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  • 1
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    Springer Nature | Springer
    Publication Date: 2022-03-16
    Description: This Open Access book’s main focus is agriculture and natural resource management, disaster risk reduction, and human resource development in the countries of East and Southeast Asia and Japan. Asia is one of the regions which is the most vulnerable to the impacts of climate change. More than sixty percent of the world’s people live in the region, making it the growth center of the world. Asia is vast and includes various countries and regions, this book is focused on East and Southeast Asia including Japan. It is essential to share the knowledge and experiences for adapting climate change among these areas. In order to tackle these issues, the book aims to: Promote inter-local lessons learnt sharing climate change adaptations; "agriculture and natural resource management" and "disaster risk reduction and human resource development" Provides insights into new adaptation measures and research approaches that can consider the regional nature of Southeast Asia Share practical adaptation options permeated by society in each country/region This book will be of interest to researchers and students examining climate change impacts in East and Southeast Asia.
    Keywords: Climate change ; Climate-Change Adaptation ; Disaster risk reduction ; East and Southeast Asia ; Agriculture ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RB Earth sciences::RBP Meteorology & climatology ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNR Natural disasters ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNF Environmental management ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNU Sustainability ; bic Book Industry Communication::T Technology, engineering, agriculture::TV Agriculture & farming::TVB Agricultural science ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPQ Central government::JPQB Central government policies
    Language: English
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  • 2
    Publication Date: 2023-08-17
    Description: Für die öffentliche Trinkwasserversorgung in Süddeutschland wird größtenteils Grund- und Quellwasser genutzt. Der Kenntnis über die Entwicklung des Bodenwasserhaushalts und insbesondere der Grundwasserneubildung kommt somit eine große Bedeutung zu. Im Rahmen der Kooperation KLIWA (Klimaveränderung und Konsequenzen für die Wasserwirtschaft, www.kliwa.de) wurde die Entwicklung des Bodenwasserhaushaltes und der Grundwasserneubildung aus Niederschlag für den Zeitraum von 1951 bis 2019 für die Länder Baden-Württemberg, Bayern, Hessen und Rheinland-Pfalz mit dem Bodenwasserhaushaltmodell GWN-BW modelliert. Seit Ende der 1980er-Jahre zeigt sich ein Anstieg der mittleren jährlichen Temperatur in Süddeutschland. Die jährlichen Niederschlagssummen haben sich in der jüngeren Vergangenheit (seit 2003) reduziert und somit eine deutliche Verringerung der Grundwasserneubildung aus Niederschlag bewirkt. Gleichzeitig ist eine Zunahme des Trockenheitsindex (Anzahl an Tagen mit Füllung des Bodenwasserspeichers 〈 30 % der nutzbaren Feldkapazität) zu erkennen. Häufiger werdende und länger anhaltende Trockenperioden stellen auch die Wasserwirtschaft zunehmend vor Herausforderungen und bedürfen der frühzeitigen Entwicklung von Handlungsoptionen, z. B. auf der Basis des hier vorgestellten „Trockenwetterdargebots“, um Nutzungskonflikte zu entschärfen.
    Description: LUBW Landesanstalt für Umwelt Baden-Württemberg (5309)
    Keywords: ddc:551.49 ; Wasserversorgung ; Bodenwasserhaushalt ; Grundwasserneubildung ; Klimawandel ; Handlungsoption ; Anpassung ; Water supply ; Soil water balance ; Groundwater recharge ; Climate change ; Action recommendation ; Adaption
    Language: German
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  • 3
    Publication Date: 2023-08-08
    Description: Die Bundesanstalt für Geowissenschaften und Rohstoffe (BGR) führte in den Jahren 2000–2014 umfangreiche (etwa 5900 km2) aerogeophysikalische Erkundungen an der niedersächsischen Nordseeküste durch. Die Aeroelektromagnetik liefert Informationen über die elektrisch leitfähigen Strukturen im Erduntergrund und ermöglicht die Unterscheidung von Süß- und Salzwasser wie auch von Tonen und Sanden. Im Landesamt für Bergbau, Energie und Geologie (LBEG) sowie am Leibniz Institut für Angewandte Geophysik (LIAG) wurden diese Daten zur Kartierung der Tiefenlage der Süß‑/Salzwassergrenze genutzt. Dadurch ist unter anderem eine detaillierte Karte der Grundwasserversalzung innerhalb der küstennahen Aquifere entlang der niedersächsischen Nordseeküste im Maßstab 1:50.000 entstanden. Diese zeigt den aktuellen Stand der Grundwasserversalzung, abgeleitet aus den gewonnenen Elektromagnetik-Modellen. Die Modelle waren auch Grundlage für eine hydraulische Modellierung der Süßwasserlinse der Nordseeinsel Borkum. Darauf aufbauende Simulationen zeigen die Entwicklung der Grundwassersituation für den Zeitraum bis 2100.
    Description: Landesamt für Bergbau, Energie und Geologie (LBEG) (4273)
    Keywords: ddc:551.49 ; Grundwasserversalzung ; Modellierung ; Aeroelektromagnetik ; Klimawandel ; Süßwasserlinse ; Fresh-saline groundwater Interface ; Climate change ; Airborne electromagnetics ; Freshwater lenses
    Language: German
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  • 4
    Publication Date: 2023-07-29
    Description: Stabilizing agricultural production is fundamental to food security. At the national level, increasing the effective diversity of cultivated crops has been found to increase temporal production stability, i.e., the year-to-year stability of total caloric production of all crops combined. Here, we specifically investigated these effects at the regional level for the European Union and tested the effect of crop diversity in relation to agricultural inputs, soil properties, climate instability, and time on caloric, protein, and fat stability, as we hypothesized that the effect of diversity is context dependent. We further investigated these relationships for specific countries. We found that greater crop diversity was consistently associated with an increase in production stability, particularly in regions with large areas equipped for irrigation and low soil type diversity. For instance, in Spain and Italy, crop diversity showed the strongest positive effect among all predictors, while on the European level, the stabilizing effect of nitrogen use was substantially higher. In Germany, the crop diversity-stability relationship was weak, suggesting that crops react similarly to climatic, economic, and political factors or are grown in the same periods. With this study, we substantiate previous findings that crop diversity stabilizes agricultural caloric production and extend these with regard to protein and fat. The results elucidate the key drivers that enhance production stability for different European countries and regions, which is of key importance for a comparably productive agricultural region like Europe.
    Description: Helmholtz-Gemeinschaft http://dx.doi.org/10.13039/501100001656
    Description: Helmholtz-Zentrum für Umweltforschung GmbH - UFZ (4215)
    Keywords: ddc: ; Agroecology ; Climate change ; Resilience ; Sustainability
    Language: English
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  • 5
    Publication Date: 2023-08-01
    Description: Cereal crop production in sub-Saharan Africa has not achieved the much-needed increase in yields to foster economic development and food security. Maize yields in the region’s semi-arid agroecosystems are constrained by highly variable rainfall, which may be worsened by climate change. Thus, the Tanzanian government has prioritized agriculture as an adaptation sector in its intended nationally determined contribution, and crop management adjustments as a key investment area in its Agricultural Sector Development Programme. In this study, we investigated how future changes in maize yields under different climate scenarios can be countered by regional adjusted crop management and cultivar adaptation strategies. A crop model was used to simulate maize yields in the Singida region of Tanzania for the baseline period 1980–2012 and under three future climate projections for 2020–2060 and 2061–2099. Adaptation strategies to improve yields were full irrigation, deficit irrigation, mulch and nitrogen addition and another cultivar. According to our model results, increase in temperature is the main driver of future maize yield decline. Increased respiration and phenological development were associated with lower maize yields of 16% in 2020–2060 and 20% in 2061–2099 compared to the 1980–2012 baseline. Surprisingly, none of the management strategies significantly improved yields; however, a different maize variety that was tested as an alternative coping strategy performed better. This study suggests that investment in accessibility of improved varieties and investigation of maize traits that have the potential to perform well in a warmer future are better suited for sustaining maize production in the semi-arid region than adjustments in crop management.
    Description: Leibniz Centre for Agricultural Landscape Research (ZALF)
    Description: Universität Hohenheim (3153)
    Keywords: ddc:631 ; Maize ; Climate change ; Adaptation ; Model ; Tanzania ; NDC
    Language: English
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  • 6
    Publication Date: 2023-08-01
    Description: Sao Tome and Principe is a small insular country in the west coast of Central Africa. The small dimensions of the islands and the limited natural resources put these islands under highly vulnerable to climate change. To assess the possible future impacts and risks on their agricultural activities, the high-resolution 4-km downscaled climate change projections using Eta regional climate model are used. A crop risk index (CRI) is proposed to assess the risk of climate change on cocoa (Theobroma cacao L.), pepper (Piper nigrum L. and Piper guinesse L.), taro (Colocasia esculenta (L.) Schott), and maize (Zea mays L.). The index takes into account the vulnerability to climate conditions and the crop yield in the future, and it is classified into very-high, high, moderate, low, and very-low. The climate change projections indicate increase in the risk of taro crop, partly due to thermal stress and partly due to the susceptibility to the leaf blight crop disease in taro. The risk of production of the pepper crop is very-high, mainly due to water stress. In mountain regions, the greater risk is due to the thermal stress caused by low temperatures. The cocoa crop is at risk due to water stress, mainly in the northwestern part of the Sao Tome Island, where major local production occurs. The projection indicates increase of the area with very-high risk to maize crops due to the increase of thermal stress and susceptibility to rust. In addition, in parts of the coastal regions, the risk changed from very-low to high risk, due to the low productivity potential. In general, the risks of the four major crops of Sao Tome and Principe increase in the future climate conditions.
    Description: UNEP, FUNDEP, Sao Tome and Principe National Institute of Meteorology
    Description: CNPq
    Keywords: ddc:631 ; Crop risk index ; Climate change ; Small Islands Developing States ; Eta model ; Agriculture risk assessment
    Language: English
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  • 7
    Publication Date: 2023-08-01
    Description: Changing climate conditions are supposed to have particularly strong impacts on agricultural production in the tropics with strong implications on food security. Ethiopia’s economy is profoundly dominated by agriculture, contributing to around 40% of the gross domestic product. Thereby, Ethiopia is one of the most vulnerable countries to the impact of climate change and has a wide gap in regional climate change impact studies. In this study, we systematically investigate climate change impacts on yields for the Gambella region in Ethiopia, exemplarily for maize. Here, we show how yields change until 2100 for RCPs 2.6, 4.5, and 8.5 from a climate model ensemble under rainfed and irrigated conditions. While rainfed yields decrease by 15% and 14% respectively for RCPs 2.6 and 4.5, yields decrease by up to 32% under RCP 8.5. Except for RCP 8.5, yields are not further decreasing after 2040–2069. We found that temperature increase, changing soil water availability, and atmospheric CO2 concentration have different effects on the simulated yield potential. Our results demonstrate the dominance of heat response under future climate conditions in the tropical Gambella region, contributing to 85% of total yield changes. Accordingly, irrigation will lose effectiveness for increasing yield when temperature becomes the limiting factor. CO2, on the other hand, contributes positively to yield changes by 8.9% for RCP 8.5. For all scenarios, the growing period is shorted due to increasing temperature by up to 29 days for RCP 8.5. Our results suggest that new varieties with higher growing degree days are primarily required to the region for adapting to future climate conditions.
    Description: Ludwig-Maximilians-Universität München (1024)
    Keywords: ddc:631 ; Climate change ; Agriculture ; Regional study ; Crop model
    Language: English
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  • 8
    Publication Date: 2023-08-09
    Description: Salinization of the upper aquifer of the northern Elbe-Weser region almost extends to the surface. Chloride content exceeds 250 mg/l and the groundwater is therefore, according to the German Drinking Water Ordinance, not suitable as drinking water. The chloride content in the aquifer originates from early flooding with seawater which occurred during the Holocene sea level rise. Depth and extent of the salinization were mapped by airborne electromagnetic surveys and validated by groundwater analyses. In the transition zone between the marshlands and geest areas, the fresh-saline groundwater interface falls to a depth of 〉 −175 m NHN. Due to the extensive drainage of the marshlands, seepage of fresh groundwater is impeded. Instead, an upconing of the fresh-saline groundwater interface appears due to an upwardly directed hydraulic gradient. Due to climate change, chloride concentrations will increase along the coastlines. Further inland, a decrease of chloride content in near-surface groundwater will occur.
    Description: Interreg http://dx.doi.org/10.13039/100013276
    Description: Landesamt für Bergbau, Energie und Geologie (LBEG) (4273)
    Keywords: ddc:551.49 ; Fresh-saline groundwater interface ; HEM ; Drainage ; Cl/Br ratio ; Climate change ; Süß‑/Salzwassergrenze ; HEM ; Cl/Br-Verhältnis ; Klimawandel
    Language: English
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  • 9
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    Springer Nature | Springer
    Publication Date: 2024-03-29
    Description: The world is currently undergoing an historic energy transition, driven by increasingly stringent decarbonisation policies and rapid advances in low-carbon technologies. The large-scale shift to low-carbon energy is disrupting the global energy system, impacting whole economies, and changing the political dynamics within and between countries. This open access book, written by leading energy scholars, examines the economic and geopolitical implications of the global energy transition, from both regional and thematic perspectives. The first part of the book addresses the geopolitical implications in the world’s main energy-producing and energy-consuming regions, while the second presents in-depth case studies on selected issues, ranging from the geopolitics of renewable energy, to the mineral foundations of the global energy transformation, to governance issues in connection with the changing global energy order. Given its scope, the book will appeal to researchers in energy, climate change and international relations, as well as to professionals working in the energy industry.
    Keywords: International Relations ; Energy Policy, Economics and Management ; Natural Resource and Energy Economics ; Climate Change/Climate Change Impacts ; Environmental Economics ; Earth System Sciences ; Energy transition geopolitics ; International decarbonisation policies ; Global warming ; Global energy system ; Geopolitics of the global energy transition ; Economic and political impacts of low-carbon technologies ; Power generation mix ; Geopolitical implications of global warming ; Governance of the global energy order ; Open Access ; International relations ; Energy technology & engineering ; Energy industries & utilities ; Environmental economics ; Climate change ; thema EDItEUR::J Society and Social Sciences::JP Politics and government::JPS International relations ; thema EDItEUR::T Technology, Engineering, Agriculture, Industrial processes::TH Energy technology and engineering ; thema EDItEUR::K Economics, Finance, Business and Management::KC Economics::KCV Economics of specific sectors::KCVG Environmental economics ; thema EDItEUR::R Earth Sciences, Geography, Environment, Planning::RN The environment::RNP Pollution and threats to the environment::RNPG Climate change
    Language: English
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  • 10
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    Springer Nature | Springer
    Publication Date: 2021-02-10
    Description: This open access textbook provides a concise introduction to economic approaches and mathematical methods for the study of water allocation and distribution problems. Written in an accessible and straightforward style, it discusses and analyzes central issues in integrated water resource management, water tariffs, water markets, and transboundary water management. By illustrating the interplay between the hydrological cycle and the rules and institutions that govern today’s water allocation policies, the authors develop a modern perspective on water management. Moreover, the book presents an in-depth assessment of the political and ethical dimensions of water management and its institutional embeddedness, by discussing distribution issues and issues of the enforceability of human rights in managing water resources. Given its scope, the book will appeal to advanced undergraduate and graduate students of economics and engineering, as well as practitioners in the water sector, seeking a deeper understanding of economic approaches to the study of water management.
    Keywords: Natural Resource and Energy Economics ; Water Policy/Water Governance/Water Management ; Waste Water Technology / Water Pollution Control / Water Management / Aquatic Pollution ; Environmental Economics ; Water ; Pollution ; Water economics ; Sustainable water management ; Water engineering ; Hydro-economic models ; Affordable water tariffs ; Eco-hydrology ; Human rights to water ; Water recycling ; Open Access book ; Climate change ; Environmental economics ; Environmental management, ; Water supply & treatment ; Energy industries & utilities ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCN Environmental economics ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNF Environmental management ; bic Book Industry Communication::T Technology, engineering, agriculture::TQ Environmental science, engineering & technology::TQS Sanitary & municipal engineering::TQSW Water supply & treatment
    Language: English
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  • 11
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    Springer Nature | Springer
    Publication Date: 2021-02-10
    Description: This open access book provides worldwide examples demonstrating the importance of the interplay between demography and disasters in regions and spatially. It marks an advance in practical and theoretical insights for understanding the role of demography in planning for and mitigating impacts from disasters in developed nations. Both slow onset (like the of loss polar ice from climate change) and sudden disasters (such as cyclones and man-made disasters) have the capacity to fundamentally change the profiles of populations at local and regional levels. Impacts vary according to the type, rapidity and magnitude of the disaster, but also according to the pre-existing population profile and its relationships to the economy and society. In all cases, the key to understanding impacts and avoiding them in the future is to understand the relationships between disasters and population change. In most chapters in this book we compare and contrast studies from at least two cases and summarize their practical and theoretical lessons.
    Keywords: Demography ; Human Geography ; Climate Change ; Statistics for Social Sciences, Humanities, Law ; Population Economics ; Natural Hazards ; Population and Demography ; Environmental Sciences ; Statistics in Social Sciences, Humanities, Law, Education, Behavorial Sciences, Public Policy ; Impact of disasters ; Demograhic change ; Regional effects of disasters ; Population dynamics ; Environmental change ; Open access ; Population & demography ; Human geography ; Climate change ; Social research & statistics ; Political economy ; Natural disasters ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology::JHBD Population & demography ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RG Geography::RGC Human geography ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNP Pollution & threats to the environment::RNPG Climate change ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology::JHBC Social research & statistics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNR Natural disasters
    Language: English
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  • 12
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    Springer Nature | Springer
    Publication Date: 2021-02-10
    Description: This open access book is a result of the Dalhousie-led research project Safe Navigation and Environment Protection, supported by a grant from the Ocean Frontier Institute’s the Canada First Research Excellent Fund (CFREF). The book focuses on Arctic shipping and investigates how ocean change and anthropogenic impacts affect our understanding of risk, policy, management and regulation for safe navigation, environment protection, conflict management between ocean uses, and protection of Indigenous peoples’ interests. A rapidly changing Arctic as a result of climate change and ice loss is rendering the North more accessible, providing new opportunities while producing impacts on the Arctic. The book explores ideas for enhanced governance of Arctic shipping through risk-based planning, marine spatial planning and scaling up shipping standards for safety, environment protection and public health.
    Keywords: Polar Geography ; Climate Change/Climate Change Impacts ; Water Policy/Water Governance/Water Management ; Environmental Management ; Freshwater & Marine Ecology ; Physical Geography ; Earth System Sciences ; Water ; Freshwater and Marine Ecology ; Arctic cruise shipping ; Arctic fisher safety ; Climate change impacts in the Arctic region ; Governance of the Arctic and Northwest Atlantic ; Marine spatial planning ; Northwest Atlantic and Canadian Eastern Arctic Gateway ; Safe navigation and environment protection ; Sea ice in the Arctic ; Search and Rescue (SAR) ; Open Access ; Physical geography & topography ; Climate change ; Environmental management, ; Ecological science, the Biosphere ; Hydrobiology ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RG Geography::RGB Physical geography & topography ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNP Pollution & threats to the environment::RNPG Climate change ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNF Environmental management ; bic Book Industry Communication::P Mathematics & science::PS Biology, life sciences::PSA Life sciences: general issues::PSAF Ecological science, the Biosphere
    Language: English
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  • 13
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    Springer Nature | Springer
    Publication Date: 2021-02-10
    Description: This open access book presents the most current research results and knowledge from five multidisciplinary themes: Vulnerability of Arctic Environments, Vulnerability of Arctic Societies, Local and Traditional Knowledge, Building Long-term Human Capacity, New Markets for the Arctic, including tourism and safety. The themes are those discussed at the first ever UArctic Congress Science Section, St. Petersburg, Russia, September 2016. The book looks at the Arctic from a holistic perspective; how the environment (both marine and terrestrial) and communities can adapt and manage the changes due to climate change. The chapters provide examples of the state-of-the-art research, bringing together both scientific and local knowledge to form a comprehensive and cohesive volume. Except where otherwise noted, this book is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. ; Provides a multidisciplinary view on topical Arctic issues and research Discusses capacity building on different scales Shares knowledge about the northern systems across the Arctic
    Keywords: Environmental Management ; Climate Change/Climate Change Impacts ; Quality of Life Research ; Environment Studies ; Political Economy/Economic Systems ; Earth System Sciences ; Environmental Sciences ; Political Economy and Economic Systems ; Climate change and the Arctic ; Human capacity and knowledge building ; Vulnerability of Arctic environments ; Marine and terrestrial polar landscapes ; Local, indigenous knowledge and tourism ; Open Access ; Environmental management, ; Climate change ; Social & ethical issues ; Society & Social Sciences ; The environment ; Political economy ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNF Environmental management ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNP Pollution & threats to the environment::RNPG Climate change ; bic Book Industry Communication::J Society & social sciences::JF Society & culture: general::JFF Social issues & processes ; bic Book Industry Communication::J Society & social sciences ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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  • 14
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    Springer Nature | Springer
    Publication Date: 2021-02-10
    Description: This open access book discusses the impact of human-induced global climate change on the regional climate and monsoons of the Indian subcontinent, adjoining Indian Ocean and the Himalayas. It documents the regional climate change projections based on the climate models used in the IPCC Fifth Assessment Report (AR5) and climate change modeling studies using the IITM Earth System Model (ESM) and CORDEX South Asia datasets. The IPCC assessment reports, published every 6–7 years, constitute important reference materials for major policy decisions on climate change, adaptation, and mitigation. While the IPCC assessment reports largely provide a global perspective on climate change, the focus on regional climate change aspects is considerably limited. The effects of climate change over the Indian subcontinent involve complex physical processes on different space and time scales, especially given that the mean climate of this region is generally shaped by the Indian monsoon and the unique high-elevation geographical features such as the Himalayas, the Western Ghats, the Tibetan Plateau and the adjoining Indian Ocean, Arabian Sea, and Bay of Bengal. This book also presents policy relevant information based on robust scientific analysis and assessments of the observed and projected future climate change over the Indian region.
    Keywords: Earth System Sciences ; Climate Change/Climate Change Impacts ; Climate Change Management and Policy ; Climatology ; Climate Change ; Environmental Sciences ; Indian Subcontinent ; Indian Ocean ; Himalayas ; Monsoon ; Temperature Changes ; Atmospheric Trace Gases ; Droughts and Floods ; Himalayan Cryosphere ; Open Access ; Earth sciences ; Environmental science, engineering & technology ; Climate change ; The environment ; Meteorology & climatology ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RB Earth sciences ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNP Pollution & threats to the environment::RNPG Climate change ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RND Environmental policy & protocols ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RB Earth sciences::RBP Meteorology & climatology
    Language: English
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  • 15
    Publication Date: 2023-06-21
    Description: North Africa is considered a climate change hot spot. Existing studies either focus on the physical aspects of climate change or discuss the social ones. The present article aims to address this divide by assessing and comparing the climate change vulnerability of Algeria, Egypt, Libya, Morocco, and Tunisia and linking it to its social implications. The vulnerability assessment focuses on climate change exposure, water resources, sensitivity, and adaptive capacity. The results suggest that all countries are exposed to strong temperature increases and a high drought risk under climate change. Algeria is most vulnerable to climate change, mainly due to the country’s high sensitivity. Across North Africa, the combination of climate change and strong population growth is very likely to further aggravate the already scarce water situation. The so-called Arab Spring has shown that social unrest is partly caused by unmet basic needs of the population for food and water. Thus, climate change may become an indirect driver of social instability in North Africa. To mitigate the impact of climate change, it is important to reduce economic and livelihood dependence on rain-fed agriculture, strengthen sustainable land use practices, and increase the adaptive capacity. Further, increased regional cooperation and sub-national vulnerability assessments are needed.
    Description: Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659
    Description: National Geographic Society http://dx.doi.org/10.13039/100006363
    Keywords: ddc:304.28 ; Climate change ; Vulnerability ; Resilience ; Water ; Conflict ; North Africa
    Language: English
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  • 16
    Publication Date: 2023-06-21
    Description: The European CORDEX (EURO-CORDEX) initiative is a large voluntary effort that seeks to advance regional climate and Earth system science in Europe. As part of the World Climate Research Programme (WCRP) - Coordinated Regional Downscaling Experiment (CORDEX), it shares the broader goals of providing a model evaluation and climate projection framework and improving communication with both the General Circulation Model (GCM) and climate data user communities. EURO-CORDEX oversees the design and coordination of ongoing ensembles of regional climate projections of unprecedented size and resolution (0.11° EUR-11 and 0.44° EUR-44 domains). Additionally, the inclusion of empirical-statistical downscaling allows investigation of much larger multi-model ensembles. These complementary approaches provide a foundation for scientific studies within the climate research community and others. The value of the EURO-CORDEX ensemble is shown via numerous peer-reviewed studies and its use in the development of climate services. Evaluations of the EUR-44 and EUR-11 ensembles also show the benefits of higher resolution. However, significant challenges remain. To further advance scientific understanding, two flagship pilot studies (FPS) were initiated. The first investigates local-regional phenomena at convection-permitting scales over central Europe and the Mediterranean in collaboration with the Med-CORDEX community. The second investigates the impacts of land cover changes on European climate across spatial and temporal scales. Over the coming years, the EURO-CORDEX community looks forward to closer collaboration with other communities, new advances, supporting international initiatives such as the IPCC reports, and continuing to provide the basis for research on regional climate impacts and adaptation in Europe.
    Keywords: ddc:551.6 ; EURO-CORDEX ; CORDEX ; Climate change ; Regional climate models ; Regional climate modelling
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  • 17
    Publication Date: 2023-06-23
    Description: Die Ergebnisse regionaler Klimaprojektionen für Deutschland weisen auf eine Zunahme der mittleren Lufttemperatur und eine innerjährliche Verschiebung der Niederschläge – mit feuchteren Wintern und trockeneren Sommern – hin. Darüber hinaus werden sich regional die Häufigkeit, Intensität und Dauer von Hitzewellen, Trockenperioden und Starkregenereignissen weiter erhöhen. Durch diese Veränderungen wird sich auch der Jahresgang der Grundwasserneubildung ändern. Als Folge dessen können sich Änderungen bei den hohen, mittleren und tiefen Grundwasserständen, Grundwasserschwankungsbreiten und dem Grundwasserdargebot ergeben. Aber nicht nur die Ressource Grundwasser wird durch die Folgen des Klimawandels betroffen. Auch die gesamte Infrastruktur – von der Förderung bis zur Verteilungsleitung zum Kunden – kann beeinträchtigt werden. Neben den direkten Einflüssen sind auch indirekte Beeinflussungen durch Kaskadeneffekte – beispielsweise ausgehend vom Energiesektor – möglich. Darum gilt es integrative, ganzheitliche und systemische Lösungen zu erarbeiten, um die Funktionalität der kritischen Infrastruktur dauerhaft auch unter Berücksichtigung der Folgen des Klimawandels gewährleisten zu können.
    Description: Helmholtz-Zentrum Geesthacht - Zentrum für Material- und Küstenforschung GmbH (HZG) (4216)
    Description: Climate change impacts on groundwater use—impacts and action needs
    Keywords: ddc:304.28 ; Klimawandel ; Wasserversorgung ; Kritische Infrastruktur ; Anpassung ; Climate change ; Impacts ; Water supply ; Critical infrastructure ; Adaptation
    Language: German
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  • 18
    Publication Date: 2022-05-25
    Description: © The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Carbon Balance and Management 12 (2017): 10, doi:10.1186/s13021-017-0077-x.
    Description: Determining national carbon stocks is essential in the framework of ongoing climate change mitigation actions. Presently, assessment of carbon stocks in the context of greenhouse gas (GHG)-reporting on a nation-by-nation basis focuses on the terrestrial realm, i.e., carbon held in living plant biomass and soils, and on potential changes in these stocks in response to anthropogenic activities. However, while the ocean and underlying sediments store substantial quantities of carbon, this pool is presently not considered in the context of national inventories. The ongoing disturbances to both terrestrial and marine ecosystems as a consequence of food production, pollution, climate change and other factors, as well as alteration of linkages and C-exchange between continental and oceanic realms, highlight the need for a better understanding of the quantity and vulnerability of carbon stocks in both systems. We present a preliminary comparison of the stocks of organic carbon held in continental margin sediments within the Exclusive Economic Zone of maritime nations with those in their soils. Our study focuses on Namibia, where there is a wealth of marine sediment data, and draws comparisons with sediment data from two other countries with different characteristics, which are Pakistan and the United Kingdom. Results indicate that marine sediment carbon stocks in maritime nations can be similar in magnitude to those of soils. Therefore, if human activities in these areas are managed, carbon stocks in the oceanic realm—particularly over continental margins—could be considered as part of national GHG inventories. This study shows that marine sediment organic carbon stocks can be equal in size or exceed terrestrial carbon stocks of maritime nations. This provides motivation both for improved assessment of sedimentary carbon inventories and for reevaluation of the way that carbon stocks are assessed and valued. The latter carries potential implications for the management of human activities on coastal environments and for their GHG inventories.
    Description: We acknowledge research support from ETH Zurich and the Swiss National Science Foundation.
    Keywords: Carbon stocks ; Sediments ; Oceans ; Climate change ; Exclusive Economic Zone ; Carbon inventory
    Repository Name: Woods Hole Open Access Server
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  • 19
    Publication Date: 2022-05-26
    Description: © The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Ambio 46, Supple. 1 (2017): 160-173, doi:10.1007/s13280-016-0870-x.
    Description: Long-term measurements of ecological effects of warming are often not statistically significant because of annual variability or signal noise. These are reduced in indicators that filter or reduce the noise around the signal and allow effects of climate warming to emerge. In this way, certain indicators act as medium pass filters integrating the signal over years-to-decades. In the Alaskan Arctic, the 25-year record of warming of air temperature revealed no significant trend, yet environmental and ecological changes prove that warming is affecting the ecosystem. The useful indicators are deep permafrost temperatures, vegetation and shrub biomass, satellite measures of canopy reflectance (NDVI), and chemical measures of soil weathering. In contrast, the 18-year record in the Greenland Arctic revealed an extremely high summer air-warming of 1.3°C/decade; the cover of some plant species increased while the cover of others decreased. Useful indicators of change are NDVI and the active layer thickness.
    Description: The Toolik research was supported in part by NSF Grants DEB 0207150, DEB 1026843, ARC 1107701, and ARC 1504006.
    Keywords: Alaska Toolik ; Climate change ; Ecological effects ; Greenland Zackenberg ; Medium pass filter ; Vegetation
    Repository Name: Woods Hole Open Access Server
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  • 20
    Publication Date: 2017-04-04
    Description: The study and management of the groundwater resources of a large, deep, coastal, karstic aquifer represent a very complex hydrogeological problem. Here, this problem is successfully approached by using an equivalent porous continuous medium (EPCM) to represent a karstic Apulian aquifer (southern Italy). This aquifer, which is located on a peninsula and extends to hundreds of metres depth, is the sole local source of high-quality water resources. These resources are at risk due to overexploitation, climate change and seawater intrusion. The model was based on MODFLOW and SEAWAT codes. Piezometric and salinity variations from 1930 to 2060 were simulated under three past scenarios (up to 1999) and three future scenarios that consider climate change, different types of discharge, and changes in sea level and salinity. The model was validated using surveyed piezometric and salinity data. An evident piezometric drop was confirmed for the past period (until 1999); a similar dramatic drop appears to be likely in the future. The lateral intrusion and upconing effects of seawater intrusion were non-negligible in the past and will be considerable in the future. All phenomena considered here, including sea level and sea salinity, showed non-negligible effects on coastal groundwater.
    Description: Published
    Description: 115-128
    Description: 5A. Energia e georisorse
    Description: JCR Journal
    Description: embargoed_20160501
    Keywords: Karstic coastal aquifer ; Numerical modelling ; Seawater intrusion ; Climate change ; 03. Hydrosphere::03.02. Hydrology::03.02.06. Water resources
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 21
    Publication Date: 2022-05-25
    Description: © The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Plant and Soil 356 (2012): 405-417, doi:10.1007/s11104-012-1130-x.
    Description: Soil warming from global climate change could increase decomposition of fine woody debris (FWD), but debris size and quality may mitigate this effect. The goal of this study was to investigate the effect of soil warming on decomposition of fine woody debris of differing size and quality. We placed FWD of two size classes (2 × 20 cm and 4 × 40 cm) and four species (Acer saccharum, Betula lenta, Quercus rubra and Tsuga canadensis) in a soil warming and ambient area at Harvard Forest in central Massachusetts. We collected the debris from each area over two years and measured mass loss and lignin concentration. Warming increased mass loss for all species and size classes (by as much as 30%), but larger debris and debris with higher initial lignin content decomposed slower than smaller debris and debris with lower initial lignin content. Lignin degradation did not follow the same trends as mass loss. Lignin loss from the most lignin-rich species, T. canadensis, was the highest despite the fact that it lost mass the slowest. Our results suggest that soil warming will increase decomposition of FWD in temperate forests. It is imperative that future models and policy efforts account for this potential shift in the carbon storage pool.
    Keywords: Woody debris ; Lignin ; Decomposition ; Soil warming ; Climate change
    Repository Name: Woods Hole Open Access Server
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  • 22
    Publication Date: 2022-05-25
    Description: © The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 2 (2012): 553, doi:10.1038/srep00553.
    Description: Sea surface temperature imagery, satellite altimetry, and a surface drifter track reveal an unusual tilt in the Gulf Stream path that brought the Gulf Stream to 39.9°N near the Middle Atlantic Bight shelfbreak—200 km north of its mean position—in October 2011, while a large meander brought Gulf Stream water within 12 km of the shelfbreak in December 2011. Near-bottom temperature measurements from lobster traps on the outer continental shelf south of New England show distinct warming events (temperature increases exceeding 6°C) in November and December 2011. Moored profiler measurements over the continental slope show high salinities and temperatures, suggesting that the warm water on the continental shelf originated in the Gulf Stream. The combination of unusual water properties over the shelf and slope in late fall and the subsequent mild winter may affect seasonal stratification and habitat selection for marine life over the continental shelf in 2012.
    Description: Profiler data were made available by the Ocean Observatory Initiative (OOI) during the construction phase of the project. The OOI is funded by the National Science Foundation and managed by the Consortium for Ocean Leadership. Drifter data were provided by Tim Shaw and David Calhoun at Cape Fear Community College.GGGwas supported by NSFGrant OCE-1129125. RET was supported by the Postdoctoral Scholar Program at the Woods Hole Oceanographic Institution, with funding provided by the Cooperative Institute for the North Atlantic Region. MA was supported by the Penzance Endowed Fund in Support of Assistant Scientists.
    Keywords: Ecology ; Climate change ; Atmospheric science ; Oceanography
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  • 23
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    Oecologia 122 (2000), S. 11-19 
    ISSN: 1432-1939
    Keywords: Key words Acclimation ; Atmospheric carbon dioxide ; Climate change ; Photosynthesis ; Shade tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  We compared the CO2- and light-dependence of photosynthesis of four tree species (Acer rubrum, Carya glabra, Cercis canadensis, Liquidambar styraciflua) growing in the understory of a loblolly pine plantation under ambient or ambient plus 200 µl l–1 CO2. Naturally-established saplings were fumigated with a free-air CO2 enrichment system. Light-saturated photosynthetic rates were 159–190% greater for Ce. canadensis saplings grown and measured under elevated CO2. This species had the greatest CO2 stimulation of photosynthesis. Photosynthetic rates were only 59% greater for A. rubrum saplings under CO2 enrichment and Ca. glabra and L. styraciflua had intermediate responses. Elevated CO2 stimulated light-saturated photosynthesis more than the apparent quantum yield. The maximum rate of carboxylation of ribulose-1,5-bisphosphate carboxylase, estimated from gas-exchange measurements, was not consistently affected by growth in elevated CO2. However, the maximum electron transport rate estimated from gas- exchange measurements and from chlorophyll fluorescence, when averaged across species and dates, was approximately 10% higher for saplings in elevated CO2. The proportionately greater stimulation of light-saturated photosynthesis than the apparent quantum yield and elevated rates of maximum electron transport suggests that saplings growing under elevated CO2 make more efficient use of sunflecks. The stimulation of light-saturated photosynthesis by CO2 did not appear to correlate with shade-tolerance ranking of the individual species. However, the species with the greatest enhancement of photosynthesis, Ce. canadensis and L. styraciflua, also invested the greatest proportion of soluble protein in Rubisco. Environmental and endogenous factors affecting N partitioning may partially explain interspecific variation in the photosynthetic response to elevated CO2.
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  • 24
    ISSN: 1432-1939
    Keywords: Key words Intraspecific genetic variation ; Photosynthesis ; Frost hardiness ; Climate change ; Growing season
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Geographic patterns of intraspecific variations in traits related to photosynthesis and biomass were examined in two separate common garden experiments using seed collected from 26 Sitka alder (Alnus sinuata Rydb.) and 18 paper birch (Betula papyrifera Marsh.) populations from climatically diverse locations in British Columbia, Canada. Exchange rates of carbon dioxide and water vapour were measured on 2-year-old seedlings to determine the maximum net instantaneous photosynthetic rate, mesophyll conductance, stomatal conductance, and photosynthetic water use efficiency. Height, stem diameter, root and shoot dry mass and fall frost hardiness data were also obtained. Mean population maximum photosynthetic rate ranged from 10.35 to 14.57 µmol CO2 m–2 s–1 in Sitka alder and from 14.76 to 17.55 µmol CO2 m–2 s–1 in paper birch. Based on canonical correlation analyses, populations from locations with colder winters and shorter (but not necessarily cooler) summers had higher maximum photosynthetic rates implying the existence of an inverse relationship between leaf longevity and photosynthetic capacity. Significant canonical variates based on climatic variables derived for the seed collection sites explained 58% and 41% of variation in the rate of photosynthesis in Sitka alder and paper birch, respectively. Since growing season length is reflected in date of frost hardiness development, an intrinsic relationship was found between photosynthetic capacity and the level of fall frost hardiness. The correlation was particularly strong for paper birch (r=–0.77) and less strong for Sitka alder (r=–0.60). Mean population biomass accumulation decreased with increased climate coldness. These patterns may be consequential for evaluation of the impact of climate change and extension of the growing season on plant communities.
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  • 25
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    Regional environmental change 1 (2000), S. 70-77 
    ISSN: 1436-378X
    Keywords: Key words Mountain vegetation ; Climate change ; Schynige Platte ; Switzerland
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract Climate change has in the past led to shifts in vegetation patterns; in a future, warmer climate due to enhanced greenhouse-gas concentrations, vegetation is also likely to be highly responsive to such warming. Mountain regions are considered to be particularly sensitive to such changes. In this paper we present an approach to assess the impact of climate change on long-term vegetation plots at the high-elevation site of the Schynige Platte, 2000 m above sea level, in the Bernese Alps (Switzerland). Records of vegetation spanning the period from 1928 to today at two different sites, each with several plots, were considered. The observed change in the species composition was then related to changes in land use and climate. We used daily values of temperature, snow and precipitation from several high-elevation weather stations to conduct these analyses. The correlation between climate and vegetation patterns revealed that species that prefer low thermal conditions move out of the plots, i.e., their frequency of occurrence is negatively correlated with the average number of degree-days over the last six decades. On the other hand, species with higher thermal demands are seen to be invading the plots, i.e., their frequency of occurrence is positively correlated to the average number of degree-days. Nutrient changes – though independent from climate – also play an important role in the observed shifts in species.
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  • 26
    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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  • 27
    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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  • 28
    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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  • 29
    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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  • 30
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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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  • 31
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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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  • 32
    ISSN: 1432-1254
    Keywords: Key words Flowering ; Phenology ; Climate change ; Temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geography , Physics
    Notes: Abstract  This paper examines the mean flowering times of 11 plant species in the British Isles over a 58-year period, and the flowering times of a further 13 (and leafing time of an additional 1) for a reduced period of 20 years. Timings were compared to Central England temperatures and all 25 phenological events were significantly related (P〈0.001 in all but 1 case) to temperature. These findings are discussed in relation to other published work. The conclusions drawn from this work are that timings of spring and summer species will get progressively earlier as the climate warms, but that the lower limit for a flowering date is probably best determined by examining species phenology at the southern limit of their distribution.
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  • 33
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    International journal of biometeorology 44 (2000), S. 60-66 
    ISSN: 1432-1254
    Keywords: Key words Phenology ; Trends ; Climate change ; Central Europe ; Urban climate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geography , Physics
    Notes: Abstract  In order to examine the impacts of both large-scale and small-scale climate changes (urban climate effect) on the development of plants, long-term observations of four spring phenophases from ten central European regions (Hamburg, Berlin, Cologne, Frankfurt, Munich, Prague, Vienna, Zurich, Basle and Chur) were analysed. The objective of this study was to identify and compare the differences in the starting dates of the pre-spring phenophases, the beginning of flowering of the snowdrop (Galanthus nivalis) and forsythia (Forsythia sp.), and of the full-spring phenophases, the beginning of flowering of the sweet cherry (Prunus avium) and apple (Malus domestica), in urban and rural areas. The results indicate that, despite regional differences, in nearly all cases the species studied flower earlier in urbanised areas than in the corresponding rural areas. The forcing in urban areas was about 4 days for the pre-spring phenophases and about 2 days for the full-spring phenophases. The analysis of trends for the period from 1951 to 1995 showed tendencies towards an earlier flowering in all regions, but only 22% were significant at the 5% level. The trends for the period from 1980 to 1995 were much stronger for all regions and phases: the pre-spring phenophases on average became earlier by 13.9 days/decade in the urban areas and 15.3 days/decade in the rural areas, while the full-spring phenophases were 6.7 days earlier/decade in the urban areas and 9.1 days/decade earlier in the rural areas. Thus rural areas showed a higher trend towards an earlier flowering than did urban areas for the period from 1980 to 1995. However, these trends, especially for the pre-spring phenophases, turned out to be extremely variable.
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  • 34
    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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  • 35
    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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  • 36
    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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  • 37
    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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  • 38
    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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  • 39
    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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  • 40
    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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  • 41
    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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  • 42
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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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  • 43
    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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  • 44
    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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  • 45
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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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  • 46
    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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  • 47
    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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  • 48
    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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  • 49
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    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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  • 50
    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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  • 51
    ISSN: 1573-5052
    Keywords: Artemisia ; Climate change ; Pentaphylloides ; Photosynthesis ; Rocky Mountains ; Subalpine ; Transpiration ; Water potential ; Water use efficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Gas exchange and water relations responses to warming were compared for two shrub species, Artemisia tridentata spp. vaseyana (Asteraceae), a widely distributed evergreen species of the Great Basin and the western slope of the Rocky Mountains, and Pentaphylloides floribunda (Rosaceae), a deciduous shrub limited in distribution to moist, high-elevation meadows. Plants were exposed to an in situ infrared (IR) climate change manipulation at the Rocky Mountain Biological Laboratory, near Crested Butte, CO. Measurements of gas exchange and water relations were made on the two species in July and August, 1993 from plants growing in situ in infrared-heated and control plots. Carbon dioxide uptake, water loss, leaf temperature, water use efficiency, and water potential were compared to test the hypothesis that leaf and soil responses to IR will cause leaf level changes in photosynthesis. Photosynthetic CO2 uptake and water use efficiency increased for A. tridentata (2.9 vs. 1.9 μmol m−2 s−1 and 1.2 vs. 0.7 mmol C/mol H2O) in the heated plots compared to the controls, while water potential was significantly lower in the heated plots (−1.1 vs. −0.5 MPa). The heating treatment decreased rates of photosynthesis for P. floribunda, but not significantly so. For A. tridentata, the results are consistent with the community-level changes observed with heating. Taken together, the evidence suggests that global warming is likely to result in increasing dominance of A. tridentata in subalpine meadow habitat now dominated by forbs.
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  • 52
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    Oecologia 120 (1999), S. 92-101 
    ISSN: 1432-1939
    Keywords: Key wordsEpirrita autumnata ; Lepidoptera: Geometridae ; Betula pubescens ssp. czrepanovii ; Insect outbreaks ; Climate change
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We studied topographical and year-to-year variation in the performance (pupal weights, survival) and larval parasitism of Epirrita autumnata larvae feeding on mountain birch in northernmost Finland in 1993–1996. We found differences in both food plant quality and parasitism between sites ranging from 80 m to 320 m above sea level. Variation in food plant quality had particularly marked effects on larval survival. The advanced phenology of the birches in relation to the start of the larval period reduced pupal weights. Parasitism rates were different between years and between sites. The clearest site differences were in the proportions of different parasitoid species: Eulophus larvarum was most abundant at the lowest-altitude sites, and Cotesia jucunda at the highest. Differences in the performance of E. autumnata were related to temperature conditions: at higher temperatures, survival and the egg production index were lower, and larval parasitism was higher than at lower temperatures. The higher parasitism at higher temperatures was probably due to greater parasitoid activity during warmer days. In the comparison of different sources of spatial and annual variation in the performance of E. autumnata, the most important factor appeared to be egg mortality related to minimum winter temperature, followed by parasitism and, finally, the variation in food plant quality. If, as predicted, the climate gradually warms up, the effects of warmer summers on the outbreaks of E. autumnata suggest a decrease in outbreak intensity.
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  • 53
    ISSN: 1432-1939
    Keywords: Key words Antarctica ; Climate change ; Colobanthus quitensis ; Deschampsia antarctica ; Ozone depletion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Along the west coast of the Antarctic Peninsula springtime ozone depletion events can lead to a two-fold increase in biologically effective UV-B radiation (UV-BBE) and summer air temperatures have risen ≈1.5°C during the past 50 years. We manipulated levels of UV radiation and temperature around Colobanthus quitensis (a cushion-forming plant, Caryophyllaceae) and Deschampsia antarctica (a tussock grass) along the Peninsula near Palmer Station for two field seasons. Ambient levels of UV were manipulated by placing filters that either transmitted UV (filter control), absorbed UV-B (reducing diurnal levels of UV-BBE by about 82%), or absorbed both UV-B and UV-A (reducing UV-BBE and UV-ABE by about 88 and 78%, respectively) on frames over naturally growing plants from November to March. Half the filters of each material completely surrounded the frames and raised diurnal and diel air temperatures around plants by an average of 2.3°C and 1.3°C, respectively. Reducing UV or warming had no effect on leaf concentrations of soluble UV-B absorbing compounds, UV-B absorbing surface waxes or chlorophylls. Warming had few effects on growth of either species over the first season. However, over the second field season warming improved growth of C. quitensis, leading to a 50% increase in leaf production (P 〈 0.10), a 26% increase in shoot production, and a 6% increase in foliar cover. In contrast, warming reduced growth of D. antarctica, leading to a 20% decline in leaf length, a 17% decline in leaf production (P 〈 0.10), and a 5% decline in foliar cover. Warming improved sexual reproduction in both species, primarily through faster development of reproductive structures and greater production of heavier seeds. Over the second field season, the percentage of reproductive structures that had reached the most developed (seed) stage in C. quitensis and D. antarctica was 20% and 15% higher, respectively, under warming. Capsules of C. quitensis produced 45% more seeds under warming and these seeds were 11% heavier. Growth of D. antarctica was improved when UV was reduced and these effects appeared to be cumulative over field seasons. Over the second season, tillers produced 55% more leaves and these leaves were 32% longer when UV-B was reduced. Tillers produced 137% more leaves that were 67% longer when both UV-B and UV-A were reduced. The effects of UV reduction were not as pronounced on C. quitensis, although over the second season cushions tended to be 17% larger and produce 21% more branches when UV-B was reduced, and tended to be 27% larger and produce 38% more branches when both UV-B and UV-A were reduced (P 〈 0.10). Few interactions were found between UV reduction and warming, although in the absence of warming, reducing UV led to slower development of reproductive structures in both species. The effects of warming and UV reduction were species specific and were often cumulative over the two field seasons, emphasizing the importance of long-term field manipulations in predicting the impacts of climate change.
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  • 54
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    International journal of biometeorology 42 (1999), S. 146-152 
    ISSN: 1432-1254
    Keywords: Key words Landscape ecology ; Area-wide management ; Modelling ; Interpolation ; Kriging ; Regression ; Climate change
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geography , Physics
    Notes: Abstract  We simulated male gypsy moth flight phenology for the location of 1371 weather stations east of 100° W longitude and north of 35° N latitude in North America. The output of these simulations, based on average weather conditions from 1961 to 1990, was submitted to two map-interpolation methods: multiple regression and universal kriging. Multiple regression was found to be as accurate as universal kriging and demands less computing power. A map of the date of peak male gypsy moth flight was generated by universal kriging. This map itself constitutes a useful pest-management planning tool; in addition, the map delineates the potential range of the gypsy moth based on its seasonality at the northern edge of its current distribution in eastern North America. The simulation and map-interpolation methods described in this paper thus constitute an interesting approach to the study and monitoring of the ecological impacts of climate change and shifts in land-use patterns at the sub-continental level.
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  • 55
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    International journal of biometeorology 42 (1999), S. 119-123 
    ISSN: 1432-1254
    Keywords: Key words Phenology ; Climate change ; Time series
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geography , Physics
    Notes: Abstract  This study analyzes a long-term phenological time series for the impact assessment of climate changes on Estonian nature and for the methodological study of the possible limitations of using phenological time series for climate trend analyses. These limiting factors can influence the results of studies more than the real impact of climate changes, which may have a much smaller numeric value. The 132-year series of the arrival of the skylark (Alauda arvensis) and the white wagtail (Motacilla alba), the 78-year series of the blossoming of the wood anemone (Anemone nemorosa), the bird cherry (Padus racemosa), apple trees (Malus domestica) and lilacs (Syringa vulgaris), and the 44-year series of the spawning of pike (Esox lucius) and bream (Abramis brama) were studied at three selected observation points in Estonia. The study of the phenological time series shows that Estonian springs have, on the basis of the database, advanced 8 days on average over the last 80-year period; the last 40-year period has warmed even faster.
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  • 56
    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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  • 57
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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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  • 58
    ISSN: 1573-904X
    Keywords: WHI-P180 ; pharmacokinetics ; quinazolines ; mast cell inhibitor
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    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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  • 59
    ISSN: 1573-904X
    Keywords: antisense ; Brown-Norway rat ; oligodeoxynucleotide ; pulmonary delivery ; ISIS 2105 ; pharmacokinetics ; airway inflammation
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    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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  • 60
    ISSN: 1573-904X
    Keywords: diffusion model ; drug delivery system ; ocular penetration ; pharmacokinetics
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    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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  • 61
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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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  • 62
    ISSN: 1573-904X
    Keywords: nonlinear mixed effects modeling (NONMEM) ; pharmacokinetics ; telmisartan ; bioavailability
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    Topics: Chemistry and Pharmacology
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  • 63
    ISSN: 1573-904X
    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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  • 64
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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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    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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  • 66
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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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    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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  • 68
    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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    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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    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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  • 71
    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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  • 72
    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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    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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  • 74
    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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  • 75
    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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  • 76
    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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  • 77
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    Biology and fertility of soils 29 (1999), S. 207-217 
    ISSN: 1432-0789
    Keywords: Key words Acari ; Climate change ; Grassland soils ; Soil microarthropods ; Soil water content
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract  Changes in precipitation and soil water availability predicted to accompany global climate change would impact grasslands, where many ecosystem processes are influenced by water availability. Soil biota, including microarthropods, also are affected by soil water content, although little is known about how climate change might affect their abundance and distribution. The goal of this study was to examine soil microarthropod responses to altered soil water availability in tallgrass prairie ecosystems. Two separate experiments were done. The first utilized control and irrigated plots along a topographic gradient to examine the effects of soil water content on microarthropod densities. Microarthropods, mainly Acari, were significantly less abundant in irrigated plots and were generally less abundant at the wetter lowland sites. The second study utilized reciprocal core transplants across an east-west regional precipitation gradient. Large, intact cores were transplanted between a more mesic tallgrass site (Konza Prairie) and a more arid mixed-grass site (Hays) to determine the effects of different soil water regimes on microarthropod abundance and vertical distribution. Data from non-transplanted cores indicated greater total microarthropod densities at the drier Hays site, relative to the wetter Konza Prairie site. Data from the transplanted cores indicated significant effects of location on Acari densities in cores originating from Hays, with higher densities in cores remaining at Hays, relative to those transplanted to Konza. Acari densities in cores originating from Konza were not affected by location; however, oribatid mite densities generally were greater in cores remaining at Konza Prairie. These results confirm the importance of soil water content in affecting microarthropod densities and distributions in grasslands, and suggest complex, non-linear responses to changes in water availability.
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  • 78
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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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  • 79
    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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  • 80
    ISSN: 1617-6278
    Keywords: Pollen analysis ; Holocene ; Climate change ; Pinus sylvestris ; Steppe belt ; Southern Russia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Archaeology , Biology
    Notes: Abstract Two14C-dated pollen profiles from mires in the steppe belt of southern Russia are presented. On the basis of these and data from earlier investigations, the Holocene forest history of the southern part of Russia and Ukraine is reconstructed. The steppe belt is very sensitive to climatic oscillations and, in particular, to changes in evapotranspiration. The most favourable climate occurred between 6000 and 4500 B.P. (6800–5200 cal. B.P.), when forest attained its maximum extent in the steppe belt. The period 4500–3500 B.P. (5200–3800 cal. B.P.) was characterised by drier climate with the most arid phase occurring between 4200–3700 B.P. (4700–4000 cal. B.P.). During arid phases, the area under forest and also peat accumulation rates declined. Subsequently, a number of less pronounced climatic oscillations occurred such as in the period 3400/3300−2800 B.P. (3600/3500−2900 cal. B.P.) when there was a return to more humid conditions. During the last 2500 years, the vegetation cover of the steppe belt in southern Russia and Ukraine took on its present-day aspect. On the one hand, there is close correlation between the Holocene vegetation history of southern Russia and Ukraine and, on the other hand, the steppe belt of Kazakhstan and transgressions in the Caspian sea. Human impact on the natural vegetation became important from the Bronze Age onwards (after 4500 B.P.; 5200 cal. B.P.). Particular attention is given to the history of Scots pine (Pinus sylvestris), which had a much wider distribution in the southern part of eastern Europe in the early Holocene. The reduction in range during recent millennia has come about as a result of the combined effects of both climatic deterioration and increased human impact.
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  • 81
    ISSN: 1617-6278
    Keywords: Vegetation dynamics ; Palynology ; Macroremains ; Plant diversity ; Laminated sediments ; Climate change ; Switzerland
    Source: Springer Online Journal Archives 1860-2000
    Topics: Archaeology , Biology
    Notes: Abstract The palynostratigraphy of two sediment cores from Soppensee, Central Switzerland (596 m asl) was correlated with nine regional pollen assemblage zones defined for the Swiss Plateau. This biostratigraphy shows that the sedimentary record of Soppensee includes the last 15 000 years, i.e. the entire Late-glacial and Holocene environmental history. The vegetation history of the Soppensee catchment was inferred by pollen and plant-macrofossil analyses on three different cores taken in the deepest part of the lake basin (27 m). On the basis of a high-resolution varve and calibrated radiocarbonchronology it was possible to estimate pollen accumulation rates, which together with the pollen percentage data, formed the basis for the interpretation of the past vegetation dynamics. The basal sediment dates back to the last glacial. After reforestation with juniper and birch at ca. 12 700 B.P., the vegetation changed at around 12 000 B.P. to a pine-birch woodland and at the onset of the Holocene to a mixed deciduous forest. At ca. 7000 B.P., fir expanded and dominated the vegetation with beech becoming predominant at ca. 50014C-years later until sometime during the Iron Age. Large-scale deforestation, especially during the Middle Ages, altered the vegetation cover drastically. During the Late-glacial period two distinct regressive phases in vegetation development are demonstrated, namely, the Aegelsee oscillation (equivalent to the Older Dryas biozone) and the Younger Dryas biozone. No unambiguous evidence for Holocene climatic change was detected at Soppensee. Human presence is indicated by early cereal pollen and distinct pulses of forest clearance as a result of human activity can be observed from the Neolithic period onwards.
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  • 82
    ISSN: 1573-0646
    Keywords: docetaxel ; plasma assay ; clinical trials ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    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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  • 83
    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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  • 84
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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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  • 85
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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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  • 86
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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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  • 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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    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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  • 89
    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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  • 90
    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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  • 91
    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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  • 92
    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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  • 93
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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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  • 94
    ISSN: 1573-5052
    Keywords: Climate change ; Life-history traits ; Plant succession ; Seedling recruitment ; Warming ; Water relations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract This study investigates the effects of field manipulations of local climate to determine the potential impact of climate change on plant community dynamics in a calcareous grassland. The experimental site is located in a grassland at the Wytham estate, Oxfordshire, UK. The one hectare study area is within a 10 ha abandoned arable field on Jurassic corallian limestone. Two climate change scenarios were used: warmer winters with increased summer rainfall and warmer winters with summer drought. Plant cover and species richness were significantly increased in plots receiving supplemented summer rainfall, while the amount of litter was significantly reduced. Litter formation was significantly increased by winter warming and drought. The responses of the plant community to the climate manipulations were related to the life-history attributes of the dominant species. Seedling recruitment was limited by microsite availability, which also varied in the different climate manipulations. The results are discussed in terms of successional dynamics. They suggest that warmer winters may delay succession, as gap formation in the sward will provide sites for colonisation of annuals, thereby enabling their persistence in the sward. Under wetter conditions during summer, perennial grasses tend to close the sward, thereby inhibiting the establishment of later successional species.
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  • 95
    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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  • 96
    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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  • 97
    ISSN: 1432-1939
    Keywords: Key wordsBetula ; Carbon dioxide ; Climate change ; heat stress ; Freezing stress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Despite predictions that both atmospheric CO2 concentrations and air temperature will rise together, very limited data are currently available to assess the possible interactive effects of these two global change factors on temperate forest tree species. Using yellow birch (Betula alleghaniensis) as a model species, we studied how elevated CO2 (800 vs. 400 μl l−1) influences seedling growth and physiological responses to a 5°C increase in summer air temperatures (31/26 vs. 26/21°C day/night), and how both elevated CO2 and air temperature during the growing season influence seedling ability to survive freezing stress during the winter dormant season. Our results show that while increased temperature decreases seedling growth, temperature-induced growth reductions are significantly lower at elevated CO2 concentrations (43% vs. 73%). The amelioration of high-temperature stress was related to CO2-induced reductions in both whole-shoot dark respiration and transpiration. Our results also show that increased summer air temperature, and to a lesser degree CO2 concentration, make dormant winter buds less susceptible to freezing stress. We show the relevance of these results to models used to predict how climate change will influence future forest species distribution and productivity, without considering the direct or interactive effects of CO2.
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  • 98
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    Oecologia 117 (1998), S. 469-475 
    ISSN: 1432-1939
    Keywords: Key words Common toad ; Winter temperatures ; Daylength ; Breeding migration ; Climate change
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A 19-year study of a common toad population in south Dorset, UK, was carried out between 1980 and 1998. The daily arrival of sexually mature male and female toads at a breeding pond was recorded each year. The timing of the main arrival of toads at the breeding pond was highly correlated with the mean daily temperatures over the 40 days immediately preceding the main arrival. When the temperatures were higher than average, breeding occurred significantly earlier in the year than if they were either average or lower than average. During the study, the toad breeding seasons were early (2–13 February) in 5 years (1989, 1990, 1993, 1995, 1998), late (16–23 March) in 2 years (1986, 1996) and average (25 February–8 March) during the remaining 12 years. Evidence was found suggesting that common toads have a daylength threshold of about 9 h, below which the migration to the breeding pond does not occur. Evidence was also found indicating that common toads in southern England have a threshold temperature for activity of about 6°C and that the onset of breeding activity is highly correlated with the number of days during the 40 days prior to the main arrival at the breeding pond that were at or above this temperature. Predicting the start of the main breeding migration to a pond in any year may be possible by comparing the pattern of the 40-day running mean daily temperatures from 21 December the preceding year with those from previous years when the start of breeding activity is known. Although all five of the earliest recorded toad breeding years occurred during the last 10 years, and were associated with the occurrence of particularly mild winters, a significant trend towards earlier breeding in recent years compared with previous years was not found.
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  • 99
    ISSN: 1432-1939
    Keywords: Key words Photosynthesis ; C4 ; Climate change ; CO2 ; Grassland
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract C4 photosynthetic physiologies exhibit fundamentally different responses to temperature and atmospheric CO2 partial pressures (pCO2) compared to the evolutionarily more primitive C3 type. All else being equal, C4 plants tend to be favored over C3 plants in warm humid climates and, conversely, C3 plants tend to be favored over C4 plants in cool climates. Empirical observations supported by a photosynthesis model predict the existence of a climatological crossover temperature above which C4 species have a carbon gain advantage and below which C3 species are favored. Model calculations and analysis of current plant distribution suggest that this pCO2-dependent crossover temperature is approximated by a mean temperature of 22°C for the warmest month at the current pCO2 (35 Pa). In addition to favorable temperatures, C4 plants require sufficient precipitation during the warm growing season. C4 plants which are predominantly graminoids of short stature can be competitively excluded by trees (nearly all C3 plants) – regardless of the photosynthetic superiority of the C4 pathway – in regions otherwise favorable for C4. To construct global maps of the distribution of C4 grasses for current, past and future climate scenarios, we make use of climatological data sets which provide estimates of the mean monthly temperature to classify the globe into areas which should favor C4 photosynthesis during at least 1 month of the year. This area is further screened by excluding areas where precipitation is 〈25 mm per month during the warm season and by selecting areas classified as grasslands (i.e., excluding areas dominated by woody vegetation) according to a global vegetation map. Using this approach, grasslands of the world are designated as C3, C4, and mixed under current climate and pCO2. Published floristic studies were used to test the accuracy of these predictions in many regions of the world, and agreement with observations was generally good. We then make use of this protocol to examine changes in the global abundance of C4 grasses in the past and the future using plausible estimates for the climates and pCO2. When pCO2 is lowered to pre-industrial levels, C4 grasses expanded their range into large areas now classified as C3 grasslands, especially in North America and Eurasia. During the last glacial maximum (∼18 ka BP) when the climate was cooler and pCO2 was about 20 Pa, our analysis predicts substantial expansion of C4 vegetation – particularly in Asia, despite cooler temperatures. Continued use of fossil fuels is expected to result in double the current pCO2 by sometime in the next century, with some associated climate warming. Our analysis predicts a substantial reduction in the area of C4 grasses under these conditions. These reductions from the past and into the future are based on greater stimulation of C3 photosynthetic efficiency by higher pCO2 than inhibition by higher temperatures. The predictions are testable through large-scale controlled growth studies and analysis of stable isotopes and other data from regions where large changes are predicted to have occurred.
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  • 100
    ISSN: 0931-1890
    Keywords: Key words Aleppo pine ; Climate change ; Water stress ; Cavitation ; Transpiration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract  The present study was carried out to elucidate the response mechanisms of 50-year-old Pinus halepensis Mill. trees to a long-term and severe drought. The amount of water available to trees was artificially restricted for 12 months by covering the soil with a plastic roof. Over the short term a direct and rapid impact of drought was evident on the water relations and gas exchanges of trees: as the soil dried out in the Spring, there was a concurrent decrease of predawn water potential; transpiration was strongly reduced by stomatal closure. Seasonal changes in the water volume fractions of twig and stem xylem were observed and interpreted as the result of cavitation and refilling in the xylem. When droughted trees recovered to a more favourable water status, refilling of embolized xylem was observed; twig predawn water potentials were still negative in the period when the embolism was reversed in the twig xylem. A few months after the removal of the covering, no differences in whole plant hydraulic resistance were observed between droughted and control trees. Needle and shoot elongation and stem radial growth were considerably reduced in droughted trees; no strategy of trees to allocate carbon preferentially to the stem conducting tissues was apparent throughout the experiment. An after-effect of the drought on growth was observed.
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