Treatment of Cutaneous Leishmaniasis with Sodium Stibogluconate and Allopurinol in a Routine Setting in Ethiopia: Clinical and Patient-Reported Outcomes and Operational Challenges.

Cutaneous leishmaniasis (CL) is common in Ethiopia, but the national guideline does not offer specific treatment recommendations. Consequently, different treatment regimens are used in the country, without quality evidence. In Boru Meda Hospital, sodium stibogluconate (SSG) is routinely used in combination with allopurinol for systemic CL treatment, although evidence on its effectiveness is limited. An observational cohort study was carried out to document clinical treatment outcomes in patients receiving SSG/allopurinol at the end of each 28-day treatment cycle and after 180 days. Patient-reported outcomes were assessed by asking patients to rate lesion severity, and by the dermatological life quality index. A total of 104 patients were included. After one treatment cycle, only four patients were clinically cured, although patient-reported outcomes significantly improved. The majority (88) of patients were appointed for a second treatment cycle, of whom only 37 (42%) attended. Among the 36 patients who came for final outcome assessment, 50% were cured. Follow-up and treatment were severely affected by conflict; drug stock-outs and insufficient ward capacity for treatment were additional challenges. The treatment outcomes of SSG/allopurinol were relatively poor, and most patients required more than one cycle of treatment. Shortages of drugs and beds indicate the existing gaps in providing CL treatment in Ethiopia.

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.

In vivo and in vitro effects of pentavalent antimony on mouse liver cytochrome P450s.

Pentavalent antimonial (Sb5+) drugs such as meglumine antimoniate (MA) are the mainstay treatment of leishmaniases in developing countries. The effects of these compounds on drug-metabolizing enzymes have not been characterized and their potential pharmacokinetic interactions with other drugs are therefore unknown. The present study investigated whether treatment with MA (300 mg Sb5+/kg body weight/day, subcutaneously) for 24 days affected the activities of cytochrome P450 (CYP)1A (ethoxyresorufin- O-deethylase), CYP2A5 (coumarin 7-hydroxylase), CYP2E1 ( p-nitrophenol-hydroxylase), CYP2B9/10 (benzyloxy-resorufin- O-debenzylase), or CYP3A11 (erythromycin- N-demethylase) in the livers of Swiss Webster (SW) and DBA-2 male and female mice. The results showed that CYP2A5-, CYP2E1-, and CYP3A11-catalyzed reactions were unaffected by MA treatment. A decrease in CYP2B9/10 activity was noted in DBA-2 females (but not males) and was not observed in SW males or females. However, repeated MA administration reduced mouse liver CYP1A activity. CYP1A2 messenger RNA (mRNA) levels were not affected by MA and in vitro exposure of mouse liver microsomes to Sb3+ and Sb5+ did not reduce CYP1A activity. These findings suggested that in vivo treatment with Sb5+ drugs depressed CYP1A activity, without downregulating CYP1A2 mRNA expression. Since in vitro treatment of liver microsomes failed to inhibit CYP1A activity, this effect may require intact cells.

Antileishmanial, DNA Interaction, and Docking Studies of Some Ferrocene-Based Heteroleptic Pentavalent Antimonials.

A series of ferrocenyl pentavalent antimonials (1-8) were synthesized and characterized by elemental analysis, FT-IR, and multinuclear ((1) H and (13) C) NMR spectroscopy. These antimonials were evaluated for their antileishmanial potential against Leishmania tropica KWH23, and by biocompatibility and membrane permeability assays. Moreover, mechanistic studies were carried out, mediated by DNA targeting followed by computational docking of ferrocenyl antimonials against the leishmanial trypanothione reductase enzyme. It was observed that the antimonials 1-8 were 390-fold more efficacious (IC50 ) as compared with the standard antimonial drug used. Cytotoxicity results showed that these antimonials are highly active even at low concentrations and are biocompatible with human macrophages. Antimonials 1-8 exhibited extensive intercalation with DNA and, furthermore, docking interactions highlighted the potential interactive binding of the anitimonials within the trypanothione reductase active site, with van der Waals interactions contributing significantly to the process. Hence, it is suggested that the reported antimonials demonstrate high efficacy, less toxicity, and target multiple sites of the Leishmania parasite.

Plant-derived compounds in treatment of leishmaniasis.

Leishmaniasis is a neglected public health problem caused by the protozoan species belonging to the genus Leishmania affecting mostly the poor populations of developing countries. The causative organism is transmitted by female sandflies. Cutaneous, mucocutaneous, and visceral clinical manifestations are the most frequent forms of leishmaniasis. Chemotherapy still relies on the use of pentavalent antimonials, amphotericin B, paromomycin, miltefosin and liposomal amphotericin B. However, the application of these drugs is limited due to low efficacy, life-threatening side effects, high toxicity, induction of parasite resistance, length of treatment and high cost. Given the fact that antileishmanial vaccines may not become available in the near future, the search for better drugs should be continued. Natural products may offer an unlimited source of chemical diversity to identify new drug modules. New medicines should be less toxic or non-toxic, safe, more efficient, less expensive and readily available antileishmanial agents, especially for low-income populations. In the present review, special focus is on medicinal plants used against leishmanaiasis. The bioactive phytocompounds present in the plant derivatives including the crude extracts, essential oils, and other useful compounds can be a good source for discovering and producing new antileishmanial medicines.

Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate

Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 >> 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen >> bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies.

Factors associaeed to adherence to different tratment schemes with meglumine aantimoniate in a clinical trial for cutaneous leishmaniasis / Fatores associados à adesão a diferentes esquemas de tratamento com antimoniato de meglumina em ensaio clínico para leishmaniose cutânea

The favorable outcome of the treatment of a disease is influenced by the adherence to therapy. Our objective was to assess factors associated with adherence to treatment of patients included in a clinical trial of equivalence between the standard and alternative treatment schemes with meglumine antimoniate (MA) in the treatment of cutaneous leishmaniasis (CL), in the state of Rio de Janeiro. Between 2008 and 2011, 57 patients with CL were interviewed using a questionnaire to collect socioeconomic data. The following methods were used for adherence monitoring: counting of vial surplus, monitoring card, Morisky test and modified Morisky test (without the question regarding the schedule); we observed 82.1% (vial return), 86.0% (monitoring card), 66.7% (Morisky test) and 86.0% (modified Morisky test) adherence. There was a strong correlation between the method of vial counting and the monitoring card and modified Morisky test. A significant association was observed between greater adherence to treatment and low dose of MA, as well as with a lower number of people sleeping in the same room. We recommend the use of the modified Morisky test to assess adherence to treatment of CL with MA, because it is a simple method and with a good performance, when compared to other methods.

O desfecho favorável ao tratamento de uma enfermidade é influenciado pela adesão à terapia. Objetivamos avaliar fatores associados à adesão ao tratamento dos pacientes incluídos em ensaio clínico de equivalência entre o esquema de tratamento padrão e alternativos com antimoniato de meglumina (AM) no tratamento da leishmaniose cutânea (LC) no estado do Rio de Janeiro. Entre 2008 e 2011, 57 pacientes com LC foram entrevistados através de questionário para coleta de dados socioeconômicos. Para monitorização da adesão foram utilizados os seguintes métodos: contagem de ampolas excedentes, cartão de acompanhamento, teste de Morisky e teste de Morisky modificado (sem a pergunta referente ao horário). Observou-se adesão de 82,1% (devolução de ampolas), 86,0% (cartão de acompanhamento), 66,7% (teste de Morisky) e 86,0% (teste de Morisky modificado). Houve forte concordância entre o método contagem de ampolas e cartão de acompanhamento, bem como teste de Morisky modificado. Verificou-se associação significativa entre maior adesão ao tratamento e baixa dose de AM, bem como com menor número de pessoas dormindo no mesmo quarto. Recomendamos a utilização do teste de Morisky modificado na avaliação da adesão ao tratamento da LC com AM por ser método simples e com bom desempenho quando comparado aos outros testes.

Treatment failure in leishmaniasis: drug-resistance or another (epi-) phenotype?

Two major leishmaniasis treatments have shown a significant decrease in effectiveness in the last few decades, mostly in the Indian subcontinent but also in other endemic areas. Drug resistance of Leishmania correlated only partially to treatment failure (TF) of pentavalent antimonials, and has so far proved not to be important for the increased miltefosine relapse rates observed in the Indian subcontinent. While other patient- or drug-related factors could also have played a role, recent studies identified several parasite features such as infectivity and host manipulation skills that might contribute to TF. This perspective aims to discuss how different parasitic features other than drug resistance can contribute to TF of leishmaniasis and how this may vary between different epidemiological contexts.

Neurological manifestations of human leishmaniasis.

Leishmaniasis is a spectral disease, caused by obligate intracellular protozoa of the species Leishmania. There are multiple reported instances where neurological manifestations, whether central or peripheral, are described. In this review we describe neurological manifestations seen during infection with Leishmania spp. Taken together, the material discussed here suggests that in patients from Leishmania-endemic areas, when observing neurological symptoms, causation secondary to infection with Leishmania spp. may be considered.

