Homology modeling, docking, molecular dynamics and in vitro studies to identify Rhipicephalus microplus acetylcholinesterase inhibitors.

Rhipicephalus microplus is an important ectoparasite of cattle, causing considerable economical losses. Resistance to chemical acaricides has stimulated the search for new antiparasitic drugs, including natural products as an eco-friendly alternative of control. Flavonoids represent a class of natural compounds with many biological activities, such as enzyme inhibitors. Acetylcholinesterase is an essential enzyme for tick survival that stands out as an important target for the development of acaricides. This work aimed to predict this 3D structure by homology modeling and use the model to identify compound with inhibitory activity. The model of R. microplus AChE1 (RmAChE1) was constructed using MODELLER program. The optimization and molecular dynamic investigation were performed in GROMACS program. The model developed was used, by molecular docking, to evaluate the anticholinesterase activity of flavonoids (quercetin, rutin, diosmin, naringin and hesperidin) and an acaricide synthetic (eserine). Additionally, in vitro inhibition of AChE and larval immersion tests were performed. The model of RmAChE1 showed to be sterically and energetically acceptable. In molecular dynamics simulations, the 3D structure remains stable with Root Mean Square Deviation = 3.58 Å and Root Mean Square Fluctuation = 1.43 Å. In molecular docking analyses, only eserine and quercetin show affinity energy to the RmAChE (Gridscore: -52.17 and -39.44 kcal/mol, respectively). Among the flavonoids, quercetin exhibited the best in vitro inhibition of AChE activity (15.8%) and mortality of larvae tick (30.2%). The use of in silico and in vitro techniques has shown that quercetin showed promising anti-tick activity and structural requirements to interact with RmAChE1. Communicated by Ramaswamy H. Sarma.

Ocotea daphnifolia: phytochemical investigation, in vitro dual cholinesterase inhibition, and molecular docking studies

This study aimed to evaluate the anticholinesterase activities of extracts and fractions of Ocotea daphnifolia in vitro and characterize its constituents. The effects of hexane, ethyl acetate, and ethanolic extracts on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity were determined with a spectrophotometry assay. All extracts inhibited cholinesterase activity, and the ethanolic extract (2 mg/mL) exhibited the highest inhibition of both enzymes (99.7% for BuChE and 82.4% for AChE). The ethanolic extract was fractionated by column chromatography resulting in 14 fractions that were also screened for their anticholinesterase effects. Fraction 9 (2 mg/mL) showed the highest activity, inhibiting AChE and BuChE by 71.8% and 90.2%, respectively. This fraction was analyzed by high-performance liquid chromatography high-resolution mass spectrometry which allowed the characterization of seven glycosylated flavonoids (containing kaempferol and quercetin nucleus) and one alkaloid (reticuline). In order to better understand the enzyme-inhibitor interaction of the reticuline toward cholinesterase, molecular modeling studies were performed. Reticuline targeted the catalytic activity site of the enzymes. Ocotea daphnifolia exhibits a dual cholinesterase inhibitory activity and displays the same pattern of intermolecular interactions as described in the literature. The alkaloid reticuline can be considered as an important bioactive constituent of this plant.

Identificação e caracterização de interações medicamentosas em prescrições médicas da unidade de terapia intensiva de um hospital público da cidade de Feira de Santana, BA / Identification and characterization of drug interactions in prescriptions of the intensive care unit of a public hospital in the city of Feira de Santana, BA

OBJETIVOS E JUSTIFICATIVA: Identificar e caracterizar as interações medicamentosas presentes em prescrições médicas da Unidade de Terapia Intensiva (UTI) de um hospital público da cidade de Feira de Santana, Bahia. Uma vez que Interações medicamentosas (IM) representam fontes potencialmente remediáveis de erros na assistência e um risco para os pacientes. MÉTODOS: O estudo realizado foi do tipo descritivo. Após aprovação do Comitê de Ética em Pesquisa foram coletadas aleatoriamente 28 prescrições médicas da Unidade de Terapia Intensiva do hospital no ano de 2013, sendo necessário o preenchimento de uma ficha de coleta previamente estabelecida. Os dados coletados foram analisados pelo programa Micromedex® Drug Interactions, este caracterizou as interações medicamentosas segundo a gravidade e documentação comprobatória. RESULTADOS: Das 28 prescrições analisadas, 2 apresentaram nenhuma interação medicamentosa, enquanto 26 apresentaram alguma interações medicamentosas, resultando 99 potenciais interações medicamentosas, sendo os fármacos mais envolvidos: Midazolam, Ácido Acetilsalicílico, Fentanil e Dipirona. Interações medicamentoas mais frequentes foram: Fentanil + Mi­ dazolam; Dipirona + Enoxaparina; Midazolam + Omeprazol; Ácido Acetilsalicílico + Insulina Humana Regular. Segundo a gravidade foram encontradas: 5 contra Indicado, 31 maior, 58 moderado e 5 menor. 29 interações medicamentosas possuíam documentação excelente, 39 boa, 31 razoável e nenhuma com documentação desconhecida O uso, simultâneo de Fentanil + Midazolam pode resultar em depressão respiratória aditiva. Já o uso de Metoclopramida + Haloperidol pode aumentar o risco de reações extrapiramidais ou síndrome maligna dos neurolépticos. CONCLUSÃO: Confirmou­se que as interações medicamentosas são um problema frequente e cada vez mais relevante, pois identificá­las tornou­se um desafio para os profissionais de saúde...

BACKGROUND AND OBJECTIVE: To identify and characterize the Drug Interaction present in prescriptions of Intensive Care Unit (ICU) of a public hospital in the city of Feira de Santana, Bahia. Since, Drug Interaction (DI) represent potentially remediable sources of errors in care and a risk to patients. METHODS: The study was observational in nature. After approval by the Research Ethics Committee were randomly collected from 28 medical prescriptions in the Intensive Care Unit of the hospital in 2013, completing a previously established data collection form is required. The collected data were analyzed by ® Drug Interactions, Micromedex this program characterized the drug interaction according to the severity and supporting documentation. RESULTS: Of the 28 prescriptions analyzed, 2 showed no drug interaction, while 26 showed some drug interaction, resulting in 99 potential drug interactions being the drugs most involved: Midazolam, Acetylsalicylic Acid, Fentanyl and Dipyrone. Frequently drugs interactions were: Midazolam + Fentanyl; Dipyrone + Enoxaparin, Midazolam + Omeprazole, Acetylsalicylic Acid + Regular Human Insulin. According to severity were found: 5 against Indicated, 31 largest, 58 moderate and 5 smaller. 29 drug interaction had excellent documentation, 39 good, 31 fair, and none with unknown Using documentation, simultaneous Midazolam + Fentanyl may result in additive respiratory depression. Already using Metoclopramide + Haloperidol may increase the risk of extrapyramidal reactions or neuroleptic malignant syndrome. CONCLUSION: It was confirmed that the drug interaction is a frequent problem and increasingly relevant because identifying it became a challenge for health professionals...