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1.
Nanotechnology ; 30(45): 455102, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31365912

RESUMO

Leishmaniasis is a group of diseases caused by a protozoa parasite from one of over 20 Leishmania species. Depending on the tissues infected, these diseases are classified as cutaneous, mucocutaneous and visceral leishmaniasis. For the treatment of leishmaniasis refractory to antimony-based drugs, pentamidine (PTM) is a molecule of great interest. However, PTM displays poor bioavailability through oral routes due to its two strongly basic amidine moieties, which restricts its administration by a parenteral route and limits its clinical use. Among various approaches, nanotechnology-based drug delivery systems (nano-DDS) have potential to overcome the challenges associated with PTM oral administration. Here, we present the development of PTM-loaded PLGA nanoparticles (NPs) with a focus on the characterization of their physicochemical properties and potential application as an oral treatment of leishmaniasis. NPs were prepared by a double emulsion methodology. The physicochemical properties were characterized through the mean particle size, polydispersity index (PdI), zeta potential, entrapment efficiency, yield process, drug loading, morphology, in vitro drug release and in vivo pharmacological activity. The PTM-loaded PLGA NPs presented with a size of 263 ± 5 nm (PdI = 0.17 ± 0.02), an almost neutral charge (-3.2 ± 0.8 mV) and an efficiency for PTM entrapment of 91.5%. The release profile, based on PTM dissolution, could be best described by a zero-order model, followed by a drug diffusion profile that fit to the Higuchi model. In addition, in vivo assay showed the efficacy of orally given PTM-loaded PLGA NPs (0.4 mg kg-1) in infected BALB/c mice, with significant reduction of organ weight and parasite load in spleen (p-value < 0.05). This work successfully reported the oral use of PTM-loaded NPs, with a high potential for the treatment of visceral leishmaniasis, opening a new perspective to utilization of this drug in clinical practice.


Assuntos
Antiprotozoários/administração & dosagem , Leishmaniose/tratamento farmacológico , Pentamidina/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Administração Oral , Animais , Antiprotozoários/química , Antiprotozoários/farmacocinética , Disponibilidade Biológica , Modelos Animais de Doenças , Leishmaniose/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Tamanho do Órgão/efeitos dos fármacos , Carga Parasitária , Tamanho da Partícula , Pentamidina/química , Pentamidina/farmacocinética
2.
Int J Pharm ; 568: 118526, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31323370

RESUMO

Nanoparticles of polymeric complexes made of hyaluronic acid and polyarginine were investigated for the encapsulation of the cationic hydrophilic drug pentamidine isethionate. The interaction between the anionic hyaluronic acid and the cationic pentamidine resulting in the formation of polyelectrolyte complexes was firstly studied. Then, nanoparticles made of hyaluronic acid and polyarginine loaded with pentamidine were developed. These drug delivery systems consist of a monodisperse population of negatively charged pentamidine-loaded nanoparticles with a high drug encapsulation rate (80%). Such high encapsulation efficiency coming from ion exchange was confirmed by measurements of the counterion isethionate released from pentamidine during nanoparticles formation. Besides, freeze-dried pentamidine-loaded nanoparticles kept their integrity after their reconstitution in water. In vitro studies on human lung (A549) and breast (MDA-MB-231) cancer cell lines showed that pentamidine-loaded nanoparticles were more cytotoxic in comparison to the free drug, suggesting an enhanced internalization of encapsulated drug by cancer cells.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/administração & dosagem , Nanopartículas/administração & dosagem , Pentamidina/administração & dosagem , Peptídeos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Liofilização , Humanos , Ácido Hialurônico/química , Nanopartículas/química , Pentamidina/química , Peptídeos/química , Solubilidade
3.
Carbohydr Res ; 482: 107742, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310940

RESUMO

Glycosaminoglycans (GAGs) is a particular class of linear anionic periodic polysaccharides, which play a key role in many cell signaling processes in the extracellular matrix by direct interactions with multiple proteins targets. Because of their periodic nature resulting in experimental challenges to study these molecules, computational approaches recently proved to be successful in complementing the experiments aimed to understand GAG interactions. However, the aspect of GAG binding of small, pharmacologically active molecules is still essentially understudied despite its significance. In this work, we apply computational approaches to rigorously characterize the interactions between GAGs and two trypanosoma active DNA targeting agents, berenil and pentamidine, which mainly differ in the structure of their intramolecular linkers connecting two benzamidine moieties. We thoroughly analyze their binding to heparin and chondroitin 6-sulfate in terms of dynamics, energetics and properties of π-stacked oligomeric structures of the drug molecules formed upon GAG association. Our work contributes to the general understanding of biologically relevant interactions between GAGs and small molecules which has potential impact in drug pharmacology and related therapeutic modalities.


Assuntos
Antiprotozoários/metabolismo , Sulfatos de Condroitina/metabolismo , Simulação por Computador , Diminazena/análogos & derivados , Heparina/metabolismo , Pentamidina/metabolismo , Diminazena/química , Diminazena/metabolismo , Ligações de Hidrogênio , Conformação Molecular , Simulação de Dinâmica Molecular , Pentamidina/química , Teoria Quântica , Termodinâmica
4.
Vet Parasitol ; 270: 40-46, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31213240

RESUMO

Parasitic nematodes pose a major threat to livestock production worldwide. The blood-feeding parasite Haemonchus contortus is a key small-ruminant pathogen that causes anaemia, and thereby seriously impacts animal health and production. Control of this parasite relies largely upon broad-spectrum anthelmintics, but new drugs are urgently needed to combat the threat of widespread multidrug resistance. Repurposing drugs can accelerate the development pipeline by reducing costs and risks, and can be an effective way of quickly bringing new antiparasitic drugs to market. Diarylamidine compounds such as pentamidine and diminazene have been employed in the treatment of trypanosomiasis and leishmaniasis in both human and veterinary settings, but their activity against parasitic worms has not yet been reported. We screened a small panel of diarylamidine compounds against H. contortus to assess their potential to be repurposed as anthelmintic drugs. Pentamidine and diminazene inhibited H. contortus larval development at low micromolar concentrations (IC50 4.9 µM and 16.1 µM, respectively, in a drug-susceptible isolate) with no existing cross-resistance in two multidrug resistant isolates and a monepantel-resistant isolate. Combinations of pentamidine with commercial anthelmintics showed additive activity, with no significant synergism detected. Pentamidine and diminazene showed different life-stage patterns of activity; both were active against early stage larvae in development assays, but only diminazene was active against the infective L3 stage in migration assays. This suggests some differences in uptake of the two drugs across the nematode cuticle, or differences in the nature and expression patterns of their molecular targets. As pentamidine and diminazene have been reported to be potent inhibitors of mammalian acid-sensing ion channels (ASIC), we tested the activity of known ASIC inhibitors against H. contortus to probe whether these channels may represent potential anthelmintic targets in nematodes. Remarkably, the spider-venom peptide Hi1a, a potent inhibitor of ASIC1a, inhibited H. contortus larval development with an IC50 of 22.9 ± 1.9 µM. This study highlights the potential use of diarylamidines as anthelmintics, although their activity needs to be confirmed in vivo. In addition, our demonstration that ASIC inhibitors have anthelmintic activity raises the possibility that this family of ion channels may represent a novel anthelmintic target.


Assuntos
Anti-Helmínticos/farmacologia , Diminazena/farmacologia , Haemonchus/efeitos dos fármacos , Pentamidina/farmacologia , Animais , Antiprotozoários/farmacologia , Técnicas In Vitro , Concentração Inibidora 50
5.
Molecules ; 24(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174390

RESUMO

Pentamidine is bis-oxybenzamidine-based antiprotozoal drug. The parenteral use of pentamidine appears to affect the processes of blood coagulation and/or fibrinolysis resulting in rare but potentially life-threatening blood clot formation. Pentamidine was also found to cause disseminated intravascular coagulation syndrome. To investigate the potential underlying molecular mechanism(s) of pentamidine's effects on coagulation and fibrinolysis, we studied its effects on clotting times in normal and deficient human plasmas. Using normal plasma, pentamidine isethionate doubled the activated partial thromboplastin time at 27.5 µM, doubled the prothrombin time at 45.7 µM, and weakly doubled the thrombin time at 158.17 µM. Using plasmas deficient of factors VIIa, IXa, XIa, or XIIa, the concentrations to double the activated partial thromboplastin time were similar to that obtained using normal plasma. Pentamidine also inhibited plasmin-mediated clot lysis with half-maximal inhibitory concentration (IC50) value of ~3.6 µM. Chromogenic substrate hydrolysis assays indicated that pentamidine inhibits factor Xa and plasmin with IC50 values of 10.4 µM and 8.4 µM, respectively. Interestingly, it did not significantly inhibit thrombin, factor XIa, factor XIIIa, neutrophil elastase, or chymotrypsin at the highest concentrations tested. Michaelis-Menten kinetics and molecular modeling studies revealed that pentamidine inhibits factor Xa and plasmin in a competitive fashion. Overall, this study provides quantitative mechanistic insights into the in vitro effects of pentamidine isethionate on coagulation and fibrinolysis via the disruption of the proteolytic activity of factor Xa and plasmin.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Pentamidina/farmacologia , Trombose/tratamento farmacológico , Testes de Coagulação Sanguínea , Fator VIIa/genética , Fator XIIa/genética , Fator XIa/genética , Fator Xa/genética , Humanos , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Trombina/química , Trombina/genética , Tempo de Trombina , Trombose/sangue , Trombose/patologia
6.
Exp Parasitol ; 201: 90-92, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059693

RESUMO

Acanthamoeba are free living amoeba that have been isolated from different environments like soil, water, air dust. Moreover, they are also able to act as opportunist pathogens, mainly causing a fatal encephalitis and also keratitis in both human and animals. This study was aimed to evaluate the activity of the Medicines for Malaria Venture (MMV) compounds against the trophozoite stage of Acanthamoeba castellanii Neff. Sixteen compounds showed ≥90% inhibition of parasite growth in the initial screen (10 µM). Those set were further evaluated to determine the inhibitor concentration that inhibit the 50% of the initial population and cytotoxicity against murine macrophages. Among the compounds included in the pathogen box, pentamidine and posaconazole were the most effective against this parasite with an of IC50 of 0.567 ±â€¯0.04 and 0.630 ±â€¯0.11, respectively.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Amebicidas/classificação , Animais , Linhagem Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Camundongos , Pentamidina/farmacologia , Triazóis/farmacologia , Trofozoítos/efeitos dos fármacos
7.
Am J Trop Med Hyg ; 101(1): 123-125, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31074413

RESUMO

We report the case of a 64-year-old woman found to have urban-acquired Trypanosoma brucei (T.b.) gambiense human African trypanosomiasis (HAT) as the cause of sustained fever starting 9 months after returning to Canada from Democratic Republic of the Congo, in the context of concomitant multiple myeloma and HIV-1 coinfection. Approaches for the management of both clinical stages of T.b. gambiense HAT are well defined for endemic settings using current diagnostics and treatments. However, few data inform the diagnosis and management of patients with bone marrow suppression from active malignancy, recent anticancer therapy, or HIV coinfection. We discuss the implications of immunosuppression for diagnosis and management of T.b. gambiense HAT.


Assuntos
Infecções por HIV/complicações , HIV-1 , Mieloma Múltiplo/complicações , Trypanosoma brucei gambiense , Tripanossomíase Africana/complicações , Coinfecção , Congo/epidemiologia , Feminino , Febre , Humanos , Pessoa de Meia-Idade , Pentamidina/uso terapêutico , Viagem , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/epidemiologia
8.
Mem Inst Oswaldo Cruz ; 114: e180535, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31090861

RESUMO

BACKGROUND: Topical treatment of New World cutaneous leishmaniasis can be affected by bacterial coinfection, hyperkeratosis, and transdermal drug delivery. OBJECTIVE: The aim of this work was to evaluate the therapeutic response and safety of the topical, sequential use of antiseptic, keratolytic, and pentamidine isethionate (PMD) creams (3-PACK kit) on CL-infected BALB/c mice. METHODS: A 0.5% chlorhexidine solution (CGH), 10% salicylic acid (SA), and 3% or 6% PMD were used as antiseptic, keratolytic, and antileishmanial drugs, respectively. During the first seven days, antiseptic, followed by 10% SA gel and PMD cream, were applied topically. Subsequently, treatment was performed only with the antiseptic and PMD creams. Skin irritation, reduction of lesion size (mm2), and parasitic load were observed until 30 days of treatment were completed. FINDINGS: The 3-PACK treatment using 6% PMD induced a complete lesion reduction in 3/6 mice and a partial reduction in 1/6 mice, with no parasites observed. In contrast, CGH and SA alone, along with the vehicle, were not effective (p < 0.05). Moderate to severe erythema was observed at the application site. MAIN CONCLUSION: The topical 3-PACK using 6% PMD was 67% effective in the treatment of CL by Leishmania (Viannia) braziliensis. Currently, work is ongoing to improve PMD isethionate formulation and to determine a dose-response.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Clorexidina/administração & dosagem , Ceratolíticos/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Pentamidina/administração & dosagem , Ácido Salicílico/administração & dosagem , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Camundongos , Camundongos Endogâmicos BALB C
9.
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
10.
Artif Cells Nanomed Biotechnol ; 47(1): 1428-1436, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31007068

RESUMO

Nanoparticles (NPs) have gained importance in addressing drug delivery challenges across biological barriers. Here, we reformulated pentamidine, a drug used to treat Human African Trypanosomiasis (HAT) in polymer based nanoparticles and liposomes and compared their capability to enhance pentamidine penetration across blood brain barrier (BBB). Size, polydispersity index, zeta potential, morphology, pentamidine loading and drug release profiles were determined by various methods. Cytotoxicity was tested against the immortalized mouse brain endothelioma cells over 96 h. Moreover, cells monolayer integrity and transportation ability were examined for 24 h. Pentamidine-loaded polycaprolactone (PCL) nanoparticles had a mean size of 267.58, PDI of 0.25 and zeta potential of -28.1 mV and pentamidine-loaded liposomes had a mean size of 119.61 nm, PDI of 0.25 and zeta potential 11.78. Pentamidine loading was 0.16 µg/mg (w/w) and 0.17 µg/mg (w/w) in PCL NPs and liposomes respectively. PCL nanoparticles and liposomes released 12.13% and 22.21% of pentamidine respectively after 24 h. Liposomes transported 87% of the dose, PCL NPs 66% of the dose and free pentamidine penetration was 63% of the dose. These results suggest that liposomes are comparatively promising nanocarriers for transportation of pentamidine across BBB.


Assuntos
Barreira Hematoencefálica/metabolismo , Portadores de Fármacos/química , Lipossomos/química , Nanopartículas/química , Pentamidina/metabolismo , Fosfatidilcolinas/química , Poliésteres/química , Animais , Linhagem Celular , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Camundongos , Pentamidina/química
11.
Rev Soc Bras Med Trop ; 52: e20180323, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30994803

RESUMO

We report the case of a 32-year-old man from Rio de Janeiro, who was infected in the Amazon region of Brazil by Leishmania (Viannia) naiffi. Generally, patients with L. naiffi cutaneous leishmaniasis exhibit a good therapeutic response to either pentavalent antimonials or pentamidine. However, after pentamidine treatment, this patient's infection evolved to therapeutic failure. To understand this clinical outcome, we investigated the presence of the Leishmania RNA virus (LRV) in parasites isolated from the cutaneous lesion; herein, we discuss the possible association between a poor response to pentamidine therapy and the presence of the LRV.


Assuntos
Leishmania/virologia , Leishmaniose Cutânea/tratamento farmacológico , Pentamidina/uso terapêutico , Vírus de RNA/genética , Tripanossomicidas/uso terapêutico , Adulto , Humanos , Masculino , Pentamidina/efeitos adversos , Reação em Cadeia da Polimerase , Falha de Tratamento , Tripanossomicidas/efeitos adversos
13.
Exp Parasitol ; 200: 1-6, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30904692

RESUMO

Nucleoside triphosphate diphosphohydrolase (NTPDase) 1 from intracellular amastigotes of Leishmania infantum-infected macrophage was identified by immunocytochemistry and confocal laser scanning microscopy using antibodies that specifically recognize its B-domain. This enzyme was previously characterized in Leishmania promastigote form, and here it is shown to be susceptible to pentamidine isethionate (PEN). In initial assays, this antileishmanial compound (100 µM) reduced 60% phosphohydrolytic activity of promastigotes preparation. An active NTPDase 1 was then isolated by non-denaturing gel electrophoresis, and PEN (10 µM) inhibited 74% and 35% of the ATPase and ADPase activities, respectively, of this pure protein. In addition, PEN 0.1-1 µM inhibited 56% potato apyrase activity, a plant protein that shares high identity with Leishmania NTPDase 1. In contrast, amphotericin B, fluconazole, ketoconazole or allopurinol did not significantly affect phosphohydrolytic activity of either promastigotes preparation or potato apyrase. This work suggests amastigote NTPDase 1 as a new molecular target, and inhibition of its catalytic activity by pentamidine can be part of the mode of action of this drug contributing with the knowledge of its antileishmanial effect.


Assuntos
Antiprotozoários/farmacologia , Apirase/antagonistas & inibidores , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/enzimologia , Pentamidina/farmacologia , Animais , Antígenos CD , Imuno-Histoquímica , Macrófagos/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal
14.
PLoS One ; 14(3): e0213713, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30861059

RESUMO

Tuberculosis (TB) is an infectious bacterial disease that kills approximately 1.3 million people every year. Despite global efforts to reduce both the incidence and mortality associated with TB, the emergence of drug resistant strains has slowed any progress made towards combating the spread of this deadly disease. The current TB drug regimen is inadequate, takes months to complete and poses significant challenges when administering to patients suffering from drug resistant TB. New treatments that are faster, simpler and more affordable are urgently required. Arguably, a good strategy to discover new drugs is to start with an old drug. Here, we have screened a library of 1200 FDA approved drugs from the Prestwick Chemical library using a GFP microplate assay. Drugs were screened against GFP expressing strains of Mycobacterium smegmatis and Mycobacterium bovis BCG as surrogates for Mycobacterium tuberculosis, the causative agent of TB in humans. We identified several classes of drugs that displayed antimycobacterial activity against both M. smegmatis and BCG, however each organism also displayed some selectivity towards certain drug classes. Variant analysis of whole genomes sequenced for resistant mutants raised to florfenicol, vanoxerine and pentamidine highlight new pathways that could be exploited in drug repurposing programmes.


Assuntos
Antibacterianos/farmacologia , Antituberculosos/farmacologia , Reposicionamento de Medicamentos/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Ágar/química , Anti-Infecciosos/farmacologia , Desenho de Drogas , Proteínas de Fluorescência Verde/química , Células Hep G2 , Humanos , Mutação , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium smegmatis/efeitos dos fármacos , Pentamidina/farmacologia , Piperazinas/farmacologia , Polimorfismo de Nucleotídeo Único , Tianfenicol/análogos & derivados , Tianfenicol/farmacologia , Estados Unidos , United States Food and Drug Administration
15.
Front Immunol ; 10: 39, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740102

RESUMO

Trypanosomiasis has been recognized as a scourge in sub-Saharan Africa for centuries. The disease, caused by protozoan parasites of the Trypanosoma genus, is a major cause of mortality and morbidity in animals and man. Human African trypanosomiasis (HAT), or sleeping sickness, results from infections with T. brucei (b.) gambiense or T. b. rhodesiense with T. b. gambiense accounting for over 95% of infections. Historically there have been major epidemics of the infection, followed by periods of relative disease control. As a result of concerted disease surveillance and treatment programmes, implemented over the last two decades, there has been a significant reduction in the number of cases of human disease reported. However, the recent identification of asymptomatic disease carriers gives cause for some concern. The parasites evade the host immune system by switching their surface coat, comprised of variable surface glycoprotein (VSG). In addition, they have evolved a variety of strategies, including the production of serum resistance associated protein (SRA) and T. b. gambiense-specific glycoprotein (TgsGP) to counter host defense molecules. Infection with either disease variant results in an early haemolymphatic-stage followed by a late encephalitic-stage when the parasites migrate into the CNS. The clinical features of HAT are diverse and non-specific with early-stage symptoms common to several infections endemic within sub-Saharan Africa which may result in a delayed or mistaken diagnosis. Migration of the parasites into the CNS marks the onset of late-stage disease. Diverse neurological manifestations can develop accompanied by a neuroinflammatory response, comprised of astrocyte activation, and inflammatory cell infiltration. However, the transition between the early and late-stage is insidious and accurate disease staging, although crucial to optimize chemotherapy, remains problematic with neurological symptoms and neuroinflammatory changes recorded in early-stage infections. Further research is required to develop better diagnostic and staging techniques as well as safer more efficacious drug regimens. Clearer information is also required concerning disease pathogenesis, specifically regarding asymptomatic carriers and the mechanisms employed by the trypanosomes to facilitate progression to the CNS and precipitate late-stage disease. Without progress in these areas it may prove difficult to maintain current control over this historically episodic disease.


Assuntos
Doenças Negligenciadas/diagnóstico , Doenças Negligenciadas/epidemiologia , Trypanosoma brucei gambiense/patogenicidade , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/epidemiologia , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/uso terapêutico , Barreira Hematoencefálica/parasitologia , Encéfalo/parasitologia , Diagnóstico Tardio , Humanos , Incidência , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/prevenção & controle , Pentamidina/administração & dosagem , Pentamidina/uso terapêutico , Índice de Gravidade de Doença , Suramina/administração & dosagem , Suramina/uso terapêutico , Resultado do Tratamento , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/prevenção & controle
16.
Artif Cells Nanomed Biotechnol ; 47(1): 436-442, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30704300

RESUMO

Gene and drug delivery systems need crucial update in the issue of nanocarriers. Layered double hydroxides (LDHs) are known as biocompatible inorganic lamellar nanomaterials with versatile properties. In the present study, Zn/Al-LDH nanoparticle was synthesized and characterized by FTIR, XRD, SEM, TEM and Zeta potential tests and then intercalated with valproate and methyldopa by co-precipitation and ion exchange methods. These nanocarriers were applied as high activity nanolayers-based delivery systems. On the other hand, Zn/Al-LDH + plasmid/gene (pCEP4/Cdk9) evaluated on C2C12 myoblast cells. Co-operation loading indicated high efficiency of sorting and release of drugs. Additionally, the Real-Time PCR and Western blotting results for plasmid-gene (pCEP4/Cdk9) delivery showed that Zn/Al-LDH nanoparticles can be used as an effective carrier in cellular uptake and release of genes for gene therapy. Easy and cost-effective production of Zn/Al-LDH nanoparticles proposed them as potential alternatives for the traditional routs of drug/gene delivery.


Assuntos
Portadores de Fármacos , Técnicas de Transferência de Genes , Hidróxidos , Mioblastos/metabolismo , Nanopartículas/química , Animais , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Hidróxidos/química , Hidróxidos/farmacologia , Camundongos , Mioblastos/citologia , Pentamidina/química , Pentamidina/farmacologia , Plasmídeos/química , Plasmídeos/farmacologia , Poliésteres/química , Poliésteres/farmacologia
18.
PLoS Negl Trop Dis ; 13(2): e0007132, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30789910

RESUMO

BACKGROUND: The long-term treatment outcome of visceral leishmaniasis (VL) patients with HIV co-infection is complicated by a high rate of relapse, especially when the CD4 count is low. Although use of secondary prophylaxis is recommended, it is not routinely practiced and data on its effectiveness and safety are limited. METHODS: A prospective cohort study was conducted in Northwest Ethiopia from August 2014 to August 2017 (NCT02011958). HIV-VL patients were followed for up to 12 months. Patients with CD4 cell counts below 200/µL at the end of VL treatment received pentamidine prophylaxis starting one month after parasitological cure, while those with CD4 count ≥200 cells/µL were followed without secondary prophylaxis. Compliance, safety and relapse-free survival, using Kaplan-Meier analysis methods to account for variable time at risk, were summarised. Risk factors for relapse or death were analysed. RESULTS: Fifty-four HIV patients were followed. The probability of relapse-free survival at one year was 50% (95% confidence interval [CI]: 35-63%): 53% (30-71%) in 22 patients with CD4 ≥200 cells/µL without pentamidine prophylaxis and 46% (26-63%) in 29 with CD4 <200 cells/µL who started pentamidine. Three patients with CD4 <200 cells/µL did not start pentamidine. Amongst those with CD4 ≥200 cells/µL, VL relapse was an independent risk factor for subsequent relapse or death (adjusted rate ratio: 5.42, 95% CI: 1.1-25.8). Except for one case of renal failure which was considered possibly related to pentamidine, there were no drug-related safety concerns. CONCLUSION: The relapse-free survival rate for VL patients with HIV was low. Relapse-free survival of patients with CD4 count <200cells/µL given pentamidine secondary prophylaxis appeared to be comparable to patients with a CD4 count ≥200 cells/µL not given prophylaxis. Patients with relapsed VL are at higher risk for subsequent relapse and should be considered a priority for secondary prophylaxis, irrespective of their CD4 count.


Assuntos
Antiprotozoários/uso terapêutico , Infecções por HIV/complicações , Leishmaniose Visceral/complicações , Pentamidina/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Coinfecção , Etiópia/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Humanos , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida , Adulto Jovem
19.
J Infect Chemother ; 25(5): 351-354, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30711257

RESUMO

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection in patients on steroid therapy for connective tissue diseases. The standard agent for primary PCP prophylaxis is trimethoprim/sulfamethoxazole (TMP-SMX), although this agent can cause common adverse reactions, including myelosuppression and renal toxicity, that result in cessation. Aerosolized pentamidine and oral atovaquone are alternatives for PCP prophylaxis. The efficacies of atovaquone, pentamidine, and TMP-SMX to prevent PCP in patients with connective tissue diseases have never been compared. METHODS: Hospitalized patients with connective tissue diseases who started steroid therapy and PCP prophylaxis were enrolled. PCP prophylaxis regimens were oral TMP-SMX, aerosolized pentamidine, or oral atovaquone. Information was retrospectively collected from medical records about laboratory findings, duration of PCP prophylaxis, and reasons for terminating PCP prophylaxis. RESULTS: Ninety-six patients received PCP prophylaxis. All of them were initially treated with TMP-SMX, but this was replaced during the study period with pentamidine in 33 patients and with atovaquone in 7. Forty-one (43%) patients discontinued TMP-SMX because of adverse events, and 5 (15%) also discontinued pentamidine. None of the patients discontinued atovaquone. The most frequent causes of TMP-SMX and pentamidine cessation were cytopenia (N = 15) and asthma (N = 2). The rates of continuing treatment with TMP-SMX, pentamidine, and atovaquone at one year after starting PCP prophylaxis were 55.3%, 68.6%, and 100%, respectively (P = 0.01). None of the patients developed PCP. CONCLUSION: Although TMP-SMX for PCP prophylaxis had to be discontinued in 43% of patients with connective tissue diseases, pentamidine and atovaquone were well tolerated.


Assuntos
Antibioticoprofilaxia/métodos , Doenças do Tecido Conjuntivo/complicações , Infecções Oportunistas/prevenção & controle , Pneumocystis carinii/isolamento & purificação , Pneumonia por Pneumocystis/prevenção & controle , Administração por Inalação , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibioticoprofilaxia/efeitos adversos , Asma/induzido quimicamente , Asma/epidemiologia , Atovaquona/uso terapêutico , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/microbiologia , Pentamidina/uso terapêutico , Pneumonia por Pneumocystis/microbiologia , Estudos Retrospectivos , Resultado do Tratamento , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Adulto Jovem
20.
Am J Trop Med Hyg ; 100(2): 306-310, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30628567

RESUMO

Local therapies have been proposed as safe and effective alternatives to systemic drugs in cutaneous leishmaniasis (CL), especially among less severe cases. However, they are not widely available and used in endemic places, including Colombia, which has a high burden of disease. Further complicating the uptake of local therapies is that different treatment guidelines have been established by the World Health Organization (WHO) and Pan American Health Organization (PAHO). Using data from a large referral center in Colombia, we determined the proportion of patients who would be eligible for and potentially benefit from local therapies according to both international guidelines. The sample included 1,891 confirmed cases of CL aged ≥ 12 years, mostly infected with Leishmania Viannia panamensis (91%, n = 601/660), between 2004 and 2014. Overall, 57% of the sample had one lesion, whereas another 31% had two to three lesions. For 74% of patients, all lesions were in an area other than head or neck. The maximum lesion size was ≤ 3 cm for 58% and < 5 cm for 88% of the sample. Based on our data, up to 56% of patients could have been eligible for local therapies according to the WHO criteria. By contrast, only 23% were eligible according to the more restrictive PAHO criteria. Regardless, these data suggest that a substantial proportion of CL patients in Colombia may benefit from local therapies given their relatively mild presentation of disease and low risk of complications. Individualized risk-benefit assessment and guideline adjustments may increase local therapy eligibility and benefit a large number of patients.


Assuntos
Antimônio/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmania braziliensis/efeitos dos fármacos , Leishmania guyanensis/efeitos dos fármacos , Leishmaniose Cutânea/terapia , Paromomicina/uso terapêutico , Pentamidina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Colômbia/epidemiologia , Estudos Transversais , Crioterapia/métodos , Feminino , Humanos , Hipertermia Induzida/métodos , Leishmania braziliensis/crescimento & desenvolvimento , Leishmania braziliensis/patogenicidade , Leishmania guyanensis/crescimento & desenvolvimento , Leishmania guyanensis/patogenicidade , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/parasitologia , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Índice de Gravidade de Doença
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