Treatment strategies for mucocutaneous leishmaniasis.

Mucocutaneous is an infection caused by a single celled parasite transmitted by sand fly bites. There are about 20 species of Leishmania that may cause mucocutaneous leishmaniasis. Some Leishmania species are closely linked to humans and are therefore found in cities (L. tropica) whereas some others are more traditionally associated with animal species and therefore considered zoonoses (L. major). The evidence for optimal treatment of mucocutaneous leishmaniasis is patchy. Although the cutaneous form of the disease is often self-limiting, it does result in significant scarring and can spread to more invasive, mucocutaneous disease. Therefore, treatment may be considered to prevent these complications. Drugs for systemic and topical treatment are presented and discussed with regard to their application, use and adverse effects.

Leishmaniosis ¿cuándo hospitalizar? / Leishmaniosis ¿When to Hospitalize?

La leishmaniosis es una enfermedad infecciosa parasitaria, endémica, de distribución mundial, que en Venezuela se presenta como leishmaniosis tegumentaria americana (cutánea localizada, cutáneomucosa y cutáneo difusa) además de la forma visceral (kala azar). La variedad cutánea localizada representa el 90 por ciento de los casos atendidos en la consulta de Endemias Rurales del Instituto de Medicina Tropical y en los Servicios de Pediatría Médica y Enfermedades Infecciosas del Adulto del Hospital Universitario de Caracas, y la mayoría son tratados ambulatoriamente con antimoniato de meglumina. En algunas situaciones clínicas es necesaria la hospitalización. Se describen ocho casos hospitalizados: 1) niña de dos años con leishmaniosis cutánea que había recibido inmunoterapia para la parasitosis; 2) paciente de 59 años con leishmaniosis de la mucosa nasal; 3) paciente de 64 años con úlcera de los chicleros en el pabellón auricular; 4) paciente de 36 años con falla terapéutica a la meglumina, quien había recibido inmunoterapia para leishmaniosis; 5) paciente de 59 años alcohólico, con ulceración extensa de cinco años de evolución; 6) mujer de 83 años con leishmaniosis cutánea en miembros inferiores; 7) paciente con leishmaniosis de la mucosa nasal y SIDA; 8) paciente de 37 años con kala azar. Se analizan las razones para la hospitalización y las dosis de antimoniato de meglumina empleadas para la solución terapéutica

Leishmaniasis is an endemic parasitic infectious disease of worldwide distribution. In Venezuela the main characteristics correspond to american tegumentary leishmaniasis (cutaneous localized, cutaneous-mucous, cutaneous diffuse) and visceral leishmaniasis (kala azar). The localized cutaneous variety represents 90 percent of the cases attended at the ambulatory medical clinic for rural endemic diseases at the Tropical Medicine Institute, Pediatric and Adult services for Infectious Diseases at the Universitary Hospital of Caracas, and these patients are treated with pentavalent antimonials. In some clinical conditions hospitalization is required. We describe eight cases of patients treated under hospitalization. Case 1) a two year old girl with cutaneous leishmaniasis who had received immunotherapy for this parasitic disease; case 2) fifty nine year old female with nasal leishmaniasis; case 3) sixty four year old male with a rubber tapper’s ulcer in the ear; case 4) thirty six year old male with treatment failure to pentavalent antimonials having received immunotherapy for leishmaniasis; case 5) fifty nine year old male alcoholic patient, with extended ulcer of five years evolution; case 6) eighty three year old female with cutaneous leishmanisis in the legs; case 7) thirty three year old male with leishmaniasis of the nasal mucosa and AIDS; case 8) thirty seven year old male with kala azar. We discuss the reasons for hospitalization and the dosage of pentavalent antimonials administered

Leishmaniosis tegumentaria americana: efectividad del antimoniato de meglumina en series terapéuticas de 10 días / American tegumentary leishmaniasis: effectiveness of meglumine antimoniate in 10-day treatment series

La leishmaniosis tegumentaria americana es un problema de salud en el medio rural venezolano. La Cátedra de Medicina Tropical (UCV) y el Hospital Universitario de Caracas reciben pacientes con diagnóstico presuntivo, se realiza el diagnóstico de certeza y son tratados ambulatoria u hospitalariamente con antimoniato de meglumina en series terapéuticas de 10 días, a dosis de 3 000 mg/día a 4 500 mg/día. Se evalúan los resultados de 221 pacientes, la mayoría adultos masculinos, con úlcera única en miembros inferiores, procedentes del medio rural del Estado Miranda. Predominó la variedad cutánea localizada, seguida de la cutáneo mucosa con 4 pacientes y cutáneo difusa con 3. Hubo cicatrización de las úlceras y desaparición de los nódulos cutáneos, excepto en 1 paciente (0,3 por ciento) que requirió anfotericina B por falla terapéutica. En el estudio participan estudiantes del curso regular de la cátedra, integrantes del programa: docencia en medicina tropical basada en publicaciones periódicas

American tegumentary leishmaniasis (ATL) is a health problem in the rural areas of Venezuela. Patients are referred to the Tropical Medicine Department (UCV) and to the University Hospital of Caracas with presumptive diagnosis of the disease, are studied to confirm the diagnosis and treated with antimoniate of meglumine in 10 days course at dose of 3 000 mg./day to 4 500 mg./day according to complications as outpatients or hospitalized. We report the results of 221 patients treated, mostly male adults from the rural area of the Miranda state with a sole ulcer in the limbs. Among the clinical presentation the cutaneous-localized form was predominating, followed by the localized muco-cutaneous with 4 and cutaneous-diffuse variety with 3. They responded with healing of the ulcers and disappearance of skin nodules, except one (0.3 percent) who required anfotericine B due to lack of response to meglumine therapy. In this investigation there was the participation of students from the Tropical Medicine course: learning based on periodic publications with students

Effect of chlorpyrifos on healing of cutaneous leishmaniasis lesions after treatment with Pentostam(®).

The insecticide chlorpyrifos (CPF) is widely used in the Kingdom of Saudi Arabia (KSA) to control agricultural pests. The present work is a preliminary investigation of the effect of CPF on healing of cutaneous leishmaniasis (CL) lesions, caused by Leishmania major in farmers exposed to this insecticide, after treatment with Pentostam(®). Lesion diameters were measured and CPF concentrations in the blood plasma of farmer and non-farmer CL patients in Al-Ahsa were detected by gas chromatography/mass spectrometry/mass spectrometry before and 6 weeks after treatment with Pentostam(®). CPF concentrations in the blood of farmer patients ranged between 4.570 and 7.096 ng/µl (mean = 6.19 ± 0.881 ng/µl) before and after treatment with Pentostam(®). The mean lesion diameter in these patients decreased by a factor of 2.21 after treatment with Pentostam(®); they measured 1.85-11.75 mm, (mean = 6.165 ± 3.500 mm) before treatment and 0.22-6.10 mm (mean = 2.796 ± 2.102 mm) after treatment. Lesion diameter increased exponentially with the increase of CPF concentration in the patients' blood. CPF was not detected in the non-farmer patients before or after treatment. Their mean lesion diameter decreased by a factor of 6.86 after treatment with Pentostam(®); they measured 1.33-7.10 mm (mean = 2.882 ± 1.764 mm) before treatment and 0.11-0.92 mm (mean = 0.425 ± 0.277 mm) after treatment. The mean lesion diameter in farmer patients was much greater than that of non-farmer patients both before (2.14×) and after (6.657×) treatment with Pentostam(®). Chronic exposure to low levels of the pesticide aggravates the development and delays the healing of CL lesions due to immunotoxicity and/or peripheral neurotoxicity caused by CPF. Further detailed studies would assess CPF effect on the severity of infection with CL in agricultural workers continuously exposed to this insecticide in different areas of KSA in conformity of their finding.

Um caso de leishmaniose cutâneo-mucosa tratado com sucesso com baixa dose de antimonial pentavalente / A case of mucocutaneous leishmaniasis treated with success with a low dose of pentavalent antimonial

Os autores relatam um caso de leishmaniose cutâneo-mucosa em uma paciente de 89 anos, diabética e hipertensa, tratada inicialmente com alopurinol por 10 meses não havendo cicatrização das lesões. Posteriormente, recebeu antimoniato de N-metil glucamina (glucantime) por 4 dias, na dose total de 2.380mg do Sbv, mas desenvolveu cardiotoxicidade e hipocalemia, sendo suspenso o tratamento, entretanto, evoluiu com regressão clínica total das lesões, apesar de ter recebido pequena dose desta medicação.

The authors report a case of a 89 years-old woman with mucocutaneous leishmaniasis and previous diabetes mellitus and high blood pressure, who had been treated with allopurinol for 10 months without healing of lesions. Afterwards, she has been treated with meglumine antimonate, [quot ]glucantime[quot ] for 4 days, with a total dose 2,380 mg of Sbv, but developed cardiac side effects and hypokalemia, hence the treatment was withdrawn. However, this patient developed total clinical regression of lesions, in spite of she has been received low dose of this drug.