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  • 1
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: Contrary to the assumption of worldwide diffusion processes of internationally circulating reform ideas in education there are examples of regions that resist. In the present study, the phenomenon of incorporating international reform ideas into local education systems is examined using new institutionalism as a theory for its explanatory power of worldwide diffusion processes in education together with a set of cases that offer semi-lab-like conditions: Not all German federated states have adopted Bachelor’s and Master’s degrees for teacher training; some have maintained the state examination. Based on this empirical finding, the question of the dissertation is: Whether and how were the Bachelor’s and Master’s degree in German teacher training implemented on the federated statelevel in the period between 1999 and 2013? It can be shown that the federal ministers of higher education specified three core characteristics of the Bologna Process, namely the introduction of Bachelor’s and Master’s degrees, a credit point system, and modularisation. A decision of the Standing Conference of the Ministers of Education and Cultural Affairs of Germany made in 2005 further ensured that the reformed degrees were recognised nationwide for teachers as well. The educational organisations’ demands were characterised by a large number of positive and only a few negative votes concerning the implementation of the Bologna Process in German teacher education. To provide specific insights into the reform process, this study focuses on teacher training for secondary school teachers, comparing the teacher training regulations as of 1999 with all subsequent changes until 2013 to obtain the degree of change for each federated state. As a result, it can be stated that eight states introduced reformed degrees into secondary school teacher education and eight states kept the state examination. Both groups are then compared as to whether a change of the degree towards Bachelor’s and Master’s is more likely to be accompanied by further reforms. The results suggest that while changes have occurred in all states, the percentage increase of courses in education and didactics, as well as the increased study duration, correlates positively with a change of the degree structure. Therefore one can interpret that the Bologna reforms, especially those concerning the degree structure, were used to implement other curricular and structural reforms that were not related to the Bologna Process itself. In the last step, plenary debates on the federated state level regarding the introduction of these Bologna reforms are analysed to examine the justifications for the introduction of a change in the degree structure, as well as for maintaining the state examination. Justifications or strategies for preserving the state examination are particularly relevant because they act against the political and public expectations analysed earlier. In a nutshell, it can be stated that the innovative strength of the partial reforms adopted in the hybrid model and the exclusion of a fundamental criticism of Bachelor’s and Master’s degrees are used as a strategy to reject the implementation of a new degree structure without being interpreted as non-innovative. Federated states that implemented the degree reform referenced decisions made in other states or regions, as well as possible negative consequences of not implementing the degrees, to support their decision while also presenting it within the discourse as a window of opportunity for more fundamental reforms in teacher training.
    Description: Entgegen der Annahme weltweiter Diffusionsprozesse international kursierender Reformideen in der Bildungspolitik gibt es Beispiele für Regionen, die sich widersetzen. In der vorliegenden Arbeit wird dieses Phänomen mithilfe eines Sets an Fällen untersucht, die in ihrer Gesamtheit quasi-laborartige Bedingungen bieten: Im Zuge des Bologna-Prozesses haben einige Bundesländer die Abschlüsse ‚Bachelor‘ und ‚Master‘ für die Lehrer*innenbildung übernommen, während andere die Staatsprüfung beibehalten haben. Ausgehend von diesem Befund wird in der Arbeit die Frage untersucht, mit welchen Strategien die Bologna-Reformen in der Lehrer*innenbildung der einzelnen Bundesländer in den Jahren von 1999 bis 2013 politisch umgesetzt bzw. wie deren Implementation verhindert wurde. Die Analyse der Erwartungen bildungspolitischer Akteure zeigt, dass die Hochschulminister*innen im Bologna-Prozess drei Kernmerkmale für die Organisation von Studiengängen festlegten, nämlich Bachelor- und Masterabschlüsse, ein Leistungspunktesystem und die Modularisierung. Darüber hinaus wurde die Bologna-Reform durch die Kultusministerkonferenz im Jahr 2005 auch für die Lehrer*innenbildung deutschlandweit anerkannt. Der Diskurs weiterer wichtiger bildungspolitischer Akteure zeichnet sich darüber hinaus durch eine Vielzahl an positiven gegenüber nur wenigen negativen Stimmen zur Implementation des Bologna-Prozesses in der Lehrer*innenbildung aus. Um die tatsächlichen Reformen differenziert betrachten zu können, wird der Fokus der zweiten Untersuchung allein auf das gymnasiale Lehramt gelegt. Dabei wird für jedes Bundesland die Gestaltung der Studienphase im Jahr 1999 mit dem Stand im Jahr 2013 verglichen. Dabei kann festgestellt werden, dass in allen Bundesländern sowohl das Leistungspunktesystem als auch die Modularisierung eingeführt wurden. Eine Reform der Staatsprüfung hin zu einem Masterabschluss wurde im Untersuchungszeitraum jedoch nur in acht der 16 Bundesländer umgesetzt. Die Einführung der Bachelor- und Masterabschlüsse ging zudem mit einer prozentualen Erhöhung des Anteils der Berufswissenschaften, definiert als Fachdidaktiken, Bildungswissenschaften und Schulpraktika, sowie einer Verlängerung der Studienzeit einher. Dies kann dahingehend interpretiert werden, dass die Bologna- Reformen insgesamt und die Einführung der Bachelor- und Masterabschlüsse im Besonderen als window of opportunity genutzt wurden, um auch andere Reformen umzusetzen. In der dritten Untersuchung werden Plenardebatten in den Bundesländern im Rahmen der Einführung der Bologna-Reformen analysiert, um die Begründungen für eine Reform bzw. für die Beibehaltung der Staatsprüfung zu untersuchen. Insbesondere Begründungen bzw. Strategien der Nicht-Einführung sind dabei besonders relevant, weil sie gängigen theoretischen Annahmen der Diffusion von international kursierenden Reformideen widersprechen. Zusammenfassend kann festgehalten werden, dass die Innovationskraft bzw. Passfähigkeit des eigenen Gesetzentwurfs unter Ausschluss einer Fundamentalkritik an den Bachelor- und Masterabschlüssen als Strategie verwendet wurden, um die Einführung dieser Abschlüsse zu umgehen, ohne gleichzeitig als rückständig im Vergleich zu den Ländern mit einer vollständigen Implementation zu gelten. Bei einer Implementation der Abschlüsse dient neben dem diskursiv hergestellten window of opportunity auch der Verweis auf an anderen Orten getroffene Entscheidungen und den daraus resultierenden negativen Konsequenzen für das eigene Bundesland bei einer etwaigen Nicht-Implementation als legitimitätsstiftend.
    Keywords: Lehrerbildung ; Lehrerausbildung ; Bologna-Prozess ; Hochschulpolitik ; Bachelor-Studiengang ; Master-Studiengang ; Lehramtsstudiengang ; Hochschulreform ; Hochschule ; Entscheidung ; Strategie ; Studiengang ; Studienordnung ; Bildungspolitik ; Gymnasium ; Modularisierung ; Staatsprüfung ; Lehramtsprüfung ; Argumentation ; Debatte ; Politik ; Bundesland ; Nationaler Vergleich ; Baden-Württemberg ; Bayern ; Berlin ; Brandenburg ; Bremen ; Hamburg ; Hessen ; Mecklenburg-Vorpommern ; Niedersachsen ; Nordrhein-Westfalen ; Rheinland-Pfalz ; Saarland ; Sachsen ; Sachsen-Anhalt ; Schleswig-Holstein ; Thüringen ; Deutschland ; Teacher education ; Teachers' training ; Teacher training ; Higher education policy ; University policy ; Bachelor course ; Master course ; Preservice Teacher Education ; Higher education reform ; University reform ; Higher education institute ; Strategy ; Channel of academic studies ; Course of studies ; Course of study ; Study regulations ; Educational policy ; German academic secondary school ; Grammar School ; Secondary school ; Modularization ; First state examination for the teaching profession ; Politics ; Baden-Wurtemberg ; Baden-Wurttemberg ; Mecklenburg-Western Pomerania ; Lower Saxony ; North Rhine-Westphalia ; North-Rhine Westphalia ; Rhineland-Palatinate ; Saxony ; Saxony-Anhalt ; Thuringia ; Germany ; Teaching post ; Teaching profession ; bic Book Industry Communication::J Society & social sciences::JN Education::JNM Higher & further education, tertiary education::JNMN Universities ; thema EDItEUR::J Society and Social Sciences::JN Education::JNM Higher education, tertiary education
    Language: German
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  • 2
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: Within and outside Germany, practical phases in teacher education have been expanded in recent years. In contrast, empirical studies show that it is not primarily the duration of the internships but their qualitative design that is significant for the acquisition of competencies by the students. Against this background, the academic examination of concepts of learning support is gaining in importance. The authors in this volume take up this assumption and present ten context-bound learning support concepts and their empirical examination. Using qualitative and quantitative research methods, theory-based hypotheses are tested and framework conditions are included in the discussion. In this respect, the results of the studies presented promise on the one hand in-depth insights into the opportunities and challenges of learning support services in the school internship, and on the other hand they point to desiderata for further studies in this field of research.
    Description: Innerhalb und außerhalb Deutschlands wurden in den vergangenen Jahren Praxisphasen in der Lehrerbildung ausgebaut. Empirische Studien zeigen demgegenüber, dass nicht vorrangig die Dauer der Praktika, sondern ihre qualitative Ausgestaltung bedeutsam für den Kompetenzerwerb der Studierenden ist. Vor diesem Hintergrund gewinnt die wissenschaftliche Auseinandersetzung mit Konzepten der Lernbegleitung an Bedeutung. Die Autorinnen und Autoren im vorliegenden Band knüpfen an dieser Annahme an und stellen zehn kontextgebundene Lernbegleitungskonzepte und deren empirische Überprüfung vor. Mittels qualitativer und quantitativer Forschungsmethoden werden dabei theoriegeleitete Hypothesen überprüft und Rahmenbedingungen in die Diskussion einbezogen. Insofern versprechen die Ergebnisse der vorgestellten Studien einerseits vertiefende Einblicke in Chancen und Herausforderungen lernbegleitender Angebote im Schulpraktikum, andererseits zeigen sie Desiderate für weiterführende Untersuchungen in diesem Forschungsfeld auf.
    Keywords: Lehrerbildung ; Lehrerausbildung ; Lernbegleitung ; Praxissemester ; Schulpraxis ; Pädagogische Praxis ; Schulpraktikum ; Lehramtsstudent ; Kompetenzerwerb ; Pädagogische Kompetenz ; Lernkonzept ; Lehrerbildner ; Unterrichtsbeobachtung ; Unterrichtsanalyse ; Reflexion 〈Phil〉 ; Mentor ; Hochschule ; Schule ; Peer Group ; Lernwerkstatt ; Coaching ; Lehrberuf ; Hochschulbildung ; Professionalisierung ; Wohlbefinden ; Lehramtsstudiengang ; Handlungskompetenz ; Einstellung 〈Psy〉 ; Dozent ; Lehrer ; Feed-back ; Interaktion ; Gespräch ; Besprechung ; Unterricht ; Audioaufzeichnung ; Diagnostik ; Kohärenz ; Mentoring ; Mentorprogramm ; Unterrichtsentwicklung ; Übergang Studium - Beruf ; Qualifizierung ; Hochschullehre ; Hochschulforschung ; Fortbildung ; Biologieunterricht ; Entwicklungsforschung ; Beziehung ; Peer-Beziehungen ; Kompetenzentwicklung ; Kompetenz ; Selbsteinschätzung ; Tandem-Methode ; Geschlechtsspezifischer Unterschied ; Kollegiale Beratung ; Qualifikationsentwicklung ; Austausch ; Beratung ; Moderator ; Moderation ; Lernprozess ; Grundschule ; Außerschulischer Lernort ; Lernumgebung ; Primarbereich ; Ethnografie ; Beobachtung ; Forschendes Lernen ; Belastung ; Stressbewältigung ; Wirksamkeit ; Digitale Medien ; Beruflicher Stress ; Lehrer-Alltag ; Bildungsangebot ; Online-Kurs ; Auditives Medium ; Zufriedenheit ; Quantitative Forschung ; Qualitative Forschung ; Empirische Untersuchung ; Empirische Forschung ; Interview ; Leitfadeninterview ; Studie ; Fragebogenerhebung ; Explorative Studie ; Grounded Theory ; Evaluation ; Niedersachsen ; Thüringen ; Nordrhein-Westfalen ; Mecklenburg-Vorpommern ; Hessen ; Deutschland ; Teacher education ; Teachers' training ; Teacher training ; Practical semester ; Semester practical training ; Practical training in school ; Practice period at school ; Student teachers ; Teacher educators ; Observation of teaching ; Analysis of teaching process ; Teaching analysis ; Higher education institute ; School ; Peer groups ; Learning workshop ; Apprenticeship trade ; Teaching profession ; Higher education ; University level of education ; Professionalization ; Well being ; Well-being ; Preservice Teacher Education ; Competence for action ; Competence to act ; Lecturer ; Teacher ; Interaction ; Conversation ; Teaching ; Diagnostic ; Learning and teaching development ; Teaching improvement ; Qualification ; Higher education lecturing ; University lecturing ; University teaching ; Academic research ; Further education ; Further training ; Biology lessons ; Teaching of Biology ; Peer relationship ; Skill development ; Competency ; Self-rating ; Gender-specific difference ; Counselling ; Deliberation ; Guidance ; Learning process ; Elementary School ; Primary school ; Primary school lower level ; Educational Environment ; Learning environment ; Primary education ; Primary level ; Ethnography ; Observation ; Stress management ; Educational offer ; Educational offerings ; Educational opportunities ; Educational possibilities ; Educational provision ; Online courses ; Satisfaction ; Quantitative research ; Qualitative research ; Empirical study ; Empirical research ; Questionnaire survey ; Lower Saxony ; Thuringia ; North Rhine-Westphalia ; North-Rhine Westphalia ; Mecklenburg-Western Pomerania ; Germany ; Practice ; bic Book Industry Communication::J Society & social sciences::JN Education::JNM Higher & further education, tertiary education::JNMT Teacher training ; thema EDItEUR::J Society and Social Sciences::JN Education::JNM Higher education, tertiary education::JNMT Teacher training
    Language: German
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  • 3
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: Good inclusive teaching needs teachers who are able to plan and implement pedagogical offers in a heterogeneity-sensitive and adaptive way - however, in university teacher training there are only a few subject-didactically implementable contents for this so far. This book presents five flexibly applicable teaching-learning modules on central topics of inclusive teaching, which were developed by subject didacticians in cooperation with rehabilitation scientists and language educators for university teaching. Starting from the theoretical foundations, the structure, content and materials of the individual teaching-learning modules are presented and commented on didactically. Following on from this, the empirical results of the quantitative and qualitative accompanying evaluation of corresponding courses are analysed. In addition, the suitability of the teaching-learning modules for stabilisation in the university context as well as their possible use in the second and third phase of teacher training are discussed. This book aims to motivate lecturers to use the presented modules in their teaching. It is also aimed at students, researchers and teachers who want to develop their teaching in an inclusive way.
    Description: Guter inklusiver Unterricht braucht Lehrkräfte, die pädagogische Angebote heterogenitätssensibel und adaptiv planen und umsetzen können – in der universitären Lehrer*innenbildung existieren dafür bislang jedoch nur wenige fachdidaktisch implementierbare Inhalte. In diesem Buch werden fünf flexibel einsetzbare Lehr-Lern-Bausteine zu zentralen Themen inklusiven Unterrichtens vorgestellt, die von Fachdidaktiker*innen in Zusammenarbeit mit Rehabilitationswissenschaftler*innen und Sprachbildner*innen für die Hochschullehre entwickelt wurden. Ausgehend von den theoretischen Grundlagen werden der Aufbau, die Inhalte und die Materialien der einzelnen Lehr-Lern-Bausteine vorgestellt und didaktisch kommentiert. Daran anknüpfend werden die empirischen Ergebnisse der quantitativen und qualitativen Begleitevaluation entsprechender Lehrveranstaltungen analysiert. Außerdem werden die Eignung der Lehr-Lern-Bausteine für die Verstetigung im Hochschulkontext sowie deren Einsatzmöglichkeiten in der zweiten und dritten Phase der Lehrer*innenbildung diskutiert. Dieses Buch möchte Dozent*innen motivieren, die vorgestellten Bausteine selbst in ihrer Lehre einzusetzen. Es richtet sich außerdem an Student*innen, an Forscher*innen und an Lehrer*innen, die ihren Unterricht inklusionsorientiert weiterentwickeln möchten.
    Keywords: Inklusion ; Unterricht ; Hochschule ; Hochschullehre ; Professionalisierung ; Lehrerausbildung ; Lehr-Lern-Prozess ; Bildungskonzept ; Lehrerbildung ; Kompetenz ; Lehr-Lern-System ; Lehrevaluation ; Lehramtsstudiengang ; Heterogenität ; Sensibilität ; Lehrkompetenz ; Integrative Pädagogik ; Professionalität ; Pädagogisches Handeln ; Fachdidaktik ; Sonderpädagogik ; Klassenführung ; Adaptiver Unterricht ; Unterrichtskonzeption ; Sprachbildung ; Lehramtsstudent ; Baustein ; Reflexion 〈Phil〉 ; Selbstreflexion ; Pädagogische Diagnostik ; Diagnostik ; Begleituntersuchung ; Evaluation ; Empirische Untersuchung ; Quantitative Analyse ; Qualitative Analyse ; Forschungsprojekt ; Deutschland ; Inclusion ; Teaching ; Higher education institute ; Higher education lecturing ; University lecturing ; University teaching ; Professionalization ; Teacher education ; Teacher training ; Teaching-learning process ; Educational conception ; Teachers' training ; Competency ; Preservice Teacher Education ; Heterogeneity ; Sensibility ; Teaching Skills ; Integrative education ; Professionalism ; Professionality ; Specialized didactics ; Subject didactics ; Remedial instruction sciences ; Special education for the handicapped ; Special needs education ; Classroom techniques ; Conception of teaching ; Linguistic input ; Student teachers ; Self-reflexion ; Pedagogical diagnostics ; Diagnostic ; Empirical study ; Germany ; Pedagogical thinking ; Teaching-learning research ; bic Book Industry Communication::J Society & social sciences::JN Education::JNF Educational strategies & policy::JNFN Inclusive education / mainstreaming ; thema EDItEUR::J Society and Social Sciences::JN Education::JNF Educational strategies and policy::JNFK Educational strategies and policy: inclusion
    Language: German
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  • 4
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: This book presents a selection of survey and evaluation instruments for recording relevant facets of institutional (written) language education. The seven methods focus on different aspects of language education as well as language and reading promotion in day-care centres and schools and address different target groups (educational professionals, teachers, children). The instruments, which were developed within the framework of the initiative "Bildung durch Sprache und Schrift" (BiSS), are primarily for research purposes, but can also be used in the training and further education of educational specialists and teachers. An online appendix provides the instruments as well as all necessary materials.
    Description: In diesem Buch wird eine Auswahl von Erhebungs- und Auswertungsinstrumenten zur Erfassung relevanter Facetten institutioneller (schrift-)sprachlicher Bildung vorgestellt. Die sieben Verfahren fokussieren unterschiedliche Aspekte der Sprachbildung sowie Sprach- und Leseförderung in Kindertageseinrichtungen und Schulen und adressieren unterschiedliche Zielgruppen (pädagogische Fachkräfte, Lehrkräfte, Kinder). Die Instrumente, die im Rahmen der Initiative „Bildung durch Sprache und Schrift“ (BiSS) entwickelt wurden, sind primär für Forschungszwecke, aber auch in der Aus- und Weiterbildung von pädagogischen Fach- und Lehrkräften einsetzbar. Ein Online-Anhang stellt die Instrumente sowie alle notwendigen Materialien zur Verfügung.
    Keywords: Bildungsforschung ; Forschung ; Schriftsprache ; Sprachbildung ; Sprachförderung ; Leseförderung ; Diagnostik ; Förderungsmaßnahme ; Sprachentwicklung ; Schriftspracherwerb ; Förderdiagnostik ; Förderung ; Sprachstandsforschung ; Lesekompetenz ; Sprachkompetenz ; Sprachdiagnostik ; Fachdidaktik ; Sprachgebrauch ; Kompetenzmessung ; Handlungskompetenz ; Fachwissen ; Wissen ; Professionalisierung ; Profession ; Kompetenz ; Wissenstest ; Mathematikunterricht ; Deutschunterricht ; Fachunterricht ; Fachsprache ; Reflexion 〈Phil〉 ; Feed-back ; Videoaufzeichnung ; Videoanalyse ; Unterricht ; Lehrer-Schüler-Interaktion ; Schülermitarbeit ; Transfer ; Kindertagesstätte ; Schule ; Grundschule ; Primarbereich ; Pädagogische Fachkraft ; Lehrer ; Lehramtsstudent ; Erzieher ; Erzieherin ; Berufliche Kompetenz ; Psychometrie ; Kind ; Schüler ; Bewertung ; Anwendung ; Software ; Bildungspraxis ; Sprachpraktische Übung ; Spracherwerb ; Kindergarten ; Kindergartenalltag ; Kindergartenpädagogik ; Korrektur ; Pädagogisches Handeln ; Sekundarstufe I ; Aktivierung ; Erhebungsinstrument ; Auswertung ; Instrument ; Messinstrument ; Methode ; Forschungsmethode ; Vignette 〈Methode〉 ; Interview ; Leitfadeninterview ; Fragebogen ; Beobachtung ; Beobachtungsmethode ; Test ; Testvalidität ; Testverfahren ; Testkonstruktion ; Quantitative Forschung ; Qualitative Forschung ; Längsschnittuntersuchung ; Dokumentation ; Protokoll ; Empirische Forschung ; Datenerfassung ; Bayern ; Baden-Württemberg ; Nordrhein-Westfalen ; Sachsen-Anhalt ; Deutschland ; Educational research ; Research ; Linguistic input ; Promotion of reading ; Support for reading improvement ; Diagnostic ; Promotional measure ; Language development ; Reading competence ; Language skill ; Linguistic Competence ; Specialized didactics ; Subject didactics ; Language usage ; Competency measurement ; Skills measurement ; Skills measurements ; Competence for action ; Competence to act ; Specialized knowledge ; Knowledge ; Professionalization ; Competency ; Mathematics lessons ; Teaching of mathematics ; German language teaching ; Teaching of German ; Teaching of a special subject ; Language for special purposes ; Technical language ; Teaching ; Pupil Participation ; Day nursery ; School ; Elementary School ; Primary school ; Primary school lower level ; Primary education ; Primary level ; Teacher ; Student teachers ; Caregiver ; Carer ; Educational childcare staff ; Educator ; Kindergarten teacher ; Nursery school teachers ; Nursery teacher ; Pre-primary school teacher ; Female Educator ; Governess ; Psychometry ; Child ; Pupil ; Pupils ; Assessment ; Judgement ; Judgment ; Educational practices ; Language acquisition ; Nursery school ; Revision (Written Composition) ; Lower level secondary education ; Lower secondary ; Lower secondary education ; Secondary education lower level ; Mail surveys ; Data analysis ; Interpretation of literature ; Measurement instrument ; Method ; Research method ; Questionnaire ; Observation ; Test validity ; Test coaching ; Quantitative research ; Qualitative research ; Longitudinal analysis ; Longitudinal study ; Documentation ; Empirical research ; Data acquisition ; Data capture ; Baden-Wurtemberg ; Baden-Wurttemberg ; North Rhine-Westphalia ; North-Rhine Westphalia ; Saxony-Anhalt ; Germany ; bic Book Industry Communication::J Society & social sciences::JN Education::JNF Educational strategies & policy::JNFD Literacy strategies ; thema EDItEUR::J Society and Social Sciences::JN Education::JNF Educational strategies and policy
    Language: German
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  • 5
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: nklusion steht als normatives Konzept in einem Spannungsverhältnis zum bisher selektiv verfassten Schulsystem. Lehrkräfte an sich inklusiv entwickelnden Schulen sind daher mit der Herausforderung konfrontiert, zwischen ihrer eigenen Praxis, einer inklusiven schulischen Programmatik, dem gesellschaftlichen Leistungsverständnis und der schulischen Selektionsfunktion vermitteln zu müssen. Die vorliegende Studie wirft zunächst einen systematischen Blick auf den Inklusionsdiskurs und untersucht hieran anschließend den Umgang mit diesem Spannungsverhältnis anhand von Gruppendiskussionen mit Lehrkräften an sich als inklusiv verstehenden Grundschulen. Mithilfe der Dokumentarischen Methode werden fallübergreifende Orientierungen rekonstruiert, die sich vor allem in der Verortung der Problemlösekompetenz unterscheiden. So sieht ein Teil Lehrkräfte die Verantwortung zur Lösung von Problemen, die bei der Realisierung von Inklusion entstehen, bei Externen, wie der Bildungsadministration. Andere sehen sich hingegen selbst in der Lage, die bei der Realisierung von Inklusion entstehenden Herausforderungen erfolgreich zu lösen. Bei Letzteren wird eine Parallele zu einem Teil des Inklusionsdiskurses deutlich, da Inklusion auch dort als pädagogisch lösbare Herausforderung angenommen wird. Die Arbeit zeigt diesbezüglich Anknüpfungspunkte für die weitere Entwicklung inklusiver Schulen auf. (DIPF/Orig.)
    Keywords: Inklusion ; Schule ; Grundschule ; Integrative Schule ; Lehrer ; Einstellung 〈Psy〉 ; Problemlösen ; Sonderpädagogik ; Gruppendiskussion ; Typisierung ; Dokumentarische Methode ; Deutschland ; Inclusion ; School ; Elementary School ; Primary school ; Primary school lower level ; Inclusive education ; Inclusive school ; Teacher ; Problem solving ; Remedial instruction sciences ; Special education for the handicapped ; Special needs education ; Group discussion ; Germany ; bic Book Industry Communication::J Society & social sciences::JN Education::JNF Educational strategies & policy::JNFN Inclusive education / mainstreaming ; bic Book Industry Communication::J Society & social sciences::JN Education::JNL Schools ; bic Book Industry Communication::J Society & social sciences::JN Education::JNS Teaching of specific groups & persons with special educational needs ; thema EDItEUR::J Society and Social Sciences::JN Education::JNF Educational strategies and policy::JNFK Educational strategies and policy: inclusion ; thema EDItEUR::J Society and Social Sciences::JN Education::JNL Schools and pre-schools ; thema EDItEUR::J Society and Social Sciences::JN Education::JNS Teaching of students with different educational needs
    Language: German
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  • 6
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: With the development of inclusive schools comes a broad range of new challenges within the whole German education system. According to the different responsibilities in the educational governance of the German system, not only the state level but also the district level has an important role in the reorganization process towards an inclusive school system. This doctoral thesis thus aims at developing a set of educational indicators at district and individual school level that provides information about the inputs, processes and outputs of inclusive schooling, i.e. conditions and school organizational aspects such as experience in dealing with heterogeneity (special educational needs, migration, gender, etc.). Thereby it can also provide a foundation for continuous, largely data-based observation and analysis of the implementation process of school inclusion. This kind of monitoring can inform both German educational policy and the public regarding contexts, process characteristics, outcomes and benefits of inclusive schooling. The main question of the thesis thus is: What indicators can be identified to describe and reflect developments in the implementation of an inclusive school system at the district level? This is addressed by a three-step analysis, exemplified by a typical German municipality in North Rhine-Westphalia. (1) Starting with an analysis of available school statistics in the period from 2007 to 2015 (2), the results are supplemented by a quantitative school-leadership survey in 2016 (3). A synthesis of the given results marks the last step with a characterization of the transformation process at school and district level. The framework of indicators is meant to identify general problems and offer an empirical foundation for the information on inclusive schooling in German municipalities, thus providing valid governance knowledge for a holistic, coherent educational management as well as contributing to improve the quality of inclusive education at district level. (DIPF/Orig.)
    Description: Die Umsetzung des Inklusionsgedankens konfrontiert das gesamte Bildungssystem mit neuen Herausforderungen. Entsprechend der föderalen Zuständigkeiten sind dafür neben dem Land auch Kreise und Schulträger in der Pflicht, die Entwicklung mitzugestalten. Derzeit gibt es nur wenig systematisierte Informationen über den Stand der inklusiven Bildung im Schulsystem auf kommunaler Ebene. Dies hängt auch mit einer weitgehenden Unklarheit zusammen, welche Bemessungsgrundlagen für eine Einschätzung der Qualität inklusiv arbeitender Schulen zur Verfügung stehen, insbesondere vor dem Hintergrund der lokal höchst unterschiedlichen Formen der Unterrichtsorganisation sowie ungleichen Voraussetzungen im Hinblick auf Ressourcenverteilung (personell, räumlich und sächlich) und Schülerklientel (sonderpädagogischer Förderbedarf, soziale Herkunft, Migrationshintergrund, etc.). Untersucht werden am Beispiel des Flächenkreises Paderborn die Möglichkeiten und Grenzen, die Entwicklung des Gemeinsamen Lernens im Bereich Schule indikatorengestützt abzubilden und Schlussfolgerungen für inklusive Schulorganisation und -planung auf kleinräumiger Ebene abzuleiten. Die Hauptfrage der Arbeit lautet: Welche Indikatoren lassen sich auf kommunaler Ebene identifizieren, um Entwicklungen in den Dimensionen Input, Prozess und Output bei der Umsetzung eines inklusiven Schulsystems zu beschreiben? Die Beantwortung der Forschungsfrage folgt einem dreistufigen Vorgehen. In einem ersten Schritt werden auf Basis kleinräumiger und einzelschulischer Daten der amtlichen Schulstatistik indikatorengestützte Analysen im Zeitraum von 2007 bis 2015 durchgeführt. Im Anschluss werden diese datengestützten Befunde durch Ergebnisse einer quantitativen Schulleiterbefragung im Kreis Paderborn 2016 ergänzt. In einem letzten Schritt erfolgt drittens eine Charakterisierung des nachgezeichneten Transformationsprozesses auf Einzelschulebene sowie auf kommunaler Ebene. Die Synthese der gewonnenen Forschungsergebnisse bildet den Ausgangspunkt für die Ableitung von aussagekräftigen Indikatoren und Desideraten einer Dauerbeobachtung des Gemeinsamen Lernens von Schülerinnen und Schülern mit und ohne sonderpädagogischen Förderbedarf. Wenngleich bestimmte Qualitätsaspekte schulischer Inklusion mit den verfügbaren amtlichen und den ergänzenden Schulleiterdaten nur näherungsweise indikatorisiert werden können, wird sowohl kommunalen Entscheidungsträgerinnen und -trägern aus Politik und Verwaltung, als auch Akteurinnen und Akteuren in den Bildungseinrichtungen ein breites Spektrum an Operationalisierungen zur Verfügung gestellt, um Ansatzpunkte zur organisationalen und systemischen Weiterentwicklung von Inklusion im Schulbereich auszumachen. (DIPF/Orig.)
    Keywords: Inklusion ; Bildungsentwicklung ; Bildungsbeteiligung ; Bildungserfolg ; Sonderpädagogischer Förderbedarf ; Schulqualität ; Integrative Schule ; Integrative Beschulung ; Schulorganisation ; Schulplanung ; Gemeinde 〈Kommune〉 ; Schulleiter ; Schulentwicklung ; Transformation ; Sozialraum ; Indikator ; Amtliche Statistik ; Umfrage ; Statistische Analyse ; Quantitative Forschung ; Paderborn ; Nordrhein-Westfalen ; Deutschland ; Inclusion ; Development of education ; Educational development ; Participation in education ; Participation Rate ; Educational Success ; Success at school ; Success in Education ; Special Educational Needs ; Inclusive education ; Inclusive school ; School organisation ; School organization ; Headteacher ; Headteachers ; School head teacher ; School development ; Indicator ; Official statistics ; Statistical analysis ; Quantitative research ; North Rhine-Westphalia ; North-Rhine Westphalia ; Germany ; bic Book Industry Communication::J Society & social sciences::JN Education::JNS Teaching of specific groups & persons with special educational needs ; thema EDItEUR::J Society and Social Sciences::JN Education::JNS Teaching of students with different educational needs
    Language: German
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  • 7
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: The way schools deal with "heterogeneity" of pupils has been the subject of a heated debate for a number of years. The present volume shows how the observation of differences between pupils - such as those in aptitude, behaviour and interest - has increasingly come into focus in schools since the last third of the 19th century. Disputes about how "suitable" learning groups should be put together against this background increasingly determined the picture of educational and school-political debates. Selection mechanisms in the school system between 1880 and 1980 are reconstructed that distinguished between the normal and the non-normal, between the gifted and the less gifted, between those who adapted and those who did not. The contributions examine practices of observing, testing and assessing pupils, the procedures and tests used for this purpose, and the individual, pedagogical and political conditions and consequences associated with them.
    Description: Über den schulischen Umgang mit einer „Heterogenität“ der Schüler*innen wird seit einer Reihe von Jahren heftig debattiert. Der vorliegende Band zeigt, wie seit dem letzten Drittel des 19. Jahrhunderts die Beobachtung von Unterschieden – solchen der Begabung, des Verhaltens und des Interesses – zwischen Schüler*innen in den Schulen mehr und mehr in das Blickfeld rückte. Auseinandersetzungen darüber, wie vor diesem Hintergrund „passende“ Lerngruppen zusammengestellt werden sollten, bestimmten zunehmend das Bild der pädagogischen und schulpolitischen Debatten. Rekonstruiert werden Selektionsmechanismen im Schulsystem zwischen 1880 und 1980, mit denen zwischen Normalen und Nicht-Normalen, zwischen Begabten und Minderbegabten, zwischen solchen, die sich anpassten, und solchen, die das nicht taten, unterschieden wurde. Die Beiträge untersuchen Praktiken des Beobachtens, Prüfens und Beurteilens von Schüler*innen, die dafür eingesetzten Verfahren und Tests sowie die damit verbundenen individuellen, pädagogischen und politischen Bedingungen und Folgen. (DIPF/Orig.)
    Keywords: Schüler ; Auslese ; Ausleseverfahren ; Schülerbeurteilung ; Historische Bildungsforschung ; Bildungsgeschichte ; Schulgeschichte ; Geschichte 〈Histor〉 ; Heterogenität ; Inklusion ; Exklusion ; Hilfsschule ; Kategorisierung ; Sonderpädagogik ; Abitur ; Aufsatz ; Begabung ; Hochbegabung ; Differenzierung ; Selektion ; Übergang Primarstufe - Sekundarstufe I ; Schulische Integration ; Beobachtung ; Lernbehinderung ; Sonderpädagogische Einrichtung ; Förderklasse ; Diagnostik ; Pädagogische Diagnostik ; Leistungsmessung ; Intelligenztest ; Schulsystem ; Intelligenzschwäche ; Lernschwäche ; Sonderschulpädagogik ; Psychiatrie ; Pädagogik ; Handschrift ; Diagnose ; Gehirn ; Schrift ; Experiment ; Geistige Behinderung ; Bildungsfähigkeit ; Primarbereich ; Sonderschule ; Schuleignung ; Gutachten ; Pädagogische Psychologie ; Differenzielle Psychologie ; Reform ; Abiturprüfung ; Leistungsbeurteilung ; Prüfungswesen ; psychometrische Tests ; Lehrergutachten ; Praktiken des Beobachtens ; Soldat ; Kriegsbeschädigter ; Gehirnschädigung ; Übungsschule ; Berufspsychologie ; Berufseignung ; Berufsberatung ; Migrant ; Migrationshintergrund ; Schulpsychologie ; Maßnahme ; Vergleich ; Stern ; William Louis ; 19. Jahrhundert ; 20. Jahrhundert ; Kaiserreich ; Weimarer Republik ; Fallbeispiel ; Test ; Historische Quelle ; Deutschland ; Schweiz ; Deutschland-BRD ; Deutschland-DDR ; Preußen ; New York ; N.Y. ; USA ; bic Book Industry Communication::J Society & social sciences::JN Education::JNB History of education ; bic Book Industry Communication::J Society & social sciences::JN Education::JNL Schools ; thema EDItEUR::J Society and Social Sciences::JN Education::JNB History of education ; thema EDItEUR::J Society and Social Sciences::JN Education::JNL Schools and pre-schools
    Language: German
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  • 8
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: The historical and theoretical relationship between education and the body is the focus of this discourse-analytical study. It is situated at the interface of systematic educational science and historical educational research and looks at both the current debate on educational theory and the pedagogical discussions at the end of the 18th century and the beginning of the 19th century. The starting point of the analyses is a theoretical phenomenon called disembodiment. This term refers to different dynamics that in their totality aim at the discursive exclusion and marginalisation of corporeality in the discourse on education. Three works from different currents of pedagogy are examined more closely for this purpose: Campe's 'Allgemeine Revision des gesammten Schul- und Erziehungswesens' (1785-1792), Niemeyer's 'Grundsätze der Erziehung und des Unterrichts' (1796-1824/5) and two writings by Schwarz, the 'Erziehungslehre' (1802-1813) and the 'Lehrbuch der Erziehung und Unterrichtslehre' (1805-1835). In addition to a presentation of the spectrum of perspectives on physical education, a reconstruction of the historical discourse of so-called physical education and case analyses of the anthropological contexts, the study is able to show that disembodiment tendencies can be traced not only in the current discourse, but already at the turn of the 19th century.
    Description: Das geschichtliche sowie theoretische Verhältnis von Erziehung und Körper steht im Zentrum dieser diskursanalytisch angelegten Studie. Diese ist an der Schnittstelle von systematischer Erziehungswissenschaft und historischer Bildungsforschung angesiedelt und betrachtet sowohl die aktuelle erziehungstheoretische Debatte als auch die pädagogischen Diskussionen am Ende des 18. und zu Beginn des 19. Jahrhunderts. Ausgangspunkt der Analysen ist ein theoretisches Phänomen, das als Entkörperung bezeichnet wird. Mit diesem Begriff sind unterschiedliche Dynamiken gemeint, die in ihrer Gesamtheit auf die diskursive Ausgrenzung und Marginalisierung von Körperlichkeit in der Rede über Erziehung zielen. Drei Werke aus unterschiedlichen Strömungen der Pädagogik sind hierfür näher untersucht: Die von Campe herausgegebene ‚Allgemeine Revision des gesammten Schul- und Erziehungswesens‘ (1785–1792), die ‚Grundsätze der Erziehung und des Unterrichts‘ (1796–1824/5) von Niemeyer und zwei Schriften von Schwarz, die ‚Erziehungslehre‘ (1802–1813) sowie das ‚Lehrbuch der Erziehung und Unterrichtslehre‘ (1805–1835). Neben einer Darstellung des Spektrums der körperpädagogischen Perspektiven, einer Rekonstruktion des historischen Diskurses der sogenannten physischen Erziehung und Fallanalysen zu den anthropologischen Kontexten, kann die Untersuchung im Ergebnis zeigen, dass nicht nur im aktuellen Diskurs, sondern bereits an der Wende zum 19. Jahrhundert Entkörperungstendenzen nachzuweisen sind. (DIPF/Orig.)
    Keywords: Historische Bildungsforschung ; Erziehungswissenschaft ; Körper 〈Biol〉 ; Körperlichkeit ; Leiblichkeit ; Menschlicher Körper ; Pädagogische Theorie ; Bildungstheorie ; Erziehung ; Geschichte 〈Histor〉 ; Diskursanalyse ; Historische Analyse ; Campe, Joachim Heinrich ; Niemeyer, August Hermann ; Schwarz, Friedrich Heinrich Christian ; 18. Jahrhundert ; 19. Jahrhundert ; Dissertationsschrift ; Deutschland ; Sciences of education ; Corporeality ; Corporealtity ; Human body ; Pedagogical theory ; Educational theory ; Theory of education ; Education ; History ; Discourse Analysis ; Historical analysis ; Doctoral Theses ; Germany ; bic Book Industry Communication::J Society & social sciences::JN Education ; thema EDItEUR::J Society and Social Sciences::JN Education
    Language: German
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  • 9
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: "1918" signifies more than the end of the First World War. The reference to the year often also justifies narratives in the history of education. On the other hand, this volume explores the simultaneities of caesurae and traditions, ruptures and continuities in regional, national, European and global perspectives. It examines diverse paradoxes of supposedly old and new pedagogical cultures and practices as well as ambivalences of youth between rebellion and attachment to educational ideals. It also focuses on the questioning of schools and pedagogy, their relegitimisation and the intertwining of social democracy and socialism with educational reforms and traditions. In this way, the volume aims at the often described "clash of ideologies" in the interwar period and at the circulation of competing knowledge, so that it discusses the complex openness of 1918 in terms of educational history.
    Description: „1918“ bezeichnet mehr als das Ende des Ersten Weltkriegs. Der Jahresbezug begründet häufig auch bildungsgeschichtliche Narrative. Hingegen fragt der Band nach Gleichzeitigkeiten von Zäsuren und Tradierungen, Brüchen und Kontinuitäten in regionalen, nationalen, europäischen und globalen Perspektiven. Er untersucht vielfältige Paradoxien vermeintlich alter und neuer pädagogischer Kulturen und Praktiken ebenso wie Ambivalenzen der Jugend zwischen Aufbegehren und Anknüpfung an Bildungsideale. Auch die Infragestellung von Schule und Pädagogik, ihre Relegitimierung sowie die Verflechtung von Sozialdemokratie und Sozialismus mit Bildungsreformen und -traditionen werden fokussiert. Damit zielt der Band auf den vielfach beschriebenen «Kampf der Ideologien» in der Zwischenkriegszeit und auf die Zirkulation konkurrierender Wissen, sodass er bildungshistorisch die komplexe Offenheit von 1918 diskutiert.
    Keywords: Historische Bildungsforschung ; Bildungsgeschichte ; Geschichte 〈Histor〉 ; Schule ; Jugend ; Schülermitwirkung ; Lehrerseminar ; Mitbestimmung ; Reformpädagogik ; Jugendbewegung ; Kritik ; Schülerbewegung ; Aufstand ; Elternmitwirkung ; Nachkriegsgeschichte ; Zwischenkriegszeit ; Weltkrieg I ; Schülerorganisation ; Kollektives Gedächtnis ; Turnverein ; Körpererziehung ; Männlichkeit ; Patriotismus ; Persönlichkeitsbildung ; Körperkultur ; Leitbild ; Körperbild ; Geschlecht ; Geschlechtsspezifische Sozialisation ; Geschlechtergeschichte ; Turnen ; Jugendkultur ; Orientalistik ; Interesse ; Indienbild ; Rezeption ; Lehrerfortbildung ; Organisation ; Politische Kultur ; Volksschule ; Selbstwahrnehmung ; Bildungspolitik ; Praxeologie ; Lehrer ; Neuorientierung ; Pädagogik ; Reform ; Gesellschaft ; Positivismus ; Evolutionismus ; Experimentelle Pädagogik ; Kinderpsychologie ; Steuerung ; Schulbuch ; Analyse ; Vergleich ; Evangelischer Religionsunterricht ; Religionsunterricht ; Schulbuchforschung ; Lebenskunde ; Mittelschule ; Lehrmittel ; Erziehung ; Lehrplan ; Lehrplanvergleich ; Curriculum ; Kirche-Staat-Beziehung ; Schulsystem ; Sozialdemokrat ; Schriftsteller ; Sozialist ; Pädagoge ; Historische Persönlichkeit ; Pädagogisierung ; Biografie ; Autobiografie ; Linke 〈Pol〉 ; Bildung ; Arbeiterbildung ; Arbeiterbewegung ; Arbeiterklasse ; Sozialistische Bildung ; Außerschulischer Lernort ; Erwachsenenbildung ; Politisches Programm ; Erziehungsprogramm ; Sozialdemokratie ; Schulreform ; Bildungsreform ; Sozialismus ; Sozialgeschichte ; Kulturgeschichte ; Bildungszugang ; Schulgemeinde ; Quellenkritik ; Historische Quelle ; Tagore ; Rabindranath ; Thorndike ; Edward L. ; Dewey ; John ; Traber ; Alfred ; Glöckel ; Otto ; Bernfeld ; Siegfried ; 20. Jahrhundert ; Zürich ; Schweiz ; Deutschland ; Indien ; Deutschland 〈bis 1945〉 ; Tschechische Republik ; Tschechoslowakei ; USA ; Weimarer Republik ; Preußen ; Preußische Reform ; Deutsches Reich ; Wien ; Österreich ; History of education ; History of educational activities ; History ; School ; Adolescence ; Youth ; Pupil Participation ; Teachers' training college ; Codetermination ; Progressive Education ; Progressive education ; Reform pedagogics ; Youth movement ; Criticism ; Revolt ; Parent participation ; Post-war period ; Peace time ; World War I ; Student organizations ; Physical education ; Masculinity ; Patriotism ; Personality development ; Ideal (model) ; Body image ; Sex ; Gender-specific socialization ; Gymnastics ; Youth culture ; Reception ; Further education for teachers ; Further education of teachers ; Further training for teachers ; Organization ; Political culture ; Elementary School ; General compulsory school ; Primary school ; Self-perception ; Educational policy ; Teacher ; Pedagogics ; Sciences of education ; Society ; Positivism ; Experimental education ; Experimental pedagogics ; Experimental teaching ; Child psychology ; Children's hospital ; Text book ; Textbook ; Religious instruction ; Teaching of religion ; Textbook research ; Intermediate school ; Educational Materials ; Teaching aids ; Training aid ; Education ; State church separation ; School system ; Pedagogue ; Biographies ; Autobiographies ; Education of workers ; Workers' education ; Labor movement ; Working Class ; Adult education ; Adult training ; Political program ; Social democracy ; School reform ; Educational reform ; Socialism ; Social history ; Cultural history ; Access to Education ; School community ; Zurich ; Switzerland ; Germany ; India ; Czech Republic ; Czechoslovakia ; Weimar Republic ; Weimar Republic (Germany ; 1918-33) ; German Reich ; Vienna ; Austria ; bic Book Industry Communication::J Society & social sciences::JN Education::JNB History of education ; thema EDItEUR::J Society and Social Sciences::JN Education::JNB History of education
    Language: German
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  • 10
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: Befürwortende ebenso wie skeptische Stimmen zum Thema Inklusion klingen häufig so, als sei ein Gelingen oder Scheitern inklusiver Prozesse kaum beeinflussbar. Entsprechend wenig ist untersucht, wie sich Gruppenprozesse in inklusiven Gruppen gestalten. Die vorliegende Studie schließt diese Lücke, indem sie die Zusammenarbeit in Kleingruppen im Kontext inklusiver Hochschulbildung untersucht. Gegenstand sind vier rekonstruktive Fallstudien aus Seminaren, an denen Studierende und behinderte Menschen – zumeist ohne Hochschulzugangsberechtigung – teilnehmen. Unter Anwendung der dokumentarischen Methode werden Arbeitsprozesse von Projektgruppen im Rahmen inklusionsorientierter Seminare analysiert. Die leitende Fragestellung besteht darin, wie die Mitglieder einer Gruppe Gemeinsamkeit herstellen, Differenz bearbeiten und Verantwortung verteilen. Somit ist die Ambivalenz von Gemeinsamkeit und Differenz und ihre ‚Herstellung’ in inklusiven Kleingruppen Gegenstand der Dissertation. Sie leistet für die Förder-/Sonder-/Rehabilitations- und Inklusionspädagogik einen Beitrag zur kritischen Auseinandersetzung mit Differenz und den damit verbundenen Zuschreibungen. Zugleich wird aber auch die Entstehung von gemeinsamen Erfahrungsräumen in Gruppenprozessen analysiert. Obwohl im Hochschulbereich angesiedelt, sind die Ergebnisse auch für außerschulische Jugendbildung und den Sekundarbereich als relevant anzusehen. (DIPF/Orig.)
    Keywords: Inklusion ; Hochschule ; Hochschulseminar ; Gruppe 〈Soz〉 ; Heterogene Lerngruppe ; Gruppendynamik ; Kleingruppe ; Gruppenpsychologie ; Heterogenität ; Sozialer Prozess ; Soziale Interaktion ; Soziale Integration ; Gemeinsamkeit ; Differenz ; Integrative Pädagogik ; Sonderpädagogik ; Dokumentarische Methode ; Fallbeispiel ; Deutschland ; Inclusion ; Higher education institute ; Group dynamics ; Small goup ; Small group ; Group psychology ; Heterogeneity ; Social process ; Social interaction ; Social integration ; Integrative education ; Remedial instruction sciences ; Special education for the handicapped ; Special needs education ; Exemplary model ; Germany ; Document ; bic Book Industry Communication::J Society & social sciences::JN Education::JNS Teaching of specific groups & persons with special educational needs ; bic Book Industry Communication::J Society & social sciences::JN Education::JNF Educational strategies & policy::JNFN Inclusive education / mainstreaming ; bic Book Industry Communication::J Society & social sciences::JN Education::JNM Higher & further education, tertiary education::JNMN Universities ; thema EDItEUR::J Society and Social Sciences::JN Education::JNS Teaching of students with different educational needs ; thema EDItEUR::J Society and Social Sciences::JN Education::JNF Educational strategies and policy::JNFK Educational strategies and policy: inclusion ; thema EDItEUR::J Society and Social Sciences::JN Education::JNM Higher education, tertiary education
    Language: German
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: Vor zehn Jahren regte die Ratifizierung der UN-Behindertenrechtskonvention und die damit einhergehende rechtliche Verankerung inklusiver Prozesse eine Vielzahl von strukturellen Veränderungen im Bildungssystem an. Daher liegt der inhaltliche Fokus auf Lehren und Lernen in inklusiven Settings. Thematisiert werden damit sowohl inklusives Lehren und Lernen im Bildungsverlauf durch Kindertagesstätten und Schulen als auch in den Hochschulen.
    Keywords: Inklusion ; Integration ; Sonderpädagogik ; Integrative Schule ; Integrative Pädagogik ; Integrative Beschulung ; Kindertagesstätte ; Grundschule ; Schule ; Hochschule ; Lehr-Lern-Prozess ; Lernforschung ; Lehrerausbildung ; Lehrerfortbildung ; Professionalisierung ; Weiterbildung ; Lehrerbildung ; Qualifizierung ; Reflexion 〈Phil〉 ; Lernwerkstatt ; Hochschulbildung ; Interview ; Interdisziplinäre Zusammenarbeit ; Kooperation ; Hochschullehre ; Differenzierung ; Einstellung 〈Psy〉 ; Heterogenität ; Lehrer ; Lehramtsstudent ; Normalisierung ; Diagnostik ; Übergang Schule - Beruf ; Schüler-Lehrer-Beziehung ; Lernprozess ; Frühförderung ; Erlebnispädagogik ; Normalität ; Vielfalt ; Unterrichtsqualität ; Schulorganisation ; Volksschule ; Lernumgebung ; Nachteilsausgleich ; Chancengleichheit ; Österreich ; Deutschland ; Inclusion ; Remedial instruction sciences ; Special education for the handicapped ; Special needs education ; Inclusive education ; Inclusive school ; Integrative education ; Day nursery ; Elementary School ; Primary school ; Primary school lower level ; School ; Higher education institute ; Teaching-learning process ; Research on learning ; Teacher education ; Teacher training ; Further education for teachers ; Further education of teachers ; Further training for teachers ; Professionalization ; Continuing education ; Further education ; Teachers' training ; Qualification ; Learning workshop ; Higher education ; University level of education ; Cooperation ; Higher education lecturing ; University lecturing ; University teaching ; Heterogeneity ; Teacher ; Student teachers ; Normalization (Disabilities) ; Diagnostic ; Pupil-teacher relation ; Pupil-teacher relationship ; Learning process ; Early remedial education ; Adventure pedagogics ; Experience pedagogics ; Teaching quality ; School organisation ; School organization ; General compulsory school ; Educational Environment ; Learning environment ; Equal opportunities ; Equal opportunity ; Austria ; Germany ; Type of school ; bic Book Industry Communication::J Society & social sciences::JN Education::JNF Educational strategies & policy::JNFN Inclusive education / mainstreaming ; bic Book Industry Communication::J Society & social sciences::JN Education::JNS Teaching of specific groups & persons with special educational needs ; thema EDItEUR::J Society and Social Sciences::JN Education::JNF Educational strategies and policy::JNFK Educational strategies and policy: inclusion ; thema EDItEUR::J Society and Social Sciences::JN Education::JNS Teaching of students with different educational needs
    Language: German
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: This volume is dedicated to the professional re-entry of teachers with a refugee background into the teaching profession. The book presents the certificate course "Educational Science Basics for Teachers with a Refugee Background" at the University of Vienna and research results on it in detail. Furthermore, the teachers and participants reflect on their experiences with this measure. Challenges and synergies in connection with the implementation of such a course are discussed as well as international perspectives on the requalification of refugee teachers.
    Description: Der Band widmet sich dem beruflichen Wiedereinstieg von Lehrkräften mit Fluchthintergrund in den Schuldienst. Das Buch stellt den Zertifikatskurs "Bildungswissenschaftliche Grundlagen für Lehrkräfte mit Fluchthintergrund" an der Universität Wien und Forschungsergebnisse dazu eingehend dar. Weiterhin reflektieren die Lehrenden und die Teilnehmenden ihre Erfahrungen mit dieser Maßnahme. Herausforderungen und Synergien im Zusammenhang mit der Implementierung eines solchen Kurses werden ebenso diskutiert wie internationale Perspektiven auf die Requalifizierung geflüchteter Lehrkräfte.
    Keywords: Lehrer ; Beruflicher Wiedereinstieg ; Flüchtling ; Zertifikatskurs ; Zertifizierung ; Berufliche Integration ; Berufspädagogik ; Flucht ; Migration ; Migrationshintergrund ; Qualifizierung ; Qualifizierungsmaßnahme ; Berufliche Qualifikation ; Anerkennung ; Lehrerbildung ; Reflexion 〈Phil〉 ; Theorie-Praxis-Beziehung ; Unterrichtspraxis ; Heterogenität ; Weiterbildung ; Hochschule ; Hochschullehre ; Deutschland ; Schweden ; Österreich ; Teacher ; Re-entry ; Refugee ; Certification ; Occupational integration ; Vocational pedagogics ; Flight ; Running away ; Immigrant background ; Migration background ; Qualification ; National Vocational Qualification ; Occupational qualification ; Vocational qualification ; Teacher education ; Teachers' training ; Theory Practice Relationship ; Teaching practice ; Heterogeneity ; Continuing education ; Further education ; Higher education institute ; Higher education lecturing ; University lecturing ; University teaching ; Germany ; Sweden ; Austria ; bic Book Industry Communication::J Society & social sciences::JN Education::JNP Adult education, continuous learning ; thema EDItEUR::J Society and Social Sciences::JN Education::JNP Adult education, continuous learning
    Language: German
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  • 13
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: The dissertation is located in the context of research on adolescence and transitions with a focus on special education. Disadvantaged adolescents are the target group of this study. Adolescents were interviewed at two points in time using biographical narrative interviews. In addition, parent interviews took place once, which serve as an addition or contrast, but primarily in order to stress the intergenerational contouring of the life phase of adolescence. The focus of the study is on how adolescents experience and handle the transition from school to post-school life. By using biographical case reconstructions, biographical coping strategies and vocational self-presentations were reconstructed from the narratives in order to illuminate the complexity that such transitions pose. The theoretical framework used in this dissertation understands adolescence as embedded in generational relations, which is also viewed in terms of inequality theory. As a result, the perspective on the adolescent life stage is not only focused on adolescent developmental tasks, but is characterized by an intergenerational view that forms the background for complex and dynamic readjustment processes. Thus, persistent familial significance in this phase of life is emphasized. By reconstructing biographical coping strategies, it becomes visible how young people deal with vocational orientation processes against their familial background and what efforts they partly expend to fulfill familial missions or to distance themselves from them. The research design of the study responds to a desideratum that exists with regard to qualitative or biographical long-term studies in the area of adolescence in school and vocational contexts. The life stories of the adolescents clearly point to the necessity of embedding transitions in an overall biographical context and of reacting to the associated ways of looking at the life phase of adolescence. (DIPF/Orig.)
    Description: Die vorliegende Studie beleuchtet mit Hilfe eines biographischen Forschungszugangs die Komplexität des Übergangsprozesses von benachteiligten Jugendlichen am Übergang von der Schule ins nachschulische Leben. Entgegen der gängigen Betonung der Ablösung vom Elternhaus wird im Rahmen der Arbeit die anhaltende familiale Bedeutung in der Lebensphase herausgearbeitet. Das Konzept der Entwicklungsaufgaben wird daher intergenerational konturiert und ungleichheitstheoretisch ausgeleuchtet. Die Ergebnisse zeigen, dass die Eltern und ihre (Berufs-)Biographien eine hohe Bedeutung für die eigene Übergangsgestaltung der Adoleszenten haben. Die biographischen Texte illustrieren die jeweiligen Bewältigungs- und Gestaltungsstrategien der Jugendlichen, die Konsequenzen für eine biographieorientierte Beratung am Übergang zulassen. Weiterhin lassen die Erkenntnisse Implikationen für Hochschullehre zu, indem biographieanalytische und ungleichheitstheoretische Aspekte in der Adoleszenzphase im Lehrplan verankert werden. (DIPF/Orig.)
    Keywords: Transition ; Übergang Schule - Beruf ; Benachteiligter Jugendlicher ; Familie ; Einflussfaktor ; Berufsbiografie ; Eltern ; Adoleszenz ; Sonderpädagogik ; Sozialer Raum ; Übergang ; Wahrnehmung ; Entscheidung ; Bewältigung ; Selbstdarstellung ; Handlungsfähigkeit ; Sozialpädagogik ; Entwicklungsaufgabe ; Benachteiligung ; Sonderpädagogischer Förderbedarf ; Förderschule ; Sozialer Hintergrund ; Forscher ; Soziale Herkunft ; Generationenverhältnis ; Bildungsaspiration ; Bourdieu, Pierre ; Empirische Untersuchung ; Biografische Methode ; Biografisches Interview ; Fallbeispiel ; Deutschland ; bic Book Industry Communication::J Society & social sciences::JN Education::JNC Educational psychology ; thema EDItEUR::J Society and Social Sciences::JN Education::JNC Educational psychology
    Language: German
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    Publication Date: 2024-03-29
    Description: Seit der Ratifizierung der UN-Behindertenrechtskonvention befindet sich Inklusion im Spannungsfeld von Normalität und Diversität. Soll sie auf mehr als die Anwesenheit von Menschen mit Behinderung in Erziehungs- und Bildungsinstitutionen verweisen, so müssen diese Institutionen und die darin befindlichen Akteur*innen und Praktiken weiterhin auf ihre Verstrickungen in die Reproduktion von Ausgrenzung und sozialer Ungleichheit hin thematisiert werden. So finden sich in diesem Band Beiträge zu folgenden Schwerpunkten: Grundfragen der Inklusion, Subjekttheoretische Perspektiven im Rahmen der Inklusion, Pädagogik und Bildung aus menschenrechtlicher und demokratischer Perspektive, Mechanismen der Exklusion und Inklusion sowie Inklusive Schulentwicklung.
    Keywords: Inklusion ; Integration ; Normalität ; Vielfalt ; Differenzierung ; Normalisierung ; Sonderpädagogik ; Erziehungsphilosophie ; Menschenrechte ; Exklusion ; Integrative Schule ; Integrative Pädagogik ; Integrative Beschulung ; Partizipation ; Benachteiligung ; Ungleichheit ; Gerechtigkeit ; Differenzierender Unterricht ; Schule ; Bildungspolitik ; Fremdheit ; Subjektorientierung ; Bildungsprozess ; Subjekt 〈Phil〉 ; Demokratische Bildung ; Lernprozess ; Schüler-Lehrer-Beziehung ; Bildungsbegriff ; Reziprozität ; Sonderpädagogischer Förderbedarf ; Verhaltensauffälligkeit ; Schulsport ; Körperkultur ; Körperbehinderung ; Geistige Behinderung ; Emotionale Entwicklung ; Soziale Entwicklung ; Autonomie ; Flüchtling ; Leistungsorientierung ; Systemtheorie ; Kindertagesstätte ; Schulreform ; Schulentwicklung ; Deutschland ; Österreich ; Thailand ; Inclusion ; Normalization (Disabilities) ; Remedial instruction sciences ; Special education for the handicapped ; Special needs education ; Philosophy of education ; Human rights ; Inclusive education ; Inclusive school ; Integrative education ; Disadvantage ; Justice ; Differentiated teaching ; School ; Educational policy ; Strangeness ; Educational process ; Learning process ; Pupil-teacher relation ; Pupil-teacher relationship ; Concept of education ; Special Educational Needs ; School sports ; Physical handicap ; Oligophrenia ; Social change ; Social development ; Autonomy ; Refugee ; Achievement orientation ; System theory ; Day nursery ; School reform ; School development ; Germany ; Austria ; bic Book Industry Communication::J Society & social sciences::JN Education::JNF Educational strategies & policy::JNFN Inclusive education / mainstreaming ; bic Book Industry Communication::J Society & social sciences::JN Education::JNS Teaching of specific groups & persons with special educational needs ; thema EDItEUR::J Society and Social Sciences::JN Education::JNF Educational strategies and policy::JNFK Educational strategies and policy: inclusion ; thema EDItEUR::J Society and Social Sciences::JN Education::JNS Teaching of students with different educational needs
    Language: German
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: The impetus and aim of this publication is to shed light on different perspectives on diversity in early childhood and to explore possibilities for researching this together with children. Reference is made to bodies of knowledge and knowledge references that have developed and become established in the context of early childhood and diversity, and attention is paid to explaining different methods and concrete experiences of using them to explore perspectives on diversity. One focus is on the description and reflection of research with children. The book is aimed at students and researchers in educational science and its neighbouring disciplines. It gives them an insight into basic theoretical frameworks with regard to the thematic horizons of childhood, childhood research and diversity and presents methods of research that enable the active inclusion of children in a concentrated manner. Furthermore, it gives professionals in elementary education and heads of organisations an impression of methods (reflections) and procedures of research with children and can be a support for them in the context of decision-making processes about participation in research projects.
    Description: Unterschiedliche Perspektiven auf Vielfalt in der frühen Kindheit zu beleuchten und Möglichkeiten auszuloten, wie mit Kindern gemeinsam dazu geforscht werden kann, sind Anstoß und Ziel dieser Publikation. Es wird auf Wissensbestände und Wissensbezüge Bezug genommen, die sich im Kontext von früher Kindheit und Diversität entwickelt und etabliert haben und der Erläuterung unterschiedlicher Methoden und konkreter Erfahrungen Beachtung geschenkt, mit ihnen Perspektiven auf Diversität zu erforschen. Ein Schwerpunkt liegt dabei auf der Beschreibung und Reflexion des Forschens mit Kindern. Das Buch richtet sich zum einen an Studierende und Forschende der Erziehungswissenschaft und ihrer Nachbardisziplinen. Ihnen gibt es einen Einblick in grundlegende theoretische Rahmungen hinsichtlich der Themenhorizonte Kindheit, Kindheitsforschung und Diversität und stellt Methoden des Forschens, die den aktiven Einbezug von Kindern ermöglichen, in konzentrierter Weise vor. Darüber hinaus vermittelt es Fachkräften der Elementarpädagogik und Organsisationsleitungen einen Eindruck von Methoden(-reflexionen) und Vorgehensweisen des Forschens mit Kindern und kann ihnen Unterstützung im Rahmen von Entscheidungsprozessen über die Beteiligung an Forschungsprojekten sein. (DIPF/Orig.)
    Keywords: Empirische Forschung ; Selbstbestimmung ; Frühpädagogik ; Inklusion ; Teilnahme ; Behinderung ; Sonderpädagogik ; Heterogenität ; Frühe Kindheit ; Forschung ; Kind ; Kindheitsforschung ; Kindheit ; Elementarbereich ; Elementarpädagogik ; Forschendes Lernen ; Differenz ; Philosophie ; Pädagogisches Handeln ; Kindertagesbetreuung ; Vielfalt ; Partizipation ; Integration ; Erziehungswissenschaft ; Interviewtechnik ; Ethnologie ; Exklusion ; Lebenswelt ; Handpuppe ; Flucht ; Ethik ; Vulnerabilität ; Pflegekind ; Raumplanung ; Stadtentwicklung ; Sozialplanung ; Grenze ; Gleichheit ; Normativität ; Kleinkindalter ; Vorschulalter ; Kinderarbeit ; Kindergarten ; Kindergartenalltag ; Kindergartenalter ; Fotografieren ; Heimkind ; Datenerhebung ; Qualitative Forschung ; Teilnehmende Beobachtung ; Forschungsmethode ; Forschungsprojekt ; Methode ; Interview ; Schweiz ; Deutschland ; Argentinien ; Nepal ; Empirical research ; Self-determination ; Early childhood education ; Inclusion ; Participation ; Handicap ; Remedial instruction sciences ; Special education for the handicapped ; Special needs education ; Heterogeneity ; Early childhood ; Research ; Child ; Childhood ; bic Book Industry Communication::J Society & social sciences::JN Education::JNF Educational strategies & policy::JNFN Inclusive education / mainstreaming ; bic Book Industry Communication::J Society & social sciences::JN Education::JNL Schools::JNLA Pre-school & kindergarten ; thema EDItEUR::J Society and Social Sciences::JN Education::JNF Educational strategies and policy::JNFK Educational strategies and policy: inclusion ; thema EDItEUR::J Society and Social Sciences::JN Education::JNL Schools and pre-schools::JNLA Pre-school and kindergarten
    Language: German
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  • 16
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    Verlag Julius Klinkhardt
    Publication Date: 2024-03-29
    Description: In social debates about inclusion, the humane, the individual person, runs the risk of being lost from view, as the discussions are often only conducted on a systemic-structural level. However, aspects of concrete pedagogical and conceptual work and educational encounters are also affected. This volume is dedicated to the diversity of individuals in their respective contexts in the spectrum between inclusions and exclusions from different theoretical and practical perspectives. From everyday situations in German and American classrooms to school inclusion models and the Federal Participation Act to humane exclusions in the internationally networked digital age; from discourses on vulnerability, ethics and exclusion to the topos of the stranger in the educational inclusion debate, multiple perspectives open up.
    Description: In gesellschaftlichen Debatten um Inklusion läuft das Humane, der einzelne Mensch, Gefahr, aus dem Blick zu geraten, da die Diskussionen oftmals nur auf systemisch-struktureller Ebene geführt werden. Betroffen sind dabei jedoch auch Aspekte der konkreten pädagogischen und konzeptionellen Arbeit und der erzieherischen Begegnung. Dieser Band widmet sich der Vielfalt von Individuen in ihren jeweiligen Kontexten im Spektrum zwischen Inklusionen und Exklusionen aus unterschiedlichen theoretischen und praktischen Perspektiven. Von alltäglichen Situationen in deutschen und amerikanischen Klassenzimmern über schulische Inklusionsmodelle und das Bundesteilhabegesetz hin zu humanen Exklusionen im international vernetzten Digitalzeitalter; von Diskursen über Vulnerabilität, Ethik und Exklusion bis hin zum Topos des Fremden in der pädagogischen Inklusionsdebatte eröffnen sich multiperspektivische Betrachtungsweisen. (DIPF/Orig.)
    Keywords: Inklusion ; Exklusion ; Humanistische Pädagogik ; Vielfalt ; Sonderpädagogik ; Interdisziplinarität ; Schule ; Unterricht ; Internationaler Vergleich ; Integrative Schule ; Partizipation ; Diagnostik ; Gesetzgebung ; Sonderpädagogischer Förderbedarf ; Vulnerabilität ; Fremdes ; Digitalisierung ; Butler, Judith ; Deutschland ; USA ; Inclusion ; Humanistic pedagogics ; Remedial instruction sciences ; Special education for the handicapped ; Special needs education ; Interdisciplinarity ; School ; Teaching ; Cross-national comparison ; International comparison ; Inclusive education ; Inclusive school ; Diagnostic ; Special Educational Needs ; Foreign culture ; Digitalization ; Germany ; bic Book Industry Communication::J Society & social sciences::JN Education::JNS Teaching of specific groups & persons with special educational needs ; thema EDItEUR::J Society and Social Sciences::JN Education::JNS Teaching of students with different educational needs
    Language: German
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    In:  GEOTECHNOLOGIEN Science Report | Advanced Technologies in Earth Sciences
    Publication Date: 2020-02-12
    Keywords: 550 - Earth sciences
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    In:  Advanced Technologies in Earth Sciences
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  • 41
    Electronic Resource
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    Springer
    Investigational new drugs 18 (2000), S. 373-381 
    ISSN: 1573-0646
    Keywords: clinical pharmacology ; dihydropyrimdine dehydrogenase ; eniluracil ; oral 5-FU ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacological inactivation of dihydropyrimidine dehydrogenase (DPD)represents one strategy to improve 5-FU therapy, which historically hasbeen associated with unpredictable pharmacological behavior andtoxicity. This is principally due to high interpatientdifferences in the activity of DPD, the enzyme that mediates theinitial and rate-limiting step in 5-FU catabolism. Byinactivating DPD and suppressing the catabolism of 5-FU,eniluracil has dramatically altered the pharmacological profileof 5-FU. The maximum tolerated dose of oral 5-FU given with oraleniluracil (1.0 to 25 mg/m2) is substantially lower thanconventional 5-FU doses. In the presence of eniluracil,bioavailability of 5-FU has increased to approximately 100%, thehalf-life is prolonged to 4 to 6 hours, and systemic clearanceis reduced 〉 20-fold to values comparable the glomerularfiltration rate (46 to 58 mL/min/m2). Renal excretion(∼ 45% to 75%), instead of DPD-related catabolism, is theprincipal route of elimination of oral 5-FU given witheniluracil. Chronic daily administration of oral 5-FU 1.0mg/m2 twice daily with eniluracil 20 mg twice dailyproduces 5-FU steady-state concentrations (8–38 ng/mL) similarto those achieved with protracted intravenous administration onclinically relevant dose-schedules. On a daily × 5regimen, higher 5-FU AUC values are related to neutropenia,whereas elevated 5-FU AUC and steady-state concentrations arerelated to diarrhea when oral 5-FU is given daily with eniluracilon a chronic schedule. The pharmacokinetic behavior of oraleniluracil is similar to that for oral 5-FU. Administration ofeniluracil 10 to 20 mg twice daily completely inactivates DPDactivity both in peripheral blood mononuclear cells and incolorectal tumor tissue, and prolonged inhibition of DPD afterdiscontinuation of eniluracil treatment has been noted. In thepresence of eniluracil, oral administration of 5-FU is feasibleand variation in 5-FU exposure is reduced, with the anticipationof further reduction in variation as dosing guidelines based onrenal function are formulated.
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  • 42
    ISSN: 1573-904X
    Keywords: allometric scaling ; interspecies scaling ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate (1) allometric scaling of systemic clearance (CL)using unbound drug concentration, (2) the potential usage of brainweight (BRW) correction in allometric scaling of both CL and oralclearance (CL/F). Methods. Human clearance was predicted allometrically (CLu = a ·Wbiv) using unbound plasma concentration for eight Parke-Daviscompounds and 29 drugs from literature sources. When the exponent bivwas higher than 0.85, BRW was incorporated into the allometricrelationship (CLu*BRW = a · Wbiv). This approach was also applied tothe prediction of CLu/F for 10 Parke-Davis compounds. Human oralt1/2, Cmax, AUC, and bioavailability were estimated based onallometrically predicted pharmacokinetic (PK) parameters. Results. Human CL and CL/F were more accurately estimated usingunbound drug concentration and the prediction was further improvedwhen BRW was incorporated into the allometric relationship. ForParke-Davis compounds, the predicted human CL and CL/F werewithin 50-200% and 50-220% of the actual values, respectively. Theestimated human oral t1/2, Cmax, and AUC were within 82-220%,56-240%, and 73-190% of the actual values for all 7 compounds,suggesting that human oral PK parameters of those drugs could bereasonably predicted from animal data. Conclusions. Results from the retrospective analysis indicate thatallometric scaling of free concentration could be applied to orallyadministered drugs to gain knowledge of drug disposition in man, and to helpdecision-making at early stages of drug development.
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  • 43
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; recombinant human interleukin-11 ; absorption ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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  • 44
    ISSN: 1573-904X
    Keywords: (R,S)-Ifosfamide ; R2-, R3-, S2-, S3-DCE-IFF ; iterative-two stage analysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe the pharmacokinetics of R- andS-Ifosfamide (IFF), and their respective 2 and 3 N-dechloroethylated (DCE)metabolites (R2-, R3-, S2, S3-DCE-IFF) in cancer patients. Methods. (R,S)-IFF was administered (1.5 g/m2)daily for 5 days in 13 cancer patients. Plasma and urine samples were collectedand analyzed using an enantioselective GC-MS method. An average of 97observations per patient were simultaneously fitted using apharmacokinetic-metabolism (PK-MB) model. A population PK analysis was performedusing an iterative 2-stage method (IT2S). Results. Auto-induction of IFF metabolism was observed over the 5day period. Increases were seen in IFF clearance (R: 4 vs 7 L/h; S: 5vs 10 L/h), and in the formation of DCE (R: 7 vs 9%; S: 14 vs 19%)and active metabolites (4-OHM-IFF; R: 71 vs 77%; S: 67 vs 71%). Anovel finding of this analysis was that the renal excretion of the DCEmetabolites was also induced. Conclusions. This population PK-MB model for (R,S)-IFF may beuseful in the optimization of patient care, and gives new insight intothe metabolism of (R,S)-IFF.
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  • 45
    ISSN: 1573-904X
    Keywords: stealth and remote loading proliposome ; doxorubicin ; pharmacokinetics ; acute toxicity ; anticancer effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The aim of the study was to prepare stealth and remoteloading proliposome (SRP-L) to carry doxorubicin (DXR) and evaluatethe pharmacokinetics, acute toxicity, and anticancer effect of DXRcarried with SRP-L. Methods. SRP-L was transparent solution. When SRP-L was injectedinto 0.9% NaCl aqueous solution containing DXR, liposomes formedand automatically loaded DXR (SRP-L-DXR). The long circulation ofSRP-L-DXR was evaluated using the pharmacokinetics ofSRP-L-DXR, cardiolipin liposomal DXR (CL-DXR) and free DXR (F-DXR).The acute toxicity and anticancer effect of SRP-L-DXR were evaluatedin C57BL/6 mice and murine hystocytoma M5076 tumor model. Results. The average diameter of SRP-L-DXR in pure water was112.9 ± 8.6 (nm) and the encapsulation efficiency of SRP-L-DXRwas 96.5 ± 0.2% in pure water, 95.5 ± 0.1% in 5% glucose and 98.01± 0.6% in 0.9% NaCl. The plasma concentration of SRP-L-DXR wasmuch higher than those of F-DXR and CL-DXR. Compared with thatof F-DXR, the SRP-L-DXR had lower acute toxicity and its anticancereffects depended upon the therapeutic treatment. Conclusions. A novel proliposome (SRP-L) was developed, whichcould automatically load DXR and form SRP-L-DXR with excellentcharacteristics. SRP-L-DXR had lower acute toxicity but was notalways more effective for the treatment of the ascitic M5076 thanF-DXR.
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  • 46
    ISSN: 1573-904X
    Keywords: morphine ; nociceptive effect ; electrical stimulation vocalisation method ; microdialysis ; retrodialysis by drug ; pharmacokinetics ; pharmacodynamics ; modelling ; blood-brain barrier transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To quantify the contribution of distributional processes across the blood-brain barrier (BBB) to the delay in antinociceptive effect of morphine in rats. Methods. Unbound morphine concentrations were monitored in venous blood and in brain extracellular fluid (ECF) using microdialysis (MD) and in arterial blood by regular sampling. Retrodialysis by drug was used for in vivo calibration of the MD probes. Morphine was infused (10 or 40 mg/kg) over 10 min intravenously. Nociception, measured by the electrical stimulation vocalisation method, and blood gas status were determined. Results. The half-life of unbound morphine in striatum was 44 min compared to 30 min in venous and arterial blood (p 〈 0.05). The BBB equilibration of morphine, expressed as the ratio of areas under the curve between striatum and venous blood, was less than unity (0.28 ± 0.09 and 0.22 ± 0.17 for 10 and 40 mg/kg), respectively, indicating active efflux of morphine across the BBB. The concentration-effect relationship exhibited a clear hysterisis with an effect delay half-life of 32 and 5 min based on arterial blood and brain ECF concentrations, respectively. Conclusions. Eighty five percent of the effect delay was caused by morphine transport across the BBB, indicating possible involvement of rate limiting mechanisms at the receptor level or distributional phenomena for the remaining effect delay of 5 min.
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  • 47
    ISSN: 1573-904X
    Keywords: bioequivalence ; dose proportionality ; mixed effects model ; pharmacokinetics ; power model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The aim of this work was a pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs. Methods. Statistical estimation is used to derive a (1-α)% confidence interval (CI) for the ratio of dose-normalized, geometric mean values (Rdnm) of a pharmacokinetic variable (PK). An acceptance interval for Rdnm defining the clinically relevant, dose-proportional region is established a priori. Proportionality is declared if the CI for Rdnm is completely contained within the critical region. The approach is illustrated with mixed-effects models based on a power function of the form PK = β0 • Doseβ1; however, the logic holds for other functional forms. Results. It was observed that the dose-proportional region delineated by a power model depends only on the dose ratio. Furthermore, a dose ratio (ρ1) can be calculated such that the CI lies entirely within the pre-specified critical region. A larger ratio (ρ2) may exist such that the CI lies completely outside that region. The approach supports inferences about the PK response that are not constrained to the exact dose levels studied. Conclusion. The proposed method enhances the information from a clinical dose-proportionality study and helps to standardize decision rules.
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  • 48
    ISSN: 1573-904X
    Keywords: SK&F 107647 ; peptide ; pharmacokinetics ; hematore gulatory ; adenocarcinoma ; cytokines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe the pharmacokinetics of SK&F 107647, a synthetichematoregulatory peptide, in healthy volunteers and in patientswith adenocarcinoma.Methods. SK&F 107647 pharmacokinetics were evaluated in 2dose-escalation studies. Volunteers received SK&F 107647 as single15-minute iv infusion doses of 1, 10, 100, 500, and 1000 μg/kg. Cancerpatients received 2-hour iv infusions of 0.001, 0.01, 0.1 and 1μg/kg once daily for 10 days. Drug concentrations were quantified in plasmaand urine of healthy volunteers and on days 1 and 10 in plasma ofcancer patients receiving the two top dose levels.Results. In volunteers, mean clearance (CL) ranged from 76.7 to 101ml/hour/kg; mean volume of distribution at steady-state (Vss)rangedfrom 175 to 268 ml/kg. Most of the administered dose was renallyexcreted as intact peptide within 24 hours postinfusion. In patients,mean CL was 57.6 ml/hour/kg, mean Vss ranged from 128 to 150ml/kg and terminal half-life from 2.1 to 3.4 hours. There was littleaccumulation of drug. In both studies, linear pharmacokinetics wasobserved. Clearance approached normal glomerular filtration rate(GFR) in volunteers and correlated with creatinine clearance incancer patients.Conclusions. SK&F 107647 exhibits linear pharmacokinetics, a smallVss, and clearance, primarily renal, approaching normal GFR.
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  • 49
    ISSN: 1573-904X
    Keywords: glycyrrhizic acid ; modeling ; enterohepatic cycling ; PBPK ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To analyze the role of the kinetics of glycyrrhizic acid (GD) in its toxicity. A physiologically-based pharmacokinetic (PBPK) model that has been developed for humans. Methods. The kinetics of GD, which is absorbed as glycyrrhetic acid (GA), were described by a human PBPK model, which is based on a rat model. After rat to human extrapolation, the model was validated on plasma concentration data after ingestion of GA and GD solutions or licorice confectionery, and an additional data derived from the literature. Observed interindividual variability in kinetics was quantified by deriving an optimal set of parameters for each individual. Results. The a-priori defined model successfully forecasted GA kinetics in humans, which is characterized by a second absorption peak in the terminal elimination phase. This peak is subscribed to enterohepatic cycling of GA metabolites. The optimized model explained most of the interindividual variance, observed in the clinical study, and adequately described data from the literature. Conclusions. Preclinical information on GD kinetics could be incorporated in the human PBPK model. Model simulations demonstrate that especially in subjects with prolonged gastrointestinal residence times, GA may accumulate after repeated licorice consumption, thus increasing the health risk of this specific subgroup of individuals.
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  • 50
    ISSN: 1573-904X
    Keywords: luteinising hormone-releasing hormone (LH-RH) antagonist ; cetrorelix ; pharmacokinetics ; population PK/PD-modeling ; testosterone ; rat ; dog
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Population models for thepharmacokinetic-pharmacodynamic relationship for cetrorelix (CET), a luteinising hormone-releasinghormone (LH-RH) antagonist, and the pharmacodynamic response ontestosterone production were investigated in rats and dogs. Methods. The plasma concentrations of CET and testosterone weredetermined after intravenous and subcutaneous injections. Thepopulation PK/PD-models were developed using P-PHARM software. Results. Absolute bioavailability of cetrorelix was 100% in rats and97% in dogs. In rats, the pharmacokinetics was explained by atwo-compartment model with saturable absorption, while athree-compartment model was used in dogs. Testosterone suppression in both specieswas described by a sigmoid Emax model with maximum effect (Emax)considered as total hormonal suppression. The duration of testosteronesuppression in rats was longer at higher doses. The populationelimination half-lifes after iv-dose were 3.0 h in rats and 9.3 h in dogs.Population mean estimates of IC50 were 1.39 and 1.24 ng/ml in ratsand dogs, respectively. Conclusions. A population pharmacokinetic model was developed toexplain the dissolution rate limited absorption from the injection site.The suppression of testosterone could be described by an indirectinhibitory sigmoid Emax model. In both species 1-2 ng/ml CET inplasma was necessary to suppress testosterone production.
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  • 51
    ISSN: 1573-904X
    Keywords: methylphenidate ; average bioequivalence ; individual bioequivalence ; human ; pharmacokinetics ; replicated design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the relative bioavailability of two marketed,immediate-release methylphenidate tablets. The study used a replicatedstudy design to characterize intrasubject variability, and determinebioequivalence using both average and individual bioequivalencecriteria. Methods. A replicated crossover design was employed using 20subjects. Each subject received a single 20 mg dose of the reference tableton two occasions and two doses of the test tablet on two occasions.Blood samples were obtained for 10 hr after dosing, and plasma wasassayed for methylphenidate by GC/MS. Results. The test product was more rapidly dissolved in vitro and morerapidly absorbed in vivo than the reference product. The mean Cmaxand AUC(0 − ∞) differed by 11% and 9%, respectively. Using anaverage bioequivalence criterion, the 90% confidence limits for theLn-transformed Cmax and AUC(0 − ∞), comparing the two replicatesof the test to the reference product, fell within the acceptable range of80–125%. Using an individual bioequivalence criterion the test productfailed to demonstrate equivalence in Cmax to the reference product. Conclusions. The test and reference tablets were bioequivalent usingan average bioequivalence criterion. The intrasubject variability of thegeneric product was greater and the subject-by-formulation interactionvariance was borderline high. For these reasons, the test tablets werenot individually bioequivalent to the reference tablets.
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  • 52
    ISSN: 1573-904X
    Keywords: 1,4-dihydropyridine calcium channel antagonist ; (+)-[3H]PN 200-110 ; senescence-accelerated prone mouse ; brain concentration ; pharmacokinetics ; in vivo receptor binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the in vivo specific binding andpharmacokinetics of a 1,4-dihydropyridine (DHP) calcium channel antagonist, PN200-110, in the senescent brain, using senescence-accelerated pronemice (SAMP8) and senescence-resistant mice (SAMR1). Methods. Blood, brain, and heart samples were taken periodically fromSAMR1 and SAMP8 following intravenous injection of (+)-[3H]PN200-110, and the concentration of (+)-[3H]PN 200-110 in the plasmaand tissues was determined. In addition, the in vivo specific bindingof (+)-[3H]PN 200-110 in the brains of SAMR1 and SAMP8 wasmeasured periodically after intravenous injection of the radioligand. Results. There was very little significant difference between SAMR1and SAMP8 in terms of the half-life (t1/2), total body clearance (CLtot),steady-state volume of distribution (Vdss), and AUC for the plasmaconcentration of (+)-[3H]PN 200-110 after intravenous injection ofthe radioligand. The brain concentration (AUCbrain) for (+)-[3H]PN200-110 and the brain/plasma AUC ratio (AUCbrain/AUCplasma) weresignificantly lower in SAMP8 than in SAMR1, and the heartconcentration (AUCheart) and the heart/plasma AUC ratio (AUCheart/AUCplasma)were similar in both strains. Also, the brain/plasma unbound AUCratio (AUCbrain/AUCplasma-free) for (+)-[3H]PN 200-110 wassignificantly lower in SAMP8 than in SAMR1. The in vivo specific binding(AUCspecific binding, maximal number of binding sites: Bmax) of(+)-[3H]PN 200-110 was significantly lower in brain particulate fractionsof SAMP8 than SAMR1. Conclusions. The concentration and in vivo specific binding of(+)-[3H]PN 200-110 was significantly reduced in the senescent brain. Thesimultaneous analysis of the concentrations of centrally acting drugsand the in vivo specific binding in the brain in relation to theirpharmacokinetics may be valuable in evaluating their CNS effects.
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  • 53
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    Pharmaceutical research 17 (2000), S. 903-905 
    ISSN: 1573-904X
    Keywords: P-glycoprotein ; hepatic metabolism ; pharmacokinetics ; first-pass metabolism ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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  • 54
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    Pharmaceutical research 17 (2000), S. 127-134 
    ISSN: 1573-904X
    Keywords: in-situ head perfusion ; pharmacokinetics ; red blood cells ; water
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To develop a viable, single pass rat head perfusion modeluseful for pharmacokinetic studies. Methods. A viable rat head preparation, perfused with MOPS-bufferedRinger's solution, was developed. Radiolabelled markers (red bloodcells, water and sucrose) were injected in a bolus into the internalcarotid artery and collected from the posterior facial vein over 28minutes. The double inverse Gaussian function was used to estimatethe statistical moments of the markers. Results. The viability of the perfusion was up to one hour, with optimalperfusate being 2% bovine serum albumin at 37°C, pH 7.4. Thedistribution volumes for red blood cells, sucrose and water (from all studies,n = 18) were 1.0 ± 0.3ml, 6.4 ± 4.2ml and 18.3 ± 11.9ml, respectively.A high normalised variance for red blood cells (3.1 ± 2.0) suggestsa marked vascular heterogeneity. A higher normalised variance forwater (6.4 ± 3.3) is consistent with additional diffusive/permeabilitylimitations. Conclusions. Analysis of the physiological parameters derived fromthe moments suggested that the kinetics of the markers were consistentwith distribution throughout the head (weight 25g) rather than justthe brain (weight 2g). This model should assist in studying solutepharmacokinetics in the head.
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  • 55
    ISSN: 1573-904X
    Keywords: α1-acid glycoprotein ; protein binding ; dissociation rate ; species difference ; physiological model ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The extremely low clearance and small distribution volumeof UCN-01 in humans could be partly due to the high degree of bindingto hAGP (1,2). The quantitative effects of hAGP on the pharmacokineticsof UCN-01 at several levels of hAGP and UCN-01 were estimatedin rats given an infusion of hAGP to mimic the clinical situation anda physiological model for analysis was developed. Methods. The plasma concentrations of UCN-01 (72.5–7250 nmol/kgiv) in rats given an infusion of hAGP, 15 or 150 nmol/h/kg, weremeasured by HPLC. Pharmacokinetic analysis under conditionsassuming rapid equilibrium of protein binding and incorporating thedissociation rate was conducted. Results. The Vdss and CLtot of UCN-01 (725 nmol/kg iv) in ratsgiven an infusion of hAGP, 150 nmol/h/kg, fell to about 1/250 and 1/700that in control rats. The Vdss and CLtot following 72.5–7250nmol/kg UCN-01 to rats given 150 nmol/h/kg hAGP were 63.9–688ml/kg and 3.18–32.9 ml/h/kg, respectively, indicating non-linearitydue to saturation of UCN-01 binding. The CLtot estimated by thephysiological model assuming rapid equilibrium of UCN-01 bindingto hAGP, was six times higher than the observed value while the CLtotestimated by the model incorporating koff, measured using DCC, wascomparable with the observed value. Conclusions. These results suggest that the slow dissociation ofUCN-01 from hAGP limits its disposition and elimination.
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  • 56
    ISSN: 1573-904X
    Keywords: IVIVC ; racemate ; enantiomers ; metoprolol ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To investigate the ability of an IVIVC developedwith a racemate drug as well as each enantiomer in predicting the invivo enantiomer drug performance. Methods. Dissolution of metoprolol extended releasetablets with different release characteristics (e.g., fast (F),moderate (M), and slow (S)) was performed using USP ApparatusI, pH 1.2, 50 rpm. Metoprolol racemate tablets (S, M, and F, 100 mg) and 50mg oral solution were administered to healthy volunteers, blood samples werecollected over 24 (solution) and 48 (tablet) hours and assayed. IVIVC modelsdeveloped were: (1) Racemate-fraction of drug dissolved (FRD) vsRacemate-fraction of drug absorbed (FRA), (2) R-FRD vs R-FRA, and (3) S-FRDvs S-FRA for combinations of formulations (S/M/F, S/M, S/F, and M/F).Enantiomer Cmax and AUC prediction errors (PEs) were estimated for modelevaluation after convolution of in vivo release rates. Results. The R-IVIVC and S-IVIVC accurately predicted theR- and S-metoprolol pharmacokinetic profiles, respectively. The averagedprediciton errors (PE) for the enantiomer Cmax and AUC were less than10% for S/M/F, M/F, and S/F IVIVC models. Racemate-IVIVC (M/F) wasable to predict S-enantiomer with an average %PE of 2.52 for S-Cmaxand 4.3 for S-AUC. However, the racemate-IVIVC was unable to predict theR-enantiomer pharmacokinetic profile. Conclusions. Metoprolol racemate data cannot be used toaccurately predict R-enantiomer drug concentrations. However, the racematedata was predictive of the active stereoisomer.
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  • 57
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    Fish physiology and biochemistry 23 (2000), S. 225-232 
    ISSN: 1573-5168
    Keywords: methylisoborneol ; catfish ; cytochrome P450 ; biotransformation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 2-Methylisoborneol (MIB) and structurally related terpenoid compounds are responsible for millions of dollars of lost revenue to catfish farmers. In an attempt to determine enzymatic pathways of biotransformation and elimination of MIB, the in vitro metabolism of MIB was examined in the Ulvade strain of channel catfish (Ictalurus punctatus). Although cytochrome P450 (CYP) activities were observed and correlated with expression of specific isoforms (i.e. steroid hydroxylation and CYP3A expression), no metabolites of MIB were observed. To determine whether extrahepatic biotransformation may be occurring the in vivo metabolism and disposition of 14C-MIB was examined in Uvalde, USDA-103 channel catfish, and a channel catfish X blue catfish (Ictalurus furcatus) hybrid species. Confirming in vitro hepatic studies, no metabolites were observed in plasma from animals treated with an intra-arterial dose of 14C-MIB. 14C-MIB elimination was predicted using a two compartment model in each strain of fish. There was no significant difference in terminal half-lives between strains but possible differences in total body clearance and apparent volumes of distribution which may be related to higher lipid content in the hybrids. Results of these studies indicate biotransformation has no involvement in MIB elimination and that other physiological processes may play a more significant role in MIB disposition within Ictalurid fish species.
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  • 58
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    Pharmaceutical research 17 (2000), S. 1426-1431 
    ISSN: 1573-904X
    Keywords: eplerenone ; selective aldosterone receptor antagonist ; dog ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. Methods. Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). Results. After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. Conclusions. EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.
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  • 59
    ISSN: 1573-904X
    Keywords: amphotericin B ; liposomes ; pharmacokinetics ; toxicokinetics ; tissue distribution ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated. Methods. Rats (174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg), dextrose, or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated. Results. Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] ≤51 mg/dl; creatinine unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma; kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues. Conclusions. Despite nonlinear accumulation, AmBisome revealed predictable hepatic and renal toxicities after 91 days, with no new or delayed effects after prolonged treatment at high doses that resulted in plasma levels 〉200 μg/ml and tissue levels 〉3000 μg/g.
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  • 60
    ISSN: 1573-904X
    Keywords: aspergillosis ; pharmacokinetics ; amphotericin B ; biodistribution ; liposomes ; cholesterol hemisuccinate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study compared the biodistribution of two amphotericin B formulations in normal and Aspergillus infected mice. Amphotericin B cholesterol hemisuccinate vesicles (ABCV) which reduces the toxicity of amphotericin B and thereby enhances its therapeutic efficacy in a murine model of aspergillosis was compared with conventional amphotericin B deoxycholate suspension (AmBDOC). Methods. ABCV (12 mg/kg wt) and AmBDOC (2 mg/kg wt) were intravenously administered to normal and A.fumigatus infected mice. The concentration of amphotericin B in plasma and other organs was determined at different time points. Results. It was observed that ABCV had a significantly different pharmacokinetic profile compared to conventional amphotericin B. In comparison to AmBDOC significantly lower levels of amphotericin B were observed in kidneys and plasma, the major target organs of toxicity. Animals receiving ABCV demonstrated high levels of amphotericin B in liver (38% retention till 48 h) and spleen (2.6% retention till 48 h) in comparison to AmBDOC (7.3% and 0.21% retention in liver and spleen respectively till 48 h). Biodistribution studies of ABCV in infected mice demonstrated that there was a moderate enhancement in levels of amphotericin B in liver, spleen, lungs and kidneys as compared to normal mice and the plasma levels were reduced. However, such observations were not made after AmBDOC administration to infected mice except for kidneys in which there was a marked increase in uptake as compared to normal mice. Conclusions. Our results suggest that prolonged retention of high concentrations of ABCV in reticuloendothelial system organs is the reason for its reduced toxicity. Enhanced localization of the drug at the infected site may lead to improvement in therapeutic efficacy.
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  • 61
    ISSN: 1573-904X
    Keywords: oral absorption ; humans ; dogs ; rats ; interspecies scale-up ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To conduct a retrospective evaluation of using dog as ananimal model to study the fraction of oral dose absorbed (F) of 43drugs in humans and to briefly discuss potential factors that mighthave contributed to the observed differences in absorption. Methods. Mean human and dog absorption data obtained under fastedstate of 43 drugs with markedly different physicochemical andpharmacological properties and with mean F values ranging from 0.015 to1.0 were obtained from the literature. Correlation of F values betweenhumans and dogs was studied. Based on the same references, additionalF data for humans and rats were also obtained for 18 drugs. Results. Among the 43 drugs studied, 22 drugs were virtuallycompletely absorbed in both dogs and humans. However, the overallcorrelation was relatively poor (r2 = 0.5123) as compared to the earlier ratvs. human study on 64 drugs (r2 = 0.975). Several drugs showed muchbetter absorption in dogs than in humans. Marked differences in thenonliner absorption profiles between the two species were found forsome drugs. Also, some drugs had much longer Tmax values andprolonged absorption in humans than in dogs that might be theoreticallypredicted. Data on 18 drugs further support great similarity in F betweenhumans and rats reported earlier from our laboratory. Conclusions. Although dog has been commonly employed as ananimal model for studying oral absorption in drug discovery anddevelopment, the present study suggests that one may need to exercise cautionin the interpretation of data obtained. Exact reasons for the observedinterspecies differences in oral absorption remain to be explored.
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  • 62
    ISSN: 1573-904X
    Keywords: benzodiazepines ; pharmacokinetics ; EEG ; operational model of agonism ; receptor binding ; muscimol-induced Cl−uptake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A mechanism-based model is applied to analyse adaptivechanges in the pharmacodynamics of benzodiazepines upon chronictreatment in rats. Methods. The pharmacodynamics of midazolam was studied in ratswhich received a constant rate infusion of the drug for 14 days, resultingin a steady-state concentration of 102 ± 8 ng·ml−1. Vehicle treated ratswere used as controls. Concentration-EEG effect data were analysed onbasis of the operational model of agonism. The results were comparedto data obtained in vitro in a brain synaptoneurosomal preparation. Results. The relationship between midazolam concentration and EEGeffect was non-linear. In midazolam pre-treated rats the maximum EEGeffect was reduced by 51 ± 23 μV from the original value of 109 ±15 μV in vehicle treated group. Analysis of this change on basis ofthe operational model of agonism showed that it can be explained bya change in the parameter tissue maximum (Em) rather than efficacy(τ). In the in vitro studies no changes in density, affinity or functionalityof the benzodiazepine receptor were observed. Conclusions. It is concluded that the observed changes in theconcentration-EEG effect relationship of midazolam upon chronic treatmentare unrelated to changes in benzodiazepine receptor function.
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  • 63
    ISSN: 1573-8221
    Keywords: acylprolyldipeptide ; GVS-111 ; pharmacokinetics ; blood-brain barrier permeability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Pharmacokinetics of GVS-111, a new acylprolyldipeptide with nootropic properties and its penetration across the blood-brain barrier were studied in rats using HPLC. It was found that the dipeptide is absorbed in the gastrointestinal tract, enters the circulation, and penetrates through the blood-brain barrier in an umodified state.
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  • 64
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    Risk analysis 19 (1999), S. 711-726 
    ISSN: 1539-6924
    Keywords: variability ; exposure ; susceptibility ; risk assessment ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: •Contact Rate (Breathing rates per body weight; fish consumption per body weight) •Uptake or Absorption as a Fraction of Intake or Contact Rate •General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) •Systemic Elimination (half life or clearance) •Active Site Concentration per Systemic Blood or Plasma Concentration •Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) •Functional Reserve Capacity–Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process–differences among people in “functional reserve capacity.” This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.
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  • 65
    ISSN: 1539-6924
    Keywords: MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
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  • 66
    ISSN: 1573-0646
    Keywords: pharmacokinetics ; capecitabine ; 5-fluorouracil ; phase I trials
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 μ Ci of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86–104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71–95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69–7.0) was collected in the feces. Over a collection period of 24–48h, a total of 84.2% (range 80–95) was recovered in the urine as the sum of the parent drug and measured metabolites (5′-DFCR, 5′-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25–1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.
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  • 67
    ISSN: 1573-0646
    Keywords: docetaxel ; plasma assay ; clinical trials ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have developed a specific and sensitive method aiming atdocetaxel (Taxotere®) determination in plasma of treatedpatients. This involved solid-phase extraction of 1 ml of plasmaonto carboxylic acid (CBA) grafted silica cartridges followed byreversed-phase liquid chromatography with UV detection. The bestselectivity was obtained through the use of C18 Uptisphere® asstationary phase. The low limit of quantitation obtained (LOQ:5 ng/ml) allowed measurements of docetaxel up to 24 hours afterone-hour infusions with low dosages of drug (60 mg/m2). Themethod was applied successfully to monitor docetaxel plasma levelswithin two protocols associating fixed dosages of either methotrexate or gemcitabine with escalating doses of Taxotere®.
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  • 68
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; effect compartment model ; indirect response ; sigmoid E max ; tiagabine ; GABA uptake inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic–pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5–30 Hz frequency band (β), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg −1 $$(\bar x \pm SE,{\text{ }}n = 23)$$ $$96 \pm 9$$ ml min -1 kg−1, 1.5ŷ0.1 L kg−1 and 20ŷ0.2 min.A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo=0.030 min −1 and kout=81 min−1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates $$(\bar x \pm SE)$$ were E0=155 ŷ 6 μV, Emax=100 ŷ 5 μV, EC50=287 ŷ 7 ng ml−1, Hill factor=1.8 ŷ 0.2 and keo=0.030 ŷ 0.002 min −1. The results of this analysis show that for tiagabine the combined “effect compartment-indirect response” model can be simplified to the classical “effect compartment” model.
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  • 69
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    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 491-512 
    ISSN: 1573-8744
    Keywords: muscle relaxants ; peripheral elimination ; pharmacokinetics ; peripheral concentrations ; volume of distribution ; pharmacokinetic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10 ) and peripheral compartments(k20 ). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss ) are also mostly significant when k20 is smaller than k10 . Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20 , the rate of transfer from the central compartment (k12 ) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.
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  • 70
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    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 325-328 
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have previously described a method of rapidly obtaining a specified steady-state plasma concentration of an intravenous drug within precise limits. However the method is limited to drugs whose disposition may be characterized by an open two-compartment system. In this paper, we illustrate how the method can be extended to drugs whose disposition may be characterized by a mammillary model with any number of compartments. Refinements of our previous technique are also described.
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  • 71
    ISSN: 1573-8744
    Keywords: psoriasis ; hu1124 ; CD11a ; CD3-positive lymphocytes ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of hu1124, a human anti-CD11a antibody, were investigated in human subjects with psoriasis. CD11a is a subunit of LFA-1, a cell surface molecule involved in T cell mediated immune responses. Subjects received a single dose of 0.03, 0.1, 0.3, 0.6, 1, 2, 3, or 10 mg/kg of hu1124 intravenously over 1–3 hr. Blood samples were collected at selected times from 60 min to 72 days after administration. Plasma samples were assayed for hu1124 by ELISA, and pharmacokinetic analyses were performed on the drug plasma concentrations. As the dose of hu1124 was increased, the clearance decreased from 322 ml/day per kg at 0.1 mg/kg to 6.6 ml/day per kg at 10 mg/kg of hu1124. The plasma hu1124 concentration–time profile suggested that the clearance of hu1124 was saturable above 10 μg/ml. In addition, treatment with hu1124 caused a rapid reduction in the level of CD11a expression on CD3-positive lymphocytes (T cells) to about 25% of pretreatment levels. Regardless of the hu1124 dose administered, cell surface CD11a remained at this reduced level as long as hu1124 was detectable (〉0.025 μg/ml) in the plasma. When hu1124 levels fell below 3 μg/ml, the drug was rapidly cleared from the circulation and expression of CD11a returned to normal within 7–10 days thereafter. In vitro, half-maximal binding of hu1124 to lymphocytes was achieved at about 0.1 μg/ml and saturation required more than 10 μg/ml. One of the receptor-mediated pharmacokinetic/pharmacodynamic models which was developed describes the dynamic interaction of hu1124 binding to CD11a, resulting in the removal of hu1124 from the circulation and reduction of cell surface CD11a. The model accounts for the continually changing number of CD11a molecules available for removing hu1124 from the circulation based on prior exposure of cells expressing CD11a to hu1124. In addition, the model also accounts for saturation of CD11a molecules by hu1124 at drug concentrations of approximately 10 μg/ml, thereby reducing the clearance rate of hu1124 with increasing dose.
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  • 72
    ISSN: 1573-8744
    Keywords: drug–drug interactions ; NPML ; experimental design ; pharmacodynamic variability ; pharmacokinetics ; entropy ; covariate ; second stage model ; controlled trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Population approaches are appealing methods for detecting then assessing drug–drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug–drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.
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  • 73
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    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 329-338 
    ISSN: 1573-8744
    Keywords: propofol ; anaesthesia ; pharmacokinetics ; compartment models ; effect compartment models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid iv administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after iv administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.
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  • 74
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    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 513-529 
    ISSN: 1573-8744
    Keywords: desmopressin ; indirect-response modeling ; overhydration ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The objective of the present study was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of desmopressin in healthy male subjects at different levels of overhydration. Also, we examined if an indirect-response model could be related to renal physiology and the pharmacological action of desmopressin. Eight healthy male subjects participated in this open, randomized crossover study with three periods. Each subject was orally water loaded (0 to 20ml·kg −1 body weight) on 3 study days in order to achieve three different levels of hydration. After the initial water load, urine was voided every 15 min and the volumes were measured. To ensure continuous overhydration the subjects replaced their fluid loss with drinking-water. When a steady-state diuresis was achieved after approximately 2 hr, 0.396 μg of desmopressin was administered intravenously as a bolus injection. Blood was sampled and urine was collected at intervals throughout the study day (10 hr). An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fit to the urine osmolarity data. There were no statistically significant effects of different levels of hydration, as expressed by urine flow rate at baseline, on the estimates of the PK and PD model parameters. The calculated terminal half-lives of elimination (t1/2 β) ranged between 2.76 and 8.37 hr with an overall mean of 4.36 hr. The overall means of plasma clearance and the volumes of distribution of the central compartment (Vc ) and at steady state (Vss ) were estimated to be 1.34 (SD 0.35) ml·min −1 ·kg −1 , 151 (SD28) ml·kg −1 , and 386 (SD 63) ml·kg −1 , respectively. High urine flow rate, indicating overhydration, produced a diluted urine and thus a low osmolarity at baseline (R0 ). The effect of the urine flow rate on the urine osmolarity at baseline was highly significant (p〈0.0001). The mean values for IC50 and the sigmoidicity factor (γ) were 3.7 (SD 1.2) pg·ml −1 and 13.0 (SD 3.5), respectively. In most cases when there was a high urine flow rate at baseline, the model and the estimated PD parameters could be related to the pharmacological action of desmopressin and renal physiology. Thus, the indirect-response model used in this study offers a mechanistic approach of modeling the effect of desmopressin in overhydrated subjects.
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  • 75
    ISSN: 1573-8744
    Keywords: prediction interval ; pharmacokinetics ; population analysis ; NONMEM ; inverse regression ; immunosuppressives
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor α-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 μg/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7–52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7–58.3 days.
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  • 76
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    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 559-575 
    ISSN: 1573-8744
    Keywords: T-helper cells ; trafficking ; rebound ; corticosteroids ; circadian rhythm ; methylprednisolone ; drug interactions ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.
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  • 77
    ISSN: 1573-904X
    Keywords: etomidate ; pharmacokinetics ; pharmacodynamics ; rat ; electroencephalogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect-plasma concentration relationship of etomidate was studied in the rat using electroencephalographic changes as a pharmacodynamic parameter. Methods. Etomidate was infused (50 mg/kg/h) in chronically instrumented rats (n = 6) until isoelectric periods of 5 s or longer were observed in the electroencephalogram (EEG). The EEG was continuously recorded during the experiment and frequent arterial blood samples were taken for determination of etomidate plasma concentrations. The changes observed in the raw EEG signal were quantified using aperiodic analysis in the 2.5−7.5 Hz frequency band. The return of the righting reflex was used as another parameter of anesthesia. Results. A mean dose of 8.58 ± 0.41 mg/kg needed to be infused to reach the end point of 5 s isoelectric EEG. The plasma concentration time profiles were most adequately fitted using a three-exponential model. Systemic clearance, volume of distribution at steady-state and elimination half-life averaged 93 ± 6 ml/min/kg, 4.03 ± 0.24 l/kg and 59.4 ± 10.7 min respectively. The EEG effect-plasma concentration relationship was biphasic exhibiting profound hysteresis. Semi-parametric minimization of this hysteresis revealed an equilibration half-life of 2.65 ± 0.15 min, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. The effect-site concentration at the return of the righting reflex was 0.44 ± 0.03 μg/ml. Conclusions. The results of the present study show that the concentration-effect relationship of etomidate can be characterized in individual rats using aperiodic analysis in the 2.5−7.5 Hz frequency band of the EEG. This characterization can be very useful for studying the influence of diseases on the pharmacodynamics of etomidate in vivo.
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  • 78
    ISSN: 1573-904X
    Keywords: bioequivalence ; neural networks ; prediction ; pharmacokinetics ; verapamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The methodology of predicting the pharmacokinetic parameters (AUC, cmax, tmax) and the assessment of their variability in bioequivalence studies has been developed with the use of artificial neural networks. Methods. The data sets included results of 3 distinct bioequivalence studies of oral verapamil products, involving a total of 98 subjects and 312 drug applications. The modeling process involved building feedforward/backpropagation neural networks. Models for pharmacokinetic parameter prediction were also used for the assessment of their variability and for detecting the most influential variables for selected pharmacokinetic parameters. Variables of input neurons based on logistic parameters of the bioequivalence study, clinical-biochemical parameters, and the physical examination of individuals. Results. The average absolute prediction errors of the neural networks for AUC, cmax, and tmax prediction were: 30.54%, 39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for verapamil the three most influential variables assigned to input neurons were: total protein concentration, aspartate aminotransferase (AST) levels, and heart-rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT) levels, for cmax, and the presence of food, blood pressure, and body-frame for tmax. Conclusions. The developed methodology could supply inclusion or exclusion criteria for subjects to be included in bioequivalence studies.
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  • 79
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    Pharmaceutical research 16 (1999), S. 1392-1398 
    ISSN: 1573-904X
    Keywords: topical application ; dermal absorption ; cutaneous perfusion ; pharmacokinetics ; binding ; half life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate. Methods. The disposition kinetics of diclofenac in a single pass perfused limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate. Results. Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate. Conclusions. The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.
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  • 80
    ISSN: 1573-904X
    Keywords: submicron lipid emulsion ; supersaturation ; tirilazad ; venous irritation ; pharmacokinetics ; tissue distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p 〉 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower Vss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p 〈 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.
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  • 81
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    Pharmaceutical research 16 (1999), S. 587-591 
    ISSN: 1573-904X
    Keywords: quinolones ; pharmacokinetics ; permeability ; tissue binding ; hindlimb
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    Topics: Chemistry and Pharmacology
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  • 82
    ISSN: 1573-904X
    Keywords: C6-glioma ; methotrexate ; microdialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Establishment of the pharmacokinetic profile of methotrexate (MTX) in the extracellular fluid (ECF) of a brain C6-glioma in rats. Methods. Serial collection of plasma samples and ECF dialysates after i.v. infusion of MTX (50 or 100 mg/kg) for 4 h. HPLC assay. Results. Histological studies revealed the presence of inflammation, edema, necrosis, and hemorrhage in most animals. In vivo recovery (reverse dialysis) was 10.8 ± 5.3%. MTX concentrations in tumor ECF represented about 1−2% of the plasma concentrations. Rapid equilibration between MTX levels in brain tumor ECF and plasma. ECF concentrations almost reached steady-state by the end of the infusion (4 h), then decayed in parallel with those in plasma. Doubling of the dose did not modify MTX pharmacokinetic parameters (t1/2α, t1/2β, MRT, fb, Vd, and CLT), except for a 1.7-fold increase of AUCPlasma and a 3.8-fold increase in AUCECF which resulted in a 2.3-fold increase in penetration (AUCECF/AUCPlasma). In spite of an important interindividual variability, a relationship between MTX concentrations in plasma and tumor ECF could be established from mean pharmacokinetic parameters. Conclusions. High plasma concentrations promote the penetration of MTX into brain tissue. However, free MTX concentrations in tumor ECF remain difficult to predict consistently.
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  • 83
    ISSN: 1573-904X
    Keywords: HI-240 ; nonnucleoside inhibitor ; pharmacokinetics ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to examine the pharmacokinetic features and tissue distribution of N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240), a novel non-nucleoside inhibitor of HIV reverse transcriptase with potent anti-viral activity against AZT-sensitive as well as multidrug-resistant HIV-1 strains. Methods. A sensitive and accurate high performance liquid chromatography (HPLC)-based quantitative detection method was established to measure concentrations of HI-240 in pharmacokinetic studies. The plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameter values. Results. HI-240 had an elimination half-life of 78.3 ± 2.0 min after i.v. administration and 196.8 ± 3.1 min after i.p. administration. The systemic clearance of HI-240 was 2194 ± 61 ml/h/kg after i.v. administration and 9339 ± 1160 ml/h/kg after i.p. administration. Following i.v. injection, HI-240 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in adipose tissue, adrenal gland, and uterus+ovary. The concentration of HI-240 in brain tissue was comparable to that in the plasma, indicating that HI-240 easily crosses the blood-brain-barrier. Following i.p. injection, HI-240 was rapidly absorbed with a t1/2ka and a tmax values of less than 10 min. Following oral administration, HI-240 was absorbed with a t1/2ka of 4.2 ±1.1 min and a tmax of 95.1 ± 25.1 min. The intraperitoneal bioavailability was estimated at 23.5%, while the oral bioavailability was only 1%. Conclusions. The HPLC-based accurate and precise analytical detection method and pilot pharmacokinetic studies described herein provide the basis for advanced preclinical pharmacodynamic studies of HI-240. The ability of HI-240 to distribute rapidly and extensively into extravascular compartments and easily cross the blood-brain barrier represent significant pharmacokinetic advantages over AZT.
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  • 84
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; Calphostin C ; HPLC ; perylenequinone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with potent antileukemic activity. Methods. HPLC-based quantitative detection methods were used to measure calphostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(API-EI) system were used to study the metabolism of calphostin C. Results. An intracellular exposure level (AUC0−6h) of 257 μM·h was achieved after in vitro treatment of NALM-6 cells with calphostin C at a 5 μM final concentration in culture medium. After intraperitoneal (i.p.) injection of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated Cmax was 2.9 μM, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administration was rapid with an absorption half-life of 24.2 min and the estimated tmax was 63.0 min. Calphostin C was cleared with an elimination half-life of 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a tmax of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metabolite (calphostin B) of the same size and elution profile. Conclusions. Target plasma calphostin C concentrations of potent antileukemic activity can be reached in mice at nontoxic dose levels. This pilot pharmacokinetic study of calphostin C combined with the availability of the described quantitative HPLC method for its detection in cells and plasma provide the basis for future preclinical evaluation of calphostin C and its potential as an anti-leukemic drug.
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  • 85
    ISSN: 1573-904X
    Keywords: bezafibrate ; hyperlipidemia ; pharmacodynamics ; pharmacokinetics ; sustained release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. Methods. The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. Results. In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. Conclusions. The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.
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  • 86
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    Cellular and molecular neurobiology 19 (1999), S. 309-323 
    ISSN: 1573-6830
    Keywords: cytochrome P450 ; enzyme inhibition ; enzyme induction ; pharmacokinetics ; drug interaction ; in vitro assessment ; clinical assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. The cytochrome P450 enzyme family is one of the major drug metabolizing systems in man. 2. Factors such as age, gender, race, environment, and drug treatment may have considerable influence on the activity of these enzymes. 3. There are now well-established in vitro techniques for assessing the role of specific cytochrome P450 enzymes in the metabolism of drugs, as well as the inhibitory or inducing effects of drugs on enzyme activity. In vitro data have been utilized to predict clinical outcomes (i.e., pharmacokinetic interactions), with close correlations between in vitro and in vivo data. 4. This information can be of considerable practical assistance to clinicians, to help with rational prescribing or to prevent or minimize the potential for drug interactions.
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  • 87
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    Cellular and molecular neurobiology 19 (1999), S. 355-372 
    ISSN: 1573-6830
    Keywords: enantiomers ; racemic ; chiral ; stereoselective ; pharmacokinetics ; cytochrome P450 ; geometric isomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Many drugs used to treat psychiatric disorders contain a chiral center or a center of unsaturation and are marketed as a mixture of the resultant enantiomers or geometric isomers, respectively. These enantiomers or geometric isomers may differ markedly with regard to their pharmacodynamic and/or pharmacokinetic properties. 2. Examples of the effects of chiral centers or geometric centers on such properties are given for drugs from the following classes: antidepressants (tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, viloxazine, bupropion, trazodone, mianserin, venlaflaxine); benzodiazepines, zoplicone, and antipsychotics. 3. As described in this review, there are several notable examples of psychiatric drugs currently available where the individual enantiomers or geometric isomers differ considerably with regard to factors such as effects on amine transport systems, interactions with receptors and metabolizing enzymes, and clearance rates from the body. Indeed, relatively recent developments in analytical and preparative resolution of racemic and geometric drug mixtures and increased interest in developing new drugs which interact with specific targets, which have been described in detail at the molecular level, have resulted in increased emphasis on stereochemistry in drug development.
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  • 88
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    Cellular and molecular neurobiology 19 (1999), S. 443-466 
    ISSN: 1573-6830
    Keywords: selective serotonin reuptake inhibitors ; metabolism ; pharmacokinetics ; fluoxetine ; fluvoxamine ; paroxetine ; sertraline ; citalopram ; cytochrome P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Five drugs with the predominant pharmacologic effect of inhibiting the neuronal reuptake of serotonin are available worldwide for clinical use. This class of psychoactive drugs, known as selective serotonin reuptake inhibitors (SSRIs), is comprised of fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. 2. The SSRIs appear to share similar pharmacodynamic properties which translate to efficacy in the treatment of depression and anxiety syndromes. The drugs are differentiated by their pharmacokinetic properties with regard to stereochemistry, metabolism, inhibition of cytochrome enzymes, and participation in drug–drug interactions. Studies focusing on the relationship of plasma drug concentration to therapeutic and adverse effects have not confirmed the value of plasma concentration monitoring. 3. This review summarizes the metabolism and relevant pharmacokinetic properties of the SSRIs.
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  • 89
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    Cellular and molecular neurobiology 19 (1999), S. 373-409 
    ISSN: 1573-6830
    Keywords: antidepressants ; tricyclic ; metabolism ; hydroxy metabolites ; pharmacokinetics ; pharmacogenetics ; drug–drug interactions ; toxicity ; plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Despite the considerable advances in the treatments available for mood disorders over the past generation, tricyclic antidepressants (TCAs) remain an important option for the pharmacotherapy of depression. 2. The pharmacokinetics of TCAs are characterized by substantial presystemic first-pass metabolism, a large volume of distribution, extensive protein binding, and an elimination half-life averaging about 1 day (up to 3 days for protriptyline). 3. Clearance of tricyclics is dependent primarily on hepatic cytochrome P450 (CYP) oxidative enzymes. Although the activities of some P450 isoenzymes are largely under genetic control, they may be influenced by external factors, such as the concomitant use of other medications or substances. Patient variables, such as ethnicity and age, also affect TCA metabolism. The impact of gender and related reproductive issues is coming under increased scrutiny. 4. Metabolism of TCAs, especially their hydroxylation, results in the formation of active metabolites, which contribute to both the therapeutic and the adverse effects of these compounds. 5. Renal clearance of the polar metabolites of TCAs is reduced by normal aging, accounting for much of the increased risk of toxicity in older patients. 6. Knowledge of factors affecting the metabolism of TCAs can further the development and understanding of newer antidepressant medications.
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  • 90
    ISSN: 1573-904X
    Keywords: antisense ; Brown-Norway rat ; oligodeoxynucleotide ; pulmonary delivery ; ISIS 2105 ; pharmacokinetics ; airway inflammation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. Methods. The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naïve and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. Results. CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITCJ-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages 〉 eosinophils = neutrophils 〉 〉 lymphocytes. Conclusions. The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics.
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  • 91
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    Keywords: nonlinear mixed effects modeling (NONMEM) ; pharmacokinetics ; telmisartan ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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  • 92
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    Keywords: antisense phosphorothioate oligonucleotide ; stealth liposome ; pharmacokinetics ; monkey ; capillary gel electrophoresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study examined the pharmacokinetics and tissue distribution of an antisense oligonucleotide ISIS 2503, formulated in stealth (pegylated) liposomes (encapsulated) or in phosphate-buffered saline (unencapsulated). Methods. Encapsulated or unencapsulated ISIS 2503 was administered to rhesus monkeys by intravenous infusion. The concentrations of ISIS 2503 and metabolites in blood, plasma, and tissue samples were determined by capillary gel electrophoresis. Results. Plasma concentrations of encapsulated ISIS 2503 decreased mono-exponentially after infusion with a mean half-life of 57.8 hours. In contrast, the concentration of unencapsulated ISIS 2503 in plasma decreased rapidly with a mean half-life of 1.07 hours. Both encapsulated and unencapsulated ISIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distributed primarily to the reticulo-endothelial system and there were few metabolites observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to tissue with highest concentration seen in kidney and liver. Nuclease-mediated metabolism was extensive for unencapsulated oligonucleotide in plasma and tissues. Conclusions. The data suggest that stealth liposomes protect ISIS 2503 from nucleases in blood and tissues, slow tissue uptake, and slow the rate of clearance from the systemic circulation. These attributes may make these formulations attractive for delivering oligonucleotides to sites with increased vasculature permeability such as tumors or sites of inflammation.
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  • 93
    ISSN: 1573-904X
    Keywords: aminolevulinic acid ; intravesical ; pharmacokinetics ; photodiagnosis ; bladder ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the stability and systemic absorption of aminolevulinic acid (ALA) in dogs during intravesical administration. Methods. Nine dogs received an intravesical dose of ALA either with no prior treatment, after receiving ammonium chloride for urinary acidification, or after receiving sodium bicarbonate for urinary alkalinization. Urine and blood samples collected during and after administration were monitored for ALA using an HPLC assay developed in our laboratories. Concentrations of pyrazine 2,5-dipropionic acid, the major ALA degradation product, and radiolabeled inulin, a nonabsorbable marker for urine volume, were also determined. Results. Less than 0.6% of intravesical ALA doses was absorbed into plasma. Urine concentrations decreased to 37% of the initial concentration during the 2 hour instillation. Decreases in urinary ALA and radiolabeled inulin concentrations were significantly correlated, indicating that urine dilution accounted for over 80% of observed decreases in urinary ALA. ALA conversion to pyrazine 2,5-dipropionic acid was negligible. Conclusions. These studies demonstrate that ALA is stable and poorly absorbed into the systemic circulation during intravesical instillation. Future studies utilizing intravesical ALA for photodiagnosis of bladder cancer should include measures to restrict fluid intake as a means to limit dilution and maximize ALA concentrations during instillation.
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  • 94
    ISSN: 1573-904X
    Keywords: diffusion model ; drug delivery system ; ocular penetration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process. Methods. The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. Thein vivo permeability of drugs was measured across cornea using a two-chamber diffusion cell. Results. Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, anin vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters. Conclusions. The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.
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  • 95
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    Pharmaceutical research 16 (1999), S. 1608-1615 
    ISSN: 1573-904X
    Keywords: tenidap ; pharmacokinetics ; EM algorithm ; nonlinear mixed-effects modelling ; covariates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To develop a pharmacokinetic model for tenidap and to identify important relationships between the pharmacokinetic parameters and available covariates. Methods. Plasma concentration data from several phase I and phase II studies were used to develop a pharmacokinetic model for tenidap, a novel anti-rheumatic drug. An appropriate pharmacokinetic model was selected on the basis of individual nonlinear regression analyses and an EM algorithm was used to perform a nonlinear mixed-effects analysis. Scatter plots of posterior individual pharmacokinetic parameters were used to identify possible covariate effects. Results. Predicted responses were in good agreement with the observed data. A bi-exponential model with zero order absorption was subsequently used to develop the mixed-effects model. Covariate relationships selected on the basis of differences in the objective function, although statistically significant, were not particularly strong. Conclusions. The pharmacokinetics of tenidap can be described by a bi-exponential model with zero order absorption. Based on differences in the log-likelihood, significant covariate-parameter relationships were identified between smoking and CL, and between gender and Vss and CLd. Simulated sparse data analyses indicated that the model would be robust for the analysis of sparse data generated in observational studies.
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  • 96
    ISSN: 1573-904X
    Keywords: amphotericin B ; liposomes ; pharmacokinetics ; tissue distribution ; toxicity ; toxicokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18−94 µg/mL.
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  • 97
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    Pharmaceutical research 16 (1999), S. 176-185 
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; pharmacodynamics ; pharmacology ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD-modeling concepts has been identified as potentially beneficial in all phases of preclinical and clinical drug development. Although today predominantly limited to research, broader application of PK/PD-concepts in clinical therapy will provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance.
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    Pharmaceutical research 16 (1999), S. 261-265 
    ISSN: 1573-904X
    Keywords: crystal habit ; trimethoprim suspension ; physical stability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The role of crystal habit in influencing the physical stability and pharmacokinetics of trimethoprim suspensions was examined. Methods. Different habits of trimethoprim (TMP) were obtained by recrystallizing the commercial sample (PD) utilizing solvent-change precipitation method. Four distinct habits (microscopic observation) belonging to the same polymorphic state (DSC studies) were selected for studies. Preformulation and formulation studies were carried out on suspension dosage forms containing these crystals. The freshly prepared suspensions were also evaluated for their pharmacokinetic behaviour on healthy human volunteers using a cross over study. Results. Variation of crystallization conditions produces different habits of TMP. Among the different crystal habits exhibiting same polymorphic state, the most anisometric crystal showed best physical stability in terms of sedimentation volume and redispersibility. However, habit did not significantly affect the extent of TMP excreted in urine. Conclusions. Modification of surface morphology without significantly altering the polymorphic state can be utilized for improving physical stability of TMP suspensions. However, the pharmacokinetic profile remains unaltered.
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  • 99
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    Pharmaceutical research 16 (1999), S. 309-313 
    ISSN: 1573-904X
    Keywords: hyperlipidemia ; hypercholesterolemia ; nifedipine ; pharmacokinetics ; protein binding ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used. Methods. Poloxamer 407 (P407)-induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg−1 given iv, ip and po). Total plasma cholesterol levels increased from 0.82−2.02 to 5.27−11.05 mmol L−1 48 h post P407 administration (Ig kg−1, ip). Protein binding studies were conducted by an ultrafiltration method. Results. Hyperlipidemia significantly decreased CLTB by 38% and CLTB/F by 45 and 42% following po and ip doses, respectively, thereby increasing AUC0−∞, Cmax and half-life. Absolute bioavailability and Vdss remained unchanged. AUC0−∞ was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%. Conclusions. The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out.
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  • 100
    ISSN: 1573-904X
    Keywords: WHI-P180 ; pharmacokinetics ; quinazolines ; mast cell inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to examine the pharma-codynamic and pharmacokinetic features of the novel mast cell inhibitor 4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P180) in mice. Methods. A high performance liquid chromatography (HPLC)-based quantitative detection method was used to measure plasma WHI-P180 levels in mice. The plasma concentration-time data was fit to a single compartment pharmacokinetic model by using the WinNonlin program to calculate the pharmacokinetic parameters. A cutaneous anaphylaxis model was used to examine the pharmacodynamic effects of WHI-P180 on anaphylaxis-associated vascular hyperpermeability. Results. The elimination half-life of WHI-P180 in CD-1 mice (BALB/ c mice) following i.v., i.p., or p.o. administration was less than 10 min. Systemic clearance of WHI-P180 was 6742 mL/h/kg in CD-1 mice and 8188 mL/h/kg in BALB/c mice. Notably, WHI-P180, when administered in two consecutive nontoxic i.p. bolus doses of 25 mg/kg, inhibited IgE/antigen-induced vascular hyperpermeability in a well-characterized murine model of passive cutaneous anaphylaxis. Conclusions. WHI-P180 is an active inhibitor of IgE-mediated mast cell responses in vitro and in vivo. Further preclinical characterization of WHI-P180 may improve the efficacy of WHI-P180 in vivo and provide the basis for design of effective treatment and prevention programs for mast cell mediated allergic reactions.
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