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Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders

Hovd, Markus Herberg; Mariussen, Espen; Uggerud, Hilde Thelle; Lashkarivand, Aslan; Christensen, Hege; Ringstad, Geir; Eide, Per Kristian

Background
Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol (Gadovist, Bayer Pharma AG, GE). For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases.

Methods
Gadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in patients with different cerebrospinal fluid disorders, i.e. symptomatic pineal and arachnoid cysts, as well as tentative spontaneous intracranial hypotension due to cerebrospinal fluid leakage, idiopathic intracranial hypertension, or different types of hydrocephalus (idiopathic normal pressure hydrocephalus, communicating- and non-communicating hydrocephalus). Individuals with no verified cerebrospinal fluid disturbance at clinical work-up were denoted references.

Results
Population pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life (time to 50% of tracer absorbed from cerebrospinal fluid to blood), time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles.

Conclusions
The present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs.

2022

Population exposure calculations using air quality management systems. EUR 21052 EN

Larssen, S.; Laupsa, H.; Slørdal, L. H.

2004

Popular dissemination of the COPOL project - lessons learned. NILU F

Ruus, A.; Gabrielsen, G.W.; Evenset, A.; Christensen, G.; Heimstad, E.S.; Øverjordet, I.B.

2010

POPs in humans.

Hanssen, L.

2016

POP's in krill from Antarctica. Report APN-430.1876

Carroll, J.L.; Götsch, A.; Evenset, A.; Berger, U.; Herzke, D.

2005

POP-monitoring in Europe. NILU F

Berg, T.

2001

POP model intercomparison study. Stage II. Comparison of mass balance estimates and sensitivity studies. DRAFT. EMEP/MSC-E Technical Report, 4/2005

Shatalov, V.; Mantseva, E.; Baart, A.; Bartlett, P.; Breivik, K.; Christensen, J.; Dutchak, S.; Gong, S.; Gusev, A.; Hansen, K.M.; Hollander, A.; Huang, P.; Hungerbuhler, K.; Jones, K.; Petersen, G.; Roemer, M.; Scheringer, M.; Stocker, J.; Suzuki, N.; Sweetman, A.; van de Meent, D.; Wegmann, F.

2005

POP model intercomparison study. Stage II. Comparison of mass balance estimates and sensitivity studies. EMEP/MSC-E Technical Report, 5/2006

Shatalov, V.; Mantseva, E.; Baart, A.; Bartlett, P.; Breivik, K.; Christensen, J.; Dutchak, S.; Gong, S.; Gusev, A.; Hansen, K.M.; Hollander, A.; Huang, P.; Hungerbuhler, K.; Jones, K.; Petersen, G.; Roemer, M.; Scheringer, M.; Stocker, J.; Suzuki, N.; Sweetman, A.; van de Meent, D.; Wegmann, F.

2006

POP model intercomparison study. Stage 1. Comparison of descriptions of main processes determining POP behaviour in various environmental compartments. EMEP MSC-E Technical Report, 1/2004

Shatalov, V.; Mantseva, E.; Baart, A.; Bartlett, P.; Breivik, K.; Christensen, J.; Dutchak, S.; Kallweit, D.; Farret, R.; Fedyunin, M.; Gong, S.; Hansen, K.M.; Holoubek, I.; Huang, P.; Jones, K.; Matthies, M.; Petersen, G.; Prevedouros, K.; Pudykiewicz, J.; Roemer, M.; Salzmann, M.; Scheringer, M.; Stocker, J.; Strukov, B.; Suzuki, N.; Sweetman, A.; van de Meent, D.; Wegmann, F.

2004

POP emission inventories on different scales and their future trends.

Theloke, J.; Breivik, K.; van der Gon, H.D.; Kugler, U.; Li, Y-F.; Pacyna, J.; Panasiuk, D.; Sundseth, K.; Sweetman, A.; Tao, S.

