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1.
Exp Parasitol ; 206: 107730, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494215

RESUMO

Phospholipids are the main component of membranes and are responsible for cell integrity. Alkylphospholipid analogues (APs) were first designed as antitumoral agents and were later tested against different cell types. Trypanosoma cruzi, the Chagas disease etiological agent, is sensitive to APs (edelfosine, miltefosine and ilmofosine) in vitro. We investigated the effect of synthetic ring substituted AP against epimastigotes, amastigotes and trypomastigotes. TCAN26, could inhibit the in vitro growth of epimastigotes and amastigotes with the 50% inhibitory concentrations (IC50) in the nanomolar range. Trypomastigotes lysis was also induced with 24-h treatment and a LC50 of 2.3 µM. Ultrastructural analysis by electron microscopy demonstrated that TCAN26 mainly affected the parasite's membranes leading to mitochondrial and Golgi cisternae swelling, membrane blebs, and autophagic figures in the different parasite developmental stages. While the Golgi of the parasites was significantly affected, the Golgi complex of the host cells remained normal suggesting a specific mechanism of action. In summary, our results suggest that TCAN 26 is a potent and selective inhibitor of T. cruzi growth probably due to disturbances of phospholipid biosynthesis.


Assuntos
Adamantano/farmacologia , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Adamantano/química , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Autofagia/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Relação Dose-Resposta a Droga , Citometria de Fluxo , Complexo de Golgi/efeitos dos fármacos , Concentração Inibidora 50 , Dose Letal Mediana , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Microscopia Imunoeletrônica , Mitocôndrias/efeitos dos fármacos , Fosforilcolina/química , Tripanossomicidas/química , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura
2.
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
3.
Chem Commun (Camb) ; 55(61): 8919-8922, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270526

RESUMO

Cancer development is often associated with lipid metabolic reprogramming, including aberrant lipid accumulation. We create novel paradigms endowed with dual functions of anticancer activity and inhibition of lipid accumulation by conjugating the natural product quercetin and synthetic alkylphospholipid drugs, and harnessing the biomedical effects of both. These conjugates offer fresh perspectives in the search for anticancer candidates.


Assuntos
Fármacos Antiobesidade/farmacologia , Antineoplásicos/farmacologia , Éteres Fosfolipídicos/farmacologia , Fosforilcolina/análogos & derivados , Quercetina/análogos & derivados , Quercetina/farmacologia , Fármacos Antiobesidade/síntese química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Gotículas Lipídicas/metabolismo , Receptores X do Fígado/metabolismo , PPAR gama/metabolismo , Éteres Fosfolipídicos/síntese química , Fosforilcolina/síntese química , Fosforilcolina/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quercetina/síntese química , Transdução de Sinais/efeitos dos fármacos
4.
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
5.
Cornea ; 38(7): 914-917, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31170106

RESUMO

PURPOSE: Acanthamoeba keratitis is a rare, vision-threatening disease. Commercially available antiamoebics are poorly cysticidal and highly toxic, and therapeutic keratoplasties can be complicated by recurrence or graft failure. We aimed to discuss the use of oral miltefosine for treatment of recalcitrant Acanthamoeba keratitis. METHODS: A 44-year-old contact lens wearer presented with a 2-week history of red painful eye and decreasing vision. After poorly responding to topical corticosteroid on the presumptive diagnosis of anterior uveitis, she developed radial keratoneuritis. Corneal scraping was positive for Acanthamoeba. No clinical response to treatment was observed with topical chlorhexidine 0.02%, polyhexamethylene biguanide 0.02%, and oral voriconazole. She then underwent 2 therapeutic keratoplasties with prompt recurrence of the disease in the keratoplasty graft. RESULTS: Oral miltefosine was added to the treatment. She underwent a third penetrating keratoplasty 8 months later. The excised button was negative for amoeba. She continued miltefosine for 3 more months. No recurrence was observed after 30 months. CONCLUSIONS: This case shows resolution of recalcitrant Acanthamoeba keratitis with oral miltefosine in an immunocompetent patient. Further clinical evidence would be needed to possibly incorporate this medication in the antiamoebic armamentarium.


Assuntos
Ceratite por Acanthamoeba/tratamento farmacológico , Antiprotozoários/administração & dosagem , Fosforilcolina/análogos & derivados , Administração Oral , Adulto , Quimioterapia Adjuvante , Lentes de Contato Hidrofílicas/efeitos adversos , Feminino , Humanos , Ceratoplastia Penetrante , Fosforilcolina/administração & dosagem , Resultado do Tratamento
6.
Adv Mater ; 31(33): e1900727, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31125138

RESUMO

The central nervous system (CNS) plays a central role in the control of sensory and motor functions, and the disruption of its barriers can result in severe and debilitating neurological disorders. Neurotrophins are promising therapeutic agents for neural regeneration in the damaged CNS. However, their penetration across the blood-brain barrier remains a formidable challenge, representing a bottleneck for brain and spinal cord therapy. Herein, a nanocapsule-based delivery system is reported that enables intravenously injected nerve growth factor (NGF) to enter the CNS in healthy mice and nonhuman primates. Under pathological conditions, the delivery of NGF enables neural regeneration, tissue remodeling, and functional recovery in mice with spinal cord injury. This technology can be utilized to deliver other neurotrophins and growth factors to the CNS, opening a new avenue for tissue engineering and the treatment of CNS disorders and neurodegenerative diseases.


Assuntos
Barreira Hematoencefálica/metabolismo , Nanocápsulas/química , Fatores de Crescimento Neural/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Resinas Acrílicas/química , Animais , Materiais Biocompatíveis/química , Barreira Hematoencefálica/ultraestrutura , Reagentes para Ligações Cruzadas/química , Liberação Controlada de Fármacos , Injeções Intravenosas , Macaca mulatta , Metacrilatos/química , Camundongos Endogâmicos BALB C , Fatores de Crescimento Neural/administração & dosagem , Fatores de Crescimento Neural/sangue , Fatores de Crescimento Neural/líquido cefalorraquidiano , Células PC12 , Permeabilidade , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Poliésteres/química , Ratos , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
7.
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
8.
Parasit Vectors ; 12(1): 266, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133064

RESUMO

BACKGROUND: Currently, there is no satisfactory treatment for leishmaniases, owing to the cost, mode of administration, side effects and to the increasing emergence of drug resistance. As a consequence, the proteins involved in Leishmania apoptosis seem a target of choice for the development of new therapeutic tools against these neglected tropical diseases. Indeed, Leishmania cell death, while phenotypically similar to mammalian apoptosis, is very peculiar, involving no homologue of the key mammalian apoptotic proteins such as caspases and death receptors. Furthermore, very few proteins involved in Leishmania apoptosis have been identified. RESULTS: We identified a protein involved in Leishmania apoptosis from a library of genes overexpressed during Leishmania differentiation during which autophagy occurs. Indeed, the gene was overexpressed when L. major cell death was induced by curcumin or miltefosine. Furthermore, its overexpression increased L. major curcumin- and miltefosine-induced apoptosis. This gene, named LmjF.22.0600, whose expression is dependent on the expression of the metacaspase, another apoptotic protein, encodes a putative acetyltransferase. CONCLUSIONS: This new protein, identified as being involved in Leishmania apoptosis, will contribute to a better understanding of Leishmania death, which is needed owing to the absence of a satisfactory treatment against leishmaniases. It will also allow a better understanding of the original apoptotic pathways of eukaryotes in general, while evidence of the existence of such pathways is accumulating.


