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1.
PLoS One ; 15(12): e0243392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370295

RESUMO

Leishmaniasis is a neglected, parasitic tropical disease caused by an intracellular protozoan from the genus Leishmania. Quinoline alkaloids, secondary metabolites found in plants from the Rutaceae family, have antiparasitic activity against Leishmania sp. N-methyl-8-methoxyflindersin (1), isolated from the leaves of Raputia heptaphylla and also known as 7-methoxy-2,2-dimethyl-2H,5H,6H-pyran[3,2-c]quinolin-5-one, shows antiparasitic activity against Leishmania promastigotes and amastigotes. This study used in silico tools to identify synthetic quinoline alkaloids having structure similar to that of compound 1 and then tested these quinoline alkaloids for their in vitro antiparasitic activity against Leishmania (Viannia) panamensis, in vivo therapeutic response in hamsters suffering from experimental cutaneous leishmaniasis (CL), and ex vivo immunomodulatory potential in healthy donors' human peripheral blood (monocyte)-derived macrophages (hMDMs). Compounds 1 (natural), 2 (synthetic), and 8 (synthetic) were effective against intracellular promastigotes (9.9, 3.4, and 1.6 µg/mL medial effective concentration [EC50], respectively) and amastigotes (5.07, 7.94, and 1.91 µg/mL EC50, respectively). Compound 1 increased nitric oxide production in infected hMDMs and triggered necrosis-related ultrastructural alterations in intracellular amastigotes, while compound 2 stimulated oxidative breakdown in hMDMs and caused ultrastructural alterations in the parasite 4 h posttreatment, and compound 8 failed to induce macrophage modulation but selectively induced apoptosis of infected hMDMs and alterations in the intracellular parasite ultrastructure. In addition, synthetic compounds 2 and 8 improved the health of hamsters suffering from experimental CL, without evidence of treatment-associated adverse toxic effects. Therefore, synthetic compounds 2 and 8 are potential therapeutic candidates for topical treatment of CL.


Assuntos
Antiprotozoários/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Leishmania guyanensis/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Alcaloides/farmacologia , Animais , Antiprotozoários/química , Cricetinae , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Leishmania guyanensis/patogenicidade , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Óxido Nítrico/genética , Folhas de Planta/química , Quinolinas/química , Quinolonas/farmacologia , Rutaceae/química
2.
Rev Soc Bras Med Trop ; 54: e20200208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338118

RESUMO

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


Assuntos
Antiprotozoários , Leishmaniose Cutânea , Leishmaniose Visceral , Uveíte , Antiprotozoários/efeitos adversos , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Visceral/complicações , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico
3.
Mem Inst Oswaldo Cruz ; 115: e200272, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33206822

RESUMO

BACKGROUND: Metformin (MET) is a hypoglycemic drug used for the treatment of diabetes, despite interference in host immunity against microorganisms. Cutaneous infection caused by pathogens such as Leishmania braziliensis (Lb), the agent responsible for cutaneous leishmaniasis (CL) in Brazil, represents an interesting model in which to evaluate the effects associated with MET. OBJECTIVE: To evaluate the modulatory effect of MET in Lb infection. MATERIAL AND METHODS: Experimental study of Lb infection and MET treatment in BALB/c mice and Raw 264.7 macrophages. FINDINGS: MET treatment interfered with lesion kinetics, increased parasite load and reduced macrophage proliferation. Low concentrations of MET in Lb culture allow for the maintenance of stationary parasite growth phase. Lb-infected cells treated with MET exhibited increased parasite load. While both MET and Lb infection alone promoted the production of intracellular reactive oxygen species (ROS), reduced levels of ROS were seen in MET-treated Lb-infected macrophages. MAIN CONCLUSION: Experimental treatment with MET interfered with the kinetics of cutaneous ulceration, increased Lb parasite load, altered ROS production and modulated cellular proliferation. Our experimental results indicate that MET interfere with the evolution of CL.


Assuntos
Leishmania/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Metformina/farmacologia , Animais , Brasil , Leishmania braziliensis , Camundongos , Camundongos Endogâmicos BALB C
4.
Ann Parasitol ; (3): 415-418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33128868

RESUMO

Cutaneous leishmaniosis (CL) transmitted by the bite of infected female phlebotomine sand flies endemic in many parts of rural and urban areas of Kashan, central Iran. Rare systemic allergic reactions, including anaphylaxis can occur in response to the bites of mosquitoes. In 2019, the patient was a 20-yr-old woman referring to the Health Care Centre in Kashan, central Iran, and complaint of symptoms allergic. After receiving anti-allergic drug therapy a month, skin lesions appeared on her forehead, forearm, and right arm. The disease was diagnosed with positive CL by direct smear. Her lesion treated with systemic meglumine antimonate (Glucantime®) (1.5 g/5ml/week) for seven-week. In conclusion, CL, as a public health problem, especially for travellers and patients with allergies to insect bites, is the most common in endemic areas. It guides us to consider the control programs of this disease, and much attention should be given to improve the environmental conditions for vector-borne control and public health education for personal protection.


Assuntos
Hipersensibilidade , Leishmaniose Cutânea , Psychodidae , Animais , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/epidemiologia , Mosquitos Vetores
5.
BMC Infect Dis ; 20(1): 645, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873242

RESUMO

BACKGROUND: During the outbreak of cutaneous leishmaniasis in the Kurdistan Region of Iraq that started in 2015, the course of the disease and the treatment were not consistent with the available literature. Physicians, particularly dermatologists, faced challenges with treating the cutaneous leishmaniasis lesions with high rates of treatment failure and resistance to treatment. We used Q-methodology to understand the range and diversities of opinions and the practical experiences of dermatologists about the treatment difficulties of cutaneous leishmaniasis. METHODS: This Q-methodology study was carried out in Erbil, Kurdistan Region of Iraq, and involved 37 dermatologists. A set of 40 statements related to different aspects of difficulties and uncertainties of treating cutaneous leishmaniasis was prepared. The dermatologists were requested to distribute the 40 statements into a scaled grid of nine piles from least agree to most agree. We applied by-person factor analysis using PQMethod 2.35 for the data analysis. RESULTS: The analysis revealed two different viewpoints about the treatment of cutaneous leishmaniasis and a consensus viewpoint. The first viewpoint emphasized the use of sodium stibogluconate-based combination therapy, concerns with treatment failure, and lack of compliance with the treatment. The second viewpoint emphasized the lack of standard treatment and advances in the treatment of cutaneous leishmaniasis. There was a consensus between both groups of respondents about many aspects of the treatment of cutaneous leishmaniasis, including considering sodium stibogluconate the first drug of choice for cutaneous leishmaniasis treatment. CONCLUSIONS: This study revealed a diversity of viewpoints and uncertainties about the effectiveness of the available treatment modalities and treatment difficulties and failure. Interrupted supply and poor quality of the available drugs and lack of a standard and advanced treatment are the main problems facing the treatment of cutaneous leishmaniasis. More research is required to determine the best treatment modalities for the different types of cutaneous leishmaniasis. There is a need for the development of treatment guidelines specific to the Iraqi context with a particular focus on the treatment of the resistant and atypical cases of cutaneous leishmaniasis.


Assuntos
Gluconato de Antimônio e Sódio/uso terapêutico , Atitude , Consenso , Dermatologistas/psicologia , Leishmania , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/epidemiologia , Adulto , Terapia Combinada , Análise Fatorial , Feminino , Humanos , Incidência , Iraque/epidemiologia , Leishmaniose Cutânea/parasitologia , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Falha de Tratamento
6.
Mikrobiyol Bul ; 54(3): 444-462, 2020 Jul.
Artigo em Turco | MEDLINE | ID: mdl-32755520

RESUMO

World Health Organization reported that approximately one billion people are at risk in endemic areas, one million cases of cutaneous leishmaniasis (CL) and approximately 300,000 cases of visceral leishmaniasis (VL) were reported per year in the last five years. The number of deaths due to VL is reported to be approximately 20,000 per year. Approximately 2500 cases/year have been reported as CL, caused by Leishmania tropica and Leishmania infantum, in Turkey. The significant increase observed in many cities mainly in the provinces of Mediterranean and Aegean regions in cases and foci in recent years, suggests that there may be an increase in this infections in the following years as well. In Turkey, the causative agent of CL is L.tropica and meglumine antimoniate is used in the treatment of CL. We aimed to determine antimony resistance genes specific for L.tropica by comparing the gene and protein expressions of antimony-resistant and non-resistant L.tropica strains. L.tropica isolates obtained from 3 CL patients without antimonate resistance from Aegean, Mediterranean and Southeastern regions of Turkey were provided to transform into 3 resistant isolates against meglumine antimony in the laboratory conditions. Gene expression alterations by microarray method; protein profiles by two-dimensional gel electrophoresis (2D-PAGE) and relevant proteins by MALDI-TOF/TOF MS of these isolates were accomplished and compared. L.tropica isolates from 10 CL patients who did not respond to antimony therapy were analyzed for resistance to antimonial compounds and quantitative real-time polymerase chain reaction was performed to detect the expression of genes responsible for resistance development. Moreover, differences in protein expression levels in isolates with and without antimony resistance were determined by comparing protein profiles and identification of proteins with different expression levels was carried out. Enolase, elongation factor-2, heat shock protein 70, tripanthione reductase, protein kinase C and metallo-peptidase proteins have been shown to play roles in L.tropica isolates developing resistance to antimonial compounds and similar expression changes have also been demonstrated in naturally resistant isolates from patients. In conclusion, it was revealed that L.tropica strains in our country may gain resistance to meglumine antimoniate in a short time. It is foreseen that if the patients living in our country or entering the country are treated inadequately and incompletely, there may be new, resistant leishmaniasis foci that may increase the number of resistant strains and cases rapidly.


Assuntos
Resistência a Medicamentos , Leishmania tropica , Leishmaniose Cutânea , Antimoniato de Meglumina , Resistência a Medicamentos/genética , Humanos , Leishmania tropica/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Turquia
7.
PLoS Negl Trop Dis ; 14(8): e0008380, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797078

RESUMO

In French Guiana, five species are associated with Cutaneous Leishmaniasis (CL). Though infections with Leishmania guyanensis, L. (V.) braziliensis and L. (L.) amazonensis have been extensively described, there are few available clinical and genetic data on L. (V.) lainsoni and L. (V.) naiffi. We determined the clinical and epidemiological features of all cases of CL due to L. (V.) naiffi and L. (V.) lainsoni diagnosed in French Guiana between 2003 and 2019. Phylogenetic analysis was performed by sequencing a portion of HSP70 and cyt b genes. Five cases of L. naiffi and 25 cases of L. lainsoni were reported. Patients infected by L. (V.) lainsoni were usually infected on gold camps, mostly along the Maroni river (60%), while L. naiffi was observed in French patients infected on the coast (100%). A high number of pediatric cases (n = 5; 20%) was observed for L. (V.) lainsoni. A mild clinical course was observed for all cases of L. (V.) naiffi. HSP70 and cyt b partial nucleotide sequence analysis revealed different geographical clusters within L. (V.) naiffi and L. (V.) lainsoni but no association were found between phylogenetic and clinical features. Our data suggest distinct socio-epidemiological features for these two Leishmania species. Patients seem to get infected with L. (V.) naiffi during leisure activities in anthropized coastal areas, while L. (V.) lainsoni shares common features with L. (V.) guyanensis and braziliensis and seems to be acquired during professional activities in primary forest regions. Phylogenetic analysis has provided information on the intraspecific genetic variability of L. (V.) naiffi and L. (V.) lainsoni and how these genotypes are distributed at the geographic level.


