Publications by authors named "Rob A Voskuyl"

35 Publications

Impaired θ-γ Coupling Indicates Inhibitory Dysfunction and Seizure Risk in a Dravet Syndrome Mouse Model.

J Neurosci 2021 01 24;41(3):524-537. Epub 2020 Nov 24.

Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied θ-γ coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical θ-γ coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. θ-γ Coupling was partly restored by cannabidiol (CBD). Locally disrupting Na1.1 expression in the hippocampus or cortex yielded early attenuation of θ-γ coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated θ-γ coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.
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http://dx.doi.org/10.1523/JNEUROSCI.2132-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821857PMC
January 2021

Apnea Associated with Brainstem Seizures in Mice Is Caused by Medullary Spreading Depolarization.

J Neurosci 2019 11 18;39(48):9633-9644. Epub 2019 Oct 18.

Departments of Human Genetics,

Seizure-related apnea is common and can be lethal. Its mechanisms however remain unclear and preventive strategies are lacking. We postulate that brainstem spreading depolarization (SD), previously associated with lethal seizures in animal models, initiates apnea upon invasion of brainstem respiratory centers. To study this, we assessed effects of brainstem seizures on brainstem function and respiration in male and female mice carrying a homozygous S218L missense mutation that leads to gain-of-function of voltage-gated Ca2.1 Ca channels and high risk for fatal seizures. Recordings of brainstem DC potential and neuronal activity, cardiorespiratory activity and local tissue oxygen were performed in freely behaving animals. Brainstem SD occurred during all spontaneous fatal seizures and, unexpectedly, during a subset of nonfatal seizures. Seizure-related SDs in the ventrolateral medulla correlated with respiratory suppression. Seizures induced by stimulation of the inferior colliculus could evoke SD that spread in a rostrocaudal direction, preceding local tissue hypoxia and apnea, indicating that invasion of SD into medullary respiratory centers initiated apnea and hypoxia rather than Fatal outcome was prevented by timely resuscitation. Moreover, NMDA receptor antagonists MK-801 and memantine prevented seizure-related SD and apnea, which supports brainstem SD as a prerequisite for brainstem seizure-related apnea in this animal model and has translational value for developing strategies that prevent fatal ictal apnea. Apnea during and following seizures is common, but also likely implicated in sudden unexpected death in epilepsy (SUDEP). This underlines the need to understand mechanisms for potentially lethal seizure-related apnea. In the present work we show, in freely behaving SUDEP-prone transgenic mice, that apnea is induced when spontaneous brainstem seizure-related spreading depolarization (SD) reaches respiratory nuclei in the ventrolateral medulla. We show that brainstem seizure-related medullary SD is followed by local hypoxia and recovers during nonfatal seizures, but not during fatal events. NMDA receptor antagonists prevented medullary SD and apnea, which may be of translational value.
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http://dx.doi.org/10.1523/JNEUROSCI.1713-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880468PMC
November 2019

Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice.

Brain 2019 02;142(2):412-425

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy in which brainstem spreading depolarization may play a pivotal role, as suggested by animal studies. However, patiotemporal details of spreading depolarization occurring in relation to fatal seizures have not been investigated. In addition, little is known about behavioural and neurophysiological features that may discriminate spontaneous fatal from non-fatal seizures. Transgenic mice carrying the missense mutation S218L in the α1A subunit of Cav2.1 (P/Q-type) Ca2+ channels exhibit enhanced excitatory neurotransmission and increased susceptibility to spreading depolarization. Homozygous Cacna1aS218L mice show spontaneous non-fatal and fatal seizures, occurring throughout life, resulting in reduced life expectancy. To identify characteristics of fatal and non-fatal spontaneous seizures, we compared behavioural and electrophysiological seizure dynamics in freely-behaving homozygous Cacna1aS218L mice. To gain insight on the role of brainstem spreading depolarization in SUDEP, we studied the spatiotemporal distribution of spreading depolarization in the context of seizure-related death. Spontaneous and electrically-induced seizures were investigated by video monitoring and electrophysiological recordings in freely-behaving Cacna1aS218L and wild-type mice. Homozygous Cacna1aS218L mice showed multiple spontaneous tonic-clonic seizures and died from SUDEP in adulthood. Death was preceded by a tonic-clonic seizure terminating with hindlimb clonus, with suppression of cortical neuronal activity during and after the seizure. Induced seizures in freely-behaving homozygous Cacna1aS218L mice were followed by multiple spreading depolarizations and death. In wild-type or heterozygous Cacna1aS218L mice, induced seizures and spreading depolarization were never followed by death. To identify temporal and regional features of seizure-induced spreading depolarization related to fatal outcome, diffusion-weighted MRI was performed in anaesthetized homozygous Cacna1aS218L and wild-type mice. In homozygous Cacna1aS218L mice, appearance of seizure-related spreading depolarization in the brainstem correlated with respiratory arrest that was followed by cardiac arrest and death. Recordings in freely-behaving homozygous Cacna1aS218L mice confirmed brainstem spreading depolarization during spontaneous fatal seizures. These data underscore the value of the homozygous Cacna1aS218L mouse model for identifying discriminative features of fatal compared to non-fatal seizures, and support a key role for cortical neuronal suppression and brainstem spreading depolarization in SUDEP pathophysiology.
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http://dx.doi.org/10.1093/brain/awy325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351775PMC
February 2019

Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression.

EJNMMI Radiopharm Chem 2018 Dec 21;3:11. Epub 2018 Sep 21.

1Department of Radiology & Nuclear Medicine, VU University Medical Center, P.O. box 7057, 1007 MB Amsterdam, The Netherlands.

Background: Several P-glycoprotein (P-gp) substrate tracers are available to assess P-gp function in vivo, but attempts to develop a tracer for measuring expression levels of P-gp have not been successful. Recently, (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)--(4-methoxyphenyl)hydrazine-carbothioamide was described as a potential selective P-gp inhibitor that is not transported by P-gp. Therefore, the purpose of this study was to radiolabel two of its analogues and to assess their potential for imaging P-gp expression using PET.

