Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.184
Filtrar
1.
PLoS Negl Trop Dis ; 14(8): e0008575, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866156

RESUMO

BACKGROUND: Treatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitro and in animal model experiments. METHODOLOGY/PRINCIPAL: Leishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK). FINDINGS: The in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug. CONCLUSIONS/SIGNIFICANCE: All experiments affirmed the efficacy of suramin against L. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.


Assuntos
Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Suramina/farmacologia , Suramina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Fosfoglicerato Quinase/efeitos dos fármacos , Células RAW 264.7/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
3.
Exp Parasitol ; 217: 107947, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32628971

RESUMO

Visceral leishmaniasis (VL) is an infectious disease caused by the protozoan parasite Leishmania (Leishmania) infantum, an intracytoplasmic parasite that affects humans and other species of domestic and wild mammals. In Brazil, the treatment of canine visceral leishmaniasis (CVL) with miltefosine has been implemented since 2016, and the reports on the clinical and immunological conditions of treated dogs are scarce. Thus, this study aimed to assess and monitor the clinical, laboratory, and immunological condition of dogs with CVL before (D0) and after (D29) using three pharmacotherapeutic protocols: miltefosine monotherapy (Milteforan™, Virbac) (G1), miltefosine plus allopurinol (G2), and allopurinol monotherapy (G3). Forty-five dogs with CVL were assigned to one of three treatment groups. The dogs were evaluated for clinical signs, was well as haematological, biochemical, serological, and cytokine levels. Significant reduction in clinical scores was observed in all protocols, with no differences between groups. We did not observe a clinical cure in any of the dogs in the groups. Haematological and biochemical parameters showed slow recovery, with better results observed in G2. Anti-Leishmania antibody titre remained increased in all groups. The quantification of serum cytokines demonstrated a mixed Th1/Th2 profile in CVL. The IL-2 levels decreased in all groups after treatment. Evaluation of IFN-y and IL-10 did not show changes in the groups analysed, and it did not contribute to short term therapeutic monitoring. All therapeutic protocols promoted, to varying degrees, an improvement in the general condition (clinical signs, haematological, and biochemical levels) of the animals. Through clinical-pathological exams, we found that the combination of miltefosine plus allopurinol promoted better effects in the short-term, representing the best choice for the treatment of CVL, even when compared to the only therapeutic protocol allowed in Brazil, miltefosine monotherapy. Through the quantification of cytokines, IL-2 proved to be a potential therapeutic marker for the monitoring and follow-up of dogs with CVL.


Assuntos
Alopurinol/uso terapêutico , Antiprotozoários/uso terapêutico , Doenças do Cão/tratamento farmacológico , Leishmaniose Visceral/veterinária , Fosforilcolina/análogos & derivados , Animais , Citocinas/sangue , Doenças do Cão/parasitologia , Cães , Quimioterapia Combinada , Feminino , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Masculino , Fosforilcolina/uso terapêutico
4.
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
5.
Exp Parasitol ; 217: 107948, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698076

RESUMO

Immunomodulation is an emerging concept to combat infection in recent years. Immunomodulators like arabinosylated-lipoarabinomannan (Ara-LAM) and glycyrrhizic-acid (GA) possess anti-leishmanial property, whereas sodium-antimony-gluconate (SAG) is still considered as the first choice for chemotherapy against leishmaniasis. During infection, invasion of Leishmania donovani needs the potential requirement of Ca2+, which is further responsible for apoptosis in intracellular amastigotes. However, suppression of elevated intracellular calcium by the activation of plasma-membrane-calcium-ATPase (PMCA4) facilitates survival of L. donovani in the host. In the present study, SAG, Ara-LAM, and GA were found to evoke significant increase in intracellular Ca2+ in L. donovani infected macrophages by inhibiting PMCA4. Moreover, PMCA4 inhibition by TFP or PMCA4 siRNA elevated the level of PKCß, whereas calcium-independent upregulation of PKCζ remained unchanged in infected macrophages. Furthermore, application of immunomodulators in infected macrophages resulted in down-regulation of PKCζ, conversion of anti-inflammatory to pro-inflammatory cytokines and inhibition of PMCA4. Plasma membrane-associated ceramide which is known to be elevated during leishmaniasis, triggered upregulation of PMCA4 via PKCζ activation. Interestingly, immunomodulators attenuated ceramide generation, which resulted into reduced PKCζ activation leading to the decreased PMCA expression in infected macrophages. Therefore, our study elucidated the efficacy of SAG, Ara-LAM, and GA in the reduction of parasite burden in macrophages by suppressing PMCA activation through inhibition of ceramide mediated upregulation of PKCζ.


Assuntos
Antiprotozoários/uso terapêutico , ATPases Transportadoras de Cálcio/sangue , Membrana Celular/enzimologia , Fatores Imunológicos/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Animais , Gluconato de Antimônio e Sódio/farmacologia , Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/farmacologia , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Ceramidas/metabolismo , Meios de Cultura Livres de Soro , Densitometria , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/uso terapêutico , Imipramina/farmacologia , Immunoblotting , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/uso terapêutico , Macrófagos/fisiologia , Camundongos , RNA de Protozoário/genética , RNA de Protozoário/isolamento & purificação , RNA Interferente Pequeno/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Reversa , Transfecção
6.
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
7.
Exp Parasitol ; 216: 107943, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32598890

RESUMO

The search for novel therapeutic candidates against animal trypanosomiasis is an ongoing scientific endevour because of the negative impacts of the disease to the African livestock industry. In this study, the in vivo therapeutic potentials of phytol toward Trypanosoma congolense infection and the inhibitory effects on trypanosomal sialidase were investigated. Rats were infected with T. congolense and administered daily oral treatment of 50 and 100 mg/kg BW of phytol. Within the first 10 days of the treatment, no antitrypanosomal activity was recorded but a moderate trypanostatic activity was observed from day 17-day 21 pi. However, at 100 mg/kg BW, phytol demonstrated a significant (p < 0.05) ameliorative potentials toward T. congolense-induced host-associated pathological damages such as anaemia, hepatic and renal damages; and the data was comparable to diminazine aceturate. Moreover, the T. congolense caused a significant (p < 0.05) increase in free serum sialic acid level which was significantly (p < 0.05) prevented in the presence of phytol (100 mg/kg BW). In an in vitro analysis, phytol inhibited partially purified T. congolense sialidase using an uncompetitive inhibition pattern with inhibition binding constant of 261.24 µmol/mL. Subsequently, molecular docking revealed that the compound binds to homology modelled trypanosomal sialidase with a binding free energy of -6.7 kcal/mol which was mediated via a single hydrogen bond while Trp324 and Pro274 were the critical binding residues. We concluded that phytol has moderate trypanostatic activity but with a great potential in mitigating the host-associated cellular damages while the anaemia amelioration was mediated, in part, through the inhibition of sialidase.


Assuntos
Antiprotozoários/uso terapêutico , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Fitol/uso terapêutico , Trypanosoma congolense/efeitos dos fármacos , Tripanossomíase Africana/veterinária , Animais , Antiprotozoários/farmacologia , Inibidores Enzimáticos/uso terapêutico , Gado , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/veterinária , Neuraminidase/química , Neuraminidase/isolamento & purificação , Fitol/farmacologia , Distribuição Aleatória , Ratos , Ratos Wistar , Trypanosoma congolense/enzimologia , Tripanossomíase Africana/tratamento farmacológico
8.
Ann Parasitol ; 66(2): 165-174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32592455

RESUMO

Neither physiological nor pathological changes following treatments explained why trypanosomes in the same group of experimentally treated animals correlated in virulence. Also, they behaved like each other but not similar to other groups despite the same T. evansi injected strain. The current study aims to discuss whether molecular changes might occur to Trypanosoma evansi isolates followed treatments are responsible for that difference or not. Ten preserved isolates from T. evansi after previous treatments besides the original strain of T. evansi that injected before treatments were used in the present study. These isolates were intraperitoneally inoculated in 11 groups of male Wister Albino rats with equal doses. Parasitological findings and the molecular changes accompanied were discussed along with the experiment based on PCR-TR3/TR4 specific-primers. The study also achieved alignments, gene sequence and phylogenetic analysis for submitted and reference strains belong to T. evansi, T. brucei, T. b. brucei, and T. b. gambiense deposited in GenBank. The present results assessed molecularly the effectiveness and highly antitrypanosomal activity of human plasmas O+ and A+ on T. evansi than others, and how their strains drifted from its original sequence to the nearest form of T. brucei. At the same time, T. evansi in other plant extract groups multiplied progressively like cancer cells and became more virulent and close to reference strains of T. evansi. Our data further indicated that T. evansi after treatment was a paraphyletic group. It also corroborated the antitrypanosomal activityspecificity and the molecular changes occurring were correlated to the type of treatment.


Assuntos
Antiprotozoários , Trypanosoma , Tripanossomíase , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Humanos , Masculino , Filogenia , Ratos , Ratos Wistar , Trypanosoma/efeitos dos fármacos , Trypanosoma/genética , Trypanosoma/patogenicidade , Tripanossomíase/sangue , Tripanossomíase/tratamento farmacológico
9.
Exp Parasitol ; 216: 107940, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32562606

RESUMO

Therapeutic options for the treatment of leishmaniasis are insufficient and need improvements owing to their low efficiency and high toxicity as well as the emergence of resistant strains. The limited number of new drugs for neglected diseases and lack of innovation in your development are still challenges. In this context, the process of discovery and development of biological assays play a pivotal role for the identification of bioactive compounds. The assays currently used for screening of drugs with cytotoxic activity against Leishmania parasites, include different processes that utilize intact parasite (free or intracellular) or specific enzymes of metabolism as a target cell. These assays allow the screening of large numbers of samples followed by more detailed secondary confirmatory assays to confirm the observed activity and assess their toxicity. In the present study, we described the development of a new functional and more complete assay that enables simultaneous assessment of potential anti-Leishmania compounds through evaluation of internalization of fluorescein-labeled L. braziliensis promastigotes by human peripheral blood monocytes and their cytotoxicity by flow cytometry. We standardized the conditions for parasite labeling to achieve better phagocytosis analysis by setting the ratio of number of parasites per cell as 1 to 2, at incubation time of 6h. The cytotoxicity assessment was performed by the quantification of cells undergoing early/late apoptosis and necrosis using a double labelling platform employing 7AAD for late apoptosis and necrosis analysis and Annexin-V for early apoptosis evaluation. Hemolysis analysis was an additional parameter to test cytotoxicity. Two drugs used on clinic (Amphotericin B and Glucantime®) were used to validate the proposed methodology, and the assay was able to detect their known leishmanicidal activity and immunotoxicity properties. This new predictive assay will contribute to the development of translational medicine strategies in drug discovery for neglected diseases such as leishmaniasis.


Assuntos
Alternativas aos Testes com Animais/métodos , Antiprotozoários/toxicidade , Citometria de Fluxo/métodos , Leishmania/efeitos dos fármacos , Doenças Negligenciadas/tratamento farmacológico , Adulto , Anfotericina B/farmacologia , Anfotericina B/toxicidade , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Humanos , Leishmania braziliensis/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Leucócitos/parasitologia , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Antimoniato de Meglumina/toxicidade , Microscopia Confocal , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/parasitologia , Fatores de Tempo , Adulto Jovem
10.
Medicine (Baltimore) ; 99(20): e20146, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443329

RESUMO

BACKGROUND: An increased frequency of toxoplasma encephalitis, caused by Toxoplasma gondii, has been reported in AIDS patients, especially in those with CD4+ T cell counts <100 cells/µL. Several guidelines recommend the combination of pyrimethamine, sulfadiazine, and leucovorin as the preferred regimen for AIDS-associated toxoplasma encephalitis. However, it is not commonly used in China due to limited access to pyrimethamine and sulfadiazine. The synergistic sulfonamides tablet formulation is a combination of trimethoprim (TMP), sulfadiazine and sulfamethoxazole (SMX), and is readily available in China. Considering its constituent components, we hypothesize that this drug may be used as a substitute for sulfadiazine and TMP-SMX. We have therefore designed the present trial, and propose to investigate the efficacy and safety of synergistic sulfonamides combined with clindamycin for the treatment of toxoplasma encephalitis. METHODS/DESIGN: This study will be an open-labeled, multi-center, prospective, randomized, and controlled trial. A total of 200 patients will be randomized into TMP-SMX plus azithromycin group, and synergistic sulfonamides plus clindamycin group at a ratio of 1:1. All participants will be invited to participate in a 48-week follow-up schedule once enrolled. The primary outcomes will be clinical response rate and all-cause mortality at 12 weeks. The secondary outcomes will be clinical response rate and all-cause mortality at 48 weeks, and adverse events at each visit during the follow-up period. DISCUSSION: We hope that the results of this study will be able to provide reliable evidence for the efficacy and safety of synergistic sulfonamides for its use in AIDS patients with toxoplasma encephalitis. TRIAL REGISTRATION: This study was registered as one of 12 clinical trials under the name of a general project at chictr.gov on February 1, 2019, and the registration number of the general project is ChiCTR1900021195. This study is still recruiting now, and the first patient was screened on March 22, 2019.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Toxoplasmose Cerebral/complicações , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Síndrome de Imunodeficiência Adquirida/mortalidade , Adolescente , Adulto , Anti-Infecciosos/uso terapêutico , Antiprotozoários/uso terapêutico , China/epidemiologia , Clindamicina/uso terapêutico , Quimioterapia Combinada/métodos , Feminino , Infecções por HIV/mortalidade , Humanos , Leucovorina/uso terapêutico , Masculino , Estudos Prospectivos , Pirimetamina/uso terapêutico , Sulfadiazina/uso terapêutico , Sulfametoxazol/uso terapêutico , Sulfonamidas/uso terapêutico , T-Linfocitopenia Idiopática CD4-Positiva , Toxoplasma/efeitos dos fármacos , Toxoplasma/parasitologia , Toxoplasmose Cerebral/tratamento farmacológico , Toxoplasmose Cerebral/parasitologia , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Complexo Vitamínico B/uso terapêutico
11.
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
12.
Hautarzt ; 71(6): 437-442, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32394080

RESUMO

Here we describe two complicated cases of complex Old World cutaneous Leishmaniasis due to L. infantum and L. aethiopica. Both of our patients infected with the Leishmania parasite presented with a completely different clinical picture, course of disease, and treatment response. Clinical healing was achieved after multiple courses of treatment with a variety of different antileishmanial drugs. Nephrotoxity was a limiting side effect.


Assuntos
Leishmania infantum/isolamento & purificação , Leishmania/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/uso terapêutico , Antiprotozoários/efeitos adversos , Antiprotozoários/uso terapêutico , Progressão da Doença , Humanos , Leishmania/classificação
13.
Am J Trop Med Hyg ; 103(1): 308-314, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32394874

RESUMO

Visceral leishmaniasis (VL) is endemic in Asia, East and North Africa, South America, and Southern Europe, and is a major public health problem in the Indian subcontinent. Miltefosine received approval in 2002 to treat VL in India, and the Indian National Vector Borne Disease Control Programme later adopted a single dose (10 mg/kg) of liposomal amphotericin B. We report results of a randomized trial comparing the efficacy of combination therapy with an Indian preparation of liposomal amphotericin B (single dose of 7.5 mg/kg) and short-course miltefosine (2.5 mg/kg/day for 14 days; n = 66) in comparison to miltefosine monotherapy (2.5 mg/kg/day for 28 days; n = 78). Nine patients in the miltefosine group and three in the combination therapy group had to discontinue therapy because of serious adverse events. At the end of the therapy, the clinical and parasitological cure rate was 100% in both groups. By per-protocol analysis, by 6 months after completion of treatment, 12 of 69 patients in the miltefosine monotherapy arm (17.4%, 95% CI: 10.24-28%) and none in the combination therapy arm had relapse. Over 5 years of follow-up, 10 patients in the miltefosine monotherapy arm (all within 0.5-2 years after completing therapy) and none in the combination therapy arm experienced post-kala-azar dermal leishmaniasis. Combination therapy offered benefits over miltefosine monotherapy for VL in India.


Assuntos
Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Adolescente , Adulto , Idoso , Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Criança , Quimioterapia Combinada , Feminino , Humanos , Índia , Leishmania donovani , Masculino , Pessoa de Meia-Idade , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico , Adulto Jovem
14.
Int J Infect Dis ; 97: 27-29, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32425641

RESUMO

BACKGROUND: Visceral leishmaniasis-related hemophagocytic lymphohistiocytosis (VL-HLH) is a secondary hemophagocytic syndrome, which can be life-threatening, caused by leishmania and transmitted by infected sandflies. Rapid and accurate identification of leishmania is crucial for clinical strategies. CASE REPORT: Here, we report an infantile infection in a non-epidemic area of China. The infant was a 9.5-month-old girl with fever, pancytopenia and hepatosplenomegaly, which meet the HLH-2004 standard, and the negative gene results exclude congenital HLH. However, chemotherapy is ineffective and is accompanied by severe infection. Fortunately, she is diagnosed with VL-HLH (visceral leishmaniasis-related hemophagocytic lymphohistiocytosis), as leishmania is detected by next-generation meta-genome sequencing (mNGS) and quickly relieved after treatment with libosomal amphotericin B (L-AMB). CONCLUSION: mNGS can detect leishmania in pediatric HLH, and should be performed as a new detection for VL-HLH, particularly for infants, who may not respond to HLH-2004 regimen.


Assuntos
Leishmaniose Visceral/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Leishmania/isolamento & purificação , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/parasitologia
15.
Parasite Immunol ; 42(6): e12719, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32248547

RESUMO

AIMS: Visceral leishmaniasis (VL), caused by Leishmania donovani in India, is fatal if untreated, having serious concern of limited chemotherapeutic options. In this study, we evaluated antileishmanial efficacy of purified chlorogenic acid (CGA) against promastigotes and intracellular amastigotes infected into RAW264.7 macrophages. METHODS AND RESULTS: Chlorogenic acid was effective both on promastigotes (IC50  = 78.394 µmol/L, i.e. 27.75 µg/mL) and intracellular amastigotes (ED50  = 26.752 µmol/L, i.e. 9.47 µg/mL). In promastigotes, significant retardation in mitotic growth was caused both by cell-death and reduction of metabolic activity, evidenced by propidium-iodide uptake and MTT assay, respectively. Flow cytometric analysis revealed that retardation of mitotic growth was due to cell-cycle arrest at G1/S checkpoint. Complete clearance of amastigotes from infected RAW264.7 cells, assessed by microscopic counting, was achieved with 60 µmol/L (21.24 µg/mL) CGA for 24 hours, with negligible toxicity to host macrophages. This parasite clearing efficacy was comparable to 1.0 µg/mL (1.082 µmol/L) Amphotericin B, and 20 µmol/L Miltefosine, two standard antileishmanial drugs. Cytokine-ELISA revealed that elevated IL-10 production by infected macrophages was reduced after parasite clearance. Consequently, IL-12, TNF and NO (assayed by Griess test) production by macrophages were significantly increased after successful resolution of infection. CONCLUSION: Chlorogenic acid might emerge as a potential antileishmanial drug.


Assuntos
Antiprotozoários/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ácido Clorogênico/uso terapêutico , Citocinas/metabolismo , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Óxido Nítrico/metabolismo , Animais , Linhagem Celular , Índia , Leishmaniose Visceral/mortalidade , Leishmaniose Visceral/parasitologia , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Células RAW 264.7
16.
Am J Trop Med Hyg ; 102(6): 1319-1322, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32228792

RESUMO

The six previously reported civilian cases of mucosal leishmaniasis (ML) diagnosed in the United States have all represented imported New World ML. We describe two new patients with ML diagnosed in New York City-a Syrian immigrant with a nasal mass (Leishmania tropica), the first report of Old World ML in the United States, and an American ecologist who worked in Bolivia and had been treated for cutaneous infection 23 years before developing lesions (L. (Viannia) braziliensis) initially of the uvula, soft palate, and posterior pharynx and subsequently the larynx.


Assuntos
Leishmaniose Mucocutânea/epidemiologia , Leishmaniose Mucocutânea/patologia , Idoso , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Humanos , Leishmania braziliensis/isolamento & purificação , Leishmaniose Mucocutânea/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico
17.
Exp Parasitol ; 212: 107874, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32179068

RESUMO

Bulgaria is one of European countries where trichinellosis continues to be regularly diagnosed and registered. The clinical and epidemiological features of 72 cases of trichinellosis associated with five outbreaks caused by Trichinella spiralis and Trichinella britovi between 2009 and 2011, are described. At hospital admission, patients were often initially treated with antibiotics, without any improvement. A range of signs and symptoms were recorded, including: myalgia, elevated temperature, arthralgia, difficulty with movement, facial oedema, conjunctival hyperaemia, ocular haemorrhages, diarrhoea, skin rash, headache, and fatigue. Due to the variable clinical course of the disease, the diagnostic process for trichinellosis is often complex and difficult. This means the diagnosis may be established late for an appropriate treatment, potentially leading to a severe course of the disease with complications. Laboratory abnormalities were expressed by marked eosinophilia (97.2%), leucocytosis (70.8%), elevated serum creatine phosphokinase levels (82%), and antibody-positive results by ELISA and indirect hemagglutination. Patients were treated with albendazole (Zentel) 10 mg/kg for 7-10 days. In two outbreaks, the aetiological agent was T. spiralis, in one outbreak T. britovi, and an unknown Trichinella species in the fourth outbreak. The sources of infection were domestic pigs, probably fed with scraps and offal of wild game. In one outbreak, T. spiralis was also detected in brown rats trapped close to where the pig had been raised in the backyard. These epidemiological factors are relevant in considering implementation of targeted control programmes.


Assuntos
Surtos de Doenças , Doenças dos Suínos/epidemiologia , Doenças dos Suínos/parasitologia , Trichinella spiralis , Triquinelose/epidemiologia , Adolescente , Adulto , Idoso , Albendazol/uso terapêutico , Animais , Antiprotozoários/uso terapêutico , Bulgária/epidemiologia , Criança , Creatina Quinase/sangue , Surtos de Doenças/prevenção & controle , Eosinofilia , Feminino , Humanos , Masculino , Carne/parasitologia , Produtos da Carne/parasitologia , Pessoa de Meia-Idade , Ratos , Sus scrofa/parasitologia , Suínos , Doenças dos Suínos/diagnóstico , Doenças dos Suínos/prevenção & controle , Trichinella/isolamento & purificação , Trichinella spiralis/isolamento & purificação , Triquinelose/sangue , Triquinelose/diagnóstico , Triquinelose/prevenção & controle , Ursidae/parasitologia , Adulto Jovem
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.
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
20.
PLoS Negl Trop Dis ; 14(2): e0007996, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32092059

RESUMO

BACKGROUND: Cutaneous leishmaniasis (CL) is a disease that often affects exposed skin areas and may heal leaving lifelong scars. Patients' expectations from treatment are rarely considered in drug development for CL. An initiative aiming to address shortcomings in clinical trial design and conduct for CL treatments involving the researchers' community is on-going. This manuscript presents patient-preferred outcomes for CL and an assessment on how to consider these in the conduct of future trials. METHODOLOGY/PRINCIPAL FINDINGS: We report preferred treatment outcomes by 74 patients with confirmed CL in endemic regions of Brazil, Burkina Faso, Colombia, Iran, Morocco, Peru and Tunisia during individual in-depth interviews. Beyond outcomes customarily considered in trials (such as lesion appearance and adverse events), patients talked about a large number of outcomes related to quality of life, such as pain, scar formation, and others affecting their work and daily activities. They also reported fears around getting rid of the parasite, disease recurrence, and possible sequelae. CONCLUSIONS/SIGNIFICANCE: The study results provide a rich insight into important outcomes for CL treatments, as well as related topics, from the perspective of a diverse patient population. Among the outcomes identified, we argue that those related to quality of life as well as recurrence should be included to a greater extent for assessment in clinical trials, and discuss the suitability of measurement instruments such as the Dermatology Quality of Life Index (DLQI). Interviews also point out the potential need to address concerns related to parasitological cure or scar formation, such as social stigmatization and disability. In addition, patients should be given information in order to clarify reported misconceptions. This study therefore suggests a methodology for consulting CL patients on outcomes as elements of clinical trial design, and how to incorporate these outcomes in trials. It also discusses how reported outcomes could be addressed in clinical care.


Assuntos
Antiprotozoários/uso terapêutico , Saúde Global , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Preferência do Paciente , Coleta de Dados , Humanos , Pesquisa Qualitativa , Qualidade de Vida , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA