Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 32
Filter
1.
Mem. Inst. Oswaldo Cruz ; 116: e210207, 2021. tab, graf
Article in English | LILACS | ID: biblio-1346578

ABSTRACT

BACKGROUND Treatment of mycoses is often ineffective, usually prolonged, and has some side effects. These facts highlight the importance of discovering new molecules to treat fungal infections. OBJECTIVES To search the Medicines for Malaria Venture COVID Box for drugs with antifungal activity. METHODS Fourteen human pathogenic fungi were tested against the 160 drugs of this collection at 1.0 µM concentration. We evaluated the ability of the drugs to impair fungal growth, their fungicidal nature, and morphological changes caused to cells. FINDINGS Thirty-four molecules (21.25%) presented antifungal activity. Seven are antifungal drugs and one is the agricultural fungicide cycloheximide. The other drugs with antifungal activity included antibiotics (n = 3), antimalarials (n = 4), antivirals (n = 2), antiparasitcs (n = 3), antitumor agents (n = 5), nervous system agents (n = 3), immunosuppressants (n = 3), antivomiting (n = 1), antiasthmatic (n = 1), and a genetic disorder agent (n = 1). Several of these drugs inhibited Histoplasma capsulatum and Paracoccidioides brasiliensis growth (15 and 20, respectively), while Fusarium solani was not affected by the drugs tested. Most drugs were fungistatic, but niclosamide presented fungicidal activity against the three dimorphic fungi tested. Cyclosporine affected morphology of Cryptococcus neoformans. MAIN CONCLUSIONS These drugs represent new alternatives to the development of more accessible and effective therapies to treat human fungal infections.


Subject(s)
Humans , Pharmaceutical Preparations , Cryptococcus neoformans , COVID-19 , Malaria/drug therapy , Microbial Sensitivity Tests , Drug Repositioning , SARS-CoV-2 , Antifungal Agents/therapeutic use , Antifungal Agents/pharmacology
2.
Arq. bras. oftalmol ; 83(4): 329-331, July-Aug. 2020. graf
Article in English | LILACS | ID: biblio-1131599

ABSTRACT

ABSTRACT Despite the recent developments in modern cataract surgery and the application of a vast array of new devices and machines, late in-the-bag intraocular lens dislocation remains a devastating, albeit rare, complication. Various nonsurgical and surgical techniques have been used to manage this complication. We report a case of spontaneous repositioning in the left eye of an anteriorly subluxated in-the-bag intraocular lens. The spontaneous repositioning may have been caused by antagonistic effects related to the topical administration of brimonidine and prednisolone. The dislocation was treated without aggressive manipulation or surgical intervention.


RESUMO Apesar dos recentes avanços na cirurgia moderna de catarata e da aplicação de uma ampla gama de novos dispositivos, o deslocamento tardio de uma lente intraocular dentro do saco capsular continua a ser uma complicação devastadora, ainda que rara. Várias técnicas cirúrgicas e não cirúrgicas têm sido usadas para tratar esta complicação. Este é o relato de um caso de reposicionamento espontâneo de uma lente intraocular sub-luxada anteriormente dentro do saco capsular do olho esquerdo. Este reposicionamento pode ter sido causado pelos efeitos opostos da aplicação tópica simultânea de brimonidina e prednisolona. O deslocamento foi tratado sem manipulação agressiva ou intervenção cirúrgica.


Subject(s)
Humans , Drug Repositioning , Lenses, Intraocular , Postoperative Complications , Visual Acuity , Lens Subluxation , Retrospective Studies
3.
Article in English | WPRIM | ID: wpr-827077

ABSTRACT

OBJECTIVE@#To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening.@*METHODS@#The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper.@*RESULTS@#It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score.@*CONCLUSIONS@#A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.


Subject(s)
China , Computer Simulation , Coronavirus Infections , Diagnosis , Drug Therapy , Drug Repositioning , Methods , Drugs, Chinese Herbal , Pharmacology , Glycoproteins , Metabolism , Humans , Imaging, Three-Dimensional , Mass Screening , Methods , Molecular Docking Simulation , Methods , Pandemics , Peptidyl-Dipeptidase A , Pneumonia, Viral , Diagnosis , Drug Therapy , Protein Binding , United States , United States Food and Drug Administration
4.
Mem. Inst. Oswaldo Cruz ; 115: e200254, 2020. tab, graf
Article in English | LILACS, SES-SP | ID: biblio-1135246

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious infection that may break the healthcare system of several countries. Here, we aimed at presenting a critical view of ongoing drug repurposing efforts for COVID-19 as well as discussing opportunities for development of new treatments based on current knowledge of the mechanism of infection and potential targets within. Finally, we also discuss patent protection issues, cost effectiveness and scalability of synthetic routes for some of the most studied repurposing candidates since these are key aspects to meet global demand for COVID-19 treatment.


Subject(s)
Humans , Pneumonia, Viral/drug therapy , Coronavirus Infections/drug therapy , Drug Discovery , Drug Repositioning , Pandemics , Betacoronavirus , SARS-CoV-2 , COVID-19
5.
Rev. panam. salud pública ; 44: e40, 2020. tab
Article in English | LILACS | ID: biblio-1101783

ABSTRACT

ABSTRACT The World Health Organization (WHO) was informed on December 2019 about a coronavirus pneumonia outbreak in Wuhan, Hubei province (China). Subsequently, on March 12, 2020, 125,048 cases and 4,614 deaths were reported. Coronavirus is an enveloped RNA virus, from the genus Betacoronavirus, that is distributed in birds, humans, and other mammals. WHO has named the novel coronavirus disease as COVID-19. More than 80 clinical trials have been launched to test coronavirus treatment, including some drug repurposing or repositioning for COVID-19. Hence, we performed a search in March 2020 of the clinicaltrials.gov database. The eligibility criteria for the retrieved studies were: contain a clinicaltrials.gov base identifier number; describe the number of participants and the period for the study; describe the participants' clinical conditions; and utilize interventions with medicines already studied or approved for any other disease in patients infected with the novel coronavirus SARS-CoV-2 (2019-nCoV). It is essential to emphasize that this article only captured trials listed in the clinicaltrials.gov database. We identified 24 clinical trials, involving more than 20 medicines, such as human immunoglobulin, interferons, chloroquine, hydroxychloroquine, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, methylprednisolone, bevacizumab, and traditional Chinese medicines (TCM). Although drug repurposing has some limitations, repositioning clinical trials may represent an attractive strategy because they facilitate the discovery of new classes of medicines; they have lower costs and take less time to reach the market; and there are existing pharmaceutical supply chains for formulation and distribution.(AU)


RESUMEN En diciembre de 2019 fue informado a la Organización Mundial de la Salud (OMS) un brote de neumonía por coronavirus en Wuhan, provincia de Hubei, China. Al 12 de marzo de 2020, se habían notificado 125 048 casos y 4 614 muertes. El coronavirus es un virus ARN envuelto del género Betacoronavirus distribuido en aves, seres humanos y otros mamíferos. La OMS ha denominado a la nueva enfermedad por coronavirus COVID-19. Se han puesto en marcha más de 80 ensayos clínicos para evaluar un tratamiento para el coronavirus, que incluyen algunos ensayos de reposicionamiento de medicamentos para la COVID-19. En marzo de 2020 se llevó a cabo una búsqueda de los ensayos clínicos registrados en la base de datos clinicaltrials.gov. Los criterios de elegibilidad para los estudios recuperados fueron tener un número de identificación de la base de datos clinicaltrials.gov; describir el número de participantes y el período del estudio; describir las condiciones clínicas de los participantes; y emplear intervenciones con medicamentos ya estudiados o aprobados para cualquier otra enfermedad en pacientes infectados con el nuevo coronavirus SARS-CoV-2 (2019-nCoV). Es esencial destacar que este artículo solo recoge los ensayos que figuran en la base de datos clinicaltrials. gov. Se identificaron 24 ensayos clínicos relacionados con más de 20 medicamentos, como inmunoglobulina humana, interferones, cloroquina, hidroxicloroquina, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, metilprednisolona, bevacizumab y medicina tradicional china. Aunque el reposicionamiento de medicamentos tiene algunas limitaciones, el reposicionamiento de los ensayos clínicos puede representar una estrategia atractiva porque facilita el descubrimiento de nuevas clases de medicamentos; estos tienen costos más bajos y tardan menos en llegar al mercado; y existen cadenas de suministro farmacéutico que apoyan la formulación y la distribución.(AU)


RESUMO A Organização Mundial da Saúde (OMS) foi informada, em dezembro de 2019, sobre um surto de pneumonia por coronavírus em Wuhan, província de Hubei (China). Posteriormente, em 12 de março de 2020, 125 048 casos e 4 614 mortes haviam sido registrados. O coronavírus é um vírus RNA envelopado do gênero Betacoronavírus, distribuído em aves e em humanos e outros mamíferos. A OMS designou a nova doença por coronavírus como COVID-19. Mais de 80 ensaios clínicos foram iniciados para testar tratamentos para o coronavírus, incluindo alguns de reposicionamento de medicamentos para o COVID-19. Assim, em março de 2020 realizou-se uma busca na base de dados clinicaltrials.gov. Os critérios de elegibilidade para os estudos recuperados foram: conter o número identificador da base de dados clinicaltrials.gov; descrever o número de participantes e o período do estudo; descrever as condições clínicas dos participantes; e utilizar intervenções para tratamento de doentes infectados com o novo coronavírus SARS-CoV-2 (2019-nCoV) com medicamentos já estudados ou aprovados para qualquer outra doença. É essencial salientar que este artigo apenas capturou ensaios listados na base de dados clinicaltrials.gov. Foram identificados 24 ensaios clínicos envolvendo mais de 20 medicamentos, tais como imunoglobulina humana, interferons, cloroquina, hidroxicloroquina, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, metilprednisolona, bevacizumabe e medicamentos chineses tradicionais. Embora o reposicionamento de medicamentos tenha algumas limitações, os ensaios clínicos de reposicionamento podem representar uma estratégia atraente, porque facilitam a descoberta de novas classes de medicamentos, têm custos mais baixos, levam menos tempo para chegar ao mercado e se beneficiam de cadeias de fornecimento farmacêutico já existentes para formulação e distribuição.(AU)


Subject(s)
Humans , Antiviral Agents/therapeutic use , Pneumonia, Viral/drug therapy , Clinical Trials as Topic , Coronavirus Infections/drug therapy , Drug Repositioning
6.
Article in English | WPRIM | ID: wpr-827439

ABSTRACT

OBJECTIVE@#To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening.@*METHODS@#The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper.@*RESULTS@#It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score.@*CONCLUSIONS@#A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.


Subject(s)
China , Computer Simulation , Coronavirus Infections , Diagnosis , Drug Therapy , Drug Repositioning , Methods , Drugs, Chinese Herbal , Pharmacology , Glycoproteins , Metabolism , Humans , Imaging, Three-Dimensional , Mass Screening , Methods , Molecular Docking Simulation , Methods , Pandemics , Peptidyl-Dipeptidase A , Pneumonia, Viral , Diagnosis , Drug Therapy , Protein Binding , United States , United States Food and Drug Administration
7.
Article in English | WPRIM | ID: wpr-719248

ABSTRACT

Ovarian cancer is the seventh most common cancer and the eighth most common cause of cancer mortality in women. Although standard chemotherapy is the established treatment for ovarian cancer, the prognosis remains poor, and it is highly anticipated that new drugs will be developed. New drugs, such as humanized anti-vascular endothelial growth factor monoclonal antibodies and poly ADP-ribose polymerase inhibitors, are expected to improve clinical outcomes of ovarian cancer. However, long-term, costly research is required to develop such new drugs, and soaring national healthcare costs are becoming a concern worldwide. In this social context, drug repositioning, wherein existing drugs are used to develop drugs with new indications for other diseases, has recently gained attention. Because trials have already confirmed the safety in humans and the pharmacokinetics of such drugs, the development period is shorter than the conventional development of a new drug, thereby reducing costs. This review discusses the available basic experimental and clinical data on drugs used for other types of cancer for which drug repositioning is anticipated to repurpose the drug for the treatment of ovarian cancer. These include statins, which are used to treat dyslipidemia; bisphosphonate, which is used to treat osteoporosis; metformin, which is used to treat diabetes; non-steroidal anti-inflammatory drugs; ivermectin, an antiparasitic agent; and itraconazole, an anti-fungal agent. These drugs will play an important role in future drug repositioning strategies for ovarian cancer. Furthermore, drug repositioning is anticipated to extend not only to ovarian cancer treatment but also to ovarian cancer prevention.


Subject(s)
Adenosine Diphosphate Ribose , Anti-Inflammatory Agents, Non-Steroidal , Antibodies, Monoclonal , Drug Repositioning , Drug Therapy , Dyslipidemias , Endothelial Growth Factors , Female , Health Care Costs , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Itraconazole , Ivermectin , Metformin , Mortality , Osteoporosis , Ovarian Neoplasms , Pharmacokinetics , Prognosis
8.
Article in English | WPRIM | ID: wpr-763809

ABSTRACT

Automatically detecting mentions of pharmaceutical drugs and chemical substances is key for the subsequent extraction of relations of chemicals with other biomedical entities such as genes, proteins, diseases, adverse reactions or symptoms. The identification of drug mentions is also a prior step for complex event types such as drug dosage recognition, duration of medical treatments or drug repurposing. Formally, this task is known as named entity recognition (NER), meaning automatically identifying mentions of predefined entities of interest in running text. In the domain of medical texts, for chemical entity recognition (CER), techniques based on hand-crafted rules and graph-based models can provide adequate performance. In the recent years, the field of natural language processing has mainly pivoted to deep learning and state-of-the-art results for most tasks involving natural language are usually obtained with artificial neural networks. Competitive resources for drug name recognition in English medical texts are already available and heavily used, while for other languages such as Spanish these tools, although clearly needed were missing. In this work, we adapt an existing neural NER system, NeuroNER, to the particular domain of Spanish clinical case texts, and extend the neural network to be able to take into account additional features apart from the plain text. NeuroNER can be considered a competitive baseline system for Spanish drug and CER promoted by the Spanish national plan for the advancement of language technologies (Plan TL).


Subject(s)
Drug Repositioning , Learning , Machine Learning , Natural Language Processing , Neural Networks, Computer , Neurons , Running
9.
Article in English | WPRIM | ID: wpr-761934

ABSTRACT

Although sciences and technology have progressed rapidly, de novo drug development has been a costly and time-consuming process over the past decades. In view of these circumstances, ‘drug repurposing’ (or ‘drug repositioning’) has appeared as an alternative tool to accelerate drug development process by seeking new indications for already approved drugs rather than discovering de novo drug compounds, nowadays accounting for 30% of newly marked drugs in the U.S. In the meantime, the explosive and large-scale growth of molecular, genomic and phenotypic data of pharmacological compounds is enabling the development of new area of drug repurposing called computational drug repurposing. This review provides an overview of recent progress in the area of computational drug repurposing. First, it summarizes available repositioning strategies, followed by computational methods commonly used. Then, it describes validation techniques for repurposing studies. Finally, it concludes by discussing the remaining challenges in computational repurposing.


Subject(s)
Data Mining , Drug Repositioning , Machine Learning
10.
São Paulo; s.n; 2019. 151 p. ilus.
Thesis in Portuguese | LILACS, SES-SP, SESSP-CTDPROD, SES-SP, SESSP-ACVSES | ID: biblio-1051680

ABSTRACT

A leishmaniose visceral (LV) é uma doença infecciosa sistêmica, causada pelos parasitos protozoários do gênero Leishmania, endêmica em países tropicais e subtropicais. Por acometer principalmente populações de baixa renda em países em desenvolvimento e subdesenvolvidos, a leishmaniose se encaixa no perfil das doenças negligenciadas, em razão de seu baixo retorno financeiro para a indústria farmacêutica. Devido ao alto custo, restrições e efeitos colaterais dos atuais fármacos utilizados na terapêutica da leishmaniose, há a real necessidade de identificar e desenvolver novas alternativas como a de reposicionamento de fármacos, que se trata de uma nova indicação terapêutica para um fármaco já disponibilizado no mercado. Desta forma, o objetivo deste trabalho foi avaliar a atividade antileishmania de fármacos anti-histamínicos e identificar marcadores celulares e moleculares relacionados à resposta terapêutica, usando um sistema de infecção in vitro. Foram realizados em Leishmania (Leishmania) intantum: i) a triagem de quatro fármacos anti-histamínicos, sendo eles: cetirizina (CTZ), ciproeptadina (CPH), fexofenadina (FXF) e meclizina (MCZ); ii) o estudo das alterações celulares e moleculares com o fármaco cinarizina (CNZ) e os que apresentaram atividade contra a forma amastigota. Para isto, foi feito estudos de concentração efetiva 50% (CE50) em promastigota e amastigota de L. (L.) infantum, concentração citotóxica 50% (CC50) em células de mamífero e após foram analisadas a permeabilidade de membrana plasmática, o potencial de membrana mitocondrial, a produção de espécies reativas de oxigênio (ERO) e a produção de tióis por meio de ensaios fluorimétricos e as ultra-estruturas celulares por microscopia eletrônica de transmissão e o perfil de expressão gênica por qPCR. Os resultados mostraram que CPH e MCZ apresentaram atividade antileishmania contra promastigotas, com CE50 de 7 e 22 µM, respectivamente. CPH e MCZ eliminaram os amastigotas, com CE50 de 30 e 35 µM, respectivamente. Os fármacos CTZ e FXF não apresentaram atividade contra ambas as formas do parasito. CNZ, CPH e MCZ provocaram em promastigota: i) alteração na permeabilidade da membrana plasmática; ii) despolarização do potencial de membrana mitocondrial, provocando danos celulares associados com o sistema bioenergético; iii) alteração no perfil de expressão gênica de 11 genes que codificam para diferentes funções celulares. Estes dados, além de apresentarem resultados direto para o tratamento das leishmanioses, com o desenvolvimento de novas alternativas, apresenta um grande potencial como sistema de avaliação de resposta terapêutica de vários tipos de fármacos.


Subject(s)
Drug Repositioning , Leishmania , Leishmaniasis, Visceral
11.
Rio de Janeiro; s.n; 2019. xvii, 86 p. ilus.
Thesis in Portuguese | LILACS | ID: biblio-1026712

ABSTRACT

As peptidases do Trypanosoma cruzi, agente etiológico da doença de Chagas, são importantes fatores de virulência e alvo para quimioterapia. As aspártico peptidases ainda não foram caracterizadas neste parasito, porém, inibidores de aspártico peptidase do vírus da imunodeficiência humana (IPs-HIV) tem ação tripanocida. O objetivo desse trabalho é caracterizar as aspártico peptidases em T. cruzi. Através de análises in silico, identificamos que dos três genes anotados como aspártico peptidases, dois genes, Presenilina símile (PS) e Peptidase Peptideo Sinal símile (PPs símile), compartilham o mesmo domínio proteico, o domínio PSN (Presenilin/Signalpeptideo peptidase familly). A presenilina símile de T. cruzi possui nove domínios transmembranas e uma ampla dobra entre os domínios seis e sete, que resulta em uma espaçosa região hidrofóbica, o que indica que a presenilina símile de T. cruzi possui uma estrutura secundária altamente similar e indispensável para origem de uma presenilina ativa. A PPs símile de T. cruzi possui uma sequência de múltiplas passagens pela membrana, e revela uma grande semelhança com as presenilinas, incluindo a conservação do seu domínio. O gene anotado como DNA damage inducible Ddi 1 (Ddi 1 símile) possui o domínio retroviral peptidase (RVP), característico dessa família de peptidases. A Ddi 1 símile de T. cruzi possui o domínio UBL (ubiquitina símile)


A modelagem molecular do domínio (RVP) da proteína Ddi 1 símile de T. cruzi mostrou que esse domínio forma um homodímero que é característico das aspártico peptidases da família A2, e que cada monômero possui a sequência conservada Asp-Ser-Gly-Ala. O estudo de atração molecular (docking) mostrou uma diferente afinidade dos IPs-HIV pelo sítio ativo do domínio RVP da proteína, enquanto que pepstatina A e benzonidazol, controles positivo e negativo, apresentaram os melhores e piores índices de docking, respectivamente. Uma proteína heteróloga Ddi 1 símile foi expressa em Escherichia coli e purificada. A enzima purificada não apresentou atividade proteolítica contra substrato fluorogênico específico para Catepsina D, indicando que alterações estruturais importantes ocorreram na enzima heteróloga. O extrato total de E. coli, rico na proteína induzida, não foi capaz de degradar soro albumina bovina. Os IPs-HIV possuem ação tripanocida, porém o alvo intracelular e mecanismo de ação ainda não estão elucidados. Esse trabalho traz importantes contribuições para este campo, e abre perspectivas de explorar esta enzima para o desenho de novos fármacos, ou para modificações químicas nos IPs-HIV disponíveis para aumentar sua especificidade e potência. (AU)


Subject(s)
Animals , Chagas Disease , Drug Therapy , Neglected Diseases , Drug Repositioning
12.
Article in English | WPRIM | ID: wpr-766013

ABSTRACT

BACKGROUND: Development of chemotherapeutics for the treatment of advanced hepatocellular carcinoma (HCC) has been lagging. Screening of candidate therapeutic agents by using patient-derived preclinical models may facilitate drug discovery for HCC patients. METHODS: Four primary cultured HCC cells from surgically resected tumor tissues and six HCC cell lines were used for high-throughput screening of 252 drugs from the Prestwick Chemical Library. The efficacy and mechanisms of action of the candidate anti-cancer drug were analyzed via cell viability, cell cycle assays, and western blotting. RESULTS: Guanabenz acetate, which has been used as an antihypertensive drug, was screened as a candidate anti-cancer agent for HCC through a drug sensitivity assay by using the primary cultured HCC cells and HCC cell lines. Guanabenz acetate reduced HCC cell viability through apoptosis and autophagy. This occurred via inhibition of growth arrest and DNA damage-inducible protein 34, increased phosphorylation of eukaryotic initiation factor 2α, increased activating transcription factor 4, and cell cycle arrest. CONCLUSIONS: Guanabenz acetate induces endoplasmic reticulum stress–related cell death in HCC and may be repositioned as an anti-cancer therapeutic agent for HCC patients.


Subject(s)
Activating Transcription Factor 4 , Apoptosis , Autophagy , Blotting, Western , Carcinoma, Hepatocellular , Cell Cycle , Cell Cycle Checkpoints , Cell Death , Cell Line , Cell Survival , DNA , Drug Discovery , Drug Repositioning , Endoplasmic Reticulum , Guanabenz , Humans , Mass Screening , Peptide Initiation Factors , Phosphorylation , Primary Cell Culture
14.
J. bras. pneumol ; 44(2): 153-160, Mar.-Apr. 2018. tab
Article in English | LILACS | ID: biblio-893913

ABSTRACT

ABSTRACT Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the "white plague", and promising results are being reported.


RESUMO A tuberculose multirresistente (TB-MDR, do inglês multidrug-resistant) e a extensivamente resistente (TB-XDR, do inglês extensively drug-resistant) continuam representando um desafio para os clínicos e as autoridades de saúde pública. Infelizmente, embora haja relatos encorajadores de taxas de sucesso maiores, a taxa global de desfechos favoráveis do tratamento da TB-MDR/XDR é de apenas 54%, ou muito menor quando o espectro de resistência aos fármacos vai além do da TB-XDR. O tratamento da TB-MDR/XDR continua sendo uma tarefa difícil, em razão da alta incidência de eventos adversos, do longo tempo de tratamento, do alto culto dos esquemas utilizados e da drenagem dos recursos de saúde. Diversos ensaios e estudos foram realizados recentemente (alguns já publicados e outros em andamento), todos visando a melhorar os desfechos do tratamento da TB-MDR/XDR por meio da alteração da abordagem geral, redução do tempo de tratamento e desenvolvimento de um esquema universal. O objetivo desta revisão foi resumir o que se conseguiu até o momento, no que se refere a novos fármacos e fármacos repropostos, dando foco especial para delamanid, bedaquilina, pretomanida, clofazimina, carbapenêmicos e linezolida. Após mais de 40 anos de negligência, recentemente foi dada mais atenção á necessidade de novos fármacos para se combater a "praga branca", e resultados promissores estão sendo relatados.


Subject(s)
Humans , Extensively Drug-Resistant Tuberculosis/drug therapy , Drug Repositioning , Antitubercular Agents/therapeutic use , Oxazoles/therapeutic use , Clinical Trials as Topic , Diarylquinolines/therapeutic use , Nitroimidazoles/therapeutic use , Antitubercular Agents/classification
15.
São Paulo; s.n; 2018. 159 p. graf, tab.
Thesis in Portuguese | LILACS, SES-SP, SESSP-CTDPROD, SES-SP, SESSP-ACVSES | ID: biblio-972115

ABSTRACT

A leishmaniose é uma doença tropical causada por protozoários do gêneroLeishmania que afeta 12 milhões de pessoas em 98 países. Seu tratamentoconta com um restrito arsenal terapêutico e exige a administração defármacos tóxicos por longos períodos. Na busca por novas terapias, oreposicionamento de fármacos e a associação terapêutica têm sidoaplicados com sucesso para doenças negligenciadas. O presente estudoteve como objetivo a avaliação in vitro, ex vivo e in vivo do potencial antiLeishmania(Leishmania) amazonensis dos fármacos amitriptilina, econazol,sertralina e triclosan, bem como o estudo de associações terapêuticas invitro e/ou ex vivo e mecanismo de ação in vitro dos fármacos amitriptilina etriclosan. Os resultados demonstraram que todos os fármacos estudados apresentaram atividade contra formas promastigotas e amastigotasintracelulares de L. (L.) amazonensis, com valores de Concentração Efetiva50% que variam de 1,50 a 51,48 µM. Os resultados obtidos a partir das associações entre os fármacos estudados e fármacos padrões foram classificados como aditivos ou indiferentes. Por meio da investigação domecanismo de ação leishmanicida, foi possível concluir que a mitocôndria é uma organela alvo do fármaco amitriptilina, enquanto que o fármaco triclosaninduz danos à membrana plasmática parasitária. Quando tratados comeconazol por via oral (10 mg/kg/dia por 28 dias consecutivos) ou triclosanpor via tópica (creme 1% por 14 dias consecutivos), houve uma redução de75 a 89% da carga parasitária dos camundongos infectados com L. (L.) amazonensis. Os resultados obtidos contribuem para a investigação de novas alternativas para o tratamento da leishmaniose cutânea e sugerem que novos estudos utilizando associação ou coadministração dessesfármacos com fármacos padrões podem ser promissores em modelosanimais.


Leishmaniasis is a tropical disease caused by protozoa of the genusLeishmania that affects 12 million people in 98 countries. There is a limitedtherapeutic arsenal and the treatment requires the administration of toxicdrugs for long periods. In the search for new therapies, the drug repositioningand therapeutic association have been successfully applied to neglecteddiseases. The aim of the present study was to evaluate in vitro, ex vivo andin vivo anti-Leishmania (Leishmania) amazonensis potential of the drugsamitriptyline, econazole, sertraline and triclosan, as well as the study of invitro and / or ex vivo therapeutic associations and mechanism of action of thedrugs amitriptyline and triclosan. The results showed that all studied drugshave activity against L. (L.) amazonensis promastigotes and intracellularamastigotes, with 50% Effective Concentration values ranging from 1.50 to51.48 μM. The results obtained from the combination between the studieddrugs and standard drugs were classified as additives or indifferent. Throughthe investigation of the leishmanicial mechanism of action, it was possible toconclude that the mitochondria is a target organelle of the drug amitriptyline,whereas the drug triclosan induces damage to the parasitic plasmamembrane. When treated with oral econazole (10 mg/kg/day for 28consecutive days) or triclosan topically (1% cream for 14 consecutive days),there was a 75 - 89% reduction in the parasite load of the mice infected withL. (L.) amazonensis. The results obtained contribute to the investigation ofnew alternatives for the treatment of cutaneous leishmaniasis and suggestthat new studies using association or coadministration of these drugs withstandard drugs may be promising in animal models.


Subject(s)
Humans , Drug Repositioning , Leishmania/parasitology , Leishmaniasis, Cutaneous , Mice
16.
J. venom. anim. toxins incl. trop. dis ; 24: 30, 2018. tab, graf, ilus
Article in English | ID: biblio-976028

ABSTRACT

Drug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease. Methods: In this work, we studied the activity of the antidepressant drug sertraline against Trypanosoma cruzi trypomastigotes and intracellular amastigotes of the Y and Tulahuen strains, and investigated its action mode using cell biology and in silico approaches. Results: Sertraline demonstrated in vitro efficacy against intracellular amastigotes of both T. cruzi strains inside different host cells, including cardiomyocytes, with IC50 values between 1 to 10 µM, and activity against bloodstream trypomastigotes, with IC50 of 14 µM. Considering the mammalian cytotoxicity, the drug resulted in a selectivity index of 17.8. Sertraline induced a change in the mitochondrial integrity of T. cruzi, resulting in a decrease in ATP levels, but not affecting reactive oxygen levels or plasma membrane permeability. In silico approaches using chemogenomic target fishing, homology modeling and molecular docking suggested the enzyme isocitrate dehydrogenase 2 of T. cruzi (TcIDH2) as a potential target for sertraline. Conclusions: The present study demonstrated that sertraline had a lethal effect on different forms and strains of T. cruzi, by affecting the bioenergetic metabolism of the parasite. These findings provide a starting point for future experimental assays and may contribute to the development of new compounds.(AU)


Subject(s)
Trypanosoma cruzi , In Vitro Techniques , Sertraline , Drug Repositioning
17.
Article in Chinese | WPRIM | ID: wpr-687780

ABSTRACT

<p><b>OBJECTIVE</b>To identify hub genes and key pathways associated with anaplastic thyroid carcinoma (ATC), and to explore possible intervention strategy.</p><p><b>METHODS</b>The differentially expressed genes (DEGs) in ATC were identified by Gene Expression Omnibus (GEO) combined with using R language; the pathway enrichment of DEGs were performed by using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The protein-protein interaction (PPI) network of DEGs was constructed by STRING database and visualized by Cytoscape. Furthermore, the hub genes and key nodes were calculated by MCODE. Finally, the drug repurposing was performed by L1000CDS.</p><p><b>RESULTS</b>A total of 2087 DEGs were identified. The DEGs were clustered based on functions and pathways with significant enrichment analysis, among which PI3K-Akt signaling pathway, p53 signaling pathway, inflammatory response, extracellular matrix organization were significantly upregulated. The PPI network was constructed and the most significant three modules and nine genes were filtered. Twenty-two potential compounds were repurposed for ATC treatment.</p><p><b>CONCLUSIONS</b>Using integrated bioinformatics analysis, we have identified hub genes and key pathways in ATC, and provide novel strategy for the treatment of ATC.</p>


Subject(s)
Computational Biology , Drug Repositioning , Gene Expression Profiling , Humans , Phosphatidylinositol 3-Kinases , Protein Interaction Maps , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms
18.
Braz. J. Pharm. Sci. (Online) ; 53(2): e16087, 2017. tab, graf
Article in English | LILACS | ID: biblio-839493

ABSTRACT

ABSTRACT The discovery of arteannuin (qinghaosu) in the 20th Century was a major advance for medicine. Besides functioning as a malaria therapy, arteannuin is a pharmacological agent in a range of other diseases, but its mechanism of action remains obscure. In this study, the reverse docking server PharmMapper was used to identify potential targets of arteannuin. The results were checked using the chemical-protein interactome servers DRAR-CPI and DDI-CPI, and verified by AutoDock Vina. The results showed that neprilysin (also known as CD10), a common acute lymphoblastic leukaemia antigen, was the top disease-related target of arteannuin. The chemical-protein interactome and docking results agreed with those of PharmMapper, further implicating neprilysin as a potential target. Although experimental verification is required, this study provides guidance for future pharmacological investigations into novel clinical applications for arteannuin.


Subject(s)
Computer Simulation/classification , Neprilysin/pharmacology , Artemisinins/analysis , Drug Repositioning/statistics & numerical data
19.
Article in English | WPRIM | ID: wpr-115765

ABSTRACT

OBJECTIVE: Rebampide is a gastroprotective agent used to treat gastritis. It possesses anti-inflammatory and anti-arthritis effects, but the mechanisms of these effects are not well understood. The objective of this study was to explore mechanisms underlying the therapeutic effects of rebamipide in inflammatory arthritis. METHODS: Collagen-induced arthritis (CIA) was induced in DBA/1J mice. DBA/1J mice were immunized with chicken type II collagen, then treated intraperitoneally with rebamipide (10 mg/kg or 30 mg/kg) or vehicle (10% carboxymethylcellulose solution) alone. Seven weeks later, plasma samples were collected. Plasma metabolic profiles were analyzed using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolomics study and metabolite biomarkers were identified through multivariate data analysis. RESULTS: Low dose rebamipide treatment reduced the clinical arthritis score compared with vehicle treatment, whereas high dose rebamipide in CIA aggravated arthritis severity. Based on multivariate analysis, 17 metabolites were identified. The plasma levels of metabolites associated with fatty acids and phospholipid metabolism were significantly lower with rebamipide treatment than with vehicle. The levels of 15-deoxy-Δ¹²,¹⁴ prostaglandin J2 and thromboxane B3 decreased only in high dose-treated groups. Certain peptide molecules, including enterostatin (VPDPR) enterostatin and bradykinin dramatically increased in rebamipide-treated groups at both doses. Additionally, corticosterone increased in the low dose-treated group and decreased in the high dose-treated group. CONCLUSION: Metabolomics analysis revealed the anti-inflammatory effects of rebamipide and suggested the potential of the drug repositioning in metabolism- and lipid-associated diseases.


Subject(s)
Animals , Arthritis , Arthritis, Experimental , Biomarkers , Bradykinin , Carboxymethylcellulose Sodium , Chickens , Collagen Type II , Corticosterone , Drug Repositioning , Fatty Acids , Gastritis , Mass Spectrometry , Metabolism , Metabolome , Metabolomics , Mice , Multivariate Analysis , Plasma , Statistics as Topic , Therapeutic Uses
20.
Article in English | WPRIM | ID: wpr-149379

ABSTRACT

A worsening scenario of drug-resistant tuberculosis has increased the need for new treatment strategies to tackle this worldwide emergency. There is a pressing need to simplify and shorten the current 6-month treatment regimen for drug-susceptible tuberculosis. Rifamycins and fluoroquinolones, as well as several new drugs, are potential candidates under evaluation. At the same time, treatment outcomes of patients with drug-resistant tuberculosis should be improved through optimizing the use of fluoroquinolones, repurposed agents and newly developed drugs. In this context, the safety and tolerance of new therapeutic approaches must be addressed.


Subject(s)
Animals , Antitubercular Agents/adverse effects , Drug Discovery , Drug Repositioning , Drug Resistance, Bacterial , Drug Therapy, Combination , Extensively Drug-Resistant Tuberculosis/drug therapy , Humans , Lung/drug effects , Mycobacterium tuberculosis/drug effects , Treatment Outcome , Tuberculosis, Multidrug-Resistant/diagnosis , Tuberculosis, Pulmonary/diagnosis
SELECTION OF CITATIONS
SEARCH DETAIL