Assuntos
Leishmania/classificação , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Citocromos b/genética , Feminino , Guiana Francesa/epidemiologia , Proteínas de Choque Térmico HSP70/genética , Humanos , Lactente , Leishmania/genética , Leishmania/patogenicidade , Leishmaniose Cutânea/patologia , Atividades de Lazer , Masculino , Pessoa de Meia-Idade , Mineração , Doenças Negligenciadas , Filogenia , Estudos Retrospectivos , Análise de Sequência de DNA
8.
PLoS Negl Trop Dis ; 14(8): e0008482, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776923

RESUMO

Current drug therapies for cutaneous leishmaniasis are often difficult to administer and treatment failure is an increasingly common occurrence. The efficacy of anti-leishmanial therapy relies on a combination of anti-parasite activity of drugs and the patient's immune response. Previous studies have reported in vitro antimicrobial activity of histamine 1-receptor antagonists (H1RAs) against different pathogens. We used an ex vivo explant culture of lymph nodes from mice infected with Leishmania major to screen H1RAs compounds. Azelastine (AZ) and Fexofenadine (FX) showed remarkable ex vivo efficacy (EC50 = 0.05 and 1.50 µM respectively) and low in vitro cytotoxicity yielding a high therapeutic index. AZ significantly decreased the expression of H1R and the proinflammatory cytokine IL-1ẞ in the ex vivo system, which were shown to be augmented by histamine addition. The anti-leishmanial efficacy of AZ was enhanced in the presence of T cells from infected mice suggesting an immune-modulatory mechanism of parasite suppression. L. major infected BALB/c mice treated per os with FX or intralesionally with AZ showed a significant reduction of lesion size (FX = 69%; AZ = 52%). Furthermore, there was significant parasite suppression in the lesion (FX = 82%; AZ = 87%) and lymph nodes (FX = 81%; AZ = 36%) with no observable side effects. AZ and FX and potentially other H1RAs are good candidates for assessing efficacy in larger studies as monotherapies or in combination with current anti-leishmanial drugs to treat cutaneous leishmaniasis.


Assuntos
Antagonistas dos Receptores Histamínicos H1 não Sedativos/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Ftalazinas/uso terapêutico , Terfenadina/análogos & derivados , Animais , Leishmania major , Linfonodos/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ftalazinas/química , Terfenadina/química , Terfenadina/uso terapêutico , Técnicas de Cultura de Tecidos
9.
AAPS PharmSciTech ; 21(5): 185, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632542

RESUMO

The present study aimed to develop, characterize and evaluate the amphotericin B-loaded nanostructured lipid carriers (AmB-NLCs) for topical treatment of cutaneous leishmaniasis (CL) and vulvovaginal candidiasis (VVC). AmB-NLCs were characterized for particle size, zeta potential, encapsulation efficiency and surface morphology. Prepared NLCs were also characterized for in vitro drug release, ex vivo skin permeation and deposition before evaluating their in vitro and in vivo efficacy. Cytotoxicity of NLCs was assessed on MRC-5 cells, whereas skin irritation potential was evaluated in vivo using rats. Significant accumulation of drug in to the skin supported the topical application potential of drug-loaded NLCs. Encapsulation of AmB in NLCs resulted in enhanced in vitro potency against promastigotes and intracellular amastigotes of L. major JISH 118 (IC50 ± SEM = 0.02 ± 0.1 µM for both) compared with free drug (IC50 ± SEM = 0.15 ± 0.2 & 0.14 ± 0.0, respectively). Similar improved potency of AmB-NLCs was also observed for other Leishmania and fungal strains compared with drug solution. Topical application of AmB-NLCs on L. major-infected BALB/c mice caused a significant reduction in parasite burden per mg of lesion (65 × 108 ± 13) compared with the control group (> 167.8 × 108 ± 11). Topical AmB-NLCs gel demonstrated superior efficacy in the vaginal C. albicans rat model for VVC as compared with plain AmB gel. Moreover, results of in vitro cytotoxicity assay and in vivo skin irritation test confirmed AmB-NLCs to be non-toxic and safe for topical use. In conclusion, NLCs may have promising potential as carrier for topical treatment of various conditions of skin and mucosa.


