Comparison of Intralesional Sodium Stibogluconate versus Intralesional Meglumine Antimoniate for the Treatment of Leishmania major Cutaneous Leishmaniasis.

Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's objective was to compare the authors' experience with different antimony intralesional treatments of Leishmania major cutaneous leishmaniasis. A retrospective evaluation was undertaken for cases of Leishmania major cutaneous leishmaniasis treated by pentavalent antimony in a university-affiliated medical centre in Israel. The previous treatment of intralesional sodium stibogluconate (Pentostam®) was compared with the current treatment of meglumine antimoniate (Glucantime®). One hundred cases of cutaneous leishmaniasis were treated during the study period, of whom 33 were treated with intralesional sodium stibogluconate and 67 were treated with intralesional meglumine antimoniate. The patients were 78 males and 22 females, mean age 24 (range 10-67) and there was a total of 354 skin lesions. Within 3 months from treatment, 91% (30/33) of the intralesional sodium stibogluconate group and 88% (59/67) of the intralesional meglumine antimoniate group had complete healing of the cutaneous lesions after an average of 3 treatment cycles (non-statistically significant). In conclusion, the 2 different medications have the same efficacy and safety for treating cutaneous leishmaniasis. Pentavalent antimoniate intralesional infiltration treatment is safe, effective, and well tolerated with minimal side effects for Old-World cutaneous leishmaniasis.

Interventions for American cutaneous and mucocutaneous leishmaniasis.

