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1.
N Engl J Med ; 383(21): 2041-2052, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-32706953

RESUMO

BACKGROUND: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. METHODS: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. RESULTS: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. CONCLUSIONS: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).


Assuntos
Antivirais/administração & dosagem , Azitromicina/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Betacoronavirus , Brasil , COVID-19 , Quimioterapia Combinada , Feminino , Hospitalização , Humanos , Hidroxicloroquina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pandemias , Gravidade do Paciente , SARS-CoV-2 , Falha de Tratamento , Tratamento Farmacológico da COVID-19
2.
Biochim Biophys Acta Gen Subj ; 1861(1 Pt A): 3199-3209, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27531710

RESUMO

BACKGROUND: One of the main challenges in snakebite envenomation treatment is the development of stable, versatile and efficient anti-venom therapies. Local myotoxicity in accidents involving snakes from the Bothrops genus is still a consequence of serum therapy inefficient neutralization that may lead to permanent sequelae in their victims. One of the classes of toxins that participate in muscle necrosis is the PLA2-like proteins. The aim of this work was to investigate the role of zinc ions in the inhibition of PLA2-like proteins and to advance the current knowledge of their action mechanism. METHODS: Myographic and electrophysiological techniques were used to evaluate the inhibitory effect of zinc ions, isothermal titration calorimetry assays were used to measure the affinity between zinc ions and the toxin and X-ray crystallography was used to reveal details of this interaction. RESULTS: We demonstrated that zinc ions can effectively inhibit the toxin by the interaction with two different sites, which are related to two different mechanism of inhibition: preventing membrane disruption and impairing the toxin state transition. Furthermore, structural study presented here included an additional step in the current myotoxic mechanism improving the comprehension of the allosteric transition that PLA2-like proteins undergo to exert their function. CONCLUSIONS: Our findings show that zinc ions are inhibitors of PLA2-like proteins and suggest two different mechanisms of inhibition for these ions. GENERAL SIGNIFICANCE: Zinc is a new candidate that can assist in anti-venom treatments and can promote the design of new and even more accurate structure-based inhibitors for PLA2-like proteins.


Assuntos
Venenos de Crotalídeos/toxicidade , Inibidores de Fosfolipase A2/farmacologia , Fosfolipases A2/toxicidade , Zinco/metabolismo , Animais , Bothrops , Calorimetria , Venenos de Crotalídeos/química , Cristalografia por Raios X , Diafragma/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Íons , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Modelos Moleculares , Fosfolipases A2/química , Nervo Frênico/efeitos dos fármacos
3.
Data Brief ; 56: 110866, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39286422

RESUMO

To enhance the field of continuous motor health monitoring, we present FAN-COIL-I, an extensive vibration sensor dataset derived from a Fan Coil motor. This dataset is uniquely positioned to facilitate the detection and prediction of motor health issues, enabling a more efficient maintenance scheduling process that can potentially obviate the need for regular checks. Unlike existing datasets, often created under controlled conditions or through simulations, FAN-COIL-I is compiled from real-world operational data, providing an invaluable resource for authentic motor diagnosis and predictive maintenance research. Gathered using a high-resolution 32 KHz sampling rate, the dataset encompasses comprehensive vibration readings from both the forward and rear sides of the Fan Coil motor over a continuous two-week period, offering a rare glimpse into the dynamic operational patterns of these systems in a corporate setting. FAN-COIL-I stands out not only for its real-world applicability but also for its potential to serve as a reliable benchmark for researchers and practitioners seeking to validate their models against genuine engine conditions.

4.
Biochimie ; 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39089640

RESUMO

Snakebite envenomations result in acute and chronic physical and psychological health effects on their victims, leading to a substantial socio-economic burden in tropical and subtropical countries. Local necrosis is one of the serious effects caused by envenomation, primarily induced by snake venoms from the Viperidae family through the direct action of components collectively denominated as myotoxins, including the phopholipase A2-like (PLA2-like) toxins. Considering the limitations of antivenoms in preventing the rapid development of local tissue damage caused by envenomation, the use of small molecule therapeutics has been suggested as potential first-aid treatments or as adjuvants to antivenom therapy. In this review, we provide an overview of the structural interactions of molecules exhibiting inhibitory activity toward PLA2-like toxins. Additionally, we discuss the implications for the myotoxic mechanism of PLA2-like toxins and the molecules involved in their activation, highlighting key differences between activators and inhibitors. Finally, we integrate all these results to propose a classification of inhibitors into three different classes and five sub-classes. Taking into account the structural and affinity information, we compare the different inhibitors/ligands to gain a deeper understanding of the structural basis for the effective inhibition of PLA2-like toxins. By offering these insights, we aim to contribute to the search for new and efficient inhibitor molecules to complement and improve current therapy by conventional antivenoms.

5.
Biochim Biophys Acta Proteins Proteom ; 1872(2): 140988, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38142025

RESUMO

Snakebite is a significant health concern in tropical and subtropical regions, particularly in Africa, Asia, and Latin America, resulting in more than 2.7 million envenomations and an estimated one hundred thousand fatalities annually. The Bothrops genus is responsible for the majority of snakebite envenomings in Latin America and Caribbean countries. Accidents involving snakes from this genus are characterized by local symptoms that often lead to permanent sequelae and death. However, specific antivenoms exhibit limited effectiveness in inhibiting local tissue damage. Phospholipase A2-like (PLA2-like) toxins emerge as significant contributors to local myotoxicity in accidents involving Bothrops species. As a result, they represent a crucial target for prospective treatments. Some natural and synthetic compounds have shown the ability to reduce or abolish the myotoxic effects of PLA2-like proteins. In this study, we employed a combination approach involving myographic, morphological, biophysical and bioinformatic techniques to investigate the interaction between chlorogenic acid (CGA) and BthTX-I, a PLA2-like toxin. CGA provided a protection of 71.8% on muscle damage in a pre-incubation treatment. Microscale thermophoresis and circular dichroism experiments revealed that CGA interacted with the BthTX-I while preserving its secondary structure. CGA exhibited an affinity to the toxin that ranks among the highest observed for a natural compound. Bioinformatics simulations indicated that CGA inhibitor binds to the toxin's hydrophobic channel in a manner similar to other phenolic compounds previously investigated. These findings suggest that CGA interferes with the allosteric transition of the non-activated toxin, and the stability of the dimeric assembly of its activated state.


Assuntos
Ácido Clorogênico , Cinamatos , Ácido Clorogênico/farmacologia , Fosfolipases A2/química , Fosfolipases A2/metabolismo , Fosfolipases A2/toxicidade
6.
Sci Rep ; 14(1): 19902, 2024 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-39191809

RESUMO

To evaluate the safety and the potential antiviral treatment of inhaled enriched heparin in patients with COVID-19. The specific objectives were to investigate the anticoagulation profile, antiviral and anti-inflammatory effects, and respiratory evolution of inhaled enriched heparin. We conducted a randomized, triple-blind, placebo-controlled Phase I/II clinical trial in hospitalized adults with COVID-19 receiving inhalation of enriched heparin or saline (placebo) every 4 h for 7 days. Among the 27 patients who completed the study, no changes in blood coagulation parameters were observed, indicating the safety of inhaled enriched heparin. The group receiving enriched heparin showed a significant reduction in the need for supplemental oxygen and improvement in respiratory parameters, such as the PaO2/FiO2 ratio. Inhalation of enriched heparin is shown to be safe and has also demonstrated potential therapeutic benefits for patients with COVID-19. These promising results justify the continuation of the study to the next phase, Phase II/III, to further evaluate the therapeutic efficacy of inhaled enriched heparin in the treatment of COVID-19-associated viral pneumonia.Trial registration: ClinicalTrials.gov. 08/02/2021. Identifier: NCT04743011.


Assuntos
Anticoagulantes , Tratamento Farmacológico da COVID-19 , COVID-19 , Heparina , Humanos , Heparina/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Administração por Inalação , Idoso , COVID-19/virologia , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Nebulizadores e Vaporizadores , SARS-CoV-2 , Adulto , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Resultado do Tratamento
7.
J Biomol Struct Dyn ; 41(5): 1715-1729, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-34996334

RESUMO

Acquired Immune Deficiency Syndrome (AIDS) is an infectious disease caused by Human Immunodeficiency Virus (HIV) infection and its replication requires the Reverse Transcriptase (RT) enzyme. RT plays a key role in the HIV life cycle, making it one of the most important targets for designing new drugs. Thus, in order to increase therapeutic options against AIDS, halolactone derivatives (D-halolactone) that have been showed as potential non-nucleoside inhibitors of the RT enzyme were studied. In the present work, a series of D-halolactone were investigated by molecular modeling studies, combining Three-dimensional Quantitative Structure-Activity Relationship (3 D-QSAR), molecular docking and Molecular Dynamics (MD) techniques, to understand the molecular characteristics that promote biological activity. The internal and external validation parameters indicated that the 3 D-QSAR model has good predictive capacity and statistical significance. Contour maps provided useful information on the structural characteristics of compounds for anti-HIV-1 activity. The docking results showed that D-halolactone present good complementarity by the RT allosteric site. In MD simulations it was observed that the formation of enzyme-ligand complexes were favorable, and from the free energy decomposition it was found that Leu100, Val106, Tyr181, Try188, and Trp229 are key residues for stabilization in the enzymatic site. Thus, the results showed that the proposed models can be used to design promising HIV-1 RT inhibitors. Communicated by Ramaswamy H. Sarma.


Assuntos
Transcriptase Reversa do HIV , Inibidores da Transcriptase Reversa , Humanos , Síndrome da Imunodeficiência Adquirida , HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química
8.
Biochimie ; 206: 105-115, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36273763

RESUMO

Snake envenomation is an ongoing global health problem and tropical neglected disease that afflicts millions of people each year. The only specific treatment, antivenom, has several limitations that affects its proper distribution to the victims and its efficacy against local effects, such as myonecrosis. The main responsible for this consequence are the phospholipases A2 (PLA2) and PLA2-like proteins, such as BthTX-I from Bothrops jararacussu. Folk medicine resorts to plants such as Tabernaemontana catharinensis to palliate these and other snakebite effects. Here, we evaluated the effect of its root bark extract and one of its isolated compounds, 12-methoxy-4-methyl-voachalotine (MMV), against the in vitro paralysis and muscle damage induced by BthTX-I. Secondary and quaternary structures of BthTX-I were not modified by the interaction with MMV. Instead, this compound interacted in an unprecedented way with the region inside the toxin hydrophobic channel and promoted a structural change in Val31, loop 58-71 and Membrane Disruption Site. Thus, we hypothesize that MMV inhibits PLA2-like proteins by preventing entrance of fatty acid into the hydrophobic channel. These data may explain the traditional use of T. catharinensis extract and confirm MMV as a promising candidate to complement antivenom or a structural guide to develop more effective inhibitors.


Assuntos
Bothrops , Venenos de Crotalídeos , Tabernaemontana , Animais , Antivenenos/farmacologia , Antivenenos/química , Tabernaemontana/metabolismo , Fosfolipases A2/química , Venenos de Serpentes , Venenos de Crotalídeos/química , Bothrops/metabolismo
9.
J Craniofac Surg ; 23(2): e138-40, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22446450

RESUMO

The best-known cervicopharyngeal pain is Eagle syndrome, in which symptomatic elongation of the stylomandibular process occurs and may be accompanied by stylohyoid ligament calcification. Among the causes of elongation of the styloid process, the following may be mentioned: history of trauma, styloid ligament calcification, and formation of bony tissue in the insertion of the styloid ligament. When there is no history of trauma or surgery, it is called the stylohyoid syndrome. In the current study, the clinical case of 34-year-old woman is reported, complaining of pain in the region of the neck, without any history of neck surgery or trauma. A panoramic radiograph and computed tomographic scan showed bilateral elongation of the styloid process. Extraoral surgical intervention was the treatment of choice. It is important to point out that dentists should be aware of this condition to contribute to a better diagnosis and therapeutic procedure.


Assuntos
Ossificação Heterotópica/diagnóstico , Ossificação Heterotópica/cirurgia , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Procedimentos Cirúrgicos Bucais , Radiografia Panorâmica , Osso Temporal/anormalidades , Osso Temporal/cirurgia , Tomografia Computadorizada por Raios X
10.
J Biomol Struct Dyn ; 40(18): 8248-8260, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-33830889

RESUMO

Schistosomiasis is a parasitic disease that is part of the neglected tropical diseases (NTDs), which cause significant levels of morbidity and mortality in millions of people throughout the world. The enzyme purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) represents a potential target for discovering new agents, and neolignans stand out as an important class of compounds. In this work, molecular modeling studies and biological assays of a set of neolignans were conducted against the PNP enzymes of the parasite and the human homologue (HssPNP). The results of the molecular docking described that the neolignans showed good complementarity by the active site of SmPNP. Molecular dynamics (MD) studies revealed that both complexes (Sm/HssPNP - neolignan compounds) were stable by analyzing the root mean square deviation (RMSD) values, and the binding free energy values suggest that the selected structures can interact and inhibit the catalytic activity of the SmPNP. Finally, the biological assay indicated that the selected neolignans presented a better molecular profile of inhibition compared to the human enzyme, as these ligands did not have the capacity to inhibit enzymatic activity, indicating that these compounds are promising candidates and that they can be used in future research in chemotherapy for schistosomiasis.Communicated by Ramaswamy H. Sarma.


Assuntos
Lignanas , Esquistossomose , Animais , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Purina-Núcleosídeo Fosforilase/química , Purina-Núcleosídeo Fosforilase/metabolismo , Schistosoma mansoni/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-36429910

RESUMO

Many industrial sectors still lack automation resources to optimize their production processes, aiming to make manufacturing leaner and offer better working conditions to operators. Without these improvements, workers can suffer physical and even psychological damage from the ergonomic risks of the activities performed. Thus, the aim of this paper is to present the ergonomic evaluation of packaging tapes workstation before and after the implementation of an automatic packaging machine, called Guzzetti. In the Guzzetti context, the paper shows the implementation of an electrical system based on controlling a mechanical device powered by servomotors and controlled by a PLC is necessary. For ergonomic evaluation, the paper presents the application of three methods: Suzanne Rodger, Strain Index, called Moore and Garg and REBA (Rapid Entire Body Assessment). With the results collection, was possible to obtain improvements in ergonomic risks that changed from the intermediate level to low level in all methods.


Assuntos
Ergonomia , Embalagem de Produtos , Humanos , Ergonomia/métodos
12.
Biochimie ; 181: 145-153, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33333169

RESUMO

Snakebite envenomation has been categorized by World Health Organization as a category A neglected tropical disease, since it causes chronic psychological disorders, physical disablement and death. Ophidian accidents may cause local myonecrosis that cause drastic sequelae, which are not efficiently neutralized via serum therapy. Phospholipase A2-like (PLA2-like) myotoxins have a major role in the local effects caused by several snake venoms. We previously demonstrated that chicoric acid (CA) is an efficient inhibitor of the BthTX-I myotoxin and solved the X-ray structure of complex. Herein, we assess the oligomeric behavior of the BthTX-I/CA complex in solution under different physical-chemical conditions and using toxin obtained by two different biochemical methodologies to fully elucidate structural bases of inhibition of myotoxins by CA. We demonstrated the ability of PLA2-like proteins to form different oligomeric assemblies in the presence of certain inhibitors, which can also be modulated by buffer polarity change. In the presence of ethanol, BthTX-I/CA remains predominantly in a monomeric conformation, which prevents it from being in its active form (dimeric conformation). In contrast, in the absence of ethanol, the tetramer assembly was observed, which hid key regions of the protein responsible for docking and disruption of the muscle membrane. Therefore, the "plasticity" of these proteins with regard to their abilities to form oligomeric assemblies is a key issue for the future development of therapeutic agents to complement of serum therapy.


Assuntos
Ácidos Cafeicos/química , Venenos de Crotalídeos/química , Fosfolipases A2/química , Multimerização Proteica , Succinatos/química , Venenos de Crotalídeos/antagonistas & inibidores
13.
Psychiatry Res ; 296: 113669, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401092

RESUMO

This study aimed to analyze the possible impacts on the prison population's mental health in the context of the new COVID-19 pandemic. Qualitative study was carried out following a lexical and content analysis using the software IRaMuTeQ, version 0.7 alpha 2, in the speech of the short communication and headlines from newspapers. Three groups emerged from the analysis: "spatial conditions for infection" (39.2% of the text segments); "disease outbreaks in prisons" (30,4%) and "public responsibility" (30,4%). Precarious conditions of prisons, high rate of infections and psychiatric illnesses, and lack of government assistance are issues that should be given special attention in order to formulate health promotion and prevention policies focusing on mental health in prison population.


Assuntos
COVID-19/epidemiologia , Transtornos Mentais/epidemiologia , Prisioneiros/estatística & dados numéricos , COVID-19/prevenção & controle , COVID-19/psicologia , Comorbidade , Estudos Transversais , Estudos de Avaliação como Assunto , Promoção da Saúde , Humanos , Transtornos Mentais/prevenção & controle , Transtornos Mentais/psicologia , Prisioneiros/psicologia , Assistência Pública , Fatores de Risco
14.
Int J Biol Macromol ; 185: 494-512, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34197854

RESUMO

Snakebite envenoming is the cause of an ongoing health crisis in several regions of the world, particularly in tropical and neotropical countries. This scenario creates an urgent necessity for new practical solutions to address the limitations of current therapies. The current study investigated the isolation, phytochemical characterization, and myotoxicity inhibition mechanism of gallic acid (GA), a myotoxin inhibitor obtained from Anacardium humile. The identification and isolation of GA was achieved by employing analytical chromatographic separation, which exhibited a compound with retention time and nuclear magnetic resonance spectra compatible with GA's commercial standard and data from the literature. GA alone was able to inhibit the myotoxic activity induced by the crude venom of Bothrops jararacussu and its two main myotoxins, BthTX-I and BthTX-II. Circular dichroism (CD), fluorescence spectroscopy (FS), dynamic light scattering (DLS), and interaction studies by molecular docking suggested that GA forms a complex with BthTX-I and II. Surface plasmon resonance (SPR) kinetics assays showed that GA has a high affinity for BthTX-I with a KD of 9.146 × 10-7 M. Taken together, the two-state reaction mode of GA binding to BthTX-I, and CD, FS and DLS assays, suggest that GA is able to induce oligomerization and secondary structure changes for BthTX-I and -II. GA and other tannins have been shown to be effective inhibitors of snake venoms' toxic effects, and herein we demonstrated GA's ability to bind to and inhibit a snake venom PLA2, thus proposing a new mechanism of PLA2 inhibition, and presenting more evidence of GA's potential as an antivenom compound.


Assuntos
Anacardium/química , Ácido Gálico/farmacologia , Miotoxicidade/tratamento farmacológico , Inibidores de Fosfolipase A2/farmacologia , Fosfolipases A2/metabolismo , Venenos de Serpentes/enzimologia , Animais , Modelos Animais de Doenças , Ácido Gálico/química , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Miotoxicidade/enzimologia , Miotoxicidade/etiologia , Inibidores de Fosfolipase A2/química , Fosfolipases A2/química , Caules de Planta/química , Proteínas de Répteis/química , Proteínas de Répteis/metabolismo , Ressonância de Plasmônio de Superfície
15.
Medicine (Baltimore) ; 100(51): e28288, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34941114

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that spreads rapidly, reaching pandemic status, causing the collapse of numerous health systems, and a strong economic and social impact. The treatment so far has not been well established and there are several clinical trials testing known drugs that have antiviral activity, due to the urgency that the global situation imposes. Drugs with specific mechanisms of action can take years to be discovered, while vaccines may also take a long time to be widely distributed while new virus variants emerge. Thus, drug repositioning has been shown to be a good strategy for defining new therapeutic approaches. Studies of the effect of enriched heparin in the replication of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) in vitro assays justify the advance for clinical tests. METHODS AND ANALYSIS: A phase I/II triple-blind parallel clinical trial will be conducted. Fifty participants with radiological diagnosis of grade IIA pneumonia will be selected, which will be allocated in 2 arms. Participants allocated in Group 1 (placebo) will receive nebulized 0.9% saline. Participants allocated in Group 2 (intervention) will receive nebulized enriched heparin (2.5 mg/mL 0.9% saline). Both groups will receive the respective solutions on a 4/4 hour basis, for 7 days. The main outcomes of interest will be safety (absence of serious adverse events) and efficacy (measured by the viral load).Protocols will be filled on a daily basis, ranging from day 0 (diagnosis) until day 8.


Assuntos
Tratamento Farmacológico da COVID-19 , Heparina/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Solução Salina , Resultado do Tratamento
16.
Med Chem ; 16(6): 784-795, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31309897

RESUMO

BACKGROUND: Leishmaniosis is a neglected tropical disease and glyceraldehyde 3- phosphate dehydrogenase (GAPDH) is a key enzyme in the design of new drugs to fight this disease. OBJECTIVE: The present study aimed to evaluate potential inhibitors of GAPDH enzyme found in Leishmania mexicana (L. mexicana). METHODS: A search for novel antileishmanial molecules was carried out based on similarities from the pharmacophoric point of view related to the binding site of the crystallographic enzyme using the ZINCPharmer server. The molecules selected in this screening were subjected to molecular docking and molecular dynamics simulations. RESULTS: Consensual analysis of the docking energy values was performed, resulting in the selection of ten compounds. These ligand-receptor complexes were visually inspected in order to analyze the main interactions and subjected to toxicophoric evaluation, culminating in the selection of three compounds, which were subsequently submitted to molecular dynamics simulations. The docking results showed that the selected compounds interacted with GAPDH from L. mexicana, especially by hydrogen bonds with Cys166, Arg249, His194, Thr167, and Thr226. From the results obtained from molecular dynamics, it was observed that one of the loop regions, corresponding to the residues 195-222, can be related to the fitting of the substrate at the binding site, assisting in the positioning and the molecular recognition via residues responsible for the catalytic activity. CONCLUSION: The use of molecular modeling techniques enabled the identification of promising compounds as inhibitors of the GAPDH enzyme from L. mexicana, and the results obtained here can serve as a starting point to design new and more effective compounds than those currently available.


Assuntos
Antipruriginosos/síntese química , Antipruriginosos/farmacologia , Gliceraldeído-3-Fosfato Desidrogenases/antagonistas & inibidores , Leishmania mexicana/enzimologia , Desenho de Fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Software , Relação Estrutura-Atividade , Termodinâmica
17.
Sci Rep ; 10(1): 16252, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004851

RESUMO

The activation process of phospholipase A2-like (PLA2-like) toxins is a key step in their molecular mechanism, which involves oligomeric changes leading to the exposure of specific sites. Few studies have focused on the characterization of allosteric activators and the features that distinguish them from inhibitors. Herein, a comprehensive study with the BthTX-I toxin from Bothrops jararacussu venom bound or unbound to α-tocopherol (αT) was carried out. The oligomerization state of BthTX-I bound or unbound to αT in solution was studied and indicated that the toxin is predominantly monomeric but tends to oligomerize when complexed with αT. In silico molecular simulations showed the toxin presents higher conformational changes in the absence of αT, which suggests that it is important to stabilize the structure of the toxin. The transition between the two states (active/inactive) was also studied, showing that only the unbound BthTX-I system could migrate to the inactive state. In contrast, the presence of αT induces the toxin to leave the inactive state, guiding it towards the active state, with more regions exposed to the solvent, particularly its active site. Finally, the structural determinants necessary for a molecule to be an inhibitor or activator were analyzed in light of the obtained results.


Assuntos
Bothrops , Venenos de Crotalídeos/química , Regulação Alostérica , Animais , Simulação por Computador , Difusão Dinâmica da Luz , Simulação de Dinâmica Molecular , Fosfolipases A2/química , Multimerização Proteica
18.
Biochimie ; 170: 163-172, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978419

RESUMO

Envenoming by snakebite is an important global health issue that has received little attention, leading the World Health Organization to naming it as neglected tropical disease. Several snakebites present serious local symptoms manifested on victims that may not be efficiently neutralized by serum therapy. Phospholipase A2-like (PLA2-like) toxins are present in Viperidae venoms and are responsible for local myotoxic activity. Herein, we investigated the association between BthTX-I toxin and caftaric acid (CFT), a molecule present in plants. CFT neutralized neuromuscular blocking and muscle-damaging activities promoted by BthTX-I. Calorimetric and light-scattering assays demonstrated that CFT inhibitor interacted with dimeric BthTX-I. Bioinformatics simulations indicated that CFT inhibitor binds to the toxin's hydrophobic channel (HCh). According to the current myotoxic mechanism, three different regions of PLA2-like toxins have specific tasks: protein allosteric activation (HCh), membrane dockage (MDoS), and membrane rupture (MDiS). We propose CFT inhibitor interferes with the allosteric activation, which is related to the conformation change leading to the exposure/alignment of MDoS/MDiS region. This is the first report of a PLA2-like toxin fully inhibited by a compound that interacts only with its HCh region. Thus, CFT is a novel candidate to complement serum therapy and improve the treatment of snakebite.


Assuntos
Venenos de Crotalídeos/toxicidade , Miotoxicidade/tratamento farmacológico , Bloqueadores Neuromusculares/toxicidade , Fenóis/farmacologia , Fosfolipases A2/química , Animais , Masculino , Camundongos , Miotoxicidade/etiologia , Fosfolipases A2/metabolismo , Conformação Proteica
19.
Sci Rep ; 9(1): 510, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679550

RESUMO

Ophidian accidents are considered an important neglected tropical disease by the World Health Organization. Particularly in Latin America, Bothrops snakes are responsible for the majority of the snakebite envenomings that are not efficiently treated by conventional serum therapy. Thus, the search for simple and efficient inhibitors to complement this therapy is a promising research area, and a combination of functional and structural assays have been used to test candidate ligands against specific ophidian venom compounds. Herein, we tested a commercial drug (acetylsalicylic acid, ASA) and a plant compound with antiophidian properties (rosmarinic acid, RA) using myographic, crystallographic and bioinformatics experiments with a phospholipase A2-like toxin, MjTX-II. MjTX-II/RA and MjTX-II/ASA crystal structures were solved at high resolution and revealed the presence of ligands bound to different regions of the toxin. However, in vitro myographic assays showed that only RA is able to prevent the myotoxic effects of MjTX-II. In agreement with functional results, molecular dynamics simulations showed that the RA molecule remains tightly bound to the toxin throughout the calculations, whereas ASA molecules tend to dissociate. This approach aids the design of effective inhibitors of PLA2-like toxins and, eventually, may complement serum therapy.


Assuntos
Aspirina , Cinamatos , Venenos de Crotalídeos , Depsídeos , Fosfolipases A2 do Grupo II , Simulação de Dinâmica Molecular , Animais , Aspirina/química , Aspirina/farmacologia , Cinamatos/química , Cinamatos/farmacologia , Venenos de Crotalídeos/química , Venenos de Crotalídeos/toxicidade , Cristalografia por Raios X , Depsídeos/química , Depsídeos/farmacologia , Fosfolipases A2 do Grupo II/química , Fosfolipases A2 do Grupo II/toxicidade , Masculino , Camundongos , Estrutura Quaternária de Proteína , Ácido Rosmarínico
20.
Zookeys ; (787): 127-134, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30310358

RESUMO

Niceforo's big-eared bat, Trinycterisnicefori (Sanborn, 1949), is a monotypic species which has been recorded in a number of Brazilian states, but has a disjunct distribution in this country. This study presents the first record of T.nicefori in the Brazilian state of Maranhão. The specimens were collected in the municipalities of Godofredo Viana and Cândido Mendes, in fragments of the Amazon forest. One male (forearm: 38.00 mm, weight: 6 g) and one female (39.68 mm, 8 g) specimens were collected. The specimens presented chestnut-colored fur, and a chin with a pair of dermal pads arranged in a V-shape, without a central papilla. The COI gene sequences were plotted in the BOLD Systems platform, which confirmed the morphological identification of the species, with a 99.1% similarity in the male, and 99.4% in the female to existing sequences. This record extends the known distribution of T.nicefori in Brazil by approximately 310 km to the most eastern part of the Amazon Biome.

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