Use of topical rSm29 in combination with intravenous meglumine antimoniate in the treatment of cutaneous leishmaniasis: A randomized controlled trial.

BACKGROUND: Cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is associated with an inflammatory response. Granzyme (GzmB) and IL-1ß play a key role in the pathology. Meglumine antimoniate (MA) is the first-choice drug for the treatment of CL, but therapy failure is observed in up to 50% of the cases. The protein, rSm29 of Schistosoma mansoni, down-modulates pro-inflammatory cytokine production. We evaluate if the combination of topical rSm29 plus MA increases the cure rate of CL. METHODS: In this randomized clinical trial, 91 CL patients were allocated in 3 groups. All cases received MA (20 mg/kg/weight) for 20 days. Group 1 used topical rSm29 (10 µg), group 2 a placebo topically applied, and group 3 received only MA. RESULTS: The cure rate on day 90 was 71% in subjects treated with rSm29 plus MA, and 43% in patients who received MA plus placebo or MA alone (P < 0.05). There was a decrease in GzmB and an increase in IFN-γ (P < 0.05) in supernatants of skin biopsies of the lesions obtained on D7 of therapy (P < 0.05) in patients who received rSm29. CONCLUSION: rSm29 associated with MA reduces GzmB levels, is more effective than MA alone, and decreases CL healing time. CLINICAL TRIALS REGISTRATION: ClinicalTrial.gov under NCT06000514.

Case Report: Cutaneous Leishmaniasis: A Case Series with Intralesional Treatment in Northeast Brazil.

In 2022, the Pan American Health Organization recommended the intralesional application (IL) of pentavalent antimonials in adult patients with localized cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis. Other guidelines differ from that recommendation, considering that infections caused by a Leishmania species that can be associated with increased risk for mucosal leishmaniasis, in particular L. (V.) braziliensis, should not be eligible for intralesional treatment. This was a prospective interventional study carried out with eight patients diagnosed with CL residing in northeast Brazil during the period from 2019 to 2022. To our knowledge, this is the first prospective study on the subject conducted in the northeast region, which has the second-highest number of cases in the country. In our sample, clinical cure was achieved with the use of intralesional treatment in all cases, and there were no serious adverse events or mucosal involvement during the 1-year follow-up period. We emphasize the importance of using the right criteria for choosing this therapeutic modality and highlight the advantages of intralesional treatment due to the lower risk of adverse events and cost reduction to health services.

An old drug and different ways to treat cutaneous leishmaniasis: Intralesional and intramuscular meglumine antimoniate in a reference center, Rio de Janeiro, Brazil.

BACKGROUND: Treatment of cutaneous leishmaniasis (CL) remains challenging since the drugs currently used are quite toxic, thus contributing to lethality unrelated to the disease itself but to adverse events (AE). The main objective was to evaluate different treatment regimens with meglumine antimoniate (MA), in a reference center in Rio de Janeiro, Brazil. METHODOLOGY: A historical cohort of 592 patients that underwent physical and laboratory examination were enrolled between 2000 and 2017. The outcome measures of effectiveness were epithelialization and complete healing of cutaneous lesions. AE were graded using a standardized scale. Three groups were evaluated: Standard regimen (SR): intramuscular (IM) MA 10-20 mg Sb5+/kg/day during 20 days (n = 46); Alternative regimen (AR): IM MA 5 mg Sb5+/kg/day during 30 days (n = 456); Intralesional route (IL): MA infiltration in the lesion(s) through subcutaneous injections (n = 90). Statistical analysis was performed through Fisher exact and Pearson Chi-square tests, Kruskal-Wallis, Kaplan-Meier and log-rank tests. RESULTS: SR, AR and IL showed efficacy of 95.3%, 84.3% and 75.9%, with abandonment rate of 6.5%, 2.4% and 3.4%, respectively. IL patients had more comorbidities (58.9%; p = 0.001), were mostly over 50 years of age (55.6%), and had an evolution time longer than 2 months (65.6%; p = 0.02). Time for epithelialization and complete healing were similar in IL and IM MA groups (p = 0.9 and p = 0.5; respectively). Total AE and moderate to severe AE that frequently led to treatment interruption were more common in SR group, while AR and IL showed less toxicity. CONCLUSIONS/SIGNIFICANCE: AR and IL showed less toxicity and may be good options especially in CL cases with comorbidities, although SR treatment was more effective. IL treatment was an effective and safe strategy, and it may be used as first therapy option as well as a rescue scheme in patients initially treated with other drugs.

Association of miltefosine with granulocyte and macrophage colony-stimulating factor (GM-CSF) in the treatment of cutaneous leishmaniasis in the Amazon region: A randomized and controlled trial.

OBJECTIVES: To compare topical granulocyte and macrophage colony-stimulating factor (GM-CSF) and miltefosine (G + M) versus placebo and miltefosine (P + M) or parenteral meglumine antimoniate (MA) in the treatment of 150 patients with cutaneous leishmaniasis (CL) caused by Leishmania guyanensis in the Amazon. DESIGN: A randomized and double-blinded clinical trial. RESULTS: At 90 days after the initiation of therapy, the cure rates were 66%, 58%, and 52% for the groups P + M, G + M, and MA, respectively (p > 0.05). Cure rates at 180 days did not differ. Healing time was similar in the 3 groups, but faster in the MA group as compared to the G + M group (p = 0.04). Mild and transitory systemic adverse events were frequent in all groups (above 85%). Nausea (85%) and vomiting (39%) predominated in the miltefosine groups and arthralgia (51%) and myalgia (48%) in the MA group. One patient (group MA) stopped treatment after presenting with fever, exanthema, and severe arthralgia. CONCLUSIONS: Miltefosine did not present a higher cure rate than MA, and the association of GM-CSF did not improve the therapeutic response. Nevertheless, because of its less toxicity, easier administration, and a similar cure rate when compared with MA, miltefosine should remain as one of the main drugs for treating CL due to L. guyanensis. (Clinicaltrials.gov Identifier NCT03023111).

Mucocutaneous leishmaniasis in a cocaine user: diagnostic and therapeutic knowledge.

Mucocutaneous leishmaniasis (MCL) is a chronic infection that can affect the skin and mucous membranes. We report a case of oral, nasopharyngeal, and penile lesions in a 35-year-old cocaine user. The patient presented with ulcerated lesions in 2014. Histopathologic analysis revealed amastigotes, and serological test results were positive for leishmaniasis. Systemic therapy with meglumine antimoniate was administered; however, the patient failed to present for follow-up. In 2018, he returned with nasal collapse, and another histopathologic test confirmed MCL. This case illustrates the importance of careful differential diagnosis of skin and mucous ulcers to identify the particular pathology.

Refractory mucocutaneous leishmaniasis resolved with combination treatment based on intravenous pentamidine, oral azole, aerosolized liposomal amphotericin B, and intralesional meglumine antimoniate.

INTRODUCTION: Mucocutaneous leishmaniasis (MCL) is a complication of tegumentary leishmaniasis, causing potentially life-threatening lesions in the ear, nose, and throat (ENT) region, and most commonly due to Leishmania (Viannia) braziliensis. We report a case of relapsing MCL in an Italian traveler returning from Argentina. CASE DESCRIPTION: A 65-year-old Italian male patient with chronic kidney disease, arterial hypertension, prostatic hypertrophy, and type-2 diabetes mellitus was referred for severe relapsing MCL acquired in Argentina. ENT examination showed severe diffuse pharyngolaryngeal edema and erythema, partially obstructing the airways. A nasopharyngeal biopsy revealed a lymphoplasmacytic inflammation and presence of Leishmania amastigotes, subsequently identified as L. (V.) braziliensis by hsp70 PCR-RFLP analysis and sequencing. Despite receiving four courses of liposomal amphotericine B (L-AmB) and two courses of miltefosine over a 2-year period, the patient presented recurrence of symptoms a few months after the end of each course. After the patient was referred to us, a combined treatment was started with intravenous pentamidine 4 mg/kg on alternate days for 10 doses, followed by one dose per week for an additional seven doses, intralesional meglumine antimoniate on the nasal lesion once per week for six doses, oral azoles for three months, and aerosolized L-AmB on alternate days for three months. The treatment led to regression of mucosal lesions and respiratory symptoms. Renal function temporarily worsened, and the addition of insulin was required to maintain glycemic compensation after pentamidine discontinuation. CONCLUSIONS: This case highlights the difficulties in managing a life-threatening refractory case of MCL in an Italian traveler with multiple comorbidities. Even though parenteral antimonial derivatives are traditionally considered the treatment of choice for MCL, they are relatively contraindicated in cases of chronic kidney disease.The required dose adjustment in cases of impaired renal function is unknown, therefore the use of alternative drugs is recommended. This case was resolved with combination treatment, including aerosolized L-AmB, which had never been used before for MCL.

Case Report: Coinfection by Leishmania amazonensis and HIV in a Brazilian Diffuse Cutaneous Leishmaniasis Patient.

Diffuse cutaneous leishmaniasis (DCL) is a rare type of leishmaniasis characterized by diffuse skin lesions. In Brazil, Leishmania (L.) amazonensis is the main etiological agent of this clinical form. The state of Maranhão has the highest prevalence of this disease in the country, as well as a high rate of HIV infection. Here, we report the first case of DCL/HIV of Brazil. A 46-year-old man from the Amazonian area of Maranhão state presented atypical lesion in the left upper limb and dissemination of diffuse erythematous nodules over his entire body. Histopathological examination confirmed the presence of intracellular amastigotes of Leishmania, and a polymerase chain reaction and molecular identification by restriction fragment profile identified L. (L.) amazonensis as the causative agent of the disease. The patient was also diagnosed with HIV virus after the leishmaniasis diagnosis. The initial treatments for leishmaniasis were liposomal amphotericin B (AmB-L) (4 mg/kg) for 10 days and prophylactic use of Glucantime® (10 mg/Sb+5/kg) for 2 months. After unsuccessful initial treatments, he was treated with a combination of AmB-L (4 mg/kg) alternated with pentamidine (4 mg/kg) for 10 days but failed in the first therapeutic cycle. Subsequently, he had a good response to treatment with pentamidine (4 mg/kg).

Safety profile of meglumine antimoniate intralesional infiltration for cutaneous leishmaniasis.

Objectives: Cutaneous leishmaniasis is a neglected disease, associated with high morbidity, which is partially due to the toxicity of available therapies. The pentavalent antimonial derivatives intralesional infiltration has proven to be as effective as the intravenous drug-based therapy, however, there is a lack of robust safety data.Methods: Phase II, uncontrolled, unicenter clinical trial to assess the safety profile of a standardized meglumine antimionate intralesional therapy, based on weekly infiltrations.Results: Fifty-three patients were studied, predominantly men (60%) and young adults (43.7 ± 17.1 years). Overall, 86.9% of the patients had at least one clinical adverse event. Local events were the most frequent (83%), followed by systemic ones (47.3%). Fourteen participants (26%) presented biochemical abnormalities. In all cases, laboratorial alterations were classified as mild and treatment discontinuation was not required. Differently, the two hypersensitivity (3.8%) reactions observed led to permanent treatment interruption. QTc interval prolongation was recorded in 14 patients (25.5%). The following risk associations to adverse events were identified in the multiple analysis: hypertension with systemic clinical events and smoking with QT interval prolongation.Expert commentary: In general, MA-IL was well tolerated and although associated with local and systemic adverse events, there was a low risk of high intensity or severe complications.

Case Report: Combination Therapy with Liposomal Amphotericin B, N-Methyl Meglumine Antimoniate, and Pentamidine Isethionate for Disseminated Visceral Leishmaniasis in a Splenectomized Adult Patient.

In immunocompromised patients, visceral leishmaniasis (VL) can present with atypical clinical symptoms that include poor response to treatment. No optimal therapeutic regimen is available for such cases. In a splenectomized male patient, we observed a disseminated form of the disease in the liver, bone marrow, lymph nodes, and gastrointestinal tract. There was an apparent clinical improvement when he was initially treated with liposomal amphotericin B (L-AmB), but this was followed by a relapse involving severe clinical symptoms. He was finally treated successfully with a combination of L-AmB, meglumine antimoniate, and pentamidine isethionate. It is important to include asplenia as an immunosuppressive condition that induces exotic VL pathologies. In such cases, combination anti-Leishmania drug therapy should be considered.