Results: [F]2-(4-fluoro-2-oxoindolin-3-ylidene)--(4-methoxyphenyl)hydrazine-carbothioamide ([F]) and [F]2-(6-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([F]) were synthesized and both their biodistribution and metabolism were evaluated in rats. In addition, PET scans were acquired in rats before and after tariquidar (P-gp inhibitor) administration as well as in P-gp knockout (KO) mice.Both [F] and [F] were synthesized in 2-3% overall yield, and showed high brain uptake in ex vivo biodistribution studies. [F] appeared to be metabolically unstable in vivo, while [F] showed moderate stability with limited uptake of radiolabelled metabolites in the brain. PET studies showed that transport of [F] across the blood-brain barrier was not altered by pre-treatment with the P-gp inhibitor tariquidar, and uptake was significantly lower in P-gp KO than in wild-type animals and indeed transported across the BBB or bound to P-gp in endothelial cells.

Conclusion: In conclusion, [F] and [F] were successfully and reproducibly synthesized, albeit with low radiochemical yields. [F] appears to be a radiotracer that binds to P-gp, as showed in P-gp knock-out animals, but is not a substrate for P-gp.
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http://dx.doi.org/10.1186/s41181-018-0046-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150866PMC
December 2018

Biomarkers in epilepsy-A modelling perspective.

Eur J Pharm Sci 2017 Nov 17;109S:S47-S52. Epub 2017 May 17.

Division of Pharmacology, Leiden Academic Centre for Drug Research, The Netherlands.

Biomarkers can be categorised from type 0 (genotype or phenotype), through 6 (clinical scales), each level representing a part of the processes involved in the biological system and drug treatment. This classification facilitates the identification and connection of information required to fully (mathematically) model a disease and its treatment using integrated information from biomarkers. Two recent reviews thoroughly discussed the current status and development of biomarkers for epilepsy, but a path towards the integration of such biomarkers for the personalisation of anti-epileptic drug treatment is lacking. Here we aim to 1) briefly categorise the available epilepsy biomarkers and identify gaps, and 2) provide a modelling perspective on approaches to fill such gaps. There is mainly a lack of biomarker types 2 (target occupancy) and 3 (target activation). Current literature typically focuses on qualitative biomarkers for diagnosis and prediction of treatment response or failure, leaving a need for biomarkers that help to quantitatively understand the overall system to explain and predict differences in disease and treatment outcome. Due to the complexity of epilepsy, filling the biomarker gaps will require collaboration and expertise from the fields of systems biology and systems pharmacology.
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http://dx.doi.org/10.1016/j.ejps.2017.05.035DOI Listing
November 2017

Parametric Methods for Dynamic C-Phenytoin PET Studies.

J Nucl Med 2017 03 22;58(3):479-483. Epub 2016 Sep 22.

Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.

In this study, the performance of various methods for generating quantitative parametric images of dynamic C-phenytoin PET studies was evaluated. Double-baseline 60-min dynamic C-phenytoin PET studies, including online arterial sampling, were acquired for 6 healthy subjects. Parametric images were generated using Logan plot analysis, a basis function method, and spectral analysis. Parametric distribution volume (V) and influx rate () were compared with those obtained from nonlinear regression analysis of time-activity curves. In addition, global and regional test-retest (TRT) variability was determined for parametric and V values. Biases in V observed with all parametric methods were less than 5%. For , spectral analysis showed a negative bias of 16%. The mean TRT variabilities of V and were less than 10% for all methods. Shortening the scan duration to 45 min provided similar V and with comparable TRT performance compared with 60-min data. Among the various parametric methods tested, the basis function method provided parametric V and values with the least bias compared with nonlinear regression data and showed TRT variabilities lower than 5%, also for smaller volume-of-interest sizes (i.e., higher noise levels) and shorter scan duration.
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http://dx.doi.org/10.2967/jnumed.116.178707DOI Listing
March 2017

Multi-omics profile of the mouse dentate gyrus after kainic acid-induced status epilepticus.

Sci Data 2016 Aug 16;3:160068. Epub 2016 Aug 16.

Neuroscience Program, Swammerdam Institute for Life Sciences, Faculty of Sciences, University of Amsterdam, Science Park 904, Amsterdam 1098XH, The Netherlands.

Temporal lobe epilepsy (TLE) can develop from alterations in hippocampal structure and circuit characteristics, and can be modeled in mice by administration of kainic acid (KA). Adult neurogenesis in the dentate gyrus (DG) contributes to hippocampal functions and has been reported to contribute to the development of TLE. Some of the phenotypical changes include neural stem and precursor cells (NPSC) apoptosis, shortly after their birth, before they produce hippocampal neurons. Here we explored these early phenotypical changes in the DG 3 days after a systemic injection of KA inducing status epilepticus (KA-SE), in mice. We performed a multi-omics experimental setup and analyzed DG tissue samples using proteomics, transcriptomics and microRNA profiling techniques, detecting the expression of 2327 proteins, 13401 mRNAs and 311 microRNAs. We here present a description of how these data were obtained and make them available for further analysis and validation. Our data may help to further identify and characterize molecular mechanisms involved in the alterations induced shortly after KA-SE in the mouse DG.
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http://dx.doi.org/10.1038/sdata.2016.68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986542PMC
August 2016

Optogenetic induction of cortical spreading depression in anesthetized and freely behaving mice.

J Cereb Blood Flow Metab 2017 May 1;37(5):1641-1655. Epub 2016 Jan 1.

1 Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Cortical spreading depression, which plays an important role in multiple neurological disorders, has been studied primarily with experimental models that use highly invasive methods. We developed a relatively non-invasive optogenetic model to induce cortical spreading depression by transcranial stimulation of channelrhodopsin-2 ion channels expressed in cortical layer 5 neurons. Light-evoked cortical spreading depression in anesthetized and freely behaving mice was studied with intracortical DC-potentials, multi-unit activity and/or non-invasive laser Doppler flowmetry, and optical intrinsic signal imaging. In anesthetized mice, cortical spreading depression induction thresholds and propagation rates were similar for invasive (DC-potential) and non-invasive (laser Doppler flowmetry) recording paradigms. Cortical spreading depression-related vascular and parenchymal optical intrinsic signal changes were similar to those evoked with KCl. In freely behaving mice, DC-potential and multi-unit activity recordings combined with laser Doppler flowmetry revealed cortical spreading depression characteristics comparable to those under anesthesia, except for a shorter cortical spreading depression duration. Cortical spreading depression resulted in a short increase followed by prolonged reduction of spontaneous active behavior. Motor function, as assessed by wire grip tests, was transiently and unilaterally suppressed following a cortical spreading depression. Optogenetic cortical spreading depression induction has significant advantages over current models in that multiple cortical spreading depression events can be elicited in a non-invasive and cell type-selective fashion.
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http://dx.doi.org/10.1177/0271678X16645113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435281PMC
May 2017

Altered GABAA receptor density and unaltered blood-brain barrier [11C]flumazenil transport in drug-resistant epilepsy patients with mesial temporal sclerosis.

J Cereb Blood Flow Metab 2017 01 19;37(1):97-105. Epub 2015 Nov 19.

Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.

Studies in rodents suggest that flumazenil is a P-glycoprotein substrate at the blood-brain barrier. This study aimed to assess whether [C]flumazenil is a P-glycoprotein substrate in humans and to what extent increased P-glycoprotein function in epilepsy may confound interpretation of clinical [C]flumazenil studies used to assess gamma-aminobutyric acid A receptors. Nine drug-resistant patients with epilepsy and mesial temporal sclerosis were scanned twice using [C]flumazenil before and after partial P-glycoprotein blockade with tariquidar. Volume of distribution, nondisplaceable binding potential, and the ratio of rate constants of [C]flumazenil transport across the blood-brain barrier (K/k) were derived for whole brain and several regions. All parameters were compared between pre- and post-tariquidar scans. Regional results were compared between mesial temporal sclerosis and contralateral sides. Tariquidar significantly increased global K/k (+23%) and volume of distribution (+10%), but not nondisplaceable binding potential. At the mesial temporal sclerosis side volume of distribution and nondisplaceable binding potential were lower in hippocampus (both ∼-19%) and amygdala (both ∼-16%), but K/k did not differ, suggesting that only regional gamma-aminobutyric acid A receptor density is altered in epilepsy. In conclusion, although [C]flumazenil appears to be a (weak) P-glycoprotein substrate in humans, this does not seem to affect its role as a tracer for assessing gamma-aminobutyric acid A receptor density.
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http://dx.doi.org/10.1177/0271678X15618219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167109PMC
January 2017

MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells.

Sci Rep 2015 Jul 24;5:12448. Epub 2015 Jul 24.

Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH, Amsterdam, The Netherlands.

Adult neurogenesis continuously contributes new neurons to hippocampal circuits and the programmed death of a subset of immature cells provides a primary mechanism controlling this contribution. Epileptic seizures induce strong structural changes in the hippocampus, including the induction of adult neurogenesis, changes in gene expression and mitochondrial dysfunction, which may all contribute to epileptogenesis. However, a possible interplay between this factors remains largely unexplored. Here, we investigated gene expression changes in the hippocampal dentate gyrus shortly after prolonged seizures induced by kainic acid, focusing on mitochondrial functions. Using comparative proteomics, we identified networks of proteins differentially expressed shortly after seizure induction, including members of the BCL2 family and other mitochondrial proteins. Within these networks, we report for the first time that the atypical BCL2 protein BCL2L13 controls caspase-3 activity and cytochrome C release in neural stem/progenitor cells. Furthermore, we identify BCL2L13 as a novel target of the cooperative action of microRNA-124 and microRNA-137, both upregulated shortly after seizure induction. This cooperative microRNA-mediated fine-tuning of BCL2L13 expression controls casp3 activity, favoring non-apoptotic caspase-3 functions in NSPC exposed to KA and thereby may contribute to the early neurogenic response to epileptic seizures in the dentate gyrus.
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http://dx.doi.org/10.1038/srep12448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513647PMC
July 2015

Quantification of Dynamic 11C-Phenytoin PET Studies.

J Nucl Med 2015 Sep 1;56(9):1372-7. Epub 2015 Jul 1.

Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.

Unlabelled: The overexpression of P-glycoprotein (Pgp) is thought to be an important mechanism of pharmacoresistance in epilepsy. Recently, (11)C-phenytoin has been evaluated preclinically as a tracer for Pgp. The aim of the present study was to assess the optimal plasma kinetic model for quantification of (11)C-phenytoin studies in humans.

Methods: Dynamic (11)C-phenytoin PET scans of 6 healthy volunteers with arterial sampling were acquired twice on the same day and analyzed using single- and 2-tissue-compartment models with and without a blood volume parameter. Global and regional test-retest (TRT) variability was determined for both plasma to tissue rate constant (K1) and volume of distribution (VT).

Results: According to the Akaike information criterion, the reversible single-tissue-compartment model with blood volume parameter was the preferred plasma input model. Mean TRT variability ranged from 1.5% to 16.9% for K1 and from 0.5% to 5.8% for VT. Larger volumes of interest showed better repeatabilities than smaller regions. A 45-min scan provided essentially the same K1 and VT values as a 60-min scan.

Conclusion: A reversible single-tissue-compartment model with blood volume seems to be a good candidate model for quantification of dynamic (11)C-phenytoin studies. Scan duration may be reduced to 45 min without notable loss of accuracy and precision of both K1 and VT, although this still needs to be confirmed under pathologic conditions.
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http://dx.doi.org/10.2967/jnumed.115.158055DOI Listing
September 2015

Kainate-induced epileptogenesis alters circular hole board learning strategy but not the performance of C57BL/6J mice.

Epilepsy Behav 2014 Dec 20;41:127-35. Epub 2014 Oct 20.

Department of Medical Pharmacology, Leiden University Medical Center (LUMC) & LACDR, Leiden, The Netherlands.

Patients with mesial temporal lobe epilepsy (mTLE) frequently show cognitive deficits. However, the relation between mTLE and cognitive impairment is poorly understood. To gain more insight into epilepsy-associated alterations in cognitive performance, we studied the spatial learning of C57BL/6J mice five weeks after kainate-induced status epilepticus (SE). Typically, structural hippocampal rearrangements take place within five weeks after SE. Mice were monitored by exposing them to four tasks with a focus on spatial memory and anxiety: the circular hole board, modified hole board, novel object-placement task, and elevated plus maze. On the circular hole board, animals showed a higher preference for hippocampus-independent strategies after SE. In contrast, no change in strategy was seen on the modified hole board, but animals with SE were able to finish the task more often. Animals did not have an increased preference for a relocated object in the novel object-placement task but showed an increased locomotion after SE. No indications for altered anxiety were found when tested on the elevated plus maze following SE. These data suggest that the circular hole board is a well-suited paradigm to detect subtle SE-induced hippocampal deficits.
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http://dx.doi.org/10.1016/j.yebeh.2014.09.038DOI Listing
December 2014

(R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: evaluation in a rat epilepsy model.

Neuropharmacology 2014 Oct 28;85:104-12. Epub 2014 May 28.

Institute of Pharmacology, Toxicology & Pharmacy, Ludwig-Maximilians-University, Munich, Germany. Electronic address:

Neuroinflammation has been suggested as a key determinant of the intrinsic severity of epilepsy. Glial cell activation and associated inflammatory signaling can influence seizure thresholds as well as the pharmacodynamics and pharmacokinetics of antiepileptic drugs. Based on these data, we hypothesized that molecular imaging of microglia activation might serve as a tool to predict drug refractoriness of epilepsy. Brain uptake of (R)-[11C]PK11195, a ligand of the translocator protein 18 kDa and molecular marker of microglia activation, was studied in a chronic model of temporal lobe epilepsy in rats with selection of phenobarbital responders and non-responders. In rats with drug-sensitive epilepsy, (R)-[11C]PK11195 brain uptake values were comparable to those in non-epileptic controls. Analysis in non-responders revealed enhanced brain uptake of up to 39% in different brain regions. The difference might be related to the fact that non-responders exhibited higher baseline seizure frequencies than responders indicating a more pronounced intrinsic disease severity. In hippocampal sections, ED1 immunostaining argued against a general difference in microglia activation between both groups. Our data suggest that TSPO PET imaging might serve as a biomarker for drug resistance in temporal lobe epilepsy. However, it needs to be considered that our findings indicate that the TSPO PET data might merely reflect seizure frequency. Future experimental and clinical studies should further evaluate the validity of TSPO PET data to predict the response to phenobarbital and other antiepileptic drugs in longitudinal studies with scanning before drug exposure and with a focus on the early phase following an epileptogenic brain insult.
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http://dx.doi.org/10.1016/j.neuropharm.2014.05.002DOI Listing
October 2014

[11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model: impact of epilepsy and drug-responsiveness.

Nucl Med Biol 2013 Aug 1;40(6):764-75. Epub 2013 Jul 1.

Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.

Introduction: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [(11)C]quinidine and [(11)C]laniquidar.

Methods: Metabolism and brain kinetics of both [(11)C]quinidine and [(11)C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders". Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar.

Results: [(11)C]quinidine was metabolized rapidly, whereas [(11)C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [(11)C]quinidine and [(11)C]laniquidar brain concentrations. In the epileptic subgroup "non-responders", brain uptake of [(11)C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15 mg/kg of tariquidar. For [(11)C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment.

Conclusions: We confirmed that both [(11)C]quinidine and [(11)C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [(11)C]quinidine between drug-resistant and drug-sensitive animals.
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http://dx.doi.org/10.1016/j.nucmedbio.2013.05.008DOI Listing
August 2013

Altered GABAA receptor density and unaltered blood-brain barrier transport in a kainate model of epilepsy: an in vivo study using 11C-flumazenil and PET.

J Nucl Med 2012 Dec 9;53(12):1974-83. Epub 2012 Nov 9.

Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.

Unlabelled: The aim of the present study was to investigate if flumazenil blood-brain barrier transport and binding to the benzodiazepine site on the γ-aminobutyric acid A (GABA(A)) receptor complex is altered in an experimental model of epilepsy and subsequently to study if changes in P-glycoprotein (P-gp)-mediated efflux of flumazenil at the blood-brain barrier may confound interpretation of (11)C-flumazenil PET in epilepsy.

Methods: The transport of flumazenil across the blood-brain barrier and the binding to the benzodiazepine site on the GABA(A) receptors in 5 different brain regions was studied and compared between controls and kainate-treated rats, a model of temporal lobe epilepsy, with and without tariquidar pretreatment. In total, 29 rats underwent 2 consecutive (11)C-flumazenil PET scans, each one lasting 30 min. The tracer was mixed with different amounts of isotopically unmodified flumazenil (4, 20, 100, or 400 μg) to cover a wide range of receptor occupancies during the scan. Before the second scan, the rats were pretreated with a 3 or 15 mg/kg dose of the P-gp inhibitor tariquidar. The second scan was then obtained according to the same protocol as the first scan.

Results: GABA(A) receptor density, B(max), was estimated as 44 ± 2 ng x mL(-1) in the hippocampus and as 33 ± 2 ng x mL(-1) in the cerebellum, with intermediate values in the occipital cortex, parietal cortex, and caudate putamen. B(max) was decreased by 12% in kainate-treated rats, compared with controls. The radiotracer equilibrium dissociation constant, K(D), was similar in both rat groups and all brain regions and was estimated as 5.9 ± 0.9 ng x mL(-1). There was no difference in flumazenil transport across the blood-brain barrier between control and kainate-treated rats, and the effect of tariquidar treatment was similar in both rat groups. Tariquidar treatment also decreased flumazenil transport out of the brain by 73%, increased the volume of distribution in the brain by 24%, and did not influence B(max) or K(D), compared with baseline.

Conclusion: B(max) was decreased in kainate-treated rats, compared with controls, but no alteration in the blood-brain barrier transport of flumazenil was observed. P-gp inhibition by tariquidar treatment increased brain concentrations of flumazenil in both groups, but B(max) estimates were not influenced, suggesting that (11)C-flumazenil scanning is not confounded by alterations in P-gp function.
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http://dx.doi.org/10.2967/jnumed.112.104588DOI Listing
December 2012

Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood-brain barriers studied with (R)-[11C]verapamil positron emission tomography.

EJNMMI Res 2012 Oct 16;2(1):58. Epub 2012 Oct 16.

Division of Pharmacology, Leiden University, Einsteinweg 55, Leiden, 2333 CC, The Netherlands.

Unlabelled:

Background: This study investigated the influence of P-glycoprotein (P-gp) inhibitor tariquidar on the pharmacokinetics of P-gp substrate radiotracer (R)-[11C]verapamil in plasma and brain of rats and humans by means of positron emission tomography (PET).

Methods: Data obtained from a preclinical and clinical study, in which paired (R)-[11C]verapamil PET scans were performed before, during, and after tariquidar administration, were analyzed using nonlinear mixed effects (NLME) modeling. Administration of tariquidar was included as a covariate on the influx and efflux parameters (Qin and Qout) in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood-brain barrier (BBB). Additionally, the influence of pilocarpine-induced status epilepticus (SE) was tested on all model parameters, and the brain-to-plasma partition coefficient (VT-NLME) was calculated.

Results: Our model indicated that tariquidar enhances brain uptake of (R)-[11C]verapamil by decreasing Qout. The reduction in Qout in rats during and immediately after tariquidar administration (sevenfold) was more pronounced than in the second PET scan acquired 2 h after tariquidar administration (fivefold). The effect of tariquidar on Qout in humans was apparent during and immediately after tariquidar administration (twofold reduction in Qout) but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment Vbr1. Tariquidar treatment lead to an increase in VT-NLME, and pilocarpine-induced SE lead to increased (R)-[11C]verapamil distribution to the peripheral brain compartment.

Conclusions: Using NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on (R)-[11C]verapamil transport across the BBB in control and 48 h post SE rats as well as in humans.
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http://dx.doi.org/10.1186/2191-219X-2-58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520775PMC
October 2012

[11C]phenytoin revisited: synthesis by [11C]CO carbonylation and first evaluation as a P-gp tracer in rats.

EJNMMI Res 2012 Jul 2;2(1):36. Epub 2012 Jul 2.

Department of Nuclear Medicine & PET Research, Radionuclide Centre, VU University Medical Center, P,O, box 7057, Amsterdam 1081, HV, The Netherlands.

Unlabelled:

Background: At present, several positron emission tomography (PET) tracers are in use for imaging P-glycoprotein (P-gp) function in man. At baseline, substrate tracers such as R-[11C]verapamil display low brain concentrations with a distribution volume of around 1. [11C]phenytoin is supposed to be a weaker P-gp substrate, which may lead to higher brain concentrations at baseline. This could facilitate assessment of P-gp function when P-gp is upregulated. The purpose of this study was to synthesize [11C]phenytoin and to characterize its properties as a P-gp tracer.

Methods: [11C]CO was used to synthesize [11C]phenytoin by rhodium-mediated carbonylation. Metabolism and, using PET, brain pharmacokinetics of [11C]phenytoin were studied in rats. Effects of P-gp function on [11C]phenytoin uptake were assessed using predosing with tariquidar.

Results: [11C]phenytoin was synthesized via [11C]CO in an overall decay-corrected yield of 22 ± 4%. At 45 min after administration, 19% and 83% of radioactivity represented intact [11C]phenytoin in the plasma and brain, respectively. Compared with baseline, tariquidar predosing resulted in a 45% increase in the cerebral distribution volume of [11C]phenytoin.

Conclusions: Using [11C]CO, the radiosynthesis of [11C]phenytoin could be improved. [11C]phenytoin appeared to be a rather weak P-gp substrate.
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http://dx.doi.org/10.1186/2191-219X-2-36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506555PMC
July 2012

[11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein.

EJNMMI Res 2012 Mar 28;2:12. Epub 2012 Mar 28.

Division of Pharmacology, LACDR, Leiden University, PO Box 9502, Leiden, 2300 RA, The Netherlands.

Background: [11C]Flumazenil and positron emission tomography (PET) are used clinically to assess gamma-aminobutyric acid (GABA)-ergic function and to localize epileptic foci prior to resective surgery. Enhanced P-glycoprotein (P-gp) activity has been reported in epilepsy and this may confound interpretation of clinical scans if [11C]flumazenil is a P-gp substrate. The purpose of this study was to investigate whether [11C]flumazenil is a P-gp substrate.

Methods: [11C]Flumazenil PET scans were performed in wild type (WT) (n = 9) and Mdr1a/1b, (the genes that encode for P-gp) double knockout (dKO) (n = 10) mice, and in naive rats (n = 10). In parallel to PET scanning, [11C]flumazenil plasma concentrations were measured in rats. For 6 of the WT and 6 of the dKO mice a second, [11C]flumazenil scan was acquired after administration of the P-gp inhibitor tariquidar. Cerebral [11C]flumazenil concentrations in WT and Mdr1a/1b dKO mice were compared (genetic disruption model). Furthermore, pre and post P-gp-blocking cerebral [11C]flumazenil concentrations were compared in all animals (pharmacological inhibition model).

Results: Mdr1a/1b dKO mice had approximately 70% higher [11C]flumazenil uptake in the brain than WT mice. After administration of tariquidar, cerebral [11C]flumazenil uptake in WT mice increased by about 80% in WT mice, while it remained the same in Mdr1a/1b dKO mice. In rats, cerebral [11C]flumazenil uptake increased by about 60% after tariquidar administration. Tariquidar had only a small effect on plasma clearance of flumazenil.

Conclusions: The present study showed that [11C]flumazenil is a P-gp substrate in rodents. Consequently, altered cerebral [11C]flumazenil uptake, as observed in epilepsy, may not reflect solely GABAA receptor density changes but also changes in P-gp activity.
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http://dx.doi.org/10.1186/2191-219X-2-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348032PMC
March 2012

Alteration in P-glycoprotein functionality affects intrabrain distribution of quinidine more than brain entry-a study in rats subjected to status epilepticus by kainate.

AAPS J 2012 Mar 4;14(1):87-96. Epub 2012 Jan 4.

Division of Pharmacology, LACDR, Leiden University, The Netherlands.

This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion. Effect of pretreatment with tariquidar (15 mg/kg, administered 30 min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the blood-brain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the blood-brain barrier is altered at 1 week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level.
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http://dx.doi.org/10.1208/s12248-011-9318-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281999PMC
March 2012

Simultaneous in vivo measurements of receptor density and affinity using [11C]flumazenil and positron emission tomography: comparison of full saturation and steady state methods.

Neuroimage 2011 Aug 14;57(3):928-37. Epub 2011 May 14.

Division of Pharmacology, LACDR, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.

The binding of PET radiotracer [(11)C]flumazenil to the GABA(A) receptors is described by the receptor density (B(max)) and binding affinity (K(D)). The estimation of B(max) and K(D) is usually based on Scatchard analysis including at least two PET scans at steady state of various specific activities. Recently, a novel full saturation method to estimate both B(max) and K(D) was proposed, in which a saturating dose of flumazenil is given to cover a wide range of different receptor occupancies within a single scan. The aim of the present study was a direct comparison of steady state and full saturation methods for determining B(max) and K(D) of [(11)C]flumazenil in the same group of male Sprague-Dawley rats. Fourteen rats underwent 3 consecutive [(11)C]flumazenil scans of 30 min duration each. A tracer dose was injected at the start of the first scan. Prior to the second scan the tracer was mixed with 5, 20, 100 or 500 μg unlabelled (cold) flumazenil to cover a wide range of receptor occupancies during the scan. The third scan was performed during a constant intravenous infusion of unlabelled flumazenil, resulting in ~50% GABA(A) receptor occupancy. The first and third scans were part of the steady state method, whilst the second scan was performed according to the full saturation method. For both methods, B(max) and K(D) were then derived by compartmental modelling. Both methods yielded similar B(max) and K(D) estimates. The full saturation method yielded B(max) values of 37 ± 5.8 ng · mL(-1) and K(D) values of 7.6 ± 2.0 ng · mL(-1), whilst the steady state method yielded B(max) values of 33 ± 5.4 ng · mL(-1) and K(D) values of 7.1 ± 0.8 ng · mL(-1). The main advantage of the full saturation method is that B(max) and K(D) can be obtained from a single PET scan.
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http://dx.doi.org/10.1016/j.neuroimage.2011.05.022DOI Listing
August 2011

(R)-[11C]verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus.

BMC Med Imaging 2011 Jan 3;11. Epub 2011 Jan 3.

Division of Pharmacology, LACDR, Leiden University, P,O, Box 9502, 2300 RA Leiden, The Netherlands.

Background: Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be mimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of spontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in P-glycoprotein (P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.

Methods: (R)-[11C]verapamil, which is currently the most frequently used positron emission tomography (PET) ligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated rats, at 7 days after treatment. To investigate the effect of P-gp on (R)-[11C]verapamil brain distribution, both groups were studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined using immunohistochemistry in post mortem brains. (R)-[11C]verapamil kinetics were analyzed with approaches common in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by population mixed effects modelling (NONMEM).

Results: All data analysis approaches indicated only modest differences in brain distribution of (R)-[11C]verapamil between saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold increase. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate and saline treated rats.

Conclusions: P-gp expression and functionality does not seem to change at early stage after induction of anticipated pharmacoresistant epilepsy by kainate.
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http://dx.doi.org/10.1186/1471-2342-11-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022839PMC
January 2011

Pharmacokinetics of clindamycin in pregnant women in the peripartum period.

Antimicrob Agents Chemother 2010 May 22;54(5):2175-81. Epub 2010 Feb 22.

Medical Centre Haaglanden (MCH), Department of Obstetrics and Gynecology, The Hague, Netherlands.

The study presented here was performed to determine the pharmacokinetics of intravenously administered clindamycin in pregnant women. Seven pregnant women treated with clindamycin were recruited. Maternal blood and arterial and venous umbilical cord blood samples were obtained. Maternal clindamycin concentrations were analyzed by nonlinear mixed-effects modeling with the NONMEM program. The data were best described by a linear three-compartment model. The clearance and the volume of distribution at steady state were 10.0 liters/h and 6.32 x 10(3) liters, respectively. Monte Carlo simulations were performed to determine the area under the concentration curve (AUC) for the free (unbound) drug (f) in maternal serum for 24 h divided by the MIC (fAUC(0-24)/MIC). At a MIC of 0.5 mg/liter, which is the EUCAST breakpoint, the attainment at the lower 95% confidence interval (CI) was 24.6 if the level of protein binding was 65%, and this value concurred well with the target value of 27. However, for higher degrees of protein binding, as has been described in the literature, the attainment was lower, down to 10.2 for a protein binding level of 85% (lower 95% CI). The concentrations in umbilical cord blood were lower than those in maternal blood. The concentration-time profiles in maternal serum indicate that the level of exposure to clindamycin may be too low in these patients. Together with the lower concentrations in umbilical cord blood, this finding suggests that the current dosing regimen may not be adequate to protect all neonates from group B streptococcal disease.
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http://dx.doi.org/10.1128/AAC.01017-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863651PMC
May 2010

Pharmacokinetics of amoxicillin in maternal, umbilical cord, and neonatal sera.

Antimicrob Agents Chemother 2009 Apr 21;53(4):1574-80. Epub 2009 Jan 21.

Department of Obstetrics and Gynecology, Medical Centre Haaglanden, The Hague , The Netherlands.

The pharmacokinetics of amoxicillin were studied in umbilical cord and neonatal sera relative to maternal concentrations in prevention of neonatal group B streptococcus infection. The subjects were 44 pregnant women receiving amoxicillin as 1 or 2 g as an intravenous infusion. To measure the concentrations, blood samples were obtained from the mother, the arterial and venous umbilical cord, and the neonate. The pharmacokinetics were characterized by a five-compartment model by using nonlinear mixed-effects (population) modeling. The population estimates for the clearance, central volume of distribution, and the two peripheral maternal volumes of distribution were 19.7 +/- 0.99 liters/h, 6.40 +/- 0.61 liters, and 5.88 +/- 0.83 liters (mean +/- standard error), respectively. The volume of distribution of the venous umbilical cord and the neonatal volume of distribution were 3.40 liters and 11.9 liters, respectively. The pharmacokinetic parameter estimates were used to simulate the concentration-time profiles in maternal, venous umbilical cord, and neonatal sera. The peak concentration in the venous umbilical cord serum was 18% of the maternal peak concentration. It was reached 3.3 min after the maternal peak concentration. The concentration-time profile in neonatal serum was determined by the profile in venous umbilical cord serum, which in turn depended on the profile in maternal serum. Furthermore, the simulated concentrations in maternal, venous umbilical cord, and neonatal sera exceeded the MIC for group B streptococcus for more than 90% of the 4-h dosing interval. In a first approximation, the 2-g infusion to the mother appears to be adequate for the prevention of group B streptococcal disease. However, to investigate the efficacy of the prophylaxis, further studies of the interindividual variability in pharmacokinetics are indicated.
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http://dx.doi.org/10.1128/AAC.00119-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663065PMC
April 2009

The influence of labour on the pharmacokinetics of intravenously administered amoxicillin in pregnant women.

Br J Clin Pharmacol 2008 Dec;66(6):866-74

Erasmus MC, University Medical Centre Rotterdam, Department of Medical Microbiology and Infectious Diseases, Rotterdam, The Netherlands.

Aims: Many physiological changes take place during pregnancy and labour. These might change the pharmacokinetics of amoxicillin, necessitating adjustment of the dose for prevention of neonatal infections. We investigated the influence of labour on the pharmacokinetics of amoxicillin.

Methods: Pregnant women before and during labour were recruited and treated with amoxicillin intravenously. A postpartum dose was offered. Blood samples were obtained and amoxicillin concentrations were determined using high-pressure liquid chromatography. The pharmacokinetics were characterized by nonlinear mixed-effects modelling using NONMEM.

Results: The pharmacokinetics of amoxicillin in 34 patients was best described by a three-compartment model. Moderate interindividual variability was identified in CL, central and peripheral volumes of distribution. The volume of distribution (V) increased with an increasing amount of oedema. Labour influenced the parameter estimate of peripheral volume of distribution (V(2)). V(2) was decreased during labour, and even more in the immediate postpartum period. For all patients the population estimates (mean +/- SE) for CL and V were 21.1 +/- 4.1 l h(-1) (CL), 8.7 +/- 6.6 l (V(1)), 11.8 +/- 7.7 l (V(2)) and 20.5 +/- 15.4 l (V(3)) respectively.

Conclusions: The peripheral distribution volume of amoxicillin in pregnant women during labour and immediately postpartum is decreased. However, these changes are not clinically relevant and do not warrant deviations from the recommended dosing regimen for amoxicillin during labour in healthy pregnant patients.
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http://dx.doi.org/10.1111/j.1365-2125.2008.03292.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675777PMC
December 2008

Changes in GABAA receptor properties in amygdala kindled animals: in vivo studies using [11C]flumazenil and positron emission tomography.

Epilepsia 2009 Jan 25;50(1):88-98. Epub 2008 Aug 25.

Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.

Purpose: The purpose of the present investigation was to quantify alterations in GABA(A) receptor density in vivo in rats subjected to amygdala kindling.

Methods: The GABA(A) receptor density was quantified by conducting a [(11)C]flumazenil (FMZ) positron emission tomography (PET) study according to the full saturation method, in which each animal received a single injection of FMZ to fully saturate the GABA(A) receptors. Subsequently, the concentration-time curves of FMZ in blood [using high-pressure liquid chromatography with UV detector (HPLC-UV) or high-performance liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS)] and brain (with PET-scanning) were analyzed by population modeling using a pharmacokinetic model, containing expressions to describe the time course of FMZ in blood and brain.

Results: The GABA(A) receptor density (B(max)) in kindled rats was decreased by 36% compared with controls. This is consistent with a reduction of 28% in electroencephalography (EEG) effect of midazolam in the same animal model, suggesting that a reduced number of GABA(A) receptors underlies the decreased efficacy of midazolam. Furthermore, receptor affinity (K(D)) was not changed, but the total volume of distribution in the brain (V(Br)), is increased to 178% of control after kindling, which might indicate an alteration in the transport of FMZ across the blood-brain barrier.

Conclusions: Both the GABA(A) receptor density (B(max)), and possibly also the blood-brain barrier transport of FMZ (V(Br)) are altered after kindling. Furthermore, this study indicates the feasibility of conducting PET studies for quantifying moderate changes in GABA(A) receptor density in a rat model of epilepsy in vivo.
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http://dx.doi.org/10.1111/j.1528-1167.2008.01763.xDOI Listing
January 2009

Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling in translational drug research.

Trends Pharmacol Sci 2008 Apr 18;29(4):186-91. Epub 2008 Mar 18.

Leiden University, Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Einsteinweg 55, PO Box 9503, 2300 RA Leiden, The Netherlands.

The use of pharmacokinetic-pharmacodynamic (PK-PD) modeling in translational drug research is a promising approach that provides better understanding of drug efficacy and safety. It is applied to predict efficacy and safety in humans using in vitro bioassay and/or in vivo animal data. Current research in PK-PD modeling focuses on the development of mechanism-based models with improved extrapolation and prediction properties. A key element in mechanism-based PK-PD modeling is the explicit distinction between parameters for describing (i) drug-specific properties and (ii) biological system-specific properties. Mechanism-based PK-PD models contain specific expressions for the characterization of processes on the causal path between drug exposure and drug response. The different terms represent: target-site distribution, target binding and activation and transduction. Ultimately, mechanism-based PK-PD models will also characterize the interaction of the drug effect with disease processes and disease progression. In this review, the principles of mechanism-based PK-PD modeling are described and illustrated by recent applications.
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http://dx.doi.org/10.1016/j.tips.2008.01.007DOI Listing
April 2008

Amoxicillin pharmacokinetics in pregnant women with preterm premature rupture of the membranes.

Am J Obstet Gynecol 2008 Jan 3;198(1):108.e1-6. Epub 2007 Dec 3.

Department of Obstetrics and Gynecology, Medical Centre Haaglanden, Lijnbaan, the Hague, The Netherlands.

Objective: This study was undertaken to study the pharmacokinetics of intravenously administered amoxicillin in pregnant women with preterm premature rupture of the membranes (PPROM).

Study Design: Healthy women with PPROM were recruited and treated with amoxicillin (2 g initially and 1 g subsequently). Blood samples were obtained from the opposite arm and concentrations determined with the use of high-pressure liquid chromatography. Nonlinear mixed-effects modeling was performed in nonlinear mixed effect (population) modeling.

Results: The pharmacokinetics of 17 patients was described by a 3-compartment model. Clearance and volume of distribution at steady state were 22.8 L/h and 21.4 L/h, respectively, similar to values in nonpregnant individuals. There was little variability between patients. No relationship was observed between values of individual pharmacokinetic parameters and various covariates.

Conclusion: The pharmacokinetics of amoxicillin in pregnant patients with PPROM similar to nonpregnant individuals. Given the small interindividual variability in pharmacokinetics, no dose adjustments are required to account for differences between subjects under normal circumstances.
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http://dx.doi.org/10.1016/j.ajog.2007.05.018DOI Listing
January 2008

Decreased Efficacy of GABAA-receptor modulation by midazolam in the kainate model of temporal lobe epilepsy.

Epilepsia 2007 Jul 18;48(7):1378-87. Epub 2007 Apr 18.

Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.

Purpose: The objective of this investigation was to characterize quantitatively the time-dependent changes in midazolam (MDL) efficacy in the silent period after induction of status epilepticus (SE) in rats. The changes in MDL efficacy were correlated to changes in ex vivo GABA(A)-receptor expression.

Methods: MDL efficacy was quantified by pharmacokinetic-pharmacodynamic (PK-PD) modeling by using the beta-frequency of the EEG as PD end point. Two PK-PD experiments were performed in each animal: the first experiment before and the second experiment at either day 4 or day 14 after SE. SE was induced by repetitive intraperitoneal injections with kainate. GABA(A)-receptor expression was determined by ex vivo autoradiography with [(3)H]flumazenil.

Results: The concentration versus EEG effect relation of midazolam was successfully described by the sigmoidal E(max) model. The maximal effect on the beta-frequency of the EEG (E(max)) was reduced to 51.6 +/- 35.6% and 25.8 +/- 33.7% of the original value at 4 and 14 days after induction of SE. The ex vivo study with [(3)H]flumazenil showed that the observed reductions in E(max) were paralleled by a reduction in GABA(A)-receptor density.

Conclusions: The efficacy of MDL is decreased in the silent period after SE, which can be partly accounted for by a reduction in GABA(A)-receptor density.
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http://dx.doi.org/10.1111/j.1528-1167.2007.01081.xDOI Listing
July 2007

Synergistic combinations of anticonvulsant agents: what is the evidence from animal experiments?

Epilepsia 2007 Mar;48(3):412-34

Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, Leiden, The Netherlands.

Purpose: Combination therapy is often used in the treatment of seizures refractory to monotherapy. At the same time, the pharmacodynamic mechanisms that determine the combined efficacy of antiepileptic drugs (AEDs) are unknown, and this prevents a rational use of these drug combinations. We critically evaluate the existing evidence for pharmacodynamic synergism between AEDs from preclinical studies in animal models of epilepsy to identify useful combinations of mechanisms and to determine whether study outcome depends on the various research methods that are in use.

Methods: Published articles were included if the studies were placebo-controlled, in vivo, or ex vivo animal studies investigating marketed or experimental AEDs. The animal models that were used in these studies, the primary molecular targets of the tested drugs, and the methods of interpretation were recorded. The potential association of these factors with the study outcome (synergism: yes or no) was assessed through logistic regression analysis.

Results: In total, 107 studies were identified, in which 536 interaction experiments were conducted. In 54% of these experiments, the possibility of a pharmacokinetic interaction was not investigated. The majority of studies were conducted in the maximal electroshock model, and other established models were the pentylenetetrazole model, amygdala kindling, and the DBA/2 model. By far the most widely used method for interpretation of the results was evaluation of the effect of a threshold dose of one agent on the median effective dose (ED50) of another agent. Experiments relying on this method found synergism significantly more often compared with experiments relying on other methods (p<0.001). Furthermore, experiments including antagonists of the AMPA receptor were more likely to find synergism in comparison with all other experiments (p<0.001).

Conclusions: Intensive preclinical research into the effects of AED combinations has not led to an understanding of the pharmacodynamic properties of AED combinations. Specifically, the majority of the preclinical studies are not adequately designed to distinguish between additive, synergistic, and antagonistic interactions. Quantitative pharmacokinetic-pharmacodynamic studies of selectively acting AEDs in a battery of animal models are necessary for the development of truly synergistic drug combinations.
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http://dx.doi.org/10.1111/j.1528-1167.2006.00952.xDOI Listing
March 2007

Mechanism-based pharmacokinetic-pharmacodynamic modeling: biophase distribution, receptor theory, and dynamical systems analysis.

Annu Rev Pharmacol Toxicol 2007 ;47:357-400

Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, 2300 RA Leiden, The Netherlands.

Mechanism-based PK-PD models differ from conventional PK-PD models in that they contain specific expressions to characterize, in a quantitative manner, processes on the causal path between drug administration and effect. This includes target site distribution, target binding and activation, pharmacodynamic interactions, transduction, and homeostatic feedback mechanisms. As the final step, the effects on disease processes and disease progression are considered. Particularly through the incorporation of concepts from receptor theory and dynamical systems analysis, important progress has been made in the field of mechanism-based PK-PD modeling. This has yielded models with much-improved properties for extrapolation and prediction. These models constitute a theoretical basis for rational drug discovery and development.
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http://dx.doi.org/10.1146/annurev.pharmtox.47.120505.105154DOI Listing
April 2007
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