BACKGROUND: On the American continent, cutaneous and mucocutaneous leishmaniasis (CL and MCL) are diseases associated with infection by several species of Leishmania parasites. Pentavalent antimonials remain the first-choice treatment. There are alternative interventions, but reviewing their effectiveness and safety is important as availability is limited. This is an update of a Cochrane Review first published in 2009. OBJECTIVES: To assess the effects of interventions for all immuno-competent people who have American cutaneous and mucocutaneous leishmaniasis (ACML). SEARCH METHODS: We updated our database searches of the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and CINAHL to August 2019. We searched five trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing either single or combination treatments for ACML in immuno-competent people, diagnosed by clinical presentation and Leishmania infection confirmed by smear, culture, histology, or polymerase chain reaction on a biopsy specimen. The comparators were either no treatment, placebo only, or another active compound. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our key outcomes were the percentage of participants 'cured' at least three months after the end of treatment, adverse effects, and recurrence. We used GRADE to assess evidence certainty for each outcome. MAIN RESULTS: We included 75 studies (37 were new), totalling 6533 randomised participants with ATL. The studies were mainly conducted in Central and South America at regional hospitals, local healthcare clinics, and research centres. More male participants were included (mean age: roughly 28.9 years (SD: 7.0)). The most common confirmed species were L. braziliensis, L. panamensis, and L. mexicana. The most assessed interventions and comparators were non-antimonial systemics (particularly oral miltefosine) and antimonials (particularly meglumine antimoniate (MA), which was also a common intervention), respectively. Three studies included moderate-to-severe cases of mucosal leishmaniasis but none included cases with diffuse cutaneous or disseminated CL, considered the severe cutaneous form. Lesions were mainly ulcerative and located in the extremities and limbs. The follow-up (FU) period ranged from 28 days to 7 years. All studies had high or unclear risk of bias in at least one domain (especially performance bias). None of the studies reported the degree of functional or aesthetic impairment, scarring, or quality of life. Compared to placebo, at one-year FU, intramuscular (IM) MA given for 20 days to treat L. braziliensis and L. panamensis infections in ACML may increase the likelihood of complete cure (risk ratio (RR) 4.23, 95% confidence interval (CI) 0.84 to 21.38; 2 RCTs, 157 participants; moderate-certainty evidence), but may also make little to no difference, since the 95% CI includes the possibility of both increased and reduced healing (cure rates), and IMMA probably increases severe adverse effects such as myalgias and arthralgias (RR 1.51, 95% CI 1.17 to 1.96; 1 RCT, 134 participants; moderate-certainty evidence). IMMA may make little to no difference to the recurrence risk, but the 95% CI includes the possibility of both increased and reduced risk (RR 1.79, 95% CI 0.17 to 19.26; 1 RCT, 127 participants; low-certainty evidence). Compared to placebo, at six-month FU, oral miltefosine given for 28 days to treat L. mexicana, L. panamensis and L. braziliensis infections in American cutaneous leishmaniasis (ACL) probably improves the likelihood of complete cure (RR 2.25, 95% CI 1.42 to 3.38), and probably increases nausea rates (RR 3.96, 95% CI 1.49 to 10.48) and vomiting (RR 6.92, 95% CI 2.68 to 17.86) (moderate-certainty evidence). Oral miltefosine may make little to no difference to the recurrence risk (RR 2.97, 95% CI 0.37 to 23.89; low-certainty evidence), but the 95% CI includes the possibility of both increased and reduced risk (all based on 1 RCT, 133 participants). Compared to IMMA, at 6 to 12 months FU, oral miltefosine given for 28 days to treat L. braziliensis, L. panamensis, L. guyanensis and L. amazonensis infections in ACML may make little to no difference to the likelihood of complete cure (RR 1.05, 95% CI 0.90 to 1.23; 7 RCTs, 676 participants; low-certainty evidence). Based on moderate-certainty evidence (3 RCTs, 464 participants), miltefosine probably increases nausea rates (RR 2.45, 95% CI 1.72 to 3.49) and vomiting (RR 4.76, 95% CI 1.82 to 12.46) compared to IMMA. Recurrence risk was not reported. For the rest of the key comparisons, recurrence risk was not reported, and risk of adverse events could not be estimated. Compared to IMMA, at 6 to 12 months FU, oral azithromycin given for 20 to 28 days to treat L. braziliensis infections in ACML probably reduces the likelihood of complete cure (RR 0.51, 95% CI 0.34 to 0.76; 2 RCTs, 93 participants; moderate-certainty evidence). Compared to intravenous MA (IVMA) and placebo, at 12 month FU, adding topical imiquimod to IVMA, given for 20 days to treat L. braziliensis, L. guyanensis and L. peruviana infections in ACL probably makes little to no difference to the likelihood of complete cure (RR 1.30, 95% CI 0.95 to 1.80; 1 RCT, 80 participants; moderate-certainty evidence). Compared to MA, at 6 months FU, one session of local thermotherapy to treat L. panamensis and L. braziliensis infections in ACL reduces the likelihood of complete cure (RR 0.80, 95% CI 0.68 to 0.95; 1 RCT, 292 participants; high-certainty evidence). Compared to IMMA and placebo, at 26 weeks FU, adding oral pentoxifylline to IMMA to treat CL (species not stated) probably makes little to no difference to the likelihood of complete cure (RR 0.86, 95% CI 0.63 to 1.18; 1 RCT, 70 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Evidence certainty was mostly moderate or low, due to methodological shortcomings, which precluded conclusive results. Overall, both IMMA and oral miltefosine probably result in an increase in cure rates, and nausea and vomiting are probably more common with miltefosine than with IMMA. Future trials should investigate interventions for mucosal leishmaniasis and evaluate recurrence rates of cutaneous leishmaniasis and its progression to mucosal disease.

A single-group trial of end-stage patients with anthroponotic cutaneous leishmaniasis: Levamisole in combination with Glucantime in field and laboratory models.

Currently, there is no satisfactory treatment modality available for cutaneous leishmaniasis (CL). The major objective of the present study was to explore the effect of immunomodulator-levamisole in combination with Glucantime in end-stage unresponsive patients with anthroponotic CL (ACL). Twenty end-stage unresponsive patients with ACL were identified for participation in this single-group trial study. Simultaneously, each patient was received a combination of levamisole pills along with Glucantime during the remedy course. Several in vitro complementary experiments were performed to evaluate the mode of action of levamisole and Glucantime alone and in combination using a macrophage model, in vitro MTT assay, flow cytometry and quantitative real time PCR (qPCR). Overall, 75% of the patients showed complete clinical cure, 10% partially improved and the remaining (15%) had underlying chronic diseases demonstrated no response to the treatment regimen. In in vitro studies, there was no cytotoxic effect associated with these drugs in the range of our experiments. The findings by the flow cytometric analysis represented that the highest apoptotic values corresponded to the drugs combination (32.23%) at 200 µg/ml concentration. Finally, the gene expression level of IL-12 p40, iNOS and TNF-α promoted while the level of IL-10 and TGF-ß genes reduced as anticipated. The findings clearly indicated that the combination of levamisole and Glucantime should be considered in end-stage unresponsive patients with ACL who have not responded to basic treatments. The immunomodulatory role of levamisole in mounting immune system as documented by the in vitro experiments and further substantiated by this single-group trail study was highlighted.

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.

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.

The activity of encapsulated meglumine antimoniate in stearylamine-bearing liposomes against cutaneous leishmaniasis in BALB/c mice.

Topical treatment of cutaneous leishmaniasis has demonstrated appropriate alternative for reducing toxicity of conventional treatments, improving patients' compliance and reducing treatment costs. Furthermore, outbreak of cutaneous leishmaniasis in war and conflict zones emerges finding an effective, economical and user-friendly treatment. In the context of liposomal topical drug delivery, we developed and characterized meglumine antimoniate (MA) loaded liposomes and investigated their effectiveness in topical treatment of cutaneous leishmaniasis. Previously, we showed the promising use of liposomal formulation of MA in treatment of cutaneous leishmaniasis in BALB/c mice. Here, we included Stearylamine (SA) in liposomes' structure which has antileishmanial activity by itself. . Size and encapsulation efficiency of liposomes were measured and in vitro permeation was performed using mice model. In vitro toxicity of liposomes was measured against leishmania promastigotes and amastigotes. Liposomes were used topically twice a day for 4 weeks to treat leishmania lesions in BALB\c mice model. In vitro permeation study showed liposomal formulations improved the percent of MA permeation compared with MA-cream. Promastigotes and amastigotes assay results showed significant enhanced toxicity in Liposomal-MA containing SA compared to Lip-MA. In BALB\c mice model of cutaneous leishmaniasis, liposomal groups exhibited significantly smaller lesion size compared to control groups (p < 0.01). In addition, the spleen parasite burden was significantly (P < 0.01) lower in mice treated with selected liposomal MA than in mice treated with PBS, control liposomes and MA cream. The results of this study showed that SA-liposomes encapsulated with MA might be useful as a candidate for the topical treatment of CL which merit further investigation.

Evaluation of nephrotoxicity and ototoxicity of aminosidine (paromomycin)-allopurinol combination in dogs with leishmaniosis due to Leishmania infantum: A randomized, blinded, controlled study.

Canine leishmaniosis due to Leishmania infantum is a widespread zoonotic disease. Although aminosidine can be an effective treatment, current therapeutic recommendations do not advocate its use, mainly due to concerns regarding the potential nephrotoxicity and ototoxicity of this drug. The aim of this randomized, blinded, controlled study was to evaluate the nephrotoxicity and ototoxicity of aminosidine-allopurinol combination and compare it with that of meglumine antimonate-allopurinol combination in non-azotemic dogs with leishmaniosis. Forty dogs with leishmaniosis were randomly assigned to be treated with either aminosidine at 15 mg/kg, subcutaneously, once daily for 28 days (group A) or with meglumine antimonate at 100 mg/kg, subcutaneously, once daily for 28 days (group B). In addition to either drug, dogs in both groups were administered allopurinol at 10 mg/kg per os twice daily for 2 months. Kidney function was evaluated through measurement of serum creatinine, urea nitrogen, inorganic phosphorus, and cystatin-c concentrations and complete urinalysis, including protein-to-creatinine ratio, at baseline and after 14, 28, and 60 days from the beginning of the treatment. At the same time points, vestibular and auditory functions were evaluated through neurological examination and brainstem auditory evoked response (BAER) recordings of wave I, wave V, inter-wave I-V latencies, and minimum hearing thresholds. None of the dogs developed clinicopathological evidence of kidney disease during the study. Serum creatinine concentration increased >0.3 mg/dl over baseline in 2 dogs in group A and in 5 dogs in group B. Parameters of kidney function were not significantly different or were improved compared to baseline and the only difference between the two groups was the lower concentration of serum creatinine in group A. None of the dogs developed peripheral vestibular syndrome or hearing impairment. At the end of the study, parameters of auditory function were not significantly different or were improved compared to baseline and there were no differences between the two groups. The results of this study show that the nephrotoxicity and ototoxicity of aminosidine, when administered to non-azotemic dogs with leishmaniosis at 15 mg/kg subcutaneously once daily for 28 days along with allopurinol, is minimal and does not differ from that of meglumine antimonate.

Clinical and laboratory evaluation of cured and non-cured patients with cutaneous leishmaniasis treated by Glucantime.

BACKGROUND & OBJECTIVES: Insufficient treatment of cutaneous leishmaniasis (CL) by conventional drugs is a major barrier in control strategies. This study was aimed to evaluate Glucantime efficacy and the susceptibility of Glucantime unresponsive and responsive CL isolates in the field and laboratory. METHODS: Chi-square test (x[2]) was used to determine the significance of difference between proportions in Glucantime-treated patients. The inhibitory activity of various concentrations of Glucantime against Leishmenia tropica stages was evaluated by a colorimetric cell viability MTT and macrophage assays. Mixed model, t-test and ANOVA were performed to determine the significance of difference between various concentrations of Glucantime unresponsive or responsive isolates and untreated control group and p <0.05 was defined as significant level. Altogether, 89.8% of the patients were cured by Glucantime, whilst 10.2% remained non-cured. RESULTS: The overall Glucantime efficacy in different age groups and genders was similar. The IC50 values of promastigotes and amastigotes for Glucanime unresponsive isolates were 2.1 and 2.6 times higher than the equivalent rates obtained for responsive cases, respectively. The overall mean number of amastigotes within macrophages in unresponsive isolates was significantly higher (32.68 ± 1.24) than that in responsive ones (18.68 ± 1.52, p <0.001). Glucantime unresponsive and responsive field isolates of anthroponotic CL (ACL) caused by L. tropica strongly correlated to in vitro assays. INTERPRETATION & CONCLUSION: Monitoring of Glucantime unresponsiveness by the health surveillance system is extremely important, where anthroponotic transmission occurs in humans. Hence, physicians should be aware of such clinical unresponsive presentations with ACL for antimonial therapeutic failure to improve management of disease in endemic regions.

Efficacy of Meglumine Antimoniate in a Low Polymerization State Orally Administered in a Murine Model of Visceral Leishmaniasis.

Progress toward the improvement of meglumine antimoniate (MA), commercially known as Glucantime, a highly effective but also toxic antileishmanial drug, has been hindered by the lack of knowledge and control of its chemical composition. Here, MA was manipulated chemically with the aim of achieving an orally effective drug. MA compounds were synthesized from either antimony pentachloride (MA-SbCl5) or potassium hexahydroxyantimonate [MA-KSb(OH)6] and prepared under a low polymerization state. These compounds were compared to Glucantime regarding chemical composition, permeation properties across a cellulose membrane and Caco-2 cell monolayer, and uptake by peritoneal macrophages. MA-SbCl5 and MA-KSb(OH)6 were characterized as less polymerized and more permeative 2:2 Sb-meglumine complexes than Glucantime, which consisted of a mixture of 2:3 and 3:3 Sb-meglumine complexes. The antileishmanial activities and hepatic uptake of all compounds were evaluated after oral administration in BALB/c mice infected with Leishmania infantum chagasi, as a model of visceral leishmaniasis (VL). The synthetic MA compounds given at 300 mg Sb/kg of body weight/12 h for 30 days significantly reduced spleen and liver parasite burdens, in contrast to those for Glucantime at the same dose. The greater activity of synthetic compounds could be attributed to their higher intestinal absorption and accumulation efficiency in the liver. MA-SbCl5 given orally was as efficacious as Glucantime by the parenteral route (80 mg Sb/kg/24 h intraperitoneally). These data taken together suggest that treatment with a less-polymerized form of MA by the oral route may be effective for the treatment of VL.

Plasma antimony determination during cutaneous leishmaniasis treatment with intralesional infiltration of meglumine antimoniate.

OBJECTIVES: To evaluate the antimony (Sb) in plasma of patients who underwent a standardised meglumine antimoniate (MA) intralesional infiltration protocol for cutaneous leishmaniasis treatment. METHODS: The level of Sb in plasma was determined by atomic absorption spectroscopy, before and 1, 2, 4 and 6 hours after the first intralesional infiltration of MA to determine the parameters peak concentrations (C1 h ), area under curve of drug concentration in plasma from zero to 6 h (AUC0-6 h ) and elimination half-life (t½) of Sb. Blood samples were also collected weekly during the treatment period, always before infiltration. RESULTS: Fourteen patients underwent MA intralesional infiltration with doses ranging from 0.8 to 9 mg Sb/kg at the first infiltration. The C1 h ranged from 3850 to 47 095 mg × h/L and was the highest concentration obtained for 11 of 14 patients after the first intralesional infiltration of MA. A rapid initial phase of distribution lasting up to 4 h (2.6 ± 0.34 h) was followed by a slower elimination phase. Total skin lesion area, C1 h and AUC(0-6 h) were related to the dose of Sb infiltered (P < 0.05). Plasma Sb in samples collected weekly before the infiltration revealed antimony concentrations below the quantification limit (15.0 µg Sb/l) during the treatment period. CONCLUSIONS: Sb is quickly absorbed and eliminated after intralesional administration of MA, in a pattern similar to that reported with the Sb systemic administration. Using a therapeutic schedule limited to weekly intralesional infiltration of doses <10 mg Sb/kg does not result in plasma Sb accumulation.

Tamoxifen and meglumine antimoniate combined therapy in cutaneous leishmaniasis patients: a randomised trial.

OBJECTIVES: There is a clear need for new strategies of leishmaniasis treatment. This work was conducted to evaluate the efficacy of the co-administration of tamoxifen and meglumine antimoniate (SbV ) in a phase II pilot clinical trial in localised cutaneous leishmaniasis patients. METHODS: A randomised controlled pilot clinical trial was conducted to evaluate the efficacy and safety of oral (40 mg/day for 20 days) or topical tamoxifen (0.1% tamoxifen citrate for 20 days) combined with meglumine antimoniate (20 mg SbV /kg/day for 20 days) vs. a standard SbV protocol (20 mg/kg/day for 20 days) for the treatment of cutaneous leishmaniasis. Primary outcome was complete epithelisation of the lesion 6 months after the end of treatment. Secondary outcomes were lesion healing 2 months after the end of treatment and frequency and severity of adverse events. RESULTS: A total of 38 subjects were included in the trial, 15 were treated with standard SbV and 23 with the combination of tamoxifen and SbV . Of the patients treated with the co-administration scheme, 12 received tamoxifen orally and 11 were treated with topical tamoxifen. Tamoxifen administered by the oral or topical routes was well tolerated. Cure rates 6 months after the end of treatment per intention to treat were 40% in the group treated with the standard SbV scheme, and 36.4% and 58%, respectively, for groups treated with SbV plus topical or oral tamoxifen. CONCLUSIONS: In the doses and schemes used in this study, co-administration of oral tamoxifen and SbV resulted in higher cure rates in comparison with the standard scheme of treatment, although not to statistically significant levels.