Mucocutaneous leishmaniasis in a cocaine user: diagnostic and therapeutic knowledge

Abstract Mucocutaneous leishmaniasis (MCL) is a chronic infection that can affect the skin and mucous membranes. We report a case of oral, nasopharyngeal, and penile lesions in a 35-year-old cocaine user. The patient presented with ulcerated lesions in 2014. Histopathologic analysis revealed amastigotes, and serological test results were positive for leishmaniasis. Systemic therapy with meglumine antimoniate was administered; however, the patient failed to present for follow-up. In 2018, he returned with nasal collapse, and another histopathologic test confirmed MCL. This case illustrates the importance of careful differential diagnosis of skin and mucous ulcers to identify the particular pathology.

Intralesional infiltration versus parenteral use of meglumine antimoniate for treatment of cutaneous leishmaniasis: A cost-effectiveness analysis.

Cutaneous leishmaniasis (LC) is a complex and variable disease in terms of epidemiology, aetiology, pathology and clinical characteristics. The mainstay of treatment is still pentavalent antimony (Sbv) compounds administered systemically, despite their recognized toxicity. The advantages of antimony intralesional (IL) infiltration are the use of lower doses of Sbv and, therefore, less toxic effects. The objective of this study was to estimate the cost-effectiveness ratio of intralesional meglumine antimoniate therapy (IL-MA) compared with endovenous meglumine antimoniate therapy (EV-MA) for the treatment of CL in the context of the Brazilian National Health System (SUS). An analytical decision model (decision tree) was developed using TreeAge Pro 2018 software. Data from the open-label, uncontrolled phase II clinical trial evaluating IL-MA were used as a reference for posology, efficacy, and adverse event rates (AE). The same premises for the intravenous approach (EV-MA) were extracted from systematic literature reviews. Macro and micro calculations of spending were included in the analysis. The IL-MA and EV-MA strategies had a total cost per patient cured of US$330.81 and US$494.16, respectively. The intralesional approach was dominant, meaning it was more economic and effective than was endovenous therapy. The incremental cost-effectiveness ratio showed that IL-MA could result in savings of US$864.37 for each additional patient cured, confirming that the IL-MA strategy is cost effective in the context of the Brazilian public health scenario.

Treatment for human visceral leishmaniasis: a cost-effectiveness analysis for Brazil.

OBJECTIVE: To estimate the cost-effectiveness of strategies for the treatment of VL in Brazil. METHODS: Cost-effectiveness study comparing three therapeutic options: meglumine antimoniate (MA), liposomal amphotericin B (LAMB) and a combination of LAMB plus MA (LAMB plus MA), from public health system and societal perspectives. An analytical decision-making model was used to compare strategies for the following outcomes: early therapeutic failure avoided at 30 days, days of hospitalisation avoided and VL cure at 180 days. The efficacy and safety parameters of the drugs came from a randomised, open-label trial and the cost data came from a cost-of-illness study, both carried out in Brazil. RESULTS: For all outcomes analysed, the LAMB strategy was more effective. The MA strategy was inferior to the LAMB plus MA strategy for the outcomes early therapeutic failure avoided and cure. When only LAMB and MA were compared from a societal perspective, a cost of US$ 278.56 was estimated for each additional early therapeutic failure avoided, a cost of US$ 26.88 for each additional day of hospitalisation avoided and a cost of US$ 89.88 for each additional case of cured VL, for the LAMB strategy vs. MA. CONCLUSION: In Brazil, the LAMB strategy proved to be cost-effective for treating VL, considering a GDP per capita as the willingness-to-pay threshold, for all of the outcomes analysed in comparison to MA.

OBJECTIF: Estimer la rentabilité des stratégies de traitement de la leishmaniose viscérale (LV) au Brésil. MÉTHODES: Etude coût-efficacité comparant trois options thérapeutiques: l'antimoniate de méglumine (AM), amphotéricine B liposomale (LAMB) et une combinaison de LAMB et MA (LAMB plus AM), du point de vue du système de santé publique et sociétal. Un modèle décisionnel analytique a été utilisé pour comparer les stratégies pour les résultats suivants: échec thérapeutique précoce évité à 30 jours, jours d'hospitalisation évités et guérison de la LV à 180 jours. Les paramètres d'efficacité et de sécurité des médicaments provenaient d'un essai randomisé ouvert et les données relatives aux coûts, d'une étude sur le coût de la maladie, toutes deux menées au Brésil. RÉSULTATS: Pour tous les résultats analysés, la stratégie LAMB était plus efficace. La stratégie AM était inférieure à la stratégie LAMB plus AM pour les résultats: échec thérapeutique précoce évité et guérison. Lorsque seules les stratégies LAMB et AM ont été comparées d'un point de vue sociétal, un coût de 278,56 USD a été estimé pour chaque échec thérapeutique précoce additionnel évité, un coût de 26,88 USD pour chaque jour d'hospitalisation additionnel évité et un coût de 89,88 USD pour chaque cas additionnel de LV guéri, pour la stratégie LAMB par rapport à AM. CONCLUSION: Au Brésil, la stratégie LAMB s'est avérée rentable pour traiter la LV, considérant un PIB par habitant comme seuil de volonté de payer, pour tous les résultats analysés par rapport à l'AM.

Antimoniato de meglumine perilesional en leishmaniasis cutánea con falla terapéutica sistémica: serie de casos / Perilesional meglumine antimonate in cutaneous leishmaniasis with systemic therapeutic failure: series of cases

En Bolivia, los medicamentos utilizados para el tratamiento de la leishmaniasis cutánea son los antimoniales, de aplicación sistémica en dosis/kg peso, los cuales provocan efectos adversos por la aplicación en largos periodos y grandes volúmenes. La aplicación perilesional de antimonio tiene similar eficacia terapéutica que la sistémica. Sin embargo, no se cuenta con información documentada respecto a la eficacia del tratamiento perilesional en pacientes con falla terapéutica, posterior al tratamiento sistémico. El objetivo de esta serie de casos fue evaluar el tratamiento perilesional con glucantime, en pacientes con leishmaniasis cutánea y falla terapéutica, posterior a un primer ciclo de tratamiento sistémico con antimoniales. El estudio se realizó con once pacientes con leishmaniasis cutánea con falla terapéutica, posterior a la administración de un primer ciclo de tratamiento sistémico con glucantime procedentes de la zona tropical de Bolivia. Se consideró como falla terapéutica la persistencia de la lesión y presencia de parásitos obtenidos de los bordes de la lesión. La intervención perilesional consistió en la aplicación día por medio de glucantime en cinco sesiones. La inoculación se realizó sobre el borde de la lesión y la dosificación del medicamento se calculó multiplicando el área de la lesión por el factor 0.008. Todos los pacientes presentaron dolor local durante el momento de inoculación del medicamento, así como también presentaron un ligero agrandamiento del área de la lesión después de la primera aplicación del medicamento En las siguientes inoculaciones se observó la reducción progresiva del área de la lesión hasta su completa cicatrización.

In Bolivia, the drugs used for the treatment of cutaneous leishmaniasis are the antimonials by systemic application in doses/kg/weight, which cause adverse effects due to the applications in long periods and large volumes. The perilesional application of antimony has similar therapeutic efficacy than the systemic one. However, there is no documented information regarding the efficacy of perilesional treatment in patients with therapeutic failure after systemic treatment. The aim of this series of cases was to evaluate the perilesional treatment with Glucantime, in patients with cutaneous leishmaniasis and therapeutic failure, after a first cycle of systemic treatment with antimonials. The study was conducted with eleven patients with cutaneous leishmaniasis and therapeutic failure, after the administration of a first cycle of systemic treatment with Glucantime. From the tropical zone of Bolivia. The persistence of the lesion and the presence of parasites at the edge of the lesion were considered as therapeutic failure. The perilesional intervention consisted in the application past one day of glucantime in five sessions. The inoculation was performed on the edge of the lesion and the dosage of the medication was calculated by multiplying the area of the lesion by the factor 0.008. All the cases presented local pain during the time of inoculation of the drug, as well as a slight enlargement of the area of the lesion after the first inoculation of the drug. In the following inoculations the progressive reduction of the area of the lesion was observed until its complete healing.

Successful treatment of cutaneous leishmaniasis with intralesional meglumine antimoniate: A case series.

Cutaneous leishmaniasis (CL) is a high-morbidity, vector-borne disease endemic to Colombia. Unlike conventional systemic antileishmanial therapy, intralesional meglumine antimoniate administration has fewer adverse effects and can be as effective and safe. We describe 12 patients treated with intralesional meglumine antimoniate: seven with primary and five with recurrent lesions. The majority (11/12) met all cure criteria after 1-7 sessions of meglumine antimoniate administration (1-5 mL). Adverse effects comprised mainly of local pain and edema. Intralesional meglumine antimoniate administration could be an excellent alternative treatment for uncomplicated CL; however, controlled clinical trials are needed to test the efficacy and safety thereof.

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

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.

Comparison between systemic and intralesional meglumine antimoniate therapy in a primary health care unit.

Cutaneous leishmaniasis (CL) is not a life-threatening condition. However, its treatment can cause serious adverse effects and may sometimes lead to death. Recently, safer local treatments have been included among therapies acceptable to New World CL cases, but the use of intralesional meglumine antimoniate (IL-MA) is recommended to be performed in reference centers, for patients with single cutaneous lesions <3 cm in diameter at any location except the head and periarticular regions; the volume of injected MA should not exceed 5 mL. In this study we compared two groups of patients with CL treated with MA in a primary health care unit in Brazil. Patients were treated with systemic MA (n = 76) or IL-MA (n = 30). In the IL-MA group, 93% of patients had one or more of the following lesion characteristics: two or more lesions, lesions >3 cm in diameter, lesions located in the head or in periarticular regions, or had been administered IL-MA volumes >5 mL. Patients responded well (68.4% and 66.7% for the MA and IL-MA groups, respectively). When a second cycle of treatment was necessary, the responses were 72.4% and 90%, respectively. There were no significant differences between groups. In the IL-MA group, 43% had mild to moderate adverse effects, without needing treatment discontinuation. Results suggest that the treatment of CL lesions with IL-MA is simple, efficient, and safe.

American tegumentary leishmaniasis in Brazil: a critical review of the current therapeutic approach with systemic meglumine antimoniate and short-term possibilities for an alternative treatment.

OBJECTIVES: Meglumine antimoniate (MA; Glucantime®), the 80-year-old first-line systemic treatment for all forms of American tegumentary leishmaniasis (ATL) caused by Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis and Leishmania (Leishmania) amazonensis, is highly toxic, presents adverse side-effects and may not attain clinical and parasitological cure. This critical review examines the necessity for intramuscular/intravenous administration of MA, the alternatives to this approach, and the possibilities of developing affordable, accessible and non-toxic drugs or new delivery methods. METHOD: PubMed searches were performed using the terms 'cutaneous leishmaniasis' or 'American tegumentary leishmaniasis' in combination with 'meglumine antimoniate' or 'N-methyl glucamine' or 'drug repositioning' or 'nanotechnology'. Searches covered a period of 20 years of peer reviewed journals and technical bulletins. We explored the mode of action, pharmacokinetics, toxicity and efficacy of MA, evaluated the progress of ATL therapy in Brazil, and examined the potential of drug repositioning and nanotechnology in accelerating the introduction and/or optimisation of an alternative treatment. RESULTS: The evidence suggests that ATL therapy will continue to rely on systemic MA in the foreseeable future even though an intralesional subcutaneous route has evolved over the last 10 years. The chances of developing a novel drug for ATL or a new mode of delivery of MA are low. While MA nanocarriers afford a promising approach, this technology is still in its infancy. A more immediate solution would be the production of a bioequivalent of miltefosine, an efficacious oral agent no longer protected by patent. CONCLUSION: Development of a contemporary treatment requires governmental commitment in bringing together private and public sectors.

OBJECTIFS: L'antimoniate de méglumine (AM; Glucantime®), le traitement systémique de première intention vieux de 80 ans pour toutes les formes de la leishmaniose tégumentaire américaine (LTA) causée par Leishmania (Viannia) braziliensis, L. (V.) guyanensis et L. (Leishmania) amazonensis, est hautement toxique, présente des effets secondaires indésirables et peut ne pas aboutir à une guérison clinique et parasitologique. Cette analyse critique examine la nécessité d'une administration intramusculaire/intraveineuse d'AM, les alternatives à cette approche et les possibilités de développement de médicaments abordables, accessibles et non toxiques ou de nouvelles méthodes d'administration. MÉTHODE: Des recherches sur PubMed ont été effectuées en utilisant les termes «leishmaniose cutanée¼ ou «leishmaniose tégumentaire américaine¼ en combinaison avec «antimoniate de méglumine ¼ ou «N-méthyl glucamine¼ ou «repositionnement de médicament¼ ou «nanotechnologie¼. Les recherches ont porté sur une période de 20 ans d'articles revue par des pairs et de bulletins techniques. Nous avons exploré le mode d'action, la pharmacocinétique, la toxicité et l'efficacité de l'AM, évalué les progrès du traitement de la LTA au Brésil et examiné le potentiel du repositionnement de médicaments et de la nanotechnologie pour accélérer l'introduction et/ou l'optimisation d'un traitement alternatif. RÉSULTATS: Les données suggèrent que le traitement de la LTA continuera à s'appuyer sur l'AM systémique dans un avenir proche, même si une voie sous-cutanée intralésionnelle a évolué au cours des 10 dernières années. Les chances de développer un nouveau médicament pour la LTA ou un nouveau mode d'administration d'AM sont faibles. Alors que les nanocarriers d'AM offrent une approche prometteuse, cette technologie en est encore à ses balbutiements. Une solution plus immédiate consisterait à produire un bioéquivalent de miltéfosine, un agent oral efficace, qui n'est plus protégé par un brevet. CONCLUSION: Le développement d'un traitement contemporain nécessite un engagement gouvernemental pour réunir les secteurs privés et publiques.

Polycaprolactone Antimony Nanoparticles as Drug Delivery System for Leishmaniasis.

BACKGROUND: Leishmaniasis is a neglected disease endemic in tropical and subtropical areas, with an incidence about 1.6 million cases/year. The first-line treatment of this disease is pentavalent antimony, and the second-line are pentamidine and amphotericin B. All the treatments available cause severe side effects and often have difficulty in accessing parasites within infected cells. STUDY QUESTION: This study aimed to determine if the use of nanoparticles loaded with meglumine antimoniate could reach and targeting infected organs with leishmaniasis, reducing the dosage used and promoting less adverse effects. STUDY DESIGN: This study was performed comparing the meglumine nanoparticle in two experimental groups. The first one healthy mice and the second one inducted mice (leishmaniasis). MEASURES AND OUTCOMES: The nanoparticles loaded with meglumine antimoniate (nanoantimony) were prepared by double-emulsion solvent evaporation method and showed a size of about 150-200 nm. BALB/c mice infected or not with Leishmania amazonensis (cutaneous leishmaniasis model) or Leishmania infantum (visceral leishmaniasis model) was used to access the biodistribution of nanoantimony and meglumine antimoniate labeled with technetium-99m. RESULTS: The biodistribution profiles showed a preferential targeting of the nanoparticles to the liver, spleen, and lungs. Because these are the main organs infected, the nanoparticle may be used for this purpose. The results for cutaneous leishmaniasis showed a low uptake by the lesion (infected region). CONCLUSIONS: The results demonstrated the potential use of these nanoparticles to improve the efficacy of meglumine antimoniate in the treatment of visceral leishmaniasis, indicating their potential as an alternative therapeutic strategy for leishmaniasis infections.

Successful treatment of cutaneous leishmaniasis with intralesional meglumine antimoniate: A case series

Abstract Cutaneous leishmaniasis (CL) is a high-morbidity, vector-borne disease endemic to Colombia. Unlike conventional systemic antileishmanial therapy, intralesional meglumine antimoniate administration has fewer adverse effects and can be as effective and safe. We describe 12 patients treated with intralesional meglumine antimoniate: seven with primary and five with recurrent lesions. The majority (11/12) met all cure criteria after 1-7 sessions of meglumine antimoniate administration (1-5 mL). Adverse effects comprised mainly of local pain and edema. Intralesional meglumine antimoniate administration could be an excellent alternative treatment for uncomplicated CL; however, controlled clinical trials are needed to test the efficacy and safety thereof.

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.