2010

Polyklorerte alkaner (PCA) i innlandsfisk. NILU F

Borgen, A.R.; Schlabach, M.; Fjeld, E.; Knutzen, J.

2001

Polycyclic Aromatic Hydrocarbons Not Declining in Arctic Air Despite Global Emission Reduction

Yu, Yong; Katsoyiannis, Athanasios A.; Bohlin-Nizzetto, Pernilla; Brorström-Lundén, Eva; Ma, Jianmin; Zhao, Yuan; Wu, Zhiyong; Tych, Wlodzimierz; Mindham, David; Sverko, Ed; Barresi, Enzo; Dryfhout-Clark, Helena; Fellin, Phil; Hung, Hayley

Two decades of atmospheric measurements of polycyclic aromatic hydrocarbons (PAHs) were conducted at three Arctic sites, i.e., Alert, Canada; Zeppelin, Svalbard; and Pallas, Finland. PAH concentrations decrease with increasing latitude in the order of Pallas > Zeppelin > Alert. Forest fire was identified as an important contributing source. Three representative PAHs, phenanthrene (PHE), pyrene (PYR), and benzo[a]pyrene (BaP) were selected for the assessment of their long-term trends. Significant decline of these PAHs was not observed contradicting the expected decline due to PAH emission reductions. A global 3-D transport model was employed to simulate the concentrations of these three PAHs at the three sites. The model predicted that warming in the Arctic would cause the air concentrations of PHE and PYR to increase in the Arctic atmosphere, while that of BaP, which tends to be particle-bound, is less affected by temperature. The expected decline due to the reduction of global PAH emissions is offset by the increment of volatilization caused by warming. This work shows that this phenomenon may affect the environmental occurrence of other anthropogenic substances, such as more volatile flame retardants and pesticides.

2019

Polycyclic aromatic hydrocarbons (PAHs), oxy- and nitro-PAHs in ambient air of the Arctic town Longyearbyen, Svalbard

Drotikova, Titiana; Ali, Aasim Musa Mohamed; Halse, Anne Karine; Reinardy, Helena; Kallenborn, Roland

Polycyclic aromatic hydrocarbons (PAHs) are not
declining in Arctic air despite reductions in their global emissions.
In Svalbard, the Longyearbyen coal-fired power plant
is considered to be one of the major local sources of PAHs.
Power plant stack emissions and ambient air samples, collected
simultaneously at 1 km (UNIS) and 6 km (Adventdalen)
transect distance, were analysed (gaseous and particulate
phases separately) for 22 nitro-PAHs, 8 oxy-PAHs,
and 16 parent PAHs by gas chromatography in combination
with single quadrupole electron capture negative ionization
mass spectrometry (GC-ECNI-MS) and gas chromatography
in combination with triple quadrupole electron ionization
mass spectrometry (GC-EI-MS/MS). Results confirm low
levels of PAH emissions (Sum 16 PAHs D 1:5 μg/kg coal)
from the power plant. Phenanthrene, 9,10-anthraquinone, 9-
fluorenone, fluorene, fluoranthene, and pyrene accounted for
85% of the plant emission (not including naphthalene). A dilution
effect was observed for the transect ambient air samples:
1.26+/- 0.16 and 0.63+/- 0.14 ng/m3 were the sum of all
47 PAH derivatives for UNIS and Adventdalen, respectively.
The PAH profile was homogeneous for these recipient stations
with phenanthrene and 9-fluorenone being most abundant.
Multivariate statistical analysis confirmed coal combustion
and vehicle and marine traffic as the predominant
sources of PAHs. Secondary atmospheric formation of 9-
nitroanthracene and 2C3-nitrofluoranthene was evaluated
and concluded. PAHs partitioning between gaseous and particulate
phases showed a strong dependence on ambient temperatures
and humidity. The present study contributes important
data which can be utilized to eliminate uncertainties in
model predictions that aim to assess the extent and impacts
of Arctic atmospheric contaminants.

2020

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