Chemotherapeutics of visceral leishmaniasis: present and future developments.

Treatment of Visceral Leishmaniasis (VL), a neglected tropical disease, is very challenging with few treatment options. Long duration of treatment and drug toxicity further limit the target of achieving VL elimination. Chemotherapy remains the treatment of choice. Single dose of liposomal amphotericin B (LAmB) and multidrug therapy (LAmB + miltefosine, LAmB + paromomycin (PM), or miltefosine + PM) are recommended treatment regimen for treatment of VL in Indian sub-continent. Combination therapy of pentavalent antimonials (Sbv) and PM in East Africa and LAmB in the Mediterranean region/South America remains the treatment of choice. Various drugs having anti-leishmania properties are in preclinical phase and need further development. An effective treatment and secondary prophylaxis of HIV-VL co-infection should be developed to decrease treatment failure and drug resistance.

Topical tamoxifen in the therapy of cutaneous leishmaniasis.

The aims of the present work were to test the effect of tamoxifen administered topically and the therapeutic efficacy of tamoxifen and pentavalent antimonial combinations in an experimental model of cutaneous leishmaniasis. BALB/c mice infected with a luciferase expressing line of Leishmania amazonensis were treated with topical tamoxifen in two different formulations (ethanol or oil-free cream) as monotherapy or in co-administration with pentavalent antimonial. Treatment efficacy was evaluated by lesion size and parasite burden, quantified through luminescence, at the end of treatment and 4 weeks later. Topical tamoxifen, formulated in ethanol or as a cream, was shown to be effective. The interaction between tamoxifen and pentavalent antimonial was additive in vitro. Treatment with combined schemes containing tamoxifen and pentavalent antimonial was effective in reducing lesion size and parasite burden. Co-administration of tamoxifen and pentavalent antimonial was superior to monotherapy with antimonial.

Owners' experiences of administering meglumine antimoniate injections to dogs with leishmaniosis: An online questionnaire study.

BACKGROUND: This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dog‒owner bond were evaluated. METHODS: Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond. RESULTS: Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%). LIMITATIONS: Some questions were answered by a limited number of people, and their responses may not be representative. CONCLUSION: Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections.

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).

Leishmanicidal potentials of Gossypium hirsutum extract and its fractions on Leishmania major in a murine model: parasite burden, gene expression, and histopathological profile.

Introduction. Leishmaniasis is a neglected tropical and subtropical disease caused by over 20 protozoan species.Hypothesis. Treatment of this complex disease with traditional synthetic drugs is a major challenge worldwide. Natural constituents are unique candidates for future therapeutic development.Aim. This study aimed to assess the in vivo anti-leishmanial effect of the Gossypium hirsutum extract, and its fractions compared to the standard drug (Glucantime, MA) in a murine model and explore the mechanism of action.Methodology. Footpads of BALB/c mice were infected with stationary phase promastigotes and treated topically and intraperitoneally with G. hirsutum extract, its fractions, or Glucantime, 4 weeks post-infection. The extract and fractions were prepared using the Soxhlet apparatus with chloroform followed by the column procedure.Results. The crude extract significantly decreased the footpad parasite load and lesion size compared to the untreated control group (P<0.05), as revealed by dilution assay, quantitative real-time PCR, and histopathological analyses. The primary mode of action involved an immunomodulatory role towards the Th1 response in the up-regulation of IFN-γ and IL-12 and the suppression of IL-10 gene expression profiling against cutaneous leishmaniasis caused by Leishmania major.Conclusion. This finding suggests that the extract possesses multiple combinatory effects of diverse bioactive phytochemical compositions that exert its mechanisms of action through agonistic-synergistic interactions. The topical extract formulation could be a suitable and unique candidate for future investigation and pharmacological development. Further studies are crucial to evaluate the therapeutic potentials of the extract alone and in combination with conventional drugs using clinical settings.

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.

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.