Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.454
Filtrar
1.
Rev Soc Bras Med Trop ; 53: e20180463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049198

RESUMO

INTRODUCTION: The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug. METHODS: : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1). RESULTS: Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died. CONCLUSIONS: By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.


Assuntos
Anfotericina B/sangue , Antifúngicos/sangue , Ácido Desoxicólico/sangue , Anfotericina B/administração & dosagem , Anfotericina B/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Ácido Desoxicólico/administração & dosagem , Ácido Desoxicólico/farmacocinética , Histoplasmose/tratamento farmacológico , Humanos , Leishmaniose/tratamento farmacológico , Meningite Criptocócica/tratamento farmacológico , Paracoccidioidomicose/tratamento farmacológico
2.
Chem Biol Interact ; 315: 108899, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31738906

RESUMO

Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC50 values between 53.23 and 357.97 µM. Concerning the evaluation against L. amazonensis promastigote forms, IC50 values ranged between 12.31 and  > 481.52 µM, while the activity against L. infantum promastigotes obtained IC50 values between 4.36 and 23.35 µM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC50 values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents.


Assuntos
Antiprotozoários/farmacologia , Indóis/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Leishmaniose/parasitologia , Macrófagos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos
4.
Eur J Med Chem ; 184: 111742, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605866

RESUMO

In this work, we report the antileishmanial activity of 15 compounds based on 2-pyrimidinyl hydrazone and N-acylhydrazone derivatives, being 13 new compounds. All compounds were tested against promastigotes and Leishmania amazonensis-GFP amastigotes, as well as murine macrophages. Besides, studies about the mechanism of action of the best antileishmanial compounds and in silico physicochemical and pharmacokinetic properties were performed. Studies about the mechanism of action of representative compounds of each class showed slight differences in mode of action and both are able to cause mitochondrial depolarization and increase of intracellular ROS levels. Through computational tool and further analysis of the physicochemical and pharmacokinetic parameters, the results indicating good oral bioavailability. These results confirm the potential of 2-pyrimidinyl derivatives as lead compounds in antileishmanial drug discovery.


Assuntos
Antiprotozoários/farmacologia , Hidrazonas/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Pirimidinas/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Hidrazonas/síntese química , Hidrazonas/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pirimidinas/síntese química , Pirimidinas/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 183: 111660, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514064

RESUMO

This mini-review focuses on leishmanicidal drugs that were sourced from small molecules previously approved for other diseases. The mechanisms of action of these molecules are herein explored, to probe the origins of their inter-species growth inhibitory activities. It is shown how the transversal action of the azoles - fluconazole, posaconazole and itraconazole - in both fungi and Leishmania is due to the occurrence of the same target, lanosterol 14-α-demethylase, in these two groups of species. In turn, the drugs miltefosine and amphotericin B are presented as truly multi-target agents, acting on small molecules, proteins, genes and even organelles. Steps towards future leishmanicidal drug candidates based on the multi-target strategy and on drug repurposing are also briefly presented.


Assuntos
Antifúngicos , Itraconazol , Leishmaniose/tratamento farmacológico , Anfotericina B/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Reposicionamento de Medicamentos , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologia , Humanos , Itraconazol/química , Itraconazol/farmacologia , Leishmaniose/enzimologia , Terapia de Alvo Molecular , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Esterol 14-Desmetilase/metabolismo , Triazóis/farmacologia , Voriconazol/farmacologia
6.
Eur J Med Chem ; 183: 111676, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31542713

RESUMO

Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 µM for Leishmania infantum, 3.4 µM for L. donovani, 6.7 µM for L. major), Trypanosoma cruzi (EC50 7.5 µM) and T. brucei (EC50 0.8 µM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.


Assuntos
Antiprotozoários , Flavonóis , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Fosforilcolina/análogos & derivados , Tiofenos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/farmacologia , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos/efeitos dos fármacos , Flavonóis/síntese química , Flavonóis/química , Flavonóis/farmacologia , Genômica , Humanos , Fosforilcolina/química , Fosforilcolina/farmacologia , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
7.
Parasitol Res ; 118(10): 2743-2752, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473855

RESUMO

Leishmaniasis is a neglected parasitic disease for which the current antileishmania therapeutics are hampered by drug toxicity, high cost, need for parenteral administration, increasing treatment failure rates, and emergence of drug resistance. The R&D pipeline had run fairly dry for several years, but fortunately some new drug candidates are now under (pre)clinical development. Identification of novel drugs will nevertheless remain essential to adequately sustain and improve effective disease control in the future. In this review, a package of standard and accessible R&D approaches is discussed with expansion to some alternative strategies focusing on parasite-host and vector-host interactions.


