RESUMO
New treatment approaches targeting cutaneous leishmaniasis (CL) are required since conventional drugs exhibit limitations due to their several adverse effects and toxicity. In this study, we aimed to evaluate the in vivo intralesional treatment efficacy of five isoxazole derivatives previously synthesized and effective in vitro against intracellular amastigote forms of Leishmania (L.) amazonensis. Among the tested analogues, 7 exhibited relevant in vivo therapeutic effects. The in silico predictions provided interesting information about the toxicity, suggesting the safety of analogue 7. Experiments performed with Salmonella typhimurium strains (TA98, TA100, and TA102) showed a non-mutagenicity profile of 7. The treatment of Leishmania-infected BALB/c mice with isoxazole 7 showed remarkably smaller CL lesions and decreased the parasitism (by 98.4%) compared to the control group. Hence, analogue 7 is a promising drug candidate and alternative treatment for CL caused by L. amazonensis.
Assuntos
Antiprotozoários , Leishmania , Leishmaniose Cutânea , Lignanas , Animais , Camundongos , Isoxazóis/farmacologia , Lignanas/farmacologia , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Antiprotozoários/farmacologia , Camundongos Endogâmicos BALB CRESUMO
The standard of care for cutaneous leishmaniasis includes the intramuscular/intravenous administration of pentavalent antimonials that are toxic and poorly tolerated. Primary health care usually lacks trained health staff for the diagnosis and treatment of leishmaniasis in Cochabamba Bolivia. Taking these aspects into account, a Bolivian consortium set out to explore the intralesional administration of meglumine antimoniate to treat cutaneous leishmaniasis during primary care under programmatic conditions. A four-step strategy consisting of clinical training for intralesional treatment and the promotion and periodic follow-up of health staff was carried out. The training process was applied in situ to personnel of nine primary health care centres. The intralesional treatment was applied five times every other day. Clinical follow-up after six-months of treatment showed a 77% healing proportion and 5% of therapeutic failure among 152 enrolled patients. The drug volume used in the intralesional procedure was on average 1.7 mL/ulcer treated. In conclusion, the strategy used was successful and effective, accomplishing a healing proportion similar to the long standardized treatment with a reduced time of administration, no severe side effects, and it is feasible to conduct by trained health staff. Our study supports the current PAHO/WHO recommendation for the intralesional administration of pentavalent antimonials for the treatment of cutaneous leishmaniasis.
RESUMO
Treatment of leishmaniasis is a challenging subject. Although available, chemotherapy is limited, presenting toxicity and adverse effects. New drugs with antileishmanial activity are being investigated, such as antiparasitic compounds derived from plants. In this work, we investigated the antileishmanial activity of the biflavonoid amentoflavone on the protozoan Leishmania amazonensis. Although the antileishmanial activity of amentoflavone has already been reported in vitro, the mechanisms involved in the parasite death, as well as its action in vivo, remain unknown. Amentoflavone demonstrated activity on intracellular amastigotes in macrophages obtained from BALB/c mice (IC50 2.3 ± 0.93 µM). No cytotoxicity was observed and the selectivity index was estimated as greater than 10. Using BALB/c mice infected with L. amazonensis we verified the effect of an intralesional treatment with amentoflavone (0.05 mg/kg/dose, in a total of 5 doses every 4 days). Parasite quantification demonstrated that amentoflavone reduced the parasite load in treated footpads (46.3% reduction by limiting dilution assay and 56.5% reduction by Real Time Polymerase Chain Reaction). Amentoflavone decreased the nitric oxide production in peritoneal macrophages obtained from treated animals. The treatment also increased the expression of ferritin and decreased iNOS expression at the site of infection. Furthemore, it increased the production of ROS in peritoneal macrophages infected in vitro. The increase of ROS in vitro, associated with the reduction of NO and iNOS expression in vivo, points to the antioxidant/prooxidant potential of amentoflavone, which may play an important role in the balance between inflammatory and anti-inflammatory patterns at the infection site. Taken together these results suggest that amentoflavone has the potential to be used in the treatment of cutaneous leishmaniasis, working as an ally in the control and development of the lesion.
Assuntos
Biflavonoides , Leishmania , Leishmaniose Cutânea , Leishmaniose , Animais , Antioxidantes , Biflavonoides/farmacologia , Leishmaniose Cutânea/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de OxigênioRESUMO
OBJETIVO: evaluar la seguridad a largo plazo frente al riesgo de complicaciones mucosas del uso intralesional de antimoniales pentavalentes en pacientes con leishmaniasis cutánea comparado con el uso sistémico de los mismos. MÉTODOS: estudio observacional, cuantitativo de tipo longitudinal retrospectivo. Se analizó un total de 66 registros clínicos de pacientes, con diagnóstico de Leishmaniasis cutánea del parque Isiboro Secure durante el periodo 2012 a 2016. Se evaluó un total de 46 tratamientos sistémicos y 20 intralesionales. RESULTADOS: la evaluación clínica realizada entre 4 y 7 años posteriores a la cicatrización de las lesiones cutáneas de Leishmaniasis mostró la ausencia de desarrollo de lesiones mucosas. Así mismo no se reportó fallas terapéuticas, recidivas ni efectos adversos a corto plazo. CONCLUSIONES: el tratamiento intralesional fue seguro y eficaz a largo plazo y es una opción confiable para el tratamiento de leishmaniasis cutánea evitando las complicaciones futuras de la enfermedad.
OBJECTIVE: to assess the long-term safety against the risk of mucosal complications of intralesional pentavalent antimonials (PA) in patients with cutaneous Leishmaniasis compared to the systemic use of PA. METHODS: retrospective longitudinal quantitative observational study. A total of 66 clinical records of patients diagnosed with cutaneous Leishmaniasis in Isiboro Secure Park were analyzed between 2012 and 2016. A total of 46 systemic and 20 intralesional treatments were evaluated. RESULTS: clinical evaluation 4-7 years after healing of Leishmaniasis skin lesions showed no development of mucosal lesions. Likewise, no therapeutic failures, relapses or short-term adverse effects were reported. CONCLUSIONS: intralesional treatment was safe and effective in the long term and is a reliable option for the treatment of cutaneous Leishmaniasis avoiding the future complications of the disease.