1,721,002 research outputs found
Prolonged glucocorticoid treatment in ARDS: Pathobiological rationale and pharmacological principles
No full textGlucocorticoids (GCs) are agonist compounds that bind to the GC receptor (GRα), producing a rapid pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GRα; the effect is systemic, including lung tissue and circulating cells. The extraordinary research advancements of the last decade have radically reshaped our understanding of the GRα's multifaceted actions, the effector of GC actions. In this chapter, we first examine the pathogenetic rationale for GC treatment by (i) placing ARDS in the context of the general adaptation to critical illness and (ii) as an acute multifactorial interstitial lung disease (not a syndrome). We examine the progression of each integrated stratum of this disease—pathogenesis—morphology—physiology—in patients with adaptive versus maladaptive responses. During the three phases of disease progression, the GC-GRα operates as the central homeostatic rheostat regulating cellular, tissue-specific, and systemic responses with fine-tuning of every process in every organ, adapting responses to constantly changing surrounding signals. We synthesize the current literature on the role of the GRα as the effector of GC therapy, including genomic and nongenomic effects, and examine pharmacological principles to guide GC administration. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving an optimal response to GC therapy in ARDS. An updated metaanalysis of randomized controlled trials (RCTs) investigating GC treatment in ARDS includes evaluating treatment protocols’ components. Based on RCT data, GC plasma concentration-time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period, and slow tapering. We finally address the substantial between-patient variability in plasma concentrations and intracellular response, a rationale for adjusting dose and duration targeting clinical and laboratory improvements. These findings have practical clinical relevance and should be incorporated into the design of future trials
Pharmacokinetics of intravenous amiodarone in children
No full textObjectives Although amiodarone is an effective treatment for severe paediatric arrhythmias, uncertainties about adverse effects such as hypotension, bradycardia and excessive serum drug concentrations persist. Therefore, the aims of this study were to: (a) determine serum concentrations of intravenous (IV) amiodarone following a widely implemented dosing regimen of 5 mg/kg bolus plus a 10 mg/kg/day continuous infusion and (b) generate descriptive data on safety parameters such as hypotension, bradycardia or corrected QT (QTc) prolongation during this regimen. Design Prospective observational study. Setting Paediatric intensive care unit. Patients Twenty paediatric patients (median age, 0.23 years; range, 6 days-15.04 years) with arrhythmia secondary to or without cardiac surgery. Interventions None. Main outcome measures Amiodarone serum concentrations, blood pressure, heart rate, QTc intervals. Results Amiodarone serum concentrations increased markedly during bolus, followed by rapid decreases during maintenance infusion. All patients had serum concentrations regarded as effective in adults (median concentration range: 1.30-2.06 mu M/L during maintenance phase). Amiodarone suppressed arrhythmias in 18 (90%) patients. Mean QTc intervals for pretherapy, during and post-therapy periods were 443 ms, 458 ms and 467 ms, respectively. Eight patients had hypotension. Conclusions Amiodarone was effective in the majority of children in this small cohort
Pharmacometric analysis of monoclonal antibodies to support clinical decision-making
Full text linkMonoclonal antibodies (mAbs) are successful treatment options in a variety of therapeutic areas, including cancer and inflammatory diseases. Even though introduction of infliximab (IFX) – the first mAb for inflammatory bowel diseases (IBD) – is considered a revolutionary step in IBD treatment, over the course of time challenges of IFX therapy arose. Given informative clinical data, quantitative approaches, such as pharmacometrics, are increasingly recognised for their potential to provide a deeper mechanistic understanding and contribute to overcoming clinical challenges, thus improving IBD therapy success.
This work aimed to contribute to improving success of IBD treatment and the rational use of IFX. Insights in (1) dynamic exposure-biomarker relationship, (2) clearance mechanisms of mAbs and relevance of study design, and (3) pharmacokinetic (PK) behaviour of IFX in pregnancy are reported.
Within this thesis the first population nonlinear mixed-effects (NLME) PK/PD model that quantitatively describes the IFX dose-exposure-CRP concentration relationship was developed. The model provides mechanistic insights, e.g. on significant factors influencing the IFX PK and the maximum inhibitory effect of IFX on CRP synthesis, and has been employed to assess the standard IFX dosing regimen, whereby potentially advantageous dosing regimens were identified. Moreover, the developed model can be further utilised to support Therapeutic Drug Monitoring and clinical decision-making.
While the quantitative approaches are powerful tools, the methodology alone cannot overcome the limitations of the clinical data used for the model development. Adequately informative data are a prerequisite for a quantitative analysis, highlighting the importance of the clinical study design. Within the herein reported work, this aspect was addressed using cetuximab – an anti-EGFR oncology mAb – as a case study, due to a highly informative dataset available for this drug. Firstly, the most comprehensive NLME PK model of cetuximab was developed, which revealed both an exposure- and a time-dependency of clearance. The model was subsequently utilised to identify clinical study design characteristics relevant for the identification of the mechanistic clearance model. The provided guidelines can be extrapolated for analyses of other mAbs as well. The importance of rich sampling for a detailed PK characterisation is emphasised, and guidance on the methodological aspects of such an analysis (e.g. model selection relative to study design) and choice of exposure metrics used for exposure-response analyses given.
Recognising the need for a more elaborate comprehension of IBD therapy in special populations, a part of the herein disclosed work focused on pregnant IBD patients receiving IFX. In addition to general therapy challenges, pregnancy opens additional clinical questions with respect to both safety and efficacy of IBD treatment, in pregnant patient and foetus alike. The herein developed population NLME PK model of IFX in pregnancy is the first such model reported. The model provided insights in the impact of pregnancy on IFX PK, revealing a decreased IFX clearance in the second and third trimesters. The need for a consensus on IFX PK target in IBD management is emphasised, as well as the importance of monitoring of anti-drug antibodies regardless of the pregnancy status.
Altogether, these findings provide a better understanding of the pharmacokinetics and pharmacodynamics of IFX in IBD patients and the developed models offer a basis for model-informed precision dosing.Monoklonale Antikörper (mAb) gehören zu den etablierten Arzneimitteltherapien für Indikationen wie Onkologie und Entzündungserkrankungen. Die Einführung von Infliximab (IFX) – dem ersten mAb zur Behandlung chronisch-entzündlicher Darmerkrankungen (IBD) – stellte eine Revolution in der Behandlung von IBD dar, die allerdings von einigen Komplikationen begleitet wird. Quantitative Ansätze wie die Pharmakometrie können ein tieferes mechanistisches Verständnis ermöglichen, um die Therapieherausforderungen zu bewältigen und die IBD-Therapie zu optimieren.
Ziel dieser Arbeit war dazu beizutragen, den Therapieerfolg in der IBD-Behandlung und den rationalen Einsatz von IFX zu verbessern. Dazu sollen Erkenntnisse in (1) den dynamische Expositions-Biomarker-Zusammenhang, (2) die Eliminationsmechanismen von mAbs sowie die Relevanz des Studiendesigns hierfür und (3) die Pharmakokinetik (PK) von IFX während der Schwangerschaft erarbeitet werden.
Das entwickelte PK/pharmakodynamische (PD) Populationsmodell ist das erste Modell, das die Zusammenhänge zwischen der IFX-Dosis, der Exposition und der Konzentration des C-reaktive Proteins (CRP) quantitativ charakterisiert. Das Modell bietet mechanistische Einblicke, wie z.B. wesentliche Faktoren, die die IFX-PK beeinflussen und den maximalen inhibitorischen Effekt von IFX auf die CRP Synthese, und wurde genutzt, um das standardmäßige IFX-Dosierungsschema neu zu bewerten. Dabei wurden potenziell verbesserte Dosierungsschemata identifiziert. Das entwickelte Modell kann für das Therapeutische Drug Monitoring sowie als Basis für klinische Entscheidungen genutzt werden.
Die erarbeiteten quantitativen Ansätze sind auf aussagekräftige und informative klinische Daten angewiesen. Daher wurde in dieser Arbeit auch die Relevanz des klinischen Studiendesigns für die pharmakometrische Analyse erforscht. Dafür wurde Cetuximab – ein anti-EGFR mAb gegen Tumorerkrankungen – aufgrund der umfangreicheren Datenverfügbarkeit als Modellarzneistoff gewählt. Das entwickelte Modell ist das erste PK-Populationsmodell für Cetuximab, das sowohl die Expositions- als auch die Zeitabhängigkeit der Cetuximab-Elimination systematisch untersucht. Das Modell wurde danach angewandt, um die entscheidenden Merkmale eines klinischen Studiendesigns, die für die Bestimmung des mechanistischen Eliminationsmodells relevant sind, zu identifizieren. Die Empfehlungen können ebenso auf Populationsanalysen von anderen mAbs extrapoliert werden. Die Wichtigkeit eines umfangreichen Samplings für eine detaillierte PK-Charakterisierung wurde besonders hervorgehoben, und es wurden Hinweise zu methodischen Aspekten einer solchen Analyse und zur Auswahl von Expositionsmetriken gegeben, die für Expositions-Wirkungs-Analysen verwendet werden.
In Speziellen Patientengruppen ist es erforderlich, ein besseres Verständnis für die IBD-Therapie zu gewinnen. Daher lag der Fokus in einem weiteren Teil dieser Arbeit auf schwangeren IBD-Patientinnen, die IFX erhalten. Neben den allgemeinen therapeutischen Herausforderungen führt eine Schwangerschaft zu zusätzlichen klinischen Fragen hinsichtlich der Sicherheit und Wirksamkeit der IBD-Behandlung, sowohl bei der schwangeren Patientin als auch beim Fötus. Das hier entwickelte Populationsmodell, das die IFX PK in der Schwangerschaft charakterisiert, ist das erste derartige Modell. Das Modell ergab neue Einblicke in die Auswirkungen der Schwangerschaft auf die IFX PK und zeigte, dass die Elimination von IFX im zweiten und dritten Trimenon vermindert war. Darüber hinaus zeigte diese Arbeit den Bedarf eines Konsensus über die IFX PK-Zielkonzentration sowie die Bedeutung des Monitorings von Anti-IFX-Antikörpern, unabhängig vom Schwangerschaftsstatus.
Insgesamt wurde im Rahmen dieser Arbeit ein verbessertes Verständnis über die PK und PD von IFX in IBD-Patienten geschaffen. Die entwickelten Modelle bieten die Grundlage für ein sogenanntes „Model-informed precision dosing“, ein modellbasiertes Therapeutisches Drug Monitoring
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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