Assuntos
Anfotericina B/administração & dosagem , Candidíase Vulvovaginal/tratamento farmacológico , Leishmaniose Cutânea/tratamento farmacológico , Nanoestruturas/administração & dosagem , Administração Tópica , Animais , Candidíase Vulvovaginal/metabolismo , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Géis/metabolismo , Humanos , Lipídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Tamanho da Partícula , Ratos , Pele/metabolismo , Absorção Cutânea
10.
Exp Parasitol ; 217: 107934, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698075

RESUMO

The inadequacy of available treatments for leishmaniasis has presented up to 40% therapeutic failure. This fact suggests an urgency in the discovery of new drugs or alternative approaches for treating this disease. The objective of this study was to evaluate the antileishmanial activity of combined therapy between crotamine (CTA) from Crotalus durissus terrificus and the pentavalent antimonial Glucantime® (GLU). The assays were in vitro performed measuring the inhibition of Leishmania amazonensis amastigotes, followed by the evaluation of cellular production of cytokines and nitrites. After that, analytical methods were performed in order to characterize the molecules involved in the study by Mass Spectrometry, molecular affinity through an in silico assay and Surface Plasmon Resonance. In vivo experiments with BALB/c mice were performed by analyzing parasitemia, lesion size and immunological mediators. In the in vitro experiments, the pharmacological association improved the inhibition of the amastigotes, modulated the production of cytokines and nitric oxide. The therapy improved the effectiveness of the GLU, demonstrating a decreased parasitemia in the infected tissues. Altogether, the results suggest that the combined approach with CTA and GLU may be a promising alternative for the treatment of cutaneous leishmaniasis.


Assuntos
Antiprotozoários/uso terapêutico , Venenos de Crotalídeos/uso terapêutico , Crotalus , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/uso terapêutico , Animais , Antiprotozoários/farmacologia , Venenos de Crotalídeos/farmacologia , Combinação de Medicamentos , Interleucina-12/sangue , Interleucina-12/metabolismo , Leishmania mexicana/isolamento & purificação , Linfonodos/parasitologia , Macrófagos Peritoneais , Espectrometria de Massas , Antimoniato de Meglumina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Nitritos/análise , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
12.
Rev Soc Bras Med Trop ; 53: e20200091, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578713

RESUMO

INTRODUCTION: The drugs currently available for leishmaniasis treatment have major limitations. METHODS: In vitro and in vivo studies were performed to evaluate the effect of a quinoline derivative, Hydraqui (7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline, against Leishmania amazonensis. In silico analyses of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were performed. RESULTS: Hydraqui showed significant in vitro anti-amastigote activity. Also, Hydraqui-treated mice exhibited high efficacy in lesion size (48.3%) and parasitic load (93.8%) reduction, did not cause hepatic and renal toxicity, and showed appropriate ADMET properties. CONCLUSIONS: Hydraqui presents a set of satisfactory criteria for its application as an antileishmanial agent.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Quinolinas/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Leishmaniose Cutânea/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Quinolinas/química
13.
Intern Med ; 59(9): 1227-1230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32378656

RESUMO

Liposomal-amphotericin B (L-AmB) is used for cutaneous leishmaniasis (CL); however, its treatment failure has not yet been described in detail. A 58-year-old man returned from the Republic of Venezuela with a cutaneous ulcer on his left lower leg. The causative pathogen was Leishmania braziliensis. We started L-AmB 3 mg/kg/day for 6 days; however, the ulcer did not resolve. The patient was successfully retreated with a higher dose L-AmB 4 mg/kg/day 9 times (total, 36 mg/kg). If L-AmB fails to treat CL and other therapeutics cannot be used, increasing the L-AmB dose is a viable option.


Assuntos
Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmania braziliensis/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Diagnóstico Diferencial , Relação Dose-Resposta a Droga , Humanos , Leishmaniose Cutânea/complicações , Leishmaniose Cutânea/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Retratamento , Falha de Tratamento
14.
Am J Trop Med Hyg ; 103(3): 1081-1084, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32314693

RESUMO

We present two cases of Leishmania (V) panamensis in returning travelers from Central America successfully treated with miltefosine. The couple presented with ulcerative skin lesions nonresponsive to antibiotics. Skin biopsy with polymerase chain reaction (PCR) revealed L. (V) panamensis. To prevent the development of mucosal disease and avoid the inconvenience of parental therapy, we treated both patients with oral miltefosine. We suggest that miltefosine represents an important therapeutic alternative in the treatment of cutaneous lesions caused by L. panamensis and in preventing mucosal involvement.


Assuntos
Antiprotozoários/administração & dosagem , Leishmania guyanensis/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Fosforilcolina/análogos & derivados , Administração Oral , Adulto , Biópsia , América Central , Feminino , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Masculino , Fosforilcolina/administração & dosagem , Reação em Cadeia da Polimerase , Pele/parasitologia , Viagem
15.
Parasitol Int ; 76: 102097, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32114085

RESUMO

How human macrophages can control the intracellular infection with Leishmania is not completely understood. IL-15 and IL-32 are cytokines produced by monocytes/macrophages that can induce antimicrobial mechanisms. Here, we evaluated the effects of recombinant human IL-15 (rhIL-15) on primary human macrophage infection and response to L. braziliensis. Priming with rhIL-15 reduced the phagocytosis of L. braziliensis and increased the killing of the parasites in monocyte-derived macrophages from healthy donors. rhIL-15 induced TNFα and IL-32 in uninfected cells. After infection, the high levels of rhIL-15-induced TNFα and IL-32 were maintained. In addition, there was an increase of NO and an inhibition of the parasite-induced IL-10 production. Inhibition of NO reversed the leishmanicidal effects of rhIL-15. Although rhIL-15 did not increase L. braziliensis-induced reactive oxygen intermediates (ROS) production, inhibition of ROS reversed the control of infection induced by rhIL-15. Treatment of the cells with rhIL-32γ increased microbicidal capacity of macrophages in the presence of high levels of vitamin D (25D3), but not in low concentrations of this vitamin. rhIL-15 together with rhIL-32 lead to the highest control of the L. braziliensis infection in high concentrations of vitamin D. In this condition, NO and ROS mediated rhIL-32γ effects on microbicidal activity. The data showed that priming of human macrophages with rhIL-15 or rhIL-32γ results in the control of L. braziliensis infection through induction of NO and ROS. In addition, rhIL-32γ appears to synergize with rhIL-15 for the control of L. braziliensis infection in a vitamin D-dependent manner.


Assuntos
Antiparasitários/metabolismo , Interleucina-15/metabolismo , Interleucinas/metabolismo , Leishmania braziliensis/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Vitamina D/metabolismo , Antiparasitários/farmacologia , Interleucina-15/farmacologia , Interleucinas/farmacologia , Leishmania braziliensis/fisiologia , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Vitamina D/farmacologia
16.
Acta Trop ; 206: 105444, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32173317

RESUMO

New drugs for the treatment of human leishmaniasis are urgently needed, considering the limitations of current available options. However, pre-clinical evaluation of drug candidates for leishmaniasis is challenging. The use of luciferase-expressing parasites for parasite load detection is a potentially powerful tool to accelerate the drug discovery process. We have previously described the use of Leishmania amazonensis mutants expressing firefly luciferase (Luc2) for drug testing. Here, we describe three new mutant L. amazonensis lines that express different variants of luciferases: NanoLuc, NanoLuc-PEST and RedLuc. These mutants were evaluated in drug screening protocols. NanoLuc-parasites, in spite of high bioluminescence intensity in vitro, were shown to be inadequate in discriminating between live and dead parasites. Bioluminescence detection from intracellular amastigotes expressing NanoLuc-PEST, RedLuc or Luc2 proved more reliable than microscopy to determine parasite killing. Increased sensitivity was observed in vivo with RedLuc-expressing parasites as compared to NanoLuc-expressing L. amazonensis. Our data indicates that NanoLuc is not suitable for in vivo parasite burden determination. Additionally, RedLuc and the conventional luciferase Luc2 demonstrated equivalent sensitivity in an in vivo model of cutaneous leishmaniasis.


Assuntos
Leishmaniose Cutânea/tratamento farmacológico , Luciferases/genética , Medições Luminescentes/métodos , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Leishmania mexicana/genética , Camundongos , Camundongos Endogâmicos BALB C
17.
PLoS Negl Trop Dis ; 14(3): e0008052, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32203500

RESUMO

Post-kala-azar dermal leishmaniasis (PKDL) is clinical outcome of visceral leishmaniasis (VL) and is thought to be the potential reservoir of parasite. Miltefosine (MF) is the only oral drug existing for treatment of post-kala-azar dermal leishmaniasis (PKDL). Increased miltefosine tolerance in clinical isolates of Leishmania donovani has been reported and is one of the major concerns in the treatment of PKDL. Here, we report a highly ulcerated PKDL case that was successfully cured after miltefosine treatment.


Assuntos
Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/etiologia , Leishmaniose Visceral/complicações , Leishmaniose Visceral/tratamento farmacológico , Antiprotozoários/uso terapêutico , Humanos , Índia , Leishmania donovani/isolamento & purificação , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Pele/diagnóstico por imagem , Pele/patologia
18.
Mem Inst Oswaldo Cruz ; 115: e190361, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130370

RESUMO

Genes associated with wound healing have been shown to be risk factors for cutaneous leishmaniasis (CL) which is caused by Leishmania braziliensis. In this study, we examined whether the genes previously associated with CL influenced the clinical outcome. Patients were genotyped and retrospectively classified as responders, who were cured with a single course of pentavalent antimony (Sbv), or as refractories, who did not respond to Sbv. Patients characterised as responders showed a stronger response to the leishmanin skin test (LST) when compared to the refractory subjects (p = 0.0003). Furthermore, we observed an association between the FLI1 CC genotype and an increased size of ulcers (p = 0.0170). We suggest that the leishmanin skin test may be a predictive tool for therapeutic outcome and reinforce FLI1 as a potential influencer of susceptibility and lesion size in CL.


Assuntos
Antimônio/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/genética , Cicatrização/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Testes Cutâneos , Adulto Jovem
19.
Eur J Pharm Sci ; 145: 105256, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32032778

RESUMO

The present study evaluates the efficacy of sodium stibogluconate (SSG) co-loaded with ketoconazole (KTZ) in nano-elastic liposomes (NELs) for the topical treatment of cutaneous leishmaniasis (CL). SSG-KTZ co-loaded NELs were developed and assessed for various physicochemical properties and anti-leishmanial potential. The optimized nano-vesicles have an average size of 212.8 ± 3.1 nm and entrapment efficiency of 61.2 ± 2.9%. SSG-KTZ co-loaded NELs displayed 5.37-fold higher skin permeation of SSG as compared to drug solution. SSG and KTZ displayed a synergistic interaction and flow cytometry revealed enhanced killing of DsRed Leishmania mexicana in infected macrophages. In-vitro and in-vivo anti-leishmanial studies indicated a 10.67-fold lower IC50 value and a 35.33-fold reduced parasitic burden as compared with plain SSG solution, respectively. SSG-KTZ co-loaded NELs were found to be a promising approach for the topical treatment of CL.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Elasticidade , Cetoconazol/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Nanopartículas/administração & dosagem , Administração Tópica , Animais , Gluconato de Antimônio e Sódio/metabolismo , Antiprotozoários/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Feminino , Cetoconazol/metabolismo , Leishmaniose Cutânea/metabolismo , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Técnicas de Cultura de Órgãos , Distribuição Aleatória , Pele/efeitos dos fármacos , Pele/metabolismo
20.
Am J Trop Med Hyg ; 102(4): 777-781, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32043440

RESUMO

Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis occurs predominantly in adult males. Herein, we compare the clinical presentation and the response to antimony therapy of CL in children versus adults. Participants included 571 patients with CL; of these, 129 were children (age ≤ 12 years). Cure was defined as the complete healing of ulcer in the absence of raised borders at day 90 after initiation of therapy. Failure was defined by the presence of an active ulcer or a scar with elevated borders at day 90. In comparison with adults, children had shorter duration of illness, more lesions in the head, and smaller ulcers. Risk factors for therapeutic failure were younger age, shorter duration of disease, higher number of lesions, and larger size of the biggest ulcer. When age was categorized in ≤ 12-year-olds (children versus adults), it predicted therapeutic failure with statistical significance at day 60 but not at day 90. In conclusion, our data indicate that there are significant differences in the clinical presentation of CL between children and adults. Physicians caring for children with CL should be aware that lesions may take longer to heal and remain alert for the possibility of higher odds of therapeutic failure in this group.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/epidemiologia , Antimoniato de Meglumina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leishmaniose Cutânea/patologia , Masculino , Pessoa de Meia-Idade
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