Assuntos
Antiprotozoários/farmacologia , Descoberta de Drogas , Leishmania/efeitos dos fármacos , Animais , Resistência a Medicamentos , Humanos , Leishmania/crescimento & desenvolvimento , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia
8.
Farm. comunitarios (Internet) ; 11(3): 13-18, sept. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-186879

RESUMO

Antecedentes: la leishmaniosis es una zoonosis vectorial que en humanos inmunodeprimidos presenta forma sistémica, estando la forma cutánea infradiagnosticada. El tratamiento para el portador tiene un elevado coste. Propietarios y centros de adopciones carecen de recursos, pero no tratar o prevenir implica tener a un portador de una zoonosis disponible para el vector. Por ello existe una tendencia a la sustitución por la presentación de humana por los agentes implicados, adelantándose a los responsables en materia de salud pública. Objetivos: conocer la incidencia de animales portadores, la proporción de medicamentos prescritos por los veterinarios, las tendencias de búsqueda en internet de medicamentos para prevención y el tratamiento. Metodología: análisis serológico por técnica de inmunoensayo de 255 perros, aplicación de precios de mercado a los resultados, encuesta sobre la prescripción de veterinarios clínicos y análisis de tendencias de búsqueda de información en internet entre usuarios. Resultados: 38 perros resultaron ser portadores inaparentes (infectados, pero no enfermos) y 28 portadores enfermos. El resto son no portadores. Se obtuvo una diferencia de precio de más del 50 % en el tratamiento entre medicamentos de humana o genéricos y el de veterinaria. En la prevención la diferencia es 11 veces el precio veterinario frente al de humana. Los veterinarios prescriben correctamente, pero informan de otras opciones más baratas y la tendencia de búsqueda en internet está orientada al precio y a la sustitución. Conclusión: el precio es la principal causa de sustitución del medicamento prescrito y la legislación no está atendiendo la relevancia de esta zoonosis. Las autoridades sanitarias han de valorar las necesidades reales en materia de salud pública


Background: Leishmaniasis is a vectorial zoonosis with systemic presentation in immunosuppressed humans, the cutaneous form is underdiagnosed. A lot of owners and Rescue kennels can not pay the treatment because it is very expensive, but not treating or not preventing is dangerous for Public Health. Therefore, there is a tendency to replace the veterinary drug by the human drug form, ahead of those responsible for Public Health. Objectives: To know the disease carrier animals, the prescription tendencies of the veterinarians, the tendencies of search in Internet of drugs for prevention and treatment. Methods: Blood test of 255 animals, application of market prices to the results, survey on the prescription of clinical veterinarians and analysis of Internet search trends among users. Results: 38 dogs were founded inapparent carriers (infected, but not ill) and 28 sick carriers. The rest were non-carriers. A price difference of more than 50 % was obtained in the treatment between human or generic drugs and that of veterinary medicine. About the prevention, the difference is 11 times the veterinary price compared to that of humans. Veterinarians prescribe correctly but report other cheaper options and the search trend on the internet is price and replacement oriented. Conclusion: The price is the main cause of substitution and the legislation is not agree the relevance of this zoonosis. The health authorities must assess the real needs in terms of Public Health


Assuntos
Animais , Cães , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Leishmaniose/veterinária , Farmácias , Substituição de Medicamentos/tendências , Drogas Veterinárias , Meglumina/uso terapêutico , Antimoniato de Meglumina/uso terapêutico , Antiprotozoários
9.
Parasitol Int ; 73: 101968, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31398485

