1,721,009 research outputs found
Oral Yohimbine as a New Probe Drug to Predict CYP2D6 Activity: Results of a Fixed-Sequence Phase I Trial
No full textObjective!#!Yohimbine pharmacokinetics were determined after oral administration of a single oral dose of yohimbine 5 mg and a microdose of yohimbine 50 µg in relation to different cytochrome P450 (CYP) 2D6 genotypes. The CYP2D6 inhibitor paroxetine was used to investigate the influence on yohimbine pharmacokinetics. Microdosed midazolam was applied to evaluate a possible impact of yohimbine on CYP3A activity and the possibility of combining microdosed yohimbine and midazolam to simultaneously determine CYP2D6 and CYP3A activity.!##!Methods!#!In a fixed-sequence clinical trial, 16 healthy volunteers with a known CYP2D6 genotype [extensive (10), intermediate (2) and poor (4) metaboliser] received an oral dose of yohimbine 50 µg, yohimbine 5 mg at baseline and during paroxetine as a CYP2D6 inhibitor. Midazolam (30 µg) was co-administered to determine CYP3A activity at each occasion. Plasma concentrations of yohimbine, its main metabolite 11-OH-yohimbine, midazolam and paroxetine were quantified using validated liquid chromatography-tandem mass spectrometry assays.!##!Results!#!Pharmacokinetics of yohimbine were highly variable and a CYP2D6 genotype dependent clearance was observed. After yohimbine 5 mg, the clearance ranged from 25.3 to 15,864 mL/min and after yohimbine 50 µg, the clearance ranged from 39.6 to 38,822 mL/min. A more than fivefold reduction in clearance was caused by paroxetine in CYP2D6 extensive metabolisers, while the clearance in poor metabolisers was not affected. Yohimbine did not alter CYP3A activity as measured by microdosed midazolam.!##!Conclusions!#!The pharmacokinetics of yohimbine were highly correlated with CYP2D6, which was further supported by the clearance inhibition caused by the CYP2D6 inhibitor paroxetine. With these data, yohimbine is proposed to be a suitable probe drug to predict CYP2D6 activity. In addition, the microdose can be used in combination with microdosed midazolam to simultaneously evaluate CYP2D6 and CYP3A activity without any interaction between the probe drugs and because the microdoses exert no pharmacological effects.!##!Clinical trial registration!#!EudraCT2017-001801-34
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Pharmacometric approaches to assess antibiotic dosing in special patient populations: Towards therapeutic decision support
Get PDFAlmost one century has passed since the discovery of the first antibiotic drug, yet bacterial infections remain a major threat to public health. Two alarming trends have been observed in the last decades: While no truly novel antibiotic drugs were developed, the emergence and spread of antimicrobial resistance dramatically increased. Therefore, a rational use of the existing antibiotic drugs is crucial. One key pillar of rational antibiotic treatment is the choice of an appropriate dosing regimen resulting in adequate antibiotic exposure at the site of infection. In special patient populations, such as critically ill patients or morbidly obese patients, appropriate dosing is particularly challenging since these patients commonly show certain patient-specific characteristics altering antibiotic exposure.
The objective of the present thesis was to leverage pharmacometric modelling and simulation approaches in order to (i) enhance the understanding of the pharmacokinetics of antibiotic drugs in special patient populations, but also of the variability in the microdialysis technique – as the method of choice to determine drug exposure at target site, (ii) to evaluate and optimise antibiotic dosing regimens via adequate antibiotic exposure, and (iii) to translate the research results into the clinics supporting future therapeutic decisions. The thesis focused on the two antibiotic drugs ‘linezolid’ (Project I, II) and ‘meropenem’ (Project III, IV) in the selected special populations of ‘obese surgical patients’ and ‘critically ill patients’, respectively.
Project I characterised the pharmacokinetics (PK) of linezolid in plasma as well as at the target site (interstitial space fluid of s.c. adipose tissue, representing a common location of infections) in obese compared to nonobese surgical patients: The distribution of linezolid to the target site was delayed and exposure was reduced compared to plasma. The body size descriptor ‘lean body weight’ together with the obesity status of the patient were identified as factors which had an impact on linezolid PK. Both factors led to lower exposure in obese patients compared to nonobese patients, with a particularly pronounced difference at the target site. Interestingly, also anaesthesia and the related haemodynamic changes were found to impact linezolid PK, which resulted in reduced linezolid tissue fluid distribution and excretion. In addition to the PK-related findings, Project I characterised the variability in the microdialysis technique by integrating all available microdialysis data into the pharmacometric model and by dissecting and quantifying various levels of variability (interpatient, intercatheter, intracatheter). While the interpatient variability was almost fully explained by the obesity status of the patient, the quantified inter- and intracatheter variability highlighted the importance of special care in the performance of microdialysis (calibration of catheter, placement of catheter etc.).
Project II, a simulation analysis, applied the developed pharmacometric model of linezolid to assess standard linezolid dosing regarding the attainment of effective linezolid exposure (i.e. attainment of a predefined PK/Pharmacodynamic target). In the setting of perioperative infection prophylaxis, single standard linezolid dosing only resulted in effective target site exposure for susceptible pathogens and/or for surgical procedures of short durations. Overall, an increase in the risk of ineffective exposure was observed with increasing body size. In the setting of acute therapy, standard linezolid dosing was related to high risk of ineffective linezolid exposure at the target site, partly even for susceptible pathogens and/or in plasma. Increasing the daily dose (from 1200 mg to 2400 mg) clearly reduced the risk of ineffective exposure. In general, also prolongation of the infusion duration (from 30 min to 4 h) or shortening of the dosing interval (from 12 h to 8 h) reduced the risk of ineffective exposure, yet, less pronounced than the intensification of the daily dose. For resistant pathogens, none of the investigated dosing alterations resulted in effective linezolid exposure, neither in obese nor in nonobese patients.
Project III and IV characterised the PK of meropenem in a heterogenous critically ill patient population with severe infections. A large PK variability was observed between patients, which was to a large extent explained by the wide disparity in the patient characteristics: creatinine clearance (according to Cockcroft and Gault, CLCRCG), body weight and serum albumin concentration. Of these three characteristics, CLCRCG showed by far the strongest impact on the (non)-attainment of effective meropenem exposure. Patients with normal or augmented renal function were at highest risk of ineffective exposure. Increasing the daily dose of meropenem, but particularly increasing the infusion duration (from 30-min to 3-h prolonged and/or continuous infusion regimens) reduced the risk of ineffective exposure.
In order to translate the findings into the clinics, two easy-to-use tools – the ‘MeroRisk Calculator’ and the ‘3-level dosing algorithm’ – were developed. By providing a simple and intuitive interface, both tools enable the application of the pharmacometric modelling and simulation results by health care professionals. The MeroRisk calculator is an Excel® tool, which allows assessing the risk of ineffective exposure when administering standard meropenem dosing, by considering a patient’s CLCRCG and the susceptibility of the identified/suspected pathogen. The 3-level dosing algorithm provides an intuitive dosing overview, which recommends dosing regimens likely to result in effective exposure. The algorithm is based on a patient’s CLCRCG, considers four different levels of knowledge about the infecting pathogen and for the first time the uncertainty in the underlying pharmacometric model for selection of meropenem dosing regimens.
To conclude, the present thesis contributed to a better understanding of the PK of clinically relevant antibiotic drugs in special patient populations and identified patient- and surgery-specific influencing factors altering antibiotic exposure in plasma and at the target site. By assessing the adequacy of standard and alternative antibiotic dosing regimens and translating the results into easy-to-use tools for clinical application, the present thesis has taken substantial steps towards therapeutic decision support to combat bacterial infections in the context of model-informed precision dosing. Future clinical studies are required to evaluate the tools with respect to clinical efficacy and safety before widespread application of the tools in clinical practice.Seit der Entdeckung des ersten Antibiotikums ist fast ein Jahrhundert vergangen, dennoch stellen bakterielle Infektionen weiterhin eine ernsthafte Bedrohung für die öffentliche Gesundheit dar. In den letzten Jahrzehnten wurden zwei alarmierende Trends beobachtet: Während keine neuartigen Antibiotika entwickelt wurden, nahm das Auftreten und die Verbreitung von Antibiotikaresistenzen dramatisch zu. Daher ist eine rationale Anwendung der aktuell vorhandenen Antibiotika von entscheidender Bedeutung. Eine wichtige Säule in der rationale Antibiotikatherapie ist die Wahl eines geeigneten Dosierungsschematas, welches in einer adäquaten Antibiotikaexposition am Infektionsort resultiert. In speziellen Patientenpopulationen wie Intensiv- oder krankhaft adipösen Patienten ist eine geeignete Dosierung besonders herausfordernd, da diese Patienten häufig bestimmte patientenspezifische Merkmale aufweisen, welche die Antibiotikaexposition verändern.
Ziel der vorliegenden Arbeit war es, pharmakometrische Modellierungs- und Simulationsansätze zu nutzen, um (i) das Verständnis der Pharmakokinetik von Antibiotika in speziellen Patientenpopulationen, aber auch der Variabilität in der Mikrodialysetechnik - als Methode der Wahl zur Bestimmung der Arzneistoffexposition am Wirkort – zu verbessern, (ii) die Antibiotikadosierung im Hinblick auf eine adäquate Antibiotikaexposition zu evaluieren und zu optimieren und (iii) die Forschungsergebnisse in die Klinik zu übertragen, um zukünftige klinische Dosierungsentscheidungen zu unterstützen. Die Arbeit konzentrierte sich auf die zwei Antibiotika ‚Linezolid‘ (Projekt I, II) und ‚Meropenem‘ (Projekt III, IV) in den speziellen Populationen der ‚adipösen chirurgischen Patienten‘ bzw. der ‚Intensivpatienten‘.
In Projekt I wurde die Pharmakokinetik (PK) von Linezolid im Plasma sowie am Wirkort (Interstitialflüssigkeit des s.c. Fettgewebes, welche einen häufigen Infektionsort darstellt) in adipösen im Vergleich zu nicht-adipösen chirurgischen Patienten charakterisiert: Die Verteilung von Linezolid zum Wirkort war verzögert und die Exposition im Vergleich zum Plasma verringert. Die Körpermassenkennzahl ‚Lean Body Weight‘ wurde zusammen mit dem Adipositasstatus des Patienten als Einflussfaktoren für die PK von Linezolid identifiziert. Beide Faktoren führten in adipösen Patienten zu einer geringeren Linezolidexposition verglichen mit nicht-adipösen Patienten, wobei der Unterschied am Wirkort besonders ausgeprägt war. Interessanterweise zeigten auch die Anästhesie und die damit verbundenen hämodynamischen Veränderungen einen Einfluss auf die PK von Linezolid, was zu einer verminderten Gewebsverteilung und Ausscheidung von Linezolid führte. Neben den Ergebnissen zur Pharmakokinetik charakterisierte Projekt I zusätzlich die Variabilität in der Mikrodialysetechnik, indem alle verfügbaren Mikrodialysedaten in das pharmakometrische Modell integriert und verschiedene Variabilitätsniveaus (Inter-Patienten, Inter-Katheter, Intra-Katheter) separiert und quantifiziert wurden. Während die Inter-Patienten Variabilität fast vollständig furch den Adipositasstatus des Patienten erklärt wurde, betonte die quantifizierte Inter- und Intra-Katheter Variabilität die Wichtigkeit einer besonderen Sorgfalt bei der Durchführung der Mikrodialyse (Kalibrierung des Katheters, Platzierung des Katheters usw.).
Projekt II, eine Simulationsstudie, nutzte das entwickelte pharmakometrische Linezolidmodell um die Standarddosierung von Linezolid hinsichtlich des Erreichens einer effektiver Linezolid Exposition (d.h., Erreichen eines vordefinierten PK/Pharmakodynamischen Zielwertes) zu evaluieren. In der perioperativen Infektionsprophylaxe führte die einmalige Standarddosierung von Linezolid nur im Falle von empfindlichen Krankheitserregern und/oder chirurgischen Eingriffen von kurzer Dauer mit hoher Wahrscheinlichkeit zu einer effektiven Exposition am Wirkort. Insgesamt wurde ein höheres Risiko für ineffektive Exposition mit zunehmender Körpermasse beobachtet. In der Akuttherapie war die Standarddosierung von Linezolid mit einem hohen Risiko für ineffektiven Linezolidexposition am Wirkort verbunden, teilweise sogar für empfindliche Krankheitserreger und/oder im Plasma. Die Erhöhung der Tagesdosis von Linezolid (von 1200 mg auf 2400 mg), verringerte das Risiko einer ineffektiven Exposition deutlich. Im Allgemeinen verringerten auch eine Verlängerung der Infusionsdauer (von 30 min auf 4 h) oder eine Verkürzung des Dosierungsintervalls (von 12 h auf 8 h) das Risiko einer ineffektiven Exposition, jedoch weniger ausgeprägt als die Intensivierung der Tagesdosis. Bei resistenten Erregern führte keine der untersuchten Dosierungsänderungen zu effektiver Linezolid Exposition, weder bei adipösen noch bei nicht-adipösen Patienten.
Projekt III und IV charakterisierten die PK von Meropenem in einer heterogenen Population von Intensivpatienten mit schweren Infektionen. Es wurde eine hohe PK-Variabilität zwischen den Patienten beobachtet, die sich zu einem Großteil durch starke Unterschiede in Patienteneigenschaften erklären ließ: Kreatinin-Clearance (gemäß Cockcroft und Gault, CLCRCG), Körpergewicht und Serumalbumin-Konzentration. Von diesen drei Charakteristika zeigte die CLCRCG bei weitem den stärksten Einfluss auf das (Nicht-)Erreichen einer effektiven Meropenemexposition. Patienten mit normaler oder erhöhter Nierenfunktion zeigten das höchste Risiko einer ineffektiven Exposition. Die Erhöhung der Tagesdosis von Meropenem, insbesondere aber die Verlängerung der Infusionsdauer (von 30-min auf 3-h prolongierte und/oder kontinuierliche Infusionsschemata) verringerten das Risiko einer ineffektiven Exposition.
Um die Ergebnisse in die Klinik zu übertragen, wurden zwei einfach zu bedienende Tools entwickelt - der ‚MeroRisk Calculator‘ und der ‚3-stufige Dosierungsalgorithmus‘. Durch eine simple und intuitive Benutzeroberfläche ermöglichen beide Tools die Anwendung der pharmakometrischen Modellierungs- und Simulationsergebnisse durch Fachpersonal im Gesundheitswesen. Der MeroRisk Calculator ist ein Excel®-Tool, mit welchem das Risiko einer ineffektiven Exposition bei Verabreichung einer Standarddosierung von Meropenem beurteilt werden kann, indem die CLCRCG des Patienten und die Empfindlichkeit des identifizierten/vermuteten Erregers berücksichtigt werden. Der 3-stufige Dosierungsalgorithmus bietet eine intuitive Dosierungsübersicht, welche Dosierungsschemata empfiehlt, die mit hoher Wahrscheinlichkeit zu einer effektiven Exposition führen. Der Algorithmus basiert auf der CLCRCG des Patienten, berücksichtigt vier verschiedene Wissensniveaus über den infektiösen Erreger, sowie erstmals die Unsicherheit in dem zugrunde liegenden pharmakometrischen Modell für die Auswahl von Dosierungsschemata.
Zusammenfassend hat die vorliegende Arbeit zu einem besseren Verständnis der PK von zwei klinisch relevanten Antibiotika in speziellen Patientenpopulationen beigetragen und patienten- und operationsspezifische Einflussfaktoren identifiziert, welche die Antibiotikaexposition im Plasma und am Wirkort verändern. Durch die Beurteilung der Angemessenheit von Standard- und alternativen Antibiotika-Dosierungsschemata und der Translation der Ergebnisse in einfach zu nutzende Tools für die klinische Anwendung hat die vorliegende Arbeit wesentliche Schritte in Richtung einer therapeutischen Entscheidungshilfe zur Bekämpfung bakterieller Infektionen, im Kontext von modellgestützte Präzisionsdosierung, unternommen. Zukünftige klinische Studien sind erforderlich, um die Tools im Hinblick auf die klinische Wirksamkeit und Sicherheit zu bewerten, bevor sie in der klinischen Praxis eingesetzt werden
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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