh, Narayan Raj Bhattarai, Surendra Uranw, Jean-claude Dujardin, Marleen Boelaert, Jos H. Beijnen
    Abstract:

    BACKGROUND: Recent reports indicated high Miltefosine treatment failure rates for visceral leishmaniasis (VL) on the Indian subcontinent. To further explore the pharmacological factors associated with these treatment failures, a population pharmacokinetic-pharmacodynamic study was performed to examine the relationship between Miltefosine drug exposure and treatment failure in a cohort of Nepalese patients with VL. METHODS: Miltefosine steady-state blood concentrations at the end of treatment were analyzed using liquid chromatography tandem mass spectrometry. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed-effects modeling and a logistic regression model. Individual estimates of Miltefosine exposure were explored for their relationship with treatment failure. RESULTS: The overall probability of treatment failure was 21%. The time that the blood concentration was >10 times the half maximal effective concentration of Miltefosine (median, 30.2 days) was significantly associated with treatment failure: each 1-day decrease in Miltefosine exposure was associated with a 1.08-fold (95% confidence interval, 1.01-1.17) increased odds of treatment failure. CONCLUSIONS: Achieving a sufficient exposure to Miltefosine is a significant and critical factor for VL treatment success, suggesting an urgent need to evaluate the recently proposed optimal allometric Miltefosine dosing regimen. This study establishes the first evidence for a drug exposure-effect relationship for Miltefosine in the treatment of VL.

  • Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis
    Journal of Antimicrobial Chemotherapy, 2012
    Co-Authors: Thomas P. C. Dorlo, Jos H. Beijnen, Manica Balasegaram, Peter J. De Vries
    Abstract:

    Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. For 10 years it has been licensed in India for the treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It is the first and still the only oral drug that can be used to treat VL and cutaneous leishmaniasis (CL). The standard 28 day Miltefosine monotherapy regimen is well tolerated, except for mild gastrointestinal side effects, although its teratogenic potential severely hampers its general use in the clinic and roll-out in national elimination programmes. The pharmacokinetics of Miltefosine are mainly characterized by its long residence time in the body, resulting in extensive drug accumulation during treatment and long elimination half-lives. At the moment, different combination therapy strategies encompassing Miltefosine are being tested in multiple controlled clinical trials in various geographical areas of endemicity, both in South Asia and East Africa. We here review the most salient pre-clinical and clinical pharmacological aspects of Miltefosine, its mechanism of action against Leishmania parasites and other pathogens, and provide a systematic overview of the efficacy and safety data from all clinical trials of Miltefosine, either alone or in combination, in the treatment of VL and CL.

  • Optimal dosing of Miltefosine in children and adults with visceral leishmaniasis.
    Antimicrobial Agents and Chemotherapy, 2012
    Co-Authors: Thomas P. C. Dorlo, Jos H. Beijnen, Alwin D R Huitema, Peter J. De Vries
    Abstract:

    Only 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 μg/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.

  • Characterization and identification of suspected counterfeit Miltefosine capsules.
    The Analyst, 2012
    Co-Authors: Thomas P. C. Dorlo, Peter J. De Vries, Teunis A. Eggelte, Jos H. Beijnen
    Abstract:

    Recently, it was revealed that generic Miltefosine capsules for the treatment of visceral leishmaniasis, a fatal parasitic disease, were possibly counterfeit products. Here we report on the methods to characterize and identify Miltefosine in pharmaceutical products and the procedures that were used to assess the quality of these suspected counterfeit products. Characterization and identification of Miltefosine were done with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), Fourier transform infrared (FT-IR) spectroscopy and near-infrared (NIR) spectroscopy. Moreover, a simple, rapid and inexpensive colorimetric test was developed and evaluated for the detection of Miltefosine in pharmaceutical products that can be used in the field. The complementary analytical techniques presented here were able to determine qualitatively or (semi-)quantitatively the presence or absence of Miltefosine in pharmaceutical preparations and could identify suspected counterfeit Miltefosine capsules. This finding of a suspected counterfeit drug intended to treat a neglected disease in a resource-poor country emphasizes the urgent need to develop more simple inexpensive assays to evaluate drug quality for use in the field.

  • pharmacokinetics of Miltefosine in old world cutaneous leishmaniasis patients
    Antimicrobial Agents and Chemotherapy, 2008
    Co-Authors: Thomas P. C. Dorlo, Jos H. Beijnen, Pieter P A M Van Thiel, Alwin D R Huitema, Ron J Keizer, Henry J C De Vries, Peter J. De Vries
    Abstract:

    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.

Simon L Croft - One of the best experts on this subject based on the ideXlab platform.

  • Topical formulations of Miltefosine for cutaneous leishmaniasis in a BALB/c mouse model
    Journal of Pharmacy and Pharmacology, 2016
    Co-Authors: Katrien Van Bocxlaer, Vanessa Yardley, Sudaxshina Murdan, Simon L Croft
    Abstract:

    UNLABELLED: Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania and affects approximately 10 million people worldwide. Currently available drugs are not ideal due to high cost, toxicity, parenteral administration and suboptimal efficacy. Miltefosine is the only oral treatment (Impavido®) available to treat CL, given over a period of 28 days with common side effects such as vomiting and diarrhoea. OBJECTIVE: To explore the local application of Miltefosine as a topical formulation to enhance activity and reduce the drug's adverse effects. METHODS: The antileishmanial activity of Miltefosine was confirmed in vitro against several Leishmania species. The permeation of Miltefosine, in different solvents and solvent combinations, through BALB/c mouse skin was evaluated in vitro using Franz diffusion cells. The topical formulations which enabled the highest drug permeation or skin disposition were tested in vivo in BALB/c mice infected with L. major. KEY FINDINGS: The overall permeation of Miltefosine through skin was low regardless of the solvents used. This was reflected in limited antileishmanial activity of the drug formulations when applied topically in vivo. All topical formulations caused skin irritation. CONCLUSIONS: We conclude that Miltefosine is not an appropriate candidate for the topical treatment of CL.

  • topical formulations of Miltefosine for cutaneous leishmaniasis in a balb c mouse model
    Journal of Pharmacy and Pharmacology, 2016
    Co-Authors: Vanessa Yardley, Katrien Van Bocxlaer, Sudaxshina Murdan, Simon L Croft
    Abstract:

    UNLABELLED: Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania and affects approximately 10 million people worldwide. Currently available drugs are not ideal due to high cost, toxicity, parenteral administration and suboptimal efficacy. Miltefosine is the only oral treatment (Impavido®) available to treat CL, given over a period of 28 days with common side effects such as vomiting and diarrhoea. OBJECTIVE: To explore the local application of Miltefosine as a topical formulation to enhance activity and reduce the drug's adverse effects. METHODS: The antileishmanial activity of Miltefosine was confirmed in vitro against several Leishmania species. The permeation of Miltefosine, in different solvents and solvent combinations, through BALB/c mouse skin was evaluated in vitro using Franz diffusion cells. The topical formulations which enabled the highest drug permeation or skin disposition were tested in vivo in BALB/c mice infected with L. major. KEY FINDINGS: The overall permeation of Miltefosine through skin was low regardless of the solvents used. This was reflected in limited antileishmanial activity of the drug formulations when applied topically in vivo. All topical formulations caused skin irritation. CONCLUSIONS: We conclude that Miltefosine is not an appropriate candidate for the topical treatment of CL.

  • In vitro susceptibility of Trypanosoma cruzi strains from Santander, Colombia, to hexadecylphosphocholine (Miltefosine), nifurtimox and benznidazole.
    Biomedica, 2009
    Co-Authors: Katherine Paola Luna, Indira Paola Hernández, Cesar M. Rueda, María Magdalena Zorro, Simon L Croft, Patricia Escobar
    Abstract:

    INTRODUCTION: The current chemotherapy for Chagas disease is unsatisfactory with only two drugs available for treatment. Research to discover new drugs for Chagas disease is urgent. Hexadecyl-phosphocholine (HPC, Miltefosine) has been demonstrated to have in vitro activity against Trypanosoma cruzi parasites, but its activity on different Colombian T. cruzi strains is not known. OBJECTIVE: To evaluate the in vitro susceptibility of T. cruzi strains isolated from humans and vectors in Santander, Colombia. to Miltefosine, nifurtimox and benznidazole. MATERIALS AND METHODS: Eight T. cruzi Colombian strains and three reference strains (Esmeraldo, SilvioX10 and Y) were studied. Drug activities against extracellular epimastigotes and intracellular amastigotes were determined by microscopic counting. The results were expressed as the concentrations that inhibited 50% and 90% growth (IC50 and IC90). RESULTS: For Miltefosine a similar range of drug activity was observed against all the Colombian strains, all parasites being more susceptible to Miltefosine than to the reference drugs. The intracellular amastigotes were more susceptible to Miltefosine (IC50 0.08 to 0.63 microM and IC90 0.21 to 2.21 microM) than extracellular forms (IC50

  • inactivation of the Miltefosine transporter ldmt causes Miltefosine resistance that is conferred to the amastigote stage of leishmania donovani and persists in vivo
    International Journal of Antimicrobial Agents, 2007
    Co-Authors: Karin Seifert, Santiago Castanys, Javier F Perezvictoria, Marianne Stettler, Maria P Sanchezcanete, Francisco Gamarro, Simon L Croft
    Abstract:

    Miltefosine (hexadecylphosphocholine) is the first oral antileishmanial drug. In this study, we addressed the question whether Miltefosine-resistant Leishmania donovani promastigotes transform to Miltefosine-resistant amastigotes. A promastigote line, M-mutR, showed defective internalisation of Miltefosine owing to mutations in LdMT, similar to previously described resistant lines. M-mutR parasites were infective to macrophages in vitro as well as in BALB/c mice in vivo. There was good correlation of in vitro resistance indices between promastigotes and intracellular amastigotes. Most importantly, M-mutR parasites retained the resistant phenotype in vivo, with no decrease of hepatic burden in BALB/c mice following Miltefosine treatment up to 30 mg/kg (ca. 90% inhibition in wild-type infections). No cross-resistance to other antileishmanial drugs was observed in M-mutR amastigotes.

  • In Vitro and In Vivo Interactions between Miltefosine and Other Antileishmanial Drugs
    Antimicrobial Agents and Chemotherapy, 2006
    Co-Authors: Karin Seifert, Simon L Croft
    Abstract:

    The interaction of Miltefosine with amphotericin B, sodium stibogluconate, paromomycin, and sitamaquine was assessed in vitro and additionally for the first three combinations in vivo. In vitro interactions were indifferent for Miltefosine combined with amphotericin B (mean sums of fractional inhibitory concentrations [mean summation operatorFICs] ranging from 1.22 to 1.51 at the 50% effective concentration [EC50] level and 1.08 to 1.38 at the EC90 level), sitamaquine (mean summation operatorFICs from 1.33 to 1.38 and 1.0 to 1.02, respectively), and paromomycin (mean summation operatorFICs from 0.79 to 0.93 at the EC50 and 0.77 to 1.35 at the EC90 level). Some synergy was observed for Miltefosine combined with sodium stibogluconate (mean summation operatorFICs from 0.61 to 0.75 at EC50 and 0.49 to 0.97 at EC90). Different interactions were found in vivo, where the highest potentiation of Miltefosine activity was achieved with amphotericin B (activity enhancement index [AEI] of up to 11.3). No significant interaction was observed when Miltefosine was combined with sodium stibogluconate (AEI of up to 2.38). The potentiation of Miltefosine in vivo was also achieved with the combination of Miltefosine and paromomycin (AEI of up to 7.22).