RESUMO

The current treatments for leishmaniasis bump into several obstacles, including low efficacy, high costs, long monitoring, and several/severe side effects. Consequently, the search for promising compounds is a tangible need. Recently, we reported the anti-Leishmania amazonensis action of asymmetric peptidomimetic compounds containing tartaric acid as core, especially the 157 derivative that contains valine/leucine substituents in its structure. Herein, we decipher the multiple effects of 157 on the L. amazonensis physiology and on the interaction process with macrophages. The peptidomimetic 157 induced significant changes on the morphometric (internal granularity reduction as judged by flow cytometer) and on the ultrastructural (round-shaped parasites, presence of plasma membrane blebs and flagellum loss as visualized by scanning electron microscopy) aspects of treated promastigotes compared to untreated ones. The alteration on the plasma membrane permeability was confirmed by the passive incorporation of propidium iodide in 157-treated promastigotes. In parallel, the low viability of promastigotes was also associated to the perturbation of mitochondrial transmembrane electric potential. These combined results demonstrated that 157 induced irreversible metabolic damages that led to L. amazonensis death. The pre-treatment of promastigotes with 157 inhibited the association index with macrophages in a typically dose-dependent manner. Additionally, 157 significantly reduced the number of intramacrophage amastigotes after 72 h of drug contact, presenting an IC50 value of 30.2 µM. Under our experimental conditions, 157 showed higher toxicity to promastigotes and amastigotes when compared to RAW cells, resulting in good selective indexes. Therefore, 157 can be considered as an interesting candidate for further optimization, since its synthesis is simple and cheap.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Peptidomiméticos/farmacologia , Tartaratos/farmacologia , Leucina/química , Macrófagos/efeitos dos fármacos , Valina/química
10.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374887

RESUMO

Dithiocarbamates represent a class of compounds that were evaluated in different biomedical applications because of their chemical versatility. For this reason, several pharmacological activities have already been attributed to these compounds, such as antiparasitic, antiviral, antifungal activities, among others. Therefore, compounds that are based on dithiocarbamates have been evaluated in different in vivo and in vitro models as potential new antimicrobials. Thus, the purpose of this review is to present the possibilities of using dithiocarbamate compounds as potential new antitrypanosomatids-drugs, which could be used for the pharmacological control of Chagas disease, leishmaniasis, and African trypanosomiasis.


Assuntos
Antiparasitários/uso terapêutico , Leishmaniose/tratamento farmacológico , Tiocarbamatos/uso terapêutico , Trypanosoma/efeitos dos fármacos , Animais , Antiparasitários/química , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Leishmaniose/parasitologia , Tiocarbamatos/química , Trypanosoma/patogenicidade , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia
11.
Georgian Med News ; (291): 122-125, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31418744

RESUMO

In this study, we studied the activity of the antibacterial drugDoxycycline (Russia), and the control was the drug of pentavalent antimony - Glucantim (France), which for a long time was the "gold standard" in the treatment of any form of leishmaniasis. In the course of the experiment, the leading positions of doxycycline established in vitro. Its minimum doses lead to absolute suppression of the mobility of the pathogen L. major. Increasing the therapeutic dose of the drug is not justified. Comparison of this drug with the gold standard of therapy with meglumine antimonate (glucantim) showed its superiority in all indicators.


Assuntos
Doxiciclina/uso terapêutico , Leishmaniose/tratamento farmacológico , Antimoniato de Meglumina/uso terapêutico , Humanos , Técnicas In Vitro
12.
Phytother Res ; 33(10): 2473-2517, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31441148

RESUMO

Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually with over 500,000 deaths. Among the NTDs, some of the most severe consist of leishmaniasis, Chagas disease, and dengue. The impact of the combined NTDs closely rivals that of malaria. According to the World Health Organization, 216 million cases of malaria were reported in 2016 with 445,000 deaths. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Flavonoids are a class of compounds that has been the subject of considerable scientific interest. New developments of flavonoids have made promising advances for the potential treatment of malaria, leishmaniasis, Chagas disease, and dengue, with less toxicity, high efficacy, and improved bioavailability. This review summarizes the current standings of the use of flavonoids to treat malaria and neglected diseases such as leishmaniasis, Chagas disease, and dengue. Natural and synthetic flavonoids are leading compounds that can be used for developing antiprotozoal and antiviral agents. However, detailed studies on toxicity, pharmacokinetics, and mechanisms of action of these compounds are required to confirm the in vitro pharmacological claims of flavonoids for pharmaceutical applications. HIGHLIGHTS: In the current review, we have tried to compile recent discoveries on natural and synthetic flavonoids as well as their implication in the treatment of malaria, leishmaniasis, Chagas disease, and dengue. A total of 373 (220 natural and 153 synthetic) flavonoids have been evaluated for antimalarial, antileishmanial, antichagasic, and antidengue activities. Most of these flavonoids showed promising results against the above diseases. Reports on molecular modeling of flavonoid compounds to the disease target indicated encouraging results. Flavonoids can be prospected as potential leads for drug development; however, more rigorously designed studies on toxicity and pharmacokinetics, as well as the quantitative structure-activity relationship studies of these compounds, need to be addressed.


