Evidence map›Paper›PMID 31243719›Full record

ArticleMolecular neurobiology2019

Neurovascular Drug Biotransformation Machinery in Focal Human Epilepsies: Brain CYP3A4 Correlates with Seizure Frequency and Antiepileptic Drug Therapy.

Sherice Williams, Mohammed Hossain, Lisa Ferguson, Robyn M Busch, Nicola Marchi, Jorge Gonzalez-Martinez, Emilio Perucca, Imad M Najm, Chaitali Ghosh

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular neurobiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed
1.3field-weighted citation impact, top 18% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

18 citing papers in PubMed, 26 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 3 institutions in 3 countries.

Sherice WilliamsCerebrovascular Research Laboratory, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
Mohammed HossainCerebrovascular Research Laboratory, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
Lisa FergusonEpilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
Robyn M BuschEpilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
Nicola MarchiCerebrovascular Mechanisms of Brain Disorders Laboratory, Department of Neuroscience, Institute of Functional Genomics (CNRS-INSERM), University of Montpellier, Montpellier, France.
Jorge Gonzalez-MartinezEpilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
Emilio PeruccaDepartment of Internal Medicine and Therapeutics, University of Pavia, Clinical Trial Center, IRCCS Mondino Foundation, Pavia, Italy.
Imad M NajmEpilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
Chaitali GhoshCerebrovascular Research Laboratory, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. GHOSHC@ccf.org.ORCID http://orcid.org/0000-0003-4078-0278
Cleveland Clinic · USCentre National de la Recherche Scientifique · FRUniversity of Pavia · IT

Funding

Cytochrome P450-mediated drug interactions at the human blood-brain barrierR01NS095825 · NINDS · CLEVELAND CLINIC LERNER COM-CWRU · PI GHOSH, CHAITALI · 2017 to 2021
$1.7M
Drug brain biotransformation in human refractory epilepsyR01NS078307 · NINDS · CLEVELAND CLINIC LERNER COM-CWRU · PI GHOSH, CHAITALI, MARCHI, NICOLA · 2012 to 2016
$1.7M
Alternatives Research & Development Foundation ARDF1508CGAmerican Heart Association 13SDG13950015Brain and Behavior Research Foundation 18815National Institute of Neurological Disorders and Stroke/National Institutes of Health R01NS078307National Institute of Neurological Disorders and Stroke/National Institutes of Health R01NS095825NINDS NIH HHS R01 NS078307NINDS NIH HHS R01 NS095825
6 · The paper itself

Abstract

Pharmacoresistance is a major clinical challenge for approximately 30% of patients with epilepsy. Previous studies indicate nuclear receptors (NRs), drug efflux transporters, and cytochrome P450 enzymes (CYPs) control drug passage across the blood-brain barrier (BBB) in drug-resistant epilepsy. Here, we (1) evaluate BBB changes, neurovascular nuclear receptors, and drug transporters in lesional/epileptic (EPI) and non-lesional/non-epileptic (NON-EPI) regions of the same brain, (2) examine regional CYP expression and activity, and (3) investigate the association among CYP brain expression, seizure frequency, duration of epilepsy, and antiepileptic drug (AED) combination. We used surgically resected brain specimens from patients with medically intractable epilepsy (n = 22) where the epileptogenic loci were well-characterized by invasive and non-invasive methods; histology confirmed distinction of small NON-EPI regions from EPI tissues. NRs, transporters, CYPs, and tight-junction proteins were assessed by western blots/immunohistochemistry, and CYP metabolic activity was determined and compared. The relationship of CYP expression with seizure frequency, duration of epilepsy, and prescribed AEDs was evaluated. Decreased BBB tight-junction proteins accompanied IgG leakage in EPI regions and correlated with upregulated NR and efflux transporter levels. CYP expression and activity significantly increased in EPI compared to NON-EPI tissues. Change in EPI and NON-EPI CYP3A4 expression increased in patients taking AEDs that were CYP substrates, was downregulated when CYP- and non-CYP-substrate AEDs were given together, and correlated with seizure frequency. Our studies suggest focal neurovascular CYP-NR-transporter alterations, as demonstrated by the relationship of seizure frequency and AED combination to brain CYP3A4, might together impact biotransformation machinery of human pharmacoresistant epilepