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Altered physiology caused by critical illness may change midazolam pharmacokinetics and thereby result in adverse reactions and outcomes in this vulnerable patient population. This study set out to determine which critical illness-related factors impact midazolam pharmacokinetics in children using population modeling. This was an observational, prospective, controlled study of children receiving IV midazolam as part of routine care. Children recruited into the study were either critically-ill receiving continuous infusions of midazolam or otherwise well, admitted for elective day-case surgery (control) who received a single IV bolus dose of midazolam. The primary outcome was to determine the population pharmacokinetics and identify covariates that influence midazolam disposition during critical illness. Thirty-five patients were recruited into the critically ill arm of the study, and 54 children into the control arm. Blood samples for assessing midazolam and 1-OH-midazolam concentrations were collected opportunistically (critically ill arm) and in pre-set time windows (control arm). Pharmacokinetic modeling demonstrated a significant change in midazolam clearance with acute inflammation (measured using C-Reactive Protein), cardio-vascular status, and weight. Simulations predict that elevated C-Reactive Protein and compromised cardiovascular function in critically ill children result in midazolam concentrations up to 10-fold higher than in healthy children. The extremely high concentrations of midazolam observed in some critically-ill children indicate that the current therapeutic dosing regimen for midazolam can lead to over-dosing. Clinicians should be aware of this risk and intensify monitoring for oversedation in such patients.
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Estado Terminal , Midazolam , Proteína C-Reativa , Criança , Humanos , Inflamação/tratamento farmacológico , Estudos ProspectivosRESUMO
We present new constraints on dark matter interactions using 1.7 years of COSINE-100 data. The COSINE-100 experiment, consisting of 106 kg of tallium-doped sodium iodide [NaI(Tl)] target material, is aimed to test DAMA's claim of dark matter observation using the same NaI(Tl) detectors. Improved event selection requirements, a more precise understanding of the detector background, and the use of a larger dataset considerably enhance the COSINE-100 sensitivity for dark matter detection. No signal consistent with the dark matter interaction is identified and rules out model-dependent dark matter interpretations of the DAMA signals in the specific context of standard halo model with the same NaI(Tl) target for various interaction hypotheses.
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Aim: Determination of plasma protein binding (PPB) is considered vital for better understanding of pharmacokinetic and pharmacodynamic activities of drugs due to the role of free concentration in pharmacological response. Methodology & results: Solid-phase microextraction (SPME) was investigated for measurement of PPB from biological matrices and compared with a gold standard approach (rapid equilibrium dialysis [RED]). Discussion & conclusion: SPME-derived values of PPB correlated well with literature values, and those determined by RED. Respectively, average protein binding across three concentrations by RED and SPME was 33.1 and 31.7% for metoprolol, 89.0 and 86.6% for propranolol and 99.2 and 99.0% for diclofenac. This study generates some evidence for SPME as an alternative platform for the determination of PPB.
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Proteínas Sanguíneas/metabolismo , Microextração em Fase Sólida/métodos , Animais , Cromatografia Líquida , Diálise , Diclofenaco/farmacocinética , Diclofenaco/farmacologia , Metoprolol/farmacocinética , Metoprolol/farmacologia , Propranolol/farmacocinética , Propranolol/farmacologia , Ligação Proteica , Ratos , Espectrometria de Massas em TandemRESUMO
Background: The hemaPEN is a liquid microsampling device for the reproducible collection and storage of blood samples as dried blood spots, for subsequent quantitative analysis. Materials & methods: We examined the device's ability to collect accurate and precise blood volumes, at different hematocrit levels, via in vitro studies using acetaminophen in human blood. We also investigated the impact of different user training approaches on device performance. Results: The hemaPEN demonstrated acceptable volumetric accuracy and precision, regardless of the training medium used. Issues with apparent hematocrit-dependent bias were found to be associated with the extraction process, rather than the volumetric performance of the device. Conclusion: The hemaPEN is capable of readily producing high quality blood microsamples for reproducible and accurate quantitative bioanalysis.
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Acetaminofen/sangue , Teste em Amostras de Sangue Seco/métodos , Técnicas In Vitro/métodos , HumanosRESUMO
Aim: Collection and quantitative analysis in dry blood using volumetric absorptive microsampling (VAMS™) potentially offers significant advantages over conventional wet whole blood analysis. This manuscript explores their use for pediatric sampling and explores additional considerations for the validation of the bioanalytical method. Results: HPLC-MS/MS methods for the determination of midazolam and its major metabolite 1-OH midazolam in both whole wet blood, and dry blood collected on VAMS were developed, validated, and used to support an observational clinical study to compare pharmacokinetic parameters in pediatric patients. Conclusion: Validation data met internationally accepted guideline criteria. A strong correlation was observed in calculated concentrations between wet and dry test samples, indicating that VAMS is a suitable technique for use in pediatric clinical studies.
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Coleta de Amostras Sanguíneas/métodos , Teste em Amostras de Sangue Seco/métodos , Hipnóticos e Sedativos/sangue , Midazolam/sangue , Adulto , Criança , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Limite de Detecção , Espectrometria de Massas em Tandem/métodosRESUMO
There is growing interest in the implementation of microsampling approaches for the quantitation of circulating concentrations of analytes in biological samples derived from nonclinical and clinical studies involved in drug development. This interest is partly due to the ethical advantages of taking smaller blood volumes, particularly for studies in rodents, children and the critically ill. In addition, these technologies facilitate sampling to be performed in previously intractable locations and occasions. Further, they enable the collection of samples for additional purposes (extra time points, biomarkers, sampling during a clinical event, etc). This article gives a comprehensive insight to the utilization of these approaches in drug discovery and development, and provides recommendations for best practice for nonclinical, clinical and bioanalytical aspects.
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Descoberta de Drogas/métodos , Métodos Analíticos de Preparação de Amostras , Humanos , Manejo de EspécimesRESUMO
A previous Senior Editor, and the present Senior Editor of Bioanalysis reflect on their journeys in the field of bioanalysis, and with the journal. They discuss the evolution and progress of journal since its launch 10 years ago, and where they would like to see it heading in the future.
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Técnicas de Química Analítica/normas , Políticas Editoriais , Escolha da Profissão , Regulamentação Governamental , Revisão da Pesquisa por Pares , Publicações Periódicas como AssuntoRESUMO
There is continuing interest in the development and application of various microsampling technologies for drug development. The AAPS bioanalytical community microsampling subgroup and the European Bioanalysis Forum conducted a survey of their members (39 individual organizations). This gives a snapshot of current practices and demonstrates that implementation of microsampling approaches is becoming increasingly commonplace, but not universal. Greater adoption was observed for nonclinical studies, particularly nonregulatory. A number of respondents reported that they have included microsampling data in regulatory submissions. Another important observation was that where microsampling is employed for clinical studies, dried blood approaches predominate, reflecting the interest in their use where they enable sample collection which is not feasible with standard approaches or to derive richer data sets.
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Coleta de Amostras Sanguíneas/métodos , Preparações Farmacêuticas/análise , Sociedades Científicas , Animais , Teste em Amostras de Sangue Seco , Avaliação Pré-Clínica de Medicamentos , Humanos , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/metabolismo , Inquéritos e QuestionáriosRESUMO
Carbon capture and storage is a transition technology from a past and present fuelled by coal, oil and gas and a planned future dominated by renewable energy sources. The technology involves the capture of carbon dioxide emissions from fossil fuel power stations and other point sources, compression of the CO2 into a fluid, transporting it and injecting it deep beneath the Earth's surface into depleted petroleum reservoirs and other porous formations. Once injected, the CO2 must be monitored to ensure that it is emplaced and assimilated as planned and that none leaks back to surface. A variety of methods have been deployed to monitor the CO2 storage site and many such methods have been adapted from oilfield practice. However, such methods are commonly indirect, episodic, require active signal generation and remain expensive throughout the monitoring period that may last for hundreds of years. A modelling framework was developed to concurrently simulate CO2 geostorage conditions and background cosmic-ray muon tomography, in which the potential was assessed for using variations in muon attenuation, due to changes in CO2 abundance, as a means of CO2 detection. From this, we developed a passive, continuous monitoring method for CO2 storage sites using muon tomography, the tools for which can be deployed during the active drilling phase (development) of the storage site. To do this, it was necessary to develop a muon detector that could be used in the hostile environment (saline, high temperature) of the well bore. A prototype detector has been built and tested at the 1.1 km deep Boulby potash mine on the northeast coast of England, supported by the existing STFC Boulby Underground Laboratory on the site. The detector is now ready to be commercialized.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.
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Técnicas de Química Analítica/instrumentação , Descoberta de Drogas/instrumentação , Indústria Farmacêutica/instrumentação , Indústria Farmacêutica/tendências , Automação Laboratorial/economia , Educação em Farmácia/tendências , Processamento Eletrônico de Dados/economia , Humanos , Colaboração Intersetorial , Laboratórios/tendências , Pessoal de Laboratório/educação , Serviços TerceirizadosRESUMO
AIM: The quality of quantitative analytical measurements is dependent on the quality of the sample collected, and dried blood spots (DBS) are no exception. As the use of DBS has matured into late-stage clinical drug-development studies, it has become apparent that a simple and straightforward approach in a controlled single-site, first-time-into-human clinic, does not always translate into multicenter clinical studies. Using synthetic blood, a method of training and assessing clinical laboratory staff has been developed to ensure the quality of sampling. METHODS: A test kit comprising of synthetic blood, a pipetting aid, blank blood spot card, drying rack and training manual was sent to each clinical site for each technician to assess and approve prior to spotting PK samples. RESULTS: The development of a DBS training kit along with a step-by-step guide has been successfully implemented. CONCLUSION: The training kit has been 100% successful across three large multisite clinical studies.
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Teste em Amostras de Sangue Seco/normas , Manejo de Espécimes/métodos , Manejo de Espécimes/normas , Humanos , Manejo de Espécimes/instrumentaçãoRESUMO
Circulating drug concentrations (clinical or preclinical) underly many interactions between industry and regulators; expressing safety coverage, pharmacokinetic-pharmacodynamic relationships or defining bioequivalence and dosing regimens. Accurate and precise measurement of these circulating concentrations is pivotal to the evolution and validation of any bioanalytical method that supports regulatory interactions. Since the bioanalyst is presented with a sub-aliquot of sampled biological matrix, how do they ensure this aliquot reflects the concentration in the subject at the time of collection? Here we share experiences from project support (internal and at CROs) that suggests we need to be ever vigilant translating the needs of bioanalysis with those of project teams. The simple mantra is for bioanalytical measurements to be physiologically relevant to the patient.
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Monitoramento de Medicamentos , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/metabolismo , Coleta de Amostras Sanguíneas , Cromatografia Líquida de Alta Pressão/normas , Estabilidade de Medicamentos , Hemólise , Humanos , Preparações Farmacêuticas/normas , Controle de Qualidade , Espectrometria de Massas em Tandem/normas , TemperaturaRESUMO
21st International Reid Bioanalytical Forum, University of Surrey, Guildford, UK, 7-10 September 2015 The 21st International Reid Bioanalytical Forum held between 7 and 10 September 2015, brought together over 100 scientists from around the world, representing industry, academia and vendors, for 4 days of engaging science at the University of Surrey in Guildford, UK. The scientific program consisted of 43 podium and 23 poster presentations from key opinion leaders and those just setting out on their scientific career. The latter being the focus of the meeting. One of the highlights of the forum was the debate. An expert panel helped spark off an active discussion among a passionate audience on the topic of 'The Current Skills Gaps in Analytical Sciences are Failing Industry.'
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Química Analítica/educação , Escolha da Profissão , Química Analítica/economia , Humanos , Indústrias , Pesquisa , Reino Unido , Universidades/economiaRESUMO
BACKGROUND: Control blood plasma is regularly used in bioanalysis, biomarkers and proteomics, and is often obtained from commercial sources. It has always been assumed that this plasma will be comparable to plasma drawn during a drug development study. RESULTS: When compared using total protein concentrations, plasma from only one species (dog) demonstrated statistical comparability, plasma from all other species tested (human, rabbit, mouse and rat) shows a statistically significant difference. CONCLUSION: If endogenous components of blood plasma are being measured, or if an assay technique does not significantly limit matrix effects, any assay controls should be prepared using control plasma from the drug development site, or using commercial plasma that has been screened against drug development site plasma.