Assuntos
Doença de Chagas/tratamento farmacológico , Dengue/tratamento farmacológico , Flavonoides/uso terapêutico , Leishmaniose/tratamento farmacológico , Malária/tratamento farmacológico , Doenças Negligenciadas/tratamento farmacológico , Humanos
13.
Biomed Res Int ; 2019: 6478187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467904

RESUMO

Aloe vera is a multifunctional plant that has gained acceptance as an excellent home remedy source in Asia and the world. The present study was intended to evaluate the phytochemical contents and in vitro antioxidant, antimicrobial, antileishmanial, and protein kinase inhibition activities in different fractions of A. vera leaf. Methanolic extract of A. vera leaves was fractionated using column chromatography and ten fractions (AV1-AV10) were obtained. Phenolics composition, antioxidant, antimicrobial, antileishmanial, and protein kinase inhibition activities were evaluated using standard protocols. Well-known compounds of A. vera were used for in silico study against enzymes involved in brine shrimp and antileishmanial and hyphae formation inhibition assay on the basis of results. Five fractions (AV3 to AV7) possess potential total phenolics and flavonoids contents along with significant biological activities. AV4 fraction exhibited the highest total phenolics content 332.4 ± 32.6µg GAE/mg and total antioxidant activity 150.4 ± 25.815µg AAE/mg determined by phosphomolybdenum complex assay. Fraction AV6 showed 95% antileishmanial effect as well as the lowest LD50 value of 0.5305µg/mL in brine shrimp lethality assay. The Protein Kinase inhibition potential in A. vera leaves was determined for the first time and three fractions AV1, AV6, and AV7 depicted activity with the highest zone of inhibition up to 21±0.5mm (AV7). Docking analysis showed that A. vera contains anthraquinones, anthrones, chromones, and polysaccharides responsible for synergistic cytotoxic, antileishmanial, antibacterial, and antioxidant potential of this plant. Therefore, with more studies, A. vera could probably have the potential to be used for drug development against leishmaniasis.


Assuntos
Aloe/química , Proliferação de Células/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Extratos Vegetais/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Humanos , Leishmaniose/parasitologia , Simulação de Acoplamento Molecular , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
14.
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
15.
Parasitol Int ; 73: 101966, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31362122

RESUMO

The identification of new therapeutics to treat leishmaniasis is desirable, since available drugs are toxic and present high cost and/or poor availability. Therefore, the discovery of safer, more effective and selective pharmaceutical options is of utmost importance. Efforts towards the development of new candidates based on molecule analogs with known biological functions have been an interesting and cost-effective strategy. In this context, quinoline derivatives have proven to be effective biological activities against distinct diseases. In the present study, a new chloroquinoline derivate, AM1009, was in vitro tested against two Leishmania species that cause leishmaniasis. The present study analyzed the necessary inhibitory concentration to preclude 50% of the Leishmania promastigotes and axenic amastigotes (EC50 value), as well as the inhibitory concentrations to preclude 50% of the murine macrophages and human red blood cells (CC50 and RBC50 values, respectively). In addition, the treatment of infected macrophages and the inhibition of infection using pre-treated parasites were also investigated, as was the mechanism of action of the molecule in L. amazonensis. To investigate the in vivo therapeutic effect, BALB/c mice were infected with L. amazonensis and later treated with AM1009. Parasitological and immunological parameters were also evaluated. Clioquinol, a known antileishmanial quinoline derivate, and amphotericin B (AmpB), were used as molecule and drug controls, respectively. Results in both in vitro and in vivo experiments showed a better and more selective action of AM1009 to kill the in vitro parasites, as well as in treating infected mice, when compared to results obtained using clioquinol or AmpB. AM1009-treated animals presented significantly lower average lesion diameter and parasite burden in the infected tissue and organs evaluated in this study, as well as a more polarized antileishmanial Th1 immune response and low renal and hepatic toxicity. This result suggests that AM1009 should be considered a possible therapeutic target to be evaluated in future studies for treatment against leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Quinolinas/farmacologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Especificidade da Espécie
16.
Int J Antimicrob Agents ; 54(4): 496-501, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31323307

RESUMO

Leishmania parasites are the causative agents of a wide spectrum of human diseases. The clinical manifestations of leishmaniasis range from self-healing skin lesions to fatality. The World Health Organization has classed leishmaniasis as a category 1 neglected tropical disease. Leishmaniasis represents a major international health challenge, affecting 12 million people per year and with nearly 310 million people at risk. The first-line chemotherapies used to treat leishmaniasis are intravenous pentavalent antimonials; however, these drugs are highly toxic. As the use of oral treatment options such as paromomycin and miltefosine has increased, the incidence of disease relapse has increased and drug resistance to antimonials has developed, emphasizing the importance of identifying new chemotherapies. A novel, target-free fluorometric high-throughput screen with an average Z-score of 0.73 +/- 0.13 has been developed to identify small molecules with antileishmanial activity. Screening of 10,000 small molecules from the ChemBridge DIVER-set™ library cassette #5 yielded 210 compounds that killed 80% of parasites, resulting in a hit rate of 2.1%. One hundred and nine molecular scaffolds were represented within the hit compounds, and one scaffold that exhibited potent antileishmanial activity was 2,4-diaminoquinazoline. Host cell toxicity was determined prior to in-vitro infection of human THP-1 macrophages with Leishmania donovani mCherry expressing promastigotes; successful drug treatment was considered when the half maximal inhibitory concentration was <10 µM. BALB/c mice were infected with Leishmania major mCherry promastigotes and treated with small molecules that were successful during in-vitro infections. Several small molecules tested were as efficacious at resolving cutaneous leishmaniasis lesions in mice as known antimonial treatments.


Assuntos
Antiprotozoários/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala , Leishmania donovani/efeitos dos fármacos , Leishmania major/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/farmacologia , Modelos Animais de Doenças , Feminino , Fluorometria/métodos , Humanos , Camundongos Endogâmicos BALB C , Recidiva , Células THP-1/parasitologia , Resultado do Tratamento
17.
Artigo em Inglês | MEDLINE | ID: mdl-31214516

RESUMO

Leishmaniases are neglected tropical diseases that threaten about 350 million people in 98 countries around the world. In order to find new antileishmanial drugs, an original approach consists in reducing the pathogenic effect of the parasite by impairing the glycoconjugate biosynthesis, necessary for parasite recognition and internalization by the macrophage. Some proteins appear to be critical in this way, and one of them, the GDP-Mannose Pyrophosphorylase (GDP-MP), is an attractive target for the design of specific inhibitors as it is essential for Leishmania survival and it presents significant differences with the host counterpart. Two GDP-MP inhibitors, compounds A and B, have been identified in two distinct studies by high throughput screening and by a rational approach based on molecular modeling, respectively. Compound B was found to be the most promising as it exhibited specific competitive inhibition of leishmanial GDP-MP and antileishmanial activities at the micromolar range with interesting selectivity indexes, as opposed to compound A. Therefore, compound B can be used as a pharmacological tool for the development of new specific antileishmanial drugs.


Assuntos
Antiprotozoários/farmacologia , Desenvolvimento de Medicamentos , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Nucleotidiltransferases/antagonistas & inibidores , Biologia Computacional , Desenho de Drogas , Glicoconjugados , Humanos , Leishmania/metabolismo , Modelos Moleculares , Nucleotidiltransferases/metabolismo
18.
Curr Pharm Des ; 25(14): 1582-1592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223081

RESUMO

BACKGROUND: Leishmania are sandfly-transmitted protozoan parasites that harbour within the macrophages of a mammalian host and cause leishmaniasis, a serious zoonotic disease that threatens the lives of millions worldwide. Its numerous forms (cutaneous, mucocutaneous, and visceral) are currently treated with a sparse arsenal of drugs, specifically antimonials, amphotericin B, miltefosine, and paromomycin, for which drug resistance and clinical failure are rampant. Medicine is presently trending towards nanotechnology to aid in the successful delivery of drugs. Vehicles such as lipid-based nanocarriers, polymer-based nanoparticles, and metal ions and oxides have been previously demonstrated to improve bioavailability of drugs and decrease toxicity for the patient. These cutting-edge solutions can be combined with existing active molecules, as well as novel drugs or plant extracts with promising antileishmanial activity. CONCLUSION: This review explores the current evidence for the treatment of leishmaniases using nanoscale drug delivery systems (specifically lipid-, polymer- and metal-based systems) and encourages further development of the aforementioned nanotechnologies for treatment of Leishmania.


Assuntos
Antiprotozoários/administração & dosagem , Sistemas de Liberação de Medicamentos , Leishmaniose/tratamento farmacológico , Nanopartículas , Animais , Emulsões , Humanos , Leishmania , Lipídeos , Lipossomos
19.
Expert Opin Drug Metab Toxicol ; 15(7): 595-612, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31174439

RESUMO

Introduction: Being on the top list of neglected tropical diseases, leishmaniasis has been marked for elimination by 2020. In the light of small armamentarium of drugs and their associated drawbacks, the understanding of pharmacodynamics and/or pharmacokinetics becomes a priority to achieve and sustain disease elimination. Areas covered: The authors have looked into pharmacological aspects of existing and emerging drugs for treatment of leishmaniasis. An in-depth understanding of pharmacodynamics and pharmacokinetics (PKPD) provides a rationale for drug designing and optimizing the treatment strategies. It forms a key to prevent drug resistance and avoid drug-associated adverse effects. The authors have compiled the researches on the PKPD of different anti-leishmanial formulations that have the potential for improved and/or effective disease intervention. Expert opinion: Understanding the pharmacological aspects of drugs forms the basis for the clinical application of novel drugs. Tailoring drug dosage and individualized treatment can avoid the adverse events and bridge gap between the in vitro models and their clinical application. An integrated approach, with pragmatic use of technological advances can improve phenotypic screening and physiochemical properties of novel drugs. Concomitantly, this can serve to improve clinical efficacies, reduce the incidence of relapse and accelerate the drug discovery/development process for leishmaniasis elimination.


Assuntos
Antiprotozoários/administração & dosagem , Desenvolvimento de Medicamentos/métodos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/farmacocinética , Antiprotozoários/farmacologia , Relação Dose-Resposta a Droga , Desenho de Drogas , Descoberta de Drogas/métodos , Resistência a Medicamentos , Humanos , Leishmaniose/parasitologia
20.
J Vet Cardiol ; 23: 32-37, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31174727

RESUMO

A 4-year-old crossbreed dog presented with a two-day history of lethargy and abdominal effusion. Physical examination and echocardiography revealed pericardial effusion with cardiac tamponade. Pericardiocentesis was performed. Intracytoplasmic Leishmania amastigotes were found on cytological examination of the pericardial fluid. The animal was treated with N-methylglucamine antimoniate and allopurinol. After an initial favorable response, cardiac tamponade reoccurred one month later. The dog died during a pericardiectomy four months after the initial diagnosis. Histology confirmed the presence of chronic pericarditis. The presence of Leishmania amastigotes on cytological examination of pericardial effusion suggests a possible association between canine leishmaniasis and chronic pericarditis. This finding also supports the importance of cytological examination of pericardial fluid in areas endemic for canine leishmaniasis.


Assuntos
Doenças do Cão/parasitologia , Leishmaniose/veterinária , Derrame Pericárdico/veterinária , Alopurinol/uso terapêutico , Animais , Antiprotozoários/uso terapêutico , Tamponamento Cardíaco/veterinária , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/fisiopatologia , Cães , Ecocardiografia/veterinária , Leishmania/isolamento & purificação , Leishmaniose/complicações , Leishmaniose/tratamento farmacológico , Antimoniato de Meglumina/uso terapêutico , Derrame Pericárdico/diagnóstico por imagem , Derrame Pericárdico/parasitologia , Líquido Pericárdico/parasitologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA