Acute uveitis: A rare adverse effect of miltefosine in the treatment of post-kala-azar dermal leishmaniasis

Abstract Post-kala-azar dermal leishmaniasis is a skin disorder occurring in 5-10% of visceral leishmaniasis patients after treatment with miltefosine,the first-line drug for this skin disorder. We reported a case of acute anterior uveitis,a rare adverse effect, experienced by a patient treated with miltefosine for post-kala-azar dermal leishmaniasis. This adverse effect developed after 15 days of miltefosine consumption, and the patient himself discontinued the treatment. The ophthalmic complication was completely resolved with antibiotics and steroid eye drops. After recovery from the ophthalmic complication, the patient was successfully treated with liposomal amphotericin B for the skin lesions.

Estimating direct costs of the treatment for mucosal leishmaniasis in Brazil

Abstract INTRODUCTION: The objective of this study was to estimate the direct medical costs of the treatment for mucosal leishmaniasis (ML) using three therapeutic approaches in the Brazilian context. METHODS: We performed this economic assessment from the perspective of the Brazilian public healthcare system. The following therapeutic approaches were evaluated: meglumine antimoniate, liposomal amphotericin B, and miltefosine. Direct medical costs were estimated considering four treatment components: a) drug, b) combined medical products, c) procedures, and d) complementary tests. RESULTS: Treatment with meglumine antimoniate had the lowest average cost per patient (US$ 167.66), followed by miltefosine (US$ 259.92) in the outpatient treatment regimen. The average cost of treatment with liposomal amphotericin B was US$ 715.35 both in inpatient regimen. In all estimates, the drugs accounted for more than 60% of the total cost for each treatment approach. CONCLUSIONS: These results demonstrate the marked differences in costs between the therapeutic alternatives for ML. In addition to efficacy rates and costs related to adverse events, our data have the potential to support a complete cost-effectiveness study in the future. Complete analyses comparing costs and benefits for interventions will assist health managers in choosing drugs for ML treatment in Brazil as well as in establishing effective public health policies.

Assessment of Treatment Outcome in Post-Kala-Azar Dermal Leishmaniasis (PKDL) Patients– A Record-Based Observational study in a Speciality Public Hospital, Kolkata

In the absence of effective vector control measures and vaccines against leishmaniasis, effective chemotherapy remains the mainstay of treatment. Identification of post-kala-azar dermal leishmaniasis (PKDL) is important due to the long and toxic treatment and the fact that PKDL patients may serve as a reservoir for visceral leishmaniasis (VL). This retrospective study was done to assess the outcome of pharmacotherapy in post-kala-azar dermal leishmaniasis (PKDL) patients in a specialty public hospital in Kolkata. Methods: The hospital records of all consecutive PKDL patients admitted at Calcutta School of Tropical Medicine (CSTM), Kolkata during the last five years - 2010-2014, were reviewed and the relevant information inputs as documented studied to realize the noted objectives. Clinical presentation on admission including presence of co-infections (particularly HIV), trends and patterns of treatment regimens and rationale thereof, if available; treatment (anti-leishmaniasis) outcomes in reference to efficacy, safety and tolerability, fatality like serious complications and mortality and adverse drug reactions (for anti-leishmaninal drugs primarily), if any was noted. Results: PKDL cases presented with insidious onset skin lesions of different types without much systemic illness. 2 out of 19 cases presented with fever and 2 other cases had mild anemia. PKDL cases presented with 4 types of skin lesions. Multiple macular or hyppigmented macular lesions were commonest, 8 out of 19 cases (42.10%). In PKDL cases treatment outcome was difficult to say unless parasitologically declared negative, though clinically regression of the lesions were visible in all cases. Tolerability was least with AmB followed by SSG and best with miltefosine. Conclusion: So, it can be concluded from this study that in this institute PKDL were treated with conventional and liposomal AmB as well as with SSG, miltefosine and combination therapy. Among the regimens short course L-AmB was found to be the most efficacious and tolerable in respect to ADRs and hospital stay.

A Study On Efficacy And Tolerability Of Miltefosine For Childhood Visceral Leishmaniasis In A Tertiary Care Centre In Eastern Bihar

Introduction: Leishmania donovani is an intracellular protozoan parasite of genus Leishmania. It causes Visceral leishmaniasis (VL), which is a disseminated and serious form of leishmaniasis. VL causes an estimated 500,000 new cases of disease and 60,000 deaths every year. VL is deadly and debilitating disease affecting children of Bihar and U.P. Antimony resistance is a serious problem, Amphotericin B and Pentamidine are effective by parenteral administration, associated with toxicities. Thus there is a need for an effective, orally administered, non–toxic and less expensive alternative drug like Miltefosine, to be used in children. Aims and Objectives: The present study was designed to observe the efficacy of Miltefosine in VL, in Bihar by evaluating the usage of adult dosage of Miltefosine (2.5 mg/kg/d for 28 days) in 160 children (age, 2–11 years). Materials and Methods: Our study is an open–label, clinical trial involving 160 patients admitted at JLNMCH, Bhagalpur, Bihar who were parasitologically proven cases of VL who received Miltefosine and were followed up for the following one year. Results: Out of 160 children, 2 died of pneumonia, other 158 patients demonstrated no parasites after treatment and improved clinically. 6 patients relapsed, 2 patients lost follow–up. Cure rate was 94% .Side effects included vomiting or diarrhea (each 25%) and transient elevations in the AST level (55%). Conclusions: The present study concludes that Miltefosine is effective, well tolerated, and easily administrable oral drug in the treatment of VL in Children in resource poor country like India

A randomized, open-label clinical trial comparing the long-term effects of miltefosine and meglumine antimoniate for mucosal leishmaniasis

Abstract INTRODUCTION: The treatment of mucosal leishmaniasis (ML) is difficult due to the toxicity and route of administration of standard drugs. Miltefosine is an oral agent used for leishmaniasis treatment; however, no data exist regarding its use for ML in Brazil. In this study, we aimed to evaluate the efficacy of miltefosine for ML treatment compared to that of pentavalent antimonial in a pilot study. METHODS: We performed a randomized clinical trial with two parallel groups. The tested intervention consisted of miltefosine 1.3-2 mg/kg/day (two capsules) for 28 days or intravenous 20 mg SbV/kg/day of meglumine antimoniate (N-MA) for 30 days. The final endpoint was defined as complete healing of the lesion four years after treatment. We also analyzed an early endpoint at 90 days after treatment. RESULTS: Forty patients were included in this study: each experimental group comprised 20 patients. Applying a multivariate model in an intention-to-treat analysis, we observed that patients treated with miltefosine had a cure probability 2.08 times greater (95% confidence interval [CI] = 1.03-4.18) than those treated with N-MA at 90 days after treatment. At the final endpoint, we observed no differences in cure probability between miltefosine and N-MA (relative risk = 0.66; 95% CI = 0.33-1.32). With respect to adverse reactions, significant differences between groups were related to gastrointestinal effects, which were more frequent in the miltefosine group. CONCLUSIONS: Miltefosine may be an interesting alternative for treating ML because of its oral administration and cure rate after long-term follow-up.

Efficacy of miltefosine compared with glucantime for the treatment of cutaneous leishmaniasis: a systematic review and meta-analysis / 한국역학회지

Cutaneous leishmaniasis (CL) is most common form of leishmaniasis and is characterized by ulcerative skin lesions. The objective of this study was to conduct a systematic review and meta-analysis of clinical trials that compared the efficacy of miltefosine and glucantime for the treatment of CL. We searched the following databases: Cochrane, PubMed, Embase, Scopus, Web of Science, ProQuest, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform search portal of World Health Organization, Sid, Irandoc, Magiran, and clinicaltrials.gov. We used keywords including “miltefosine,” “glucantime,” and “Leishmania.” The quality of studies was assessed using the Cochrane risk of bias tool. A random-effects model was employed for the analysis. We assessed heterogeneity by the chi-square test and the I² index statistic. When heterogeneity was present, meta-regression analyses were performed. The Egger method was used to assess publication bias; when it was significant, the trim-and-fill method was used to test and adjust for publication bias. A total of 1,570 reports were identified, of which 10 studies were included in the meta-analysis. In the meta-analysis, there was no significant difference between the efficacy of miltefosine and glucantime; however, subgroup analysis showed that, regarding parasite species other than Leishmania braziliensis, miltefosine was significantly superior to glucantime (intention to treat; relative risk, 1.15; 95% confidence interval, 1.01 to 1.32). In the meta-regression, only the glucantime injection type was significant at the p=0.1 level. The Egger test found statistically significant publication bias; however, including the 3 missing studies in the trim-and-fill analysis did not change the results. This meta-analysis found that miltefosine seems to be more effective than glucantime, at least in species other than L. braziliensis, for treating CL.

Efficacy of miltefosine compared with glucantime for the treatment of cutaneous leishmaniasis: a systematic review and meta-analysis / 한국역학회지

Cutaneous leishmaniasis (CL) is most common form of leishmaniasis and is characterized by ulcerative skin lesions. The objective of this study was to conduct a systematic review and meta-analysis of clinical trials that compared the efficacy of miltefosine and glucantime for the treatment of CL. We searched the following databases: Cochrane, PubMed, Embase, Scopus, Web of Science, ProQuest, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform search portal of World Health Organization, Sid, Irandoc, Magiran, and clinicaltrials.gov. We used keywords including “miltefosine,” “glucantime,” and “Leishmania.” The quality of studies was assessed using the Cochrane risk of bias tool. A random-effects model was employed for the analysis. We assessed heterogeneity by the chi-square test and the I² index statistic. When heterogeneity was present, meta-regression analyses were performed. The Egger method was used to assess publication bias; when it was significant, the trim-and-fill method was used to test and adjust for publication bias. A total of 1,570 reports were identified, of which 10 studies were included in the meta-analysis. In the meta-analysis, there was no significant difference between the efficacy of miltefosine and glucantime; however, subgroup analysis showed that, regarding parasite species other than Leishmania braziliensis, miltefosine was significantly superior to glucantime (intention to treat; relative risk, 1.15; 95% confidence interval, 1.01 to 1.32). In the meta-regression, only the glucantime injection type was significant at the p=0.1 level. The Egger test found statistically significant publication bias; however, including the 3 missing studies in the trim-and-fill analysis did not change the results. This meta-analysis found that miltefosine seems to be more effective than glucantime, at least in species other than L. braziliensis, for treating CL.

Leishmaniasis cutánea inducida por especies de leishmanial Viannia en ratones BALB/c y eficacia de un tratamiento tópico / Cutaneous leishmaniasis by Leishmania Viannia species in BALB/c mice and efficacy of a topical treatment

Resumen Introducción: La diversidad de las formas clínicas de la leishmaniasis del Nuevo Mundo (desde formas cutáneas localizadas a diseminadas o formas mucosas) causada por especies del subgénero Viannia podría inferir en la eficacia de los tratamientos tópicos. El objetivo del presente trabajo fue determinar las características de la leishmaniasis cutánea producida por infecciones con Leishmania (V.) braziliensis y L.(V.) panamensis en ratones BALB/c y la eficacia de un mismo tratamiento tópico. Materiales y métodos: Después de la infección con cada una de las especies se realizó seguimiento de las lesiones determinando su tamaño (mm ) y características macroscópicas, cada siete días por 150 días. Las características histopatológicas (en lesiones y órganos) fueron determinadas 70, 106 y 150 días post-infección y la eficacia de un tratamiento tópico (cura de lesión y parasitológica) fue determinada después del tratamiento con un gel de miltefosina aplicado una vez al día por 20 días sobre las lesiones. Resultados: Se observó un aumento del tamaño de las lesiones en ambos grupos de ratones, sin embargo, un mayor tamaño de las lesiones e intensidad de la respuesta inflamatoria con menos alteraciones epidérmicas fue encontrada en los ratones infectados con L. (V.) braziliensis. En ningún grupo se encontraron parásitos en órganos (nódulos, bazo e hígado) ni diferencias en la efectividad del tratamiento tópico utilizado. Conclusión: La eficacia del tratamiento tópico utilizado no fue afectada por las diferencias macro y microscópicas encontradas en la leishmaniasis producida por las dos especies de Leishmania evaluadas.

Abstract Introduction: The efficacy of topical treatments could be affected by the diversity of clinical forms (localized or disseminated cutaneous forms, mucosal forms) of New World-leishmaniasis caused by species of Leishmania from the subgenus Viannia. The aim of this study was to determine the cutaneous leishmaniasis features produced after infection with Leishmania (V.) braziliensis and L. (V.) panamensis in BALB/c mice and to determine the efficacy of one topical treatment. Materials and methods: Cutaneous leishmaniasis lesions were followed up after infection determining their lesion-size (mm2) and other macroscopic characteristics every 7 days for 150 days. Histopathological patterns (in lesions and organs) were determined 70, 106 and 150 days post-infection and the efficacy (lesion and parasitological cure) of miltefosine gel applied topical once a day for 20 days was determined. Results: An increase of size-lesions was observed in both groups of mice, however, a higher lesion- size and inflammatory response but lower epidermal changes were observed in L. (V.) braziliensis compared with L. (V.) panamensis infected ones. No parasites were observed in organs (nodules, spleen and liver) and no differences were observed in the effectiveness of the used topical treatment. Conclusion: The efficacy of the topical treatment used was not affected by the macro and microscopic differences produced after infection by the two Leishmania species evaluated.

Effects of albendazole, artesunate, praziquantel and miltefosine, on Opisthorchis viverrini cercariae and mature metacercariae

Objective To explore larvicidal effects of anthelmintic drugs on Opisthorchis viverrini (O. viverrini) for alternative approach to interrupting its cycle for developing a field-based control program. Methods The larvicidal activities of albendazole (Al), artesunate (Ar), praziquantel (Pzq) and miltefosine (Mf) on O. viverrini cercariae and mature metacercariae were investigated. Lethal concentrations (LC

Effects of albendazole, artesunate, praziquantel and miltefosine, on Opisthorchis viverrini cercariae and mature metacercariae

OBJECTIVE@#To explore larvicidal effects of anthelmintic drugs on Opisthorchis viverrini (O. viverrini) for alternative approach to interrupting its cycle for developing a field-based control program.@*METHODS@#The larvicidal activities of albendazole (Al), artesunate (Ar), praziquantel (Pzq) and miltefosine (Mf) on O. viverrini cercariae and mature metacercariae were investigated. Lethal concentrations (LC and LC) of these drugs were determined. Mature metacercariae previously exposed to various concentrations of the drugs were administered to hamsters. Worms were harvested 30 d post infection and worm recovery rates calculated. Al, Ar, Pzq and Mf produced morphological degeneration and induced shedding tails of cercariae after 24 h exposure.@*RESULTS@#The LC and LC of Al, Ar, Pzq and Mf on cercariae were 0.720 and 1.139, 0.350 and 0.861, 0.017 and 0.693, and 0.530 and 1.134 ppm, respectively. LC and LC of Ar on mature metacercariae were 303.643 and 446.237 ppm and of Mf were 289.711 and 631.781 ppm, respectively but no lethal effect in Pzq- and Al-treated groups (up to 1 ppt). No worms were found in hamsters administered Pzq-treated metacercariae. The adult worms from Al-treated metacercariae were significantly bigger in size compared to the control group (P < 0.05). Fecundity and body width were greater in adults from Mf-treated metacercariae compared to the control group (P < 0.05).@*CONCLUSIONS@#The larvicidal effects of these drugs were high efficacy to O. viverrini cercariae but lesser efficacy to metacercariae. It should be further studied with the eventual aim of developing a field-based control program.

Adamantylidene-substituted alkylphosphocholine TCAN26 is more active against Sporothrix schenckii than miltefosine

Sporotrichosis is the most frequent subcutaneous mycosis in the world and its increasing incidence has led to the search for new therapeutic options for its treatment. In this study, we demonstrated that three structural analogues of miltefosine (TCAN26, TC19, and TC70) showed inhibitory activity against Sporothrix schenckii sensu stricto and that TCAN26 was more active in vitro than miltefosine against several isolates. Scanning electron microscopy showed that S. schenckii exposure to TCAN26 resulted in cells that were slightly more elongated than untreated cells. Transmission electron microscopy showed that TCAN26 treatment induced loss of the regular cytoplasmic electron-density and altered the cell envelope (disruption of the cell membrane and cell wall, and increased cell wall thickness). Additionally, TCAN26 concentrations required to kill S. schenckii cells were lower than concentrations that were cytotoxic in mammalian cells, and TCAN26 was more selective than miltefosine. Thus, the adamantylidene-substituted alkylphosphocholine TCAN26 is a promising molecule for the development of novel antifungal compounds, although further investigations are required to elucidate the mode of action of TCAN26 in S. schenckii cells.

Leishmanasis mucocutánea tratada con miltefosine / Mucocutaneous leishmaniasis treated with miltefosine

El miltefosine (Impávido(r)) es un medicamento de componente antineoplásico que ha encontrado efectividad muy alta contra la leishmaniasis mucocutánea y visceral en el mundo, y se ha convertido en una opción muy atractiva para pacientes con enfermedades de fondo y tratamientos de base que contraindican el uso de amoniato de meglumina (Glucantime(r)) o stibogluconato de sodio (Pentostam(r)). Seguidamente se presenta el caso de un paciente de 78 años con antecedentes de diabetes mellitustipo 2, hipertenso, anticoagulado con warfarina por una fibrilación auricular crónica, que inició una dermatosis ulcerosa de bordes violáceos elevados, única en el hélix del oído derecho, de evolución crónica asociada a múltiples ulceraciones en la mucosa nasal. La biopsia cutánea se reportó como inespecífica, pero como la sospecha clínica era alta de leishmaniasis, se realizó una reacción de cadena polimerasa de tejido de mucosa nasal que fue reportada positiva por Leishmania panamensis. Por las comorbilidades y el tratamiento del paciente se decidió tratarlo con miltefosine (Impávido(r)).

Miltefosine (Impavido(r)) is an anticancer medicine that has been found highly effective against mucocutaneous and visceral leishmaniasis worldwide, making it a very attractive option for patients with underlying diseases and treatments that contraindicate the use of glucamine antimoniate (Glucantime(r)) or sodium stibogluconate (Pentostam(r)). Here we present the case of a 78 years old male, with a history of type 2 diabetes mellitus, high blood preasure, anticoagulated with warfarin for chronic atrial fibrillation, who started with a solitary cutaneous ulcer of purplish edges on the right ear helix of chronic evolution associated with multiple ulcerations on the nasal mucosa. Skin biopsy was reported as nonspecific, but as clinical suspicion of leishmaniasis was high, a polymerase chain reaction of nasal mucosa tissue was performed for Leishmania with positive results for Leishmania panamensis. Due to comorbidities and the treatment of our patient we decided to use miltefosine (Impavido(r)) for 2 months with very good results.

Actividad in vitro contra Leishmania y permeación en piel humana de liposomas ultradeformables de miltefosina / In vitro activity against Leishmania and human skin permeation of miltefosine ultradeformable liposomes

Introducción: los liposomas ultradeformables de miltefosina (LUD-MIL) constituyen una opción para el tratamiento tópico en leishmaniasis cutánea penetrando los estratos de la piel hasta la dermis, sitio donde habita el parásito. Objetivo: diseñar LUD-MIL y determinar su actividad contra L. (Viannia) panamensis y L. (V.) braziliensis y la permeación en piel humana. Métodos: los LUD-MIL, liposomas convencionales de fosfatidilcolina (LConv) y LUD-MIL-fluorescente (LUD-MIL-Fluo) fueron preparados por el método de rehidratación de película lipídica. Se caracterizaron fisicoquímicamente y se determinaron: la liberación en membrana semisintéticas, la retención en las capas de la piel y la permeación en piel humana. La citotoxicidad en THP-1 fue determinada por el ensayo colorimétrico de MTT y la actividad en promastigotes y amastigotes intracelulares por recuento microscópico. Resultados: el tamaño, índice de polidispersión, potencial Z y concentración de fosfolípidos de los LUD-MIL fue de 100,7 nm, 0,147, -12,0 mV y 53,24 mM respectivamente. El flujo de MIL a través de la membrana fue mayor con LUD-MIL que con MIL-libre. El tratamiento con LUD-MIL indujo menor acumulación de la MIL en el estrato corneo y mayor permeación que el tratamiento con MIL libre. Los LUD-MIL y los LConv-MIL mantuvieron la actividad de la MIL en los parásitos y células. Los LUD-MIL fueron más tóxicos para las células que los LConv y la MIL y más activos en amastigotes intracelulares de L. (V.) braziliensis. Conclusión: los LUD-MIL preparados conservaron la actividad anti-Leishmania de la MIL y permitieron la liberación del compuesto en membranas y piel humana. Ensayos en modelos experimentales de leishmaniasis cutánea para evaluar la actividad de estas formulaciones son urgentes de realizar(AU)

Introduction: miltefosine ultradeformable liposomes (MIL-LUD) are an option for the topical treatment of cutaneous leishmaniasis penetrating the skin layers to the dermis where the parasite inhabits. Objective: to design MIL-LUD and determine their in vitro activity against L. (Viannia) panamensis and L. (V.) braziliensis and to determine human skin permeation. Methods: MIL-LUD, phosphatidylcholine liposomes (MIL-LConv) and fluorescent MIL-LUD (MIL-LUD-Fluo) were prepared by lipid film rehydration method. They were physicochemically characterized to determine drug release in semisynthetic membrane, retention in skin layers and permeation on human skin membranes. Cytotoxicity in THP-1 was determined by the MTT colorimetric test and activity in promastigotes and intracellular amastigotes by microscopic counting. Results: the size, the polydispersion index, the Zeta potential and phospholipid content were 100.7 nm, 0.147, -12.0mV and 53.24mM, respectively for MIL-LUD. MIL flow through the semisynthetic membrane was greater with MIL-LUD than MIL-free treatment. MIL-LUD treatment induced lower MIL accumulation in the stratum corneum and increased permeation than MIL free treatment. The MIL-LUD and MIL-Conv maintained MIL activity in parasites and cells. The MIL-LUD was more toxic to cells than MIL-Conv and more active against intracellular amastigotes of L. (V.) braziliensis. Conclusion: prepared LUD -MIL retained the anti-leishmanial activity of the MIL and allowed the compound release in human skin and membranes. Testing of experimental cutaneous leishmaniasis models to evaluate the activity of these formulations are urgently needed(AU)

Miltefosina versus antimoniato de meglumina en el tratamiento de la leishmaniasis mucosa

El tratamiento convencional para la leishmaniasis tegumentaria es el antimoniato de meglumina, el cual presenta falla terapéutica creciente, producción de efectos adversos graves, y necesidad de administración parenteral, justificando la búsqueda de alternativas terapéuticas. Presentamos aquí los resultados preliminares de un ensayo clínico de fase II en pacientes con leishmaniasis mucosa, en el que se comparó la eficacia de miltefosina por vía oral con respecto a la del compuesto antimonial. La evaluación de la respuesta a los tratamientos se realizó mediante un seguimiento con videofibroscopia nasofaríngea, utilizándose un score de gravedad de lesiones mucosas para aplicar en cada momento del seguimiento de los pacientes. No se encontraron hasta ahora diferencias significativas entre el número de pacientes curados con miltefosina o con la quimioterapia convencional. Los resultados favorables de este trabajo sugieren que miltefosina podría constituir una alternativa terapéutica efectiva y segura en la región.

The conventional treatment for tegumentary leishmaniasis is meglumine antimoniate, which needs parenteral administration, has increased therapeutic failure, and produces serious adverse effects, justifying the search for therapeutic alternatives. We report here the preliminary results of a phase II clinical trial in patients with mucosal leishmaniasis, in which the efficacy of oral miltefosine versus the antimonial compound was assessed. The evaluation of response to the treatment was performed by monitoring with nasopharyngeal video-fibroscopy, using a score of mucosal injury severity for patients at each follow-up point. We found no significant differences so far between the number of patients cured with miltefosine or conventional chemotherapy. The favorable results of this study suggest that miltefosine could be an effective and safe oral therapeutic alternative in the region.

Evaluation of anti-leishmanial activity of artemisinin combined with amphotericin B or miltefosine in Leishmania donovani promastigotes.

Background: The increasing incidence of drug resistance in Leishmaniasis necessitates evaluation of combination chemotherapy. Miltefosine and amphotericin B are established anti-leishmanial drugs, while artemisinin has shown significant leishmanicidal activity in experimental models. In this study, we have evaluated the additive/synergistic effect of artemisinin with amphotericin B or miltefosine. Methods: Leishmania parasites were isolated from the bone marrow aspirate of a patient with visceral leishmaniasis. Parasites were typed as Leishmania donovani by restriction fragment length polymorphism of internal transcribed spacer 1 region of Leishmania genome. Promastigotes were incubated in a fixed ratio combination of artemisinin (0-500 μM) and amphotericin B (0-100 nM) or miltefosine (0-100 μM) and cell viability was assessed. An isobologram was constructed to evaluate the additive/synergistic effect, wherein it was considered additive if the mean sum fractional inhibitory concentration (mean ΣFIC) at the IC50 level was <2, but ≥1 and synergism, if the mean ΣFIC was <1. Results: The isobologram showed an additive effect for three combinations of artemisinin-amphotericin B and artemisinin-miltefosine, the mean ΣFICs ranging from 1.02 to 1.44 and 1.08 to 1.33 along with a synergistic effect with one combination, the mean ΣFICs being 0.58 and 0.81 respectively. Conclusions: This study supports the combination use of artemisinin-amphotericin B and artemisinin-miltefosine, worthy of future pharmacological consideration.

Post-kala-azar Dermal Leishmaniasis with Mucosal Involvement: An Unusual Case Presentation including Successful Treatment with Miltefosine.

Post-kala-azar dermal leishmaniasis (PKDL) is a dermatologic manifestation that usually occurs after visceral leishmaniasis (VL) caused by Leishmania donovani. It is characterized by hypopigmented patches, a macular or maculopapular rash and nodular skin lesions on the body surface. Involvement of the mucosae is very rare and unusual in PKDL. We report a case of PKDL that presented with polymorphic skin lesions, along with involvement of peri-oral mucosa and tongue from an endemic area for kala-azar in Bangladesh. In the absence of a definite past history of kala-azar, a clinical suspicion for PKDL was confirmed by positive rapid serological tests against two recombinant (rK39 and rK28) leishmanial antigens, demonstration of Leishmania donovani (LD) body in the slit skin smear, and isolation of promastigotes by culture from a nodular lesion. The patient was treated with oral Miltefosine for three consecutive months and showed significant clinical improvement as demonstrated by a negative slit skin smear at two months after initiation of therapy. We report this case as an unusual presentation of mucosal involvement in PKDL and subsequent treatment success with Miltefosine.

Thermoterapy effective and safer than miltefosine in the treatment of cutaneous leishmaniasis in Colombia / Termoterapia efectiva y más segura que la miltefosina en el tratamiento de la leishmaniasis cutánea en Colombia

In Colombia, pentavalent antimonials and miltefosine are the drugs of choice for the treatment of cutaneous leishmaniasis; however, their toxicity, treatment duration, (treatment adherence problems), cost, and decreased parasite sensitivity make the search for alternative treatments of American cutaneous leishmaniasis necessary. Based on the results found in a controlled, open, randomized, phase III clinical trial, the efficacy and safety of miltefosine was compared to that of thermotherapy for the treatment of cutaneous leishmaniasis in Colombia. Adult patients from the Colombian army participated in the study; they received either 50 mg of miltefosine three times per day for 28 days by the oral route (n = 145) or a thermotherapy (Thermomed®) application of 50 °C for 30 seconds over the lesion and surrounding area (n = 149). Both groups were comparable with respect to their sociodemographic, clinical, and parasitological characteristics. The efficacy of miltefosine by protocol and by intention to treat was 70% (85/122 patients) and 69% (85/145 patients), respectively. The adverse effects were primarily gastrointestinal for miltefosine and pain at the lesion site after treatment for thermotherapy. No statistically significant difference was found in the efficacy analysis (intention to treat and protocol) between the two treatments. ClinicalTrials.gov: NCT00471705.

En Colombia antimoniales pentavalentes y miltefosina son los medicamentos de primera elección para el tratamiento de la leishmaniosis cutánea; sin embargo, su toxicidad, duración (que lleva a problemas de adherencia), costo y la disminución de la sensibilidad de los parásitos a los mismos, hacen necesaria la búsqueda de nuevas alternativas de tratamiento para la leishmaniosis cutánea americana. A partir de resultados derivados de un ensayo clínico controlado abierto, aleatorizado, fase III, se comparó la eficacia y seguridad de la miltefosina con la de la termoterapia, para el tratamiento de la leishmaniosis cutánea en Colombia. Adultos pertenecientes al Ejército de Colombia participaron el estudio. Miltefosina, una cápsula de 50 mg tres veces día durante 28 días, vía oral (n = 145). Termoterapia (Thermomed®) aplicación de 50 °C/30" sobre la lesión y el área circundante (n = 149). Ambos grupos fueron comparables en características sociodemográficas, clínicas y parasitológicas. Eficacia de la miltefosina por protocolo 70% (85/122 pacientes) y 69% (85/145 pacientes) por intención a tratar. Termoterapia eficacia por protocolo 64% (86/134 pacientes) y 58% (86/149 pacientes) por intención a tratar. En miltefosina los eventos adversos fueron principalmente de tipo gastrointestinal y en termoterapia se encontró dolor en el sitio de la lesión luego del tratamiento. En el análisis de eficacia (intención a tratar y protocolo) no se encontró diferencia estadísticamente significativa entre los tratamientos evaluados. ClinicalTrials.gov: NCT00471705.

Relapse of kala-azar after use of multiple drugs: A case report and brief review of literature.

We present a case of kala-azar infection that recurred in a patient after completion of the standard treatment course of miltefosine, amphotericin B-deoxycholate (short course), and amphotericin B lipid formulations. The patient was cured after continuous amphotericin B-deoxycholate administration for 4 weeks. This is a unique case of relapse following the use of three important drugs. Although amphotericin B-deoxycholate is a second line drug in Nepal, it has shown a satisfactory clinical response with continuous treatment for 4 weeks. Therefore, an extended course of amphotericin B-deoxycholate may be beneficial in patients with resistance to the standard short course and other anti-leishmania drugs.

The in vitro leishmanicidal activity of hexadecylphosphocholine (miltefosine) against four medically relevant Leishmania species of Brazil

The in vitro leishmanicidal activity of miltefosine® (Zentaris GmbH) was assessed against four medically relevant Leishmania species of Brazil: Leishmania (Leishmania) amazonensis, Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis and Leishmania (Leishmania) chagasi. The activity of miltefosine against these New World species was compared to its activity against the Old World strain, Leishmania (Leishmania) donovani, which is known to be sensitive to the effects of miltefosine. The IC50 and IC90 results suggested the New World species harboured similar in vitro susceptibilities to miltefosine; however, miltefosine was approximately 20 times more active against the Old World L. (L.) donovani than against the New World L. (L.) chagasi species. The selectivity index varied from 17.2-28.9 for the New World Leishmania species and up to 420.0 for L. (L.) donovani. The differences in susceptibility to miltefosine suggest that future clinical trials with this drug should include a laboratory pre-evaluation and a dose-defining step.

Miltefosine-Induced Apoptotic Cell Death on Leishmania major and L. tropica Strains

The aim of this study was to assess the cytotoxic effects of various concentrations of miltefosine on Leishmania major (MRHO/IR/75/ER) and L. tropica (MHOM/IR/02/Mash10) promastigotes and to observe the programmed cell death features. The colorimetric MTT assay was used to find L. major and L. tropica viability and the obtained results were expressed as 50% inhibitory concentration (IC50). Also, 50% effective doses (ED50) for L. major and L. tropica amastigotes were also determined. Annexin-V FLUOS staining was performed to study the cell death properties of miltefosine using FACS analysis. Qualitative analysis of the total genomic DNA fragmentation was performed by agarose gel electrophoresis. Furthermore, to observe changes in cell morphology, promastigotes were examined using light microscopy. In both strains of L. major and L. tropica, miltefosine induced dose-dependent death with features of apoptosis, including cell shrinkage, DNA laddering, and externalization of phosphatidylserine. The IC50 was achieved at 22 microM and 11 microM for L. major and L. tropica after 48 hr of incubation, respectively. ED50 of L. major and L. tropica amastigotes were 5.7 microM and 4.2 microM, respectively. Our results indicate that miltefosine induces apoptosis of the causative agent of cutaneous leishmaniasis in a dose-dependent manner. Interestingly, L. major did not display any apoptotic changes when it was exposed to miltefosine in concentrations sufficient to kill L. tropica.