Assuntos
Acetiltransferases/genética , Apoptose , Leishmania major/enzimologia , Proteínas de Protozoários/genética , Acetiltransferases/isolamento & purificação , Caspases/genética , Curcumina/farmacologia , Leishmania major/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Proteínas de Protozoários/isolamento & purificação
9.
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
10.
PLoS Negl Trop Dis ; 13(4): e0007264, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31017892

RESUMO

Trypanosomatids are flagellated protozoan parasites that are very unusual in terms of cytoskeleton organization but also in terms of cell death. Most of the Trypanosomatid cytoskeleton consists of microtubules, forming different substructures including a subpellicular corset. Oddly, the actin network appears structurally and functionally different from other eukaryotic actins. And Trypanosomatids have an apoptotic phenotype under cell death conditions, but the pathways involved are devoid of key mammal proteins such as caspases or death receptors, and the triggers involved in apoptotic induction remain unknown. In this article, we have studied the role of the post-translational modifications, deglutamylation and polyglutamylation, in Leishmania. We have shown that Leishmania apoptosis was linked to polyglutamylation and hypothesized that the cell survival process autophagy was linked to deglutamylation. A balance seems to be established between polyglutamylation and deglutamylation, with imbalance inducing microtubule or other protein modifications characterizing either cell death if polyglutamylation was prioritized, or the cell survival process of autophagy if deglutamylation was prioritized. This emphasizes the role of post-translational modifications in cell biology, inducing cell death or cell survival of infectious agents.


Assuntos
Apoptose/efeitos dos fármacos , Leishmania/citologia , Microtúbulos/fisiologia , Processamento de Proteína Pós-Traducional , Actinas/metabolismo , Sobrevivência Celular , Curcumina/farmacologia , Citoesqueleto/fisiologia , Imunofluorescência , Leishmania/efeitos dos fármacos , Leishmania/genética , Peptídeo Sintases/genética , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia
11.
Mater Sci Eng C Mater Biol Appl ; 101: 696-706, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029363

RESUMO

Despite the tremendous acceptance of additively manufactured (AM) Titanium alloys (Ti6Al4V) in the field of biomedical engineering, the high surface roughness due to partially-melted particles (fabricated in selective laser melting (SLM) process), limits their uses as hip implants. The objective of this study, therefore, is to modify the SLM fabricated Ti6Al4V implant interfaces with 2-Methacryloyloxyethyl phosphorylcholine (MPC) polymer, in the hope of enhancing surface properties and preventing the attachment of the cell simultaneously without affecting the mechanical properties significantly. Three different monomer concentrations were examined to determine the influence of monomer concentrations on polymerisation rate, chain length, and surface properties of the implants. Samples grafted with 0.6 M monomer concentration showed more uniform surface and less surface roughness in comparison with other samples and untreated Ti6Al4V surfaces. 0.6 M monomer concentration was found to be the best option for grafting PMPC to the hip implant interfaces because of its improved surface morphology, surface roughness, polymerisation rate, penetration depth and hardness results. Moreover, cell study on optimal surfaces revealed that PMPC grafted surfaces prevent the implant interfaces from uncontrollable cell attachment which is of utmost importance in smoothing the motion of the hip implant under cyclic loading. Overall, the PMPC grafting demonstrated the potentiality of its application on SLM Ti6Al4V substrate for improved hip arthroplasty performance.


Assuntos
Fosforilcolina/química , Polímeros/química , Titânio/química , Artroplastia de Quadril/métodos , Humanos , Metacrilatos/química , Fosforilcolina/análogos & derivados
12.
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
13.
Rev Soc Bras Med Trop ; 52: e20180292, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30942258

RESUMO

INTRODUCTION: The treatment of mucosal leishmaniasis (ML) is difficult due to the toxicity and route of administration of standard drugs. Miltefosine is an oral agent used for leishmaniasis treatment; however, no data exist regarding its use for ML in Brazil. In this study, we aimed to evaluate the efficacy of miltefosine for ML treatment compared to that of pentavalent antimonial in a pilot study. METHODS: We performed a randomized clinical trial with two parallel groups. The tested intervention consisted of miltefosine 1.3-2 mg/kg/day (two capsules) for 28 days or intravenous 20 mg SbV/kg/day of meglumine antimoniate (N-MA) for 30 days. The final endpoint was defined as complete healing of the lesion four years after treatment. We also analyzed an early endpoint at 90 days after treatment. RESULTS: Forty patients were included in this study: each experimental group comprised 20 patients. Applying a multivariate model in an intention-to-treat analysis, we observed that patients treated with miltefosine had a cure probability 2.08 times greater (95% confidence interval [CI] = 1.03-4.18) than those treated with N-MA at 90 days after treatment. At the final endpoint, we observed no differences in cure probability between miltefosine and N-MA (relative risk = 0.66; 95% CI = 0.33-1.32). With respect to adverse reactions, significant differences between groups were related to gastrointestinal effects, which were more frequent in the miltefosine group. CONCLUSIONS: Miltefosine may be an interesting alternative for treating ML because of its oral administration and cure rate after long-term follow-up.


Assuntos
Antiprotozoários/administração & dosagem , Leishmaniose Mucocutânea/tratamento farmacológico , Antimoniato de Meglumina/administração & dosagem , Fosforilcolina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilcolina/administração & dosagem , Projetos Piloto , Fatores de Tempo , Resultado do Tratamento
14.
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
15.
Parasitol Int ; 71: 163-166, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30991111

RESUMO

Leishmaniasis is a poverty-related disease, the chemotherapy of which is based on few drugs. The in vitro macrophage-amastigote model using mouse peritoneal cells, human-monocyte transformed macrophages and immortalized cell lines have been used to test new and safe antileishmanial drugs. Considering the differences for drug sensitivities between these Leishmania infected cells, the efficacy of amphotericin B, pentavalent antimonial, miltefosine and resveratrol was evaluated in a recently developed ex vivo culture of macrophages isolated from mouse lesion induced by L. amazonensis (CD11b+F4/80+CD68+CD14+) compared with infected peritoneal macrophages (CD11b+F4/80+CD68+CD14+). The results show that IC50 values of amphotericin B, miltefosine and pentavalent antimonial for parasites in lesional and peritoneal macrophages were similar, although high doses of these compounds did not result in total clearance of parasites in lesional cells (amphotericin B), peritoneal cells (miltefosine) and both cell cultures (pentavalent antimonial). Amastigotes infecting lesional macrophages were more resistant to resveratrol as compared to parasites in peritoneal macrophages. The cytoxicity of miltefosine and resveratrol was higher in infected peritoneal macrophages than in lesional cells. These data suggest that the antileishmanial effect and citotoxicity of some anti leishmanial compounds are dependent of macrophage source and mouse peritoneal macrophages loaded with amastigotes do not represent the lesion cell.


Assuntos
Antiprotozoários/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Macrófagos/parasitologia , Anfotericina B/farmacologia , Animais , Técnicas de Cultura de Células , Feminino , Concentração Inibidora 50 , Leishmaniose/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia
16.
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
17.
Int J Infect Dis ; 81: 221-224, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30790722

RESUMO

Post-kala-azar dermal leishmaniasis (PKDL) is a neglected tropical disease characterized by a dermatosis which often appears after successful treatment of visceral leishmaniasis caused by Leishmania donovani. PKDL treatment options are few and have severe limitations. In East-Africa, the standard treatment of PKDL is with daily painful potentially toxic sodium stibogluconate injections, administered for a prolonged duration of 30-60 days. In the Indian subcontinent, PKDL is mainly treated with miltefosine, a safer orally administered drug. However, in East-Africa, there is very limited experience in the use of miltefosine for treatment of severe PKDL, with only one published case report. Here we report a severe PKDL case in an Ethiopian HIV patient successfully treated with oral miltefosine (100mg/day for 28 days). Miltefosine was efficacious, safe and well tolerated, suggesting that it can play an important role in the treatment of severe PKDL also in East-African patients. Further research is warranted.


Assuntos
Antiprotozoários/administração & dosagem , Infecções por HIV/complicações , Leishmaniose Cutânea/tratamento farmacológico , Fosforilcolina/análogos & derivados , Administração Oral , Adulto , Etiópia , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/fisiologia , Leishmaniose Cutânea/etiologia , Masculino , Fosforilcolina/administração & dosagem
18.
Parasit Vectors ; 12(1): 79, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736866

RESUMO

BACKGROUND: Visceral leishmaniasis (VL) is an infectious disease with a variety of clinical signs. The main form of parasite transmission to humans and other mammalian hosts is through the bite of infected arthropod females with Lutzomyia longipalpis serving as the main vector in the Americas. Dogs are the main urban domestic reservoirs of the parasite and the main source of vector infection due to their high prevalence in endemic areas and the large number of parasites in the skin of infected animals. Although miltefosine has been used in Europe since 2002 for treatment of VL infected dogs, in the Americas the treatment of dogs has not been recommended. Therefore, this study aimed to evaluate efficacy of miltefosine observing a reduction of clinical signs in infected dogs and the infectiveness to the vector by Leishmania (L.) infantum. METHODS: To our knowledge, this is the first controlled study using qPCR and xenodiagnosis to evaluate the efficacy of miltefosine (Milteforan®, Virbac) as a single treatment in Brazil. Thirty-five adult dogs with canine visceral leishmaniasis (CVL), confirmed by clinical and laboratory tests, were included in this study. They received miltefosine at a dose of 2 mg/kg every 24 h for 28 days. The dogs were observed over a three-month period, during which clinical evaluations based on a scoring system were conducted at pre-established times. Parasite load was assessed by cytology and real-time polymerase chain reaction (qPCR). Transmissibility to the vector was evaluated by xenodiagnosis. RESULTS: At the end of the period, the following were observed: (i) the remission of clinical signs with a reduction in clinical scores for 94.2% of the animals; (ii) a statistically significant reduction (98.7%) in parasitic load by qPCR; and (iii) a reduction in infectivity to sand flies. After treatment, 74.2% of the animals remained or had become non-infectious. CONCLUSIONS: Our study indicates that the use of miltefosine administered orally for 4 weeks contributes to a clinical improvement and reduction in infectivity of dogs to L. infantum.


Assuntos
Antiprotozoários/administração & dosagem , Doenças do Cão/tratamento farmacológico , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/veterinária , Fosforilcolina/análogos & derivados , Administração Oral , Animais , Doenças do Cão/parasitologia , Cães , Feminino , Insetos Vetores/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Masculino , Carga Parasitária/veterinária , Fosforilcolina/administração & dosagem , Psychodidae/parasitologia , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Pele/parasitologia , Resultado do Tratamento , Xenodiagnóstico/veterinária
19.
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
20.
PLoS Negl Trop Dis ; 13(2): e0007133, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30763330

RESUMO

BACKGROUND: Visceral leishmaniasis is a neglected parasitic disease with no vaccine available and its pharmacological treatment is reduced to a limited number of unsafe drugs. The scarce readiness of new antileishmanial drugs is even more alarming when relapses appear or the occurrence of hard-to-treat resistant strains is detected. In addition, there is a gap between the initial and late stages of drug development, which greatly delays the selection of leads for subsequent studies. METHODOLOGY/PRINCIPAL FINDINGS: In order to address these issues, we have generated a red-shifted luminescent Leishmania infantum strain that enables long-term monitoring of parasite burden in individual animals with an in vivo limit of detection of 106 intracellular amastigotes 48 h postinfection. For this purpose, we have injected intravenously different infective doses (104-5x108) of metacyclic parasites in susceptible mouse models and the disease was monitored from initial times to 21 weeks postinfection. The emission of light from the target organs demonstrated the sequential parasite colonization of liver, spleen and bone marrow. When miltefosine was used as proof-of-concept, spleen weight parasite burden and bioluminescence values decreased significantly. CONCLUSIONS: In vivo bioimaging using a red-shifted modified Leishmania infantum strain allows the appraisal of acute and chronic stage of infection, being a powerful tool for accelerating drug development against visceral leishmaniasis during both stages and helping to bridge the gap between early discovery process and subsequent drug development.


Assuntos
Antiprotozoários/farmacologia , Descoberta de Drogas/métodos , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/diagnóstico por imagem , Medições Luminescentes , Fosforilcolina/análogos & derivados , Animais , Modelos Animais de Doenças , Feminino , Leishmaniose Visceral/tratamento farmacológico , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/farmacologia , Baço/parasitologia
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