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1.
Int J Nanomedicine ; 14: 5187-5199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371955

RESUMO

Introduction and objective: Previous studies indicate that miltefosine (MFS) may be an alternative as an antifungal agent; however, it presents several adverse effects. Thus, the aim of this study was to produce miltefosine-loaded alginate nanoparticles (MFS.Alg) for toxicity reduction to be used as an alternative for the treatment of cryptococcosis and candidiasis. Methods: Alginate nanoparticles were produced using the external emulsification/gelation method, and their physicochemical and morphological characteristics were analyzed. MFS encapsulation efficiency, release assay and toxicity on red blood cells and on Galleria mellonella larvae were assessed. The antifungal activity was evaluated using in vitro and in vivo larval models of G. mellonella infected with Candida albicans (SC5314 and IAL-40), Cryptococcus neoformans H99 and Cryptococcus gattii ATCC 56990. The treatment efficacy was evaluated by survival curve, colony forming unit (CFU) counting and histopathological analysis. Results: MFS.Alg nanoparticles presented a mean size of 279.1±56.7 nm, a polydispersity index of 0.42±0.15 and a zeta potential of -39.7±5.2 mV. The encapsulation efficiency of MFS was 81.70±6.64%, and its release from the nanoparticles occurred in a sustained manner. MFS in alginate nanoparticles presented no hemolytic effect and no toxicity in G. mellonella larvae. Treatment with MFS.Alg extended the survival time of larvae infected with C. albicans and C. gattii. In addition, the fungal burden reduction was confirmed by CFU and histopathological data for all groups treated with 200 mg/Kg of MFS.Alg. Conclusion: These results support the use of alginate-based drug delivery systems as carriers for MFS for drug toxicity reduction and control of the fungal infection in the in vivo model of G. mellonella.


Assuntos
Alginatos/química , Candidíase/tratamento farmacológico , Criptococose/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Fosforilcolina/análogos & derivados , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/microbiologia , Criptococose/microbiologia , Liberação Controlada de Fármacos , Larva/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nanopartículas/ultraestrutura , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Fosforilcolina/toxicidade , Ovinos
2.
Chem Biol Interact ; 310: 108731, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265827

RESUMO

Lung cancer is one of the most common and lethal types of oncological diseases. Despite the advanced therapeutic approaches, the prognosis for lung cancer still remains poor. Apparently, there is an imperative need for more efficient therapeutic strategies. In this work we report that concurrent treatment of human adenocarcinoma A549 cells with specific concentrations of two antitumor agents, the sphingosine kinase 1 inhibitor N, N dimethylsphingosine (DMS) and the alkylphosphocholine miltefosine, induced synergistic cytotoxic effect, which was confirmed by calculation of the combination index. The simultaneous action of these agents, induced significant decrease of A549 cell number, as well as pronounced morphological alterations. Combined drugs caused substantial apoptotic events, and significant reduction of the pro-survival marker sphingosine- 1-phosphate (S1P), when compared to the individual treatments with each of the anticancer drugs alone. Miltefosine is known to affect the synthesis of choline-containing phospholipids, including sphingomyelin, but we report for the first time that it also reduces S1P. Here we suggest a putative mechanism underlying the effect of miltefosine on sphingosine kinase 1, involving miltefosine-induced inhibition of protein kinase C. In conclusion, our findings provide a possibility for treatment of lung cancer cells with lower concentrations of the two antitumor drugs, DMS and miltefosine, which is favorable, regarding their potential cytotoxicity to normal cells.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Apoptose/efeitos dos fármacos , Fosforilcolina/análogos & derivados , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Adenocarcinoma de Pulmão/patologia , Protocolos de Quimioterapia Combinada Antineoplásica , Sinergismo Farmacológico , Humanos , Lisofosfolipídeos/análise , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Esfingosina/análogos & derivados , Esfingosina/análise
3.
Mymensingh Med J ; 28(2): 328-332, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31086147

RESUMO

Post Kala-azar Dermal Leishmaniasis (PKDL) is the sequel of visceral leishmaniasis in Indian subcontinent and may appear among patients with or without previous history of visceral leishmaniasis (VL). The aim of the study is to understand the male reproductive safety profile of miltefosine used for the treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) in Bangladesh. From January 2017 to March 2017, an exploratory study was carried out on male fertility capacity in Bangladesh among male patients above 14 years old with PKDL treated with miltefosine. Twenty nine male patients were included to observe the effect of miltefosine on reproductive health. All PKDL patients had history of visceral leishmaniasis (VL) in different time periods. Among them three (10.3%) patients were unable to ejaculate semen. In semen analysis, 3 patients (10.3%) were found azoospermia (sperm count & motility- 0, viscosity- good, pH- 7 to 8), microscopically there was presence of RBC (5-15/HPF), WBC (8-15/HPF). Another 3 patients (10.3%) were found oligospermia (sperm count- 4.2 to 15.3 million/ml, motility- 20 to 50%, viscosity- good, pH- 6 to 9, RBC- 4 to 15/HPF, WBC- 4 to 15/HPF). The study documented some important findings in evaluating male infertility and selection of drug regimens in treating PKDL patients with miltefosine for 12 weeks.


Assuntos
Antiprotozoários/uso terapêutico , Infertilidade Masculina/induzido quimicamente , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Adolescente , Antiprotozoários/efeitos adversos , Bangladesh , Fertilidade , Humanos , Masculino , Fosforilcolina/efeitos adversos , Fosforilcolina/uso terapêutico , Resultado do Tratamento
4.
Acta Trop ; 196: 142-149, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103698

RESUMO

Herein, we investigated the efficacy of liposomes for the topical delivery of miltefosine (ML) to treat cutaneous leishmaniasis (CL). Liposomes containing varying concentrations of ML (0.5, 1, 2 and 4%) were prepared and characterized by their size and entrapment efficiency. The liposome diameters were between 100-150 nm. The penetration of ML from liposomal formulations through and in the skin was assessed using ex-vivo Franz diffusion cells fitted with mouse skin at 37 °C for 24 h. Data indicated that Lip-ML-4% showed the highest percent of retention across mouse skin (82%). in vitro promastigote and amastigote assays showed that ML and Lip-ML inhibit the growth of parasites either in the culture medium or intracellularly. Lip-ML formulations were topically applied twice a day for 4 weeks to the skin of BALB/c mice infected with L. major. Results showed a significantly (p < 0.001) smaller lesion size in Lip-ML-2 and 4% when compared to controls. At week 8 post-infection, the number of parasites was higher in Lip-ML-0.5% compared to Lip-ML-2 and 4%, however, the difference was not significant. At week 12, the splenic parasite burden was significantly (p < 0.001) lower in mice treated with different Lip-ML formulations when compared to controls. The lesion parasite burden was significantly (p < 0.001) lower in mice treated with either Lip-ML-2 and 4% compared to Lip-ML-0.5% at week 12 post-infection. The results suggested that topical Lip-ML-4% showed optimal ex-vivo penetration and in vivo anti-leishmanial activity against CL caused by L. major when compared to ML cream and other liposomes and thus, merits further investigation.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania major , Leishmaniose Cutânea/parasitologia , Fosforilcolina/análogos & derivados , Administração Tópica , Animais , Antiprotozoários/administração & dosagem , Lipossomos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico , Pele/patologia , Baço/parasitologia
5.
Exp Parasitol ; 201: 57-66, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004571

RESUMO

In the present study, we investigated the in vitro and in vivo leishmanicidal activity of synthetic compounds, containing a semicarbazone scaffold as a peptide mimetic framework. The leishmanicidal effect against amastigotes of Leishmania amazonensis was also evaluated at concentration of 100 µM-0.01 nM. The derivatives 2e, 2f, 2g and 1g, beyond the standards miltefosine and pentamidine, significantly diminished the number of L. amazonensis amastigotes in macrophages. These derivatives were also active against amastigotes of L. braziliensis. As 2g presented potent leishmanicidal activity against the amastigotes of L. amazonensis in macrophages, we also investigated the in vivo leishmanicidal activity of this compound against L. amazonensis. Approximately 105L. amazonensis promastigotes were subcutaneously inoculated into the dermis of the right ear of BALB/c mice, which were subsequently treated with 2g (p.o. or i.p.), miltefosine (p.o.) or glucantime (i.p.) at 30 µmol/kg/day x 28 days. Thus, a similar reduction in the lesion size was observed after the administration of 2g through oral (63.7 ±â€¯10.1%) and intraperitoneal (61.8 ±â€¯3.7%) routes. A larger effect was observed after treatment with miltefosine (97.7 ±â€¯0.4%), and glucantime did not exhibit activity at the dose administered. With respect to the ear parasite load, 2g diminished the number of parasites by p.o. (30.5 ±â€¯5.1%) and i.p. (33.3 ±â€¯4.3%) administration. In addition, 2g induced in vitro apoptosis, autophagy and cell cycle alterations on L. amazonensis promastigotes. In summary, the derivative 2g might represent a lead candidate for antileishmanial drugs, as this compound displayed pronounced leishmanicidal activity.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Semicarbazonas/uso terapêutico , Análise de Variância , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Caspases/análise , Ciclo Celular , Linhagem Celular , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Feminino , Citometria de Fluxo , Concentração Inibidora 50 , Macrófagos/parasitologia , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos BALB C , Pentamidina/química , Pentamidina/farmacologia , Pentamidina/uso terapêutico , Fosfolipídeos/metabolismo , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Semicarbazonas/química , Semicarbazonas/farmacologia
6.
Epidemiol Health ; 41: e2019011, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30999735

RESUMO

Cutaneous leishmaniasis (CL) is most common form of leishmaniasis and is characterized by ulcerative skin lesions. The objective of this study was to conduct a systematic review and meta-analysis of clinical trials that compared the efficacy of miltefosine and glucantime for the treatment of CL. We searched the following databases: Cochrane, PubMed, Embase, Scopus, Web of Science, ProQuest, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform search portal of World Health Organization, Sid, Irandoc, Magiran, and clinicaltrials.gov. We used keywords including "miltefosine," "glucantime," and "Leishmania." The quality of studies was assessed using the Cochrane risk of bias tool. A random-effects model was employed for the analysis. We assessed heterogeneity by the chi-square test and the I2 index statistic. When heterogeneity was present, meta-regression analyses were performed. The Egger method was used to assess publication bias; when it was significant, the trim-and-fill method was used to test and adjust for publication bias. A total of 1,570 reports were identified, of which 10 studies were included in the meta-analysis. In the meta-analysis, there was no significant difference between the efficacy of miltefosine and glucantime; however, subgroup analysis showed that, regarding parasite species other than Leishmania braziliensis, miltefosine was significantly superior to glucantime (intention to treat; relative risk, 1.15; 95% confidence interval, 1.01 to 1.32). In the meta-regression, only the glucantime injection type was significant at the p=0.1 level. The Egger test found statistically significant publication bias; however, including the 3 missing studies in the trim-and-fill analysis did not change the results. This meta-analysis found that miltefosine seems to be more effective than glucantime, at least in species other than L. braziliensis, for treating CL.


Assuntos
Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/uso terapêutico , Fosforilcolina/análogos & derivados , Humanos , Ensaios Clínicos Controlados não Aleatórios como Assunto , Fosforilcolina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
7.
Vet J ; 245: 22-28, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30819422

RESUMO

The objective of this study was to compare changes in serum concentrations of acute phase proteins (APPs) and paraoxanase (PON-1) in response to two treatments in dogs with leishmaniosis (CanL). For this purpose, 20 dogs with CanL were assigned to two treatment groups: antimonial plus allopurinol (Group G, n=12) and miltefosine plus allopurinol (Group M, n=8). Serum concentrations of PON-1 and APPs including C-reactive protein, haptoglobin (Hp), ferritin (Ft) and albumin were monitored over a period of 3 months after treatment. At the beginning of the study (day 0), most of the dogs had APP abnormalities. None of the variables differed significantly between groups in the first or subsequent visits. There was a significantly higher reduction in serum Ft in Group G than in Group M from day 0 to day 30 (P=0.0085), and also from day 0 to day 90 (P=0.0214). There was a higher increase in serum PON-1 in Group G than in than Group M from day 0 to day 30 (P=0.0039), and also from day 0 to day 90 (P=0.0404). This is the first report of APPs in dogs with natural clinical leishmaniosis treated with miltefosine. There was faster resolution of serum APP concentrations in dogs treated with antimonials (P<0.05).


Assuntos
Proteínas da Fase Aguda/análise , Antiprotozoários/uso terapêutico , Doenças do Cão/sangue , Doenças do Cão/tratamento farmacológico , Leishmaniose Visceral/veterinária , Alopurinol/uso terapêutico , Animais , Arildialquilfosfatase/análise , Cães , Leishmania infantum , Leishmaniose Visceral/sangue , Leishmaniose Visceral/tratamento farmacológico , Antimoniato de Meglumina/uso terapêutico , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico
9.
PLoS Negl Trop Dis ; 13(2): e0007173, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30742620

RESUMO

BACKGROUND: Miltefosine (MF) is the only oral drug available for treatment of visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). Although the drug is effective and well tolerated in treatment of VL, the efficacy and safety of MF for longer treatment durations (>28 days) in PKDL remains unclear. This study provides an overview of the current knowledge about safety and efficacy of long treatment courses with MF in PKDL, as a strategy in the VL elimination in South Asia. METHODOLOGY/PRINCIPAL FINDINGS: Literature was searched systematically for articles investigating MF treatment in PKDL. A meta-analysis included eight studies (total 324 PKDL patients) to estimate the efficacy of MF in longer treatment regimens (range 6-16 weeks). We found a per-protocol (PP) initial cure rate of 95.2% (95%CI 89.6-100.8) and a PP definite cure rate of 90% (95%CI 81.6-96.3). Descriptive analysis showed that 20% of patients experienced adverse events, which mostly had an onset in the first week of treatment and were likely to get more severe after four weeks of treatment. Gastrointestinal (GI) side effects such as vomiting, nausea, diarrhoea, and abdominal pain were most common. CONCLUSIONS/SIGNIFICANCE: Longer treatment regimens with MF are effective in PKDL patients in India, however with the caveat that the efficacy has recently been observed to decline. GI side effects are frequent, although mostly mild or moderate. However, on the basis of limited data, we cannot conclude that longer MF treatment regimens are safe. Moreover, VL and PKDL pharmacovigilance studies indicate a risk for serious adverse events, questioning the safety of MF. The provision of safer treatment regimens for PKDL patients are therefore recommended. Until these regimens are identified, it should be considered to halt the use of MF monotherapy for PKDL in order to preserve the drug's efficacy.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/etiologia , Leishmaniose Visceral/complicações , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Ásia/epidemiologia , Humanos , Leishmaniose Cutânea/epidemiologia , Leishmaniose Visceral/epidemiologia , Fosforilcolina/uso terapêutico
10.
PLoS Negl Trop Dis ; 13(1): e0006988, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653490

RESUMO

BACKGROUND: Visceral leishmaniasis (VL) in human immunodeficiency virus (HIV) co-infected patients requires special case management. AmBisome monotherapy at 40 mg/kg is recommended by the World Health Organization. The objective of the study was to assess if a combination of a lower dose of AmBisome with miltefosine would show acceptable efficacy at the end of treatment. METHODOLOGY/PRINCIPAL FINDINGS: An open-label, non-comparative randomized trial of AmBisome (30 mg/kg) with miltefosine (100 mg/day for 28 days), and AmBisome monotherapy (40 mg/kg) was conducted in Ethiopian VL patients co-infected with HIV (NCT02011958). A sequential design was used with a triangular continuation region. The primary outcome was parasite clearance at day 29, after the first round of treatment. Patients with clinical improvement but without parasite clearance at day 29 received a second round of the allocated treatment. Efficacy was evaluated again at day 58, after completion of treatment. Recruitment was stopped after inclusion of 19 and 39 patients in monotherapy and combination arms respectively, as per pre-specified stopping rules. At D29, intention-to-treat efficacy in the AmBisome arm was 70% (95% CI 45-87%) in the unadjusted analysis, and 50% (95% CI 27-73%) in the adjusted analysis, while in the combination arm, it was 81% (95% CI 67-90%) and 67% (95% CI 48-82%) respectively. At D58, the adjusted efficacy was 55% (95% CI 32-78%) in the monotherapy arm, and 88% (95% CI 79-98%) in the combination arm. No major safety concerns related to the study medication were identified. Ten SAEs were observed within the treatment period, and 4 deaths unrelated to the study medication. CONCLUSIONS/SIGNIFICANCE: The extended treatment strategy with the combination regimen showed the highest documented efficacy in HIV-VL patients; these results support a recommendation of this regimen as first-line treatment strategy for HIV-VL patients in eastern Africa. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov NCT02011958.


Assuntos
Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Adulto , Antirretrovirais/uso terapêutico , Coinfecção/tratamento farmacológico , Coinfecção/virologia , Quimioterapia Combinada , Etiópia , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Leishmania donovani/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Carga Parasitária , Fosforilcolina/uso terapêutico , Resultado do Tratamento , Adulto Jovem
12.
Trop Med Int Health ; 24(4): 380-391, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30681239

RESUMO

OBJECTIVES: Meglumine antimoniate (MA; Glucantime®), the 80-year-old first-line systemic treatment for all forms of American tegumentary leishmaniasis (ATL) caused by Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis and Leishmania (Leishmania) amazonensis, is highly toxic, presents adverse side-effects and may not attain clinical and parasitological cure. This critical review examines the necessity for intramuscular/intravenous administration of MA, the alternatives to this approach, and the possibilities of developing affordable, accessible and non-toxic drugs or new delivery methods. METHOD: PubMed searches were performed using the terms 'cutaneous leishmaniasis' or 'American tegumentary leishmaniasis' in combination with 'meglumine antimoniate' or 'N-methyl glucamine' or 'drug repositioning' or 'nanotechnology'. Searches covered a period of 20 years of peer reviewed journals and technical bulletins. We explored the mode of action, pharmacokinetics, toxicity and efficacy of MA, evaluated the progress of ATL therapy in Brazil, and examined the potential of drug repositioning and nanotechnology in accelerating the introduction and/or optimisation of an alternative treatment. RESULTS: The evidence suggests that ATL therapy will continue to rely on systemic MA in the foreseeable future even though an intralesional subcutaneous route has evolved over the last 10 years. The chances of developing a novel drug for ATL or a new mode of delivery of MA are low. While MA nanocarriers afford a promising approach, this technology is still in its infancy. A more immediate solution would be the production of a bioequivalent of miltefosine, an efficacious oral agent no longer protected by patent. CONCLUSION: Development of a contemporary treatment requires governmental commitment in bringing together private and public sectors.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/uso terapêutico , Fosforilcolina/análogos & derivados , Antiprotozoários/administração & dosagem , Antiprotozoários/efeitos adversos , Brasil , Humanos , Leishmania braziliensis , Leishmania guyanensis , Leishmaniose Cutânea/parasitologia , Antimoniato de Meglumina/administração & dosagem , Antimoniato de Meglumina/efeitos adversos , Patentes como Assunto , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico
13.
Artigo em Inglês | MEDLINE | ID: mdl-30578864

RESUMO

Leishamaniasis is a neglected disease caused by over 20 Leishmania species, occurring in more than a hundred countries. Miltefosine (hexadecylphosphocholine) is the single oral drug used in treatment for leshmaniases, including cases of infections resistant to pentavalent antimony. Our group has recently demonstrated the ability of miltefosine to cause genomic lesions by DNA oxidation. Acknowledging that antioxidant compounds can potentially modulate Reactive Oxygen Species (ROS), our study verified whether ascorbic acid reduces the genotoxic and mutagenic effects caused by miltefosine, and whether it interferes with drug efficacy. For this purpose, uninfected Swiss mice received simultaneous (single dose treatment) miltefosine and ascorbic acid (gavage and intraperitoneally), besides pre and post treatments (ascorbic acid 24 h before and after drug administration); furthermore, Balb/c mice infected with Leishmania infantum received miltefosine plus ascorbic acid (repeated doses treatment). We conducted comet assays, micronucleus tests, dosages of superoxide dismutase enzyme and parasitic burden by the limiting dilution assay. We observed that ascorbic acid administered intraperitoneally displayed a protective effect over damage caused by miltefosine. However, this effect was not not observed when the same doses were administered via gavage, possibly due to low serum levels of this antioxidant. Ascorbic acid's protective effect reinforces that miltefosine damages DNA by oxidizing its nitrogenous bases, which is reduced by ascorbic acid due to its ability of protecting genetic material from the action of ROS. Therefore, our results show that this drug is efficient in reducing parasitic burden of L. infantum.


Assuntos
Antiprotozoários/efeitos adversos , Ácido Ascórbico/administração & dosagem , Dano ao DNA/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Fosforilcolina/análogos & derivados , Animais , Antiprotozoários/uso terapêutico , Injeções Intraperitoneais , Leishmania infantum/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Fosforilcolina/efeitos adversos , Fosforilcolina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
14.
PLoS Negl Trop Dis ; 12(12): e0006986, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30550538

RESUMO

BACKGROUND: Case management in children with cutaneous leishmaniasis (CL) is mainly based on studies performed in adults. We aimed to determine the efficacy and harms of interventions to treat CL in children. METHODS: We conducted a systematic review of clinical trials and cohort studies, assessing treatments of CL in children (≤12 years old). We performed structured searches in PubMed, CENTRAL, LILACS, SciELO, Scopus, the International Clinical Trials Registry Platform (ICTRP), clinicaltrials.gov and Google Scholar. No restrictions regarding ethnicity, country, sex or year of publication were applied. Languages were limited to English, Spanish and Portuguese. Two reviewers screened articles, completed the data extraction and assessment of risk of bias. A qualitative summary of the included studies was performed. RESULTS: We identified 1092 records, and included 8 manuscripts (6 Randomized Clinical Trials [RCT] and 2 non-randomized studies). Most of the articles excluded in full-text review did not report outcomes separately for children. In American CL (ACL), 5 studies evaluated miltefosine and/or meglumine antimoniate (MA). Their efficacy varied from 68-83% and 17-69%, respectively. In Old-World CL (OWCL), two studies evaluated systemic therapies: rifampicin and MA; and one study assessed efficacy of cryotherapy (42%, Per Protocol [PP]) vs intralesional MA (72%, PP). Few studies (4) provided information on adverse events (AEs) for children, and no serious AEs were reported in participants. Risk of bias was generally low to unclear in ACL studies, and unclear to high in OWCL studies. CONCLUSION: Information on efficacy of treatment for CL in children is scarce. There is an unmet need to develop specific formulations, surveillance of AEs, and guidelines both for the management of CL and clinical trials involving the pediatric population. REGISTRATION: The protocol of this review was registered in the PROSPERO International register of systematic reviews, number CRD42017062164.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Leishmania/genética , Leishmania/fisiologia , Leishmaniose Cutânea/parasitologia , Antimoniato de Meglumina/uso terapêutico , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Rifampina/uso terapêutico
15.
Immunol Res ; 66(6): 637-641, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30554380

RESUMO

The distinction that in areas where helminthic infections are common, autoimmune diseases are less prevalent, led to the investigation of immune modulatory properties of helminths and their derivatives. Such are phosphorylcholine (PC) moieties which are a component of secreted products of helminths. PC has been broadly studied for its attenuating effects on the human immune system. In an attempt to develop a novel therapeutic small molecule for the treatment of autoimmune conditions, we have conjugated PC with tuftsin, a natural immunomodulatory tetrapeptide, to create TPC. Herein, we review our findings regarding the effects of TPC in murine models of three autoimmune diseases-systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and rheumatic arthritis (RA), as well as ex-vivo samples from giant cell arteritis (GCA) patients. In all four disease models examined, TPC was shown to attenuate the inflammatory response by reducing expression of pro-inflammatory cytokines and altering the phenotype of T cell expression. In murine models, TPC has further produced a significant improvement in clinical disease scores with no significant side effects noted. Our findings suggest TPC presents promising potential as a novel therapeutic agent for the effective treatment of various autoimmune conditions.


Assuntos
Autoimunidade/efeitos dos fármacos , Helmintos/efeitos dos fármacos , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Tuftsina/farmacologia , Tuftsina/uso terapêutico , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/parasitologia , Helmintíase/tratamento farmacológico , Helmintíase/parasitologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/parasitologia
16.
Chem Biol Interact ; 293: 141-151, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30098941

RESUMO

Leishmaniases are infectious diseases, caused by protozoa of the Leishmania genus. These drugs present high toxicity, long-term administration, many adverse effects and are expensive, besides the identification of resistant parasites. In this work, the antileishmanial activity of quinoline derivative salts (QDS) was evaluated, as well as the toxicity on mammalian cells and the mechanism of action of the most promising compound. Among the compound tested, only the compound QDS3 showed activity against promastigotes and amastigotes of Leishmania spp., being more active against the intracellular amastigotes of L. amazonensis-GFP (IC50 of 5.48 µM). This value is very close to the one observed for miltefosine (IC50 of 4.05 µM), used as control drug. Furthermore, the compound QDS3 exhibited a selective effect, being 40.35 times more toxic to the amastigote form than to the host cell. Additionally, promastigotes of L. amazonensis treated with this compound exhibited characteristics of cells in the process of apoptosis such as mitochondrial membrane depolarization, mitochondrial swelling, increase of ROS production, phosphatidylserine externalization, reduced and rounded shape, and cell cycle alteration. The integrity of the plasma membrane remained unaltered, excluding necrosis in treated promastigotes. The compound QDS3 inhibited the formation of autophagic vacuoles, which may have contributed to parasite death by preventing autophagic mechanisms in the removal of damaged organelles, intensifying the damage caused by the treatment, highlighting the antileishmanial effect of this compound. In addition, treatment with QDS3 induced increased ROS levels in L. amazonensis-infected macrophages, but not in uninfected host cell. These data reinforce that the induction of oxidative stress is one of the main toxic effects caused by the treatment with the compound QDS3 in L. amazonensis, causing irreversible damage and triggering a selective death of intracellular parasites. Data shown here confirm the biological activity of quinoline derivatives and encourage future in vivo studies with this compound in the murine model.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Feminino , Leishmania/crescimento & desenvolvimento , Leishmania/metabolismo , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Leishmaniose/patologia , Leishmaniose/veterinária , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilserinas/metabolismo , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Quinolinas/química , Quinolinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Sais/química
17.
Acta Trop ; 185: 69-76, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29733808

RESUMO

Leishmaniasis is a group of parasitic disease caused by protozoa of Leishmania genus. Leishmania major accounts for the cutaneous leishmaniasis (CL). The current treatments of this disease are expensive with high toxicity and are associated to difficulties of healing and parasite resistance. Miltefosine and ketoconazole have been found to be effective against CL. In this study, miltefosine- and ketoconazole-loaded nanoniosomes were prepared by the thin film-hydration method, and their anti-leishmanial effects against Leishmania major promastigotes and amastigotes were evaluated. The particle size and zeta potential of the nanoniosomes were determined. Release from the formulations showed enhanced and controlled dissolution of the drugs. The miltefosine- and ketoconazole-loaded nanoniosomes inhibited the growth of promastigote and amastigote forms of Leishmania major in vitro after 48 h of incubation and had IC50 values of 53.39 ±â€¯0.02 and 86.38 ±â€¯0.07 µg mL-1, respectively. The formulations provided improved anti-leishmanial activities for the treatment of cutaneous leishmaniasis.


Assuntos
Antiprotozoários/uso terapêutico , Cetoconazol/uso terapêutico , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Nanoestruturas , Fosforilcolina/análogos & derivados , Animais , Antiprotozoários/farmacologia , Cetoconazol/farmacologia , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico
18.
Exp Parasitol ; 187: 12-21, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29518448

RESUMO

Plant products are an important source of bioactive agents against parasitic diseases, including leishmaniasis. Among these products, vegetable oils have gained ground in the pharmaceutical field. Here we report the development of nanoemulsions as a delivery system for copaiba and andiroba oils (nanocopa and nanoandi) in order to test their effects on Leishmania infantum and L. amazonensis. The nanocopa and nanoandi had an average particle size of 76.1 and 88.1, respectively with polydispersity index 0.14 to 0.16 and potential zeta -2.54 to -3.9. The data indicated toxic activity of nanocopa and nanoandi against promastigotes of both Leishmania species ultrastructural analyses by scanning electron microscopy revealed that exposition to nanoemulsions induced oval cell shape and retracted flagella. The treatment with nanocopa and nanoandi led to a reduction in L. infantum and L. amazonensis infection levels in macrophage cultures. The nanoemulsions treatment have significant beneficial effects on all the parameters evaluated in lesions induced by L. amazonensis (lesion size, parasite burden and histopathology) on BALB/c mice. The treatment of L. infantum-infected BALB/c mice with nanoemulsions also showed promising results reducing parasite burden in spleen and liver and improving histopathological features.


Assuntos
Fabaceae/química , Leishmania infantum/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Óleos Voláteis/administração & dosagem , Animais , Antiprotozoários/uso terapêutico , Emulsões , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Concentração Inibidora 50 , Intestinos/patologia , Rim/patologia , Leishmania infantum/ultraestrutura , Leishmania mexicana/ultraestrutura , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Nanopartículas/ultraestrutura , Óleos Voláteis/química , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Estômago/patologia
19.
PLoS Negl Trop Dis ; 12(1): e0006082, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29324838

RESUMO

This article reviews essential topics of canine visceral leishmaniasis (CVL) due to Leishmania infantum infection. It focuses on the current serological and molecular diagnostic methods used in epidemiological research and veterinary clinics to diagnose CVL and includes new point-of-care (POC) tests under development. The efficacy of different treatment regimens on the clinical improvement and infectiousness of dogs is also addressed. In the last section, the review provides a critical appraisal of the effectiveness of different control measures that have been implemented to curb disease transmission.


Assuntos
Antiprotozoários/uso terapêutico , Doenças do Cão/diagnóstico , Doenças do Cão/tratamento farmacológico , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/veterinária , Técnicas de Diagnóstico Molecular , Alopurinol/uso terapêutico , Animais , Reservatórios de Doenças/parasitologia , Reservatórios de Doenças/veterinária , Doenças do Cão/parasitologia , Cães , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/parasitologia , Meglumina/uso terapêutico , Antimoniato de Meglumina , Compostos Organometálicos/uso terapêutico , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Sistemas Automatizados de Assistência Junto ao Leito , Testes Sorológicos
20.
Clin Microbiol Infect ; 24(6): 591-598, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29138100

RESUMO

OBJECTIVES: To evaluate the evidence for use of different formulations of amphotericin B (AmB), minimum effective dose for each formulation and its comparative efficacy against other drugs in achieving definitive cure of visceral leishmaniasis. METHODS: This systematic review and meta-analysis included following data sources: PubMed, Embase, Scopus, Web of Science and CINAHL. Controlled prospective clinical trials (randomized or nonrandomized, including dose-ranging studies) conducted between 1996 and 2017 with at least one treatment group receiving AmB were included (published data only). The primary outcome was definitive cure at 6 months. Adverse events and mortality were assessed as secondary outcomes. The PROSPERO registration number for this review is CRD42017067488. RESULTS: Thirty-one studies (26 from India) that enrolled 6903 patients into 84 study groups met the selection criteria. In India, liposomal AmB was not inferior to AmB deoxycholate (relative risk 1.00, 95% confidence interval (CI) 0.96-1.03, two randomized controlled trials (RCTs), 514 participants, high-quality evidence), and a single dose of the earlier formulation as low as 3.75 mg/kg achieved a cure rate of over 89% (95% CI 70.6-97.2). AmB deoxycholate was as effective as miltefosine (relative risk 0.99, 95% CI 0.95-1.03, two trials, 523 participants, high-quality evidence) and may be better than paromomycin (relative risk 1.04, 95% CI 1.02-1.07, one trial, 667 participants, low-quality evidence) in achieving definitive cure. CONCLUSIONS: AmB is an efficacious drug in the Indian subcontinent. Further evidence is needed from prospective clinical trials in other endemic geographical regions.


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Visceral/tratamento farmacológico , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Ensaios Clínicos como Assunto , Ácido Desoxicólico/administração & dosagem , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Composição de Medicamentos , Medicina Baseada em Evidências , Feminino , Humanos , Masculino , Paromomicina/administração & dosagem , Paromomicina/uso terapêutico , Fosforilcolina/administração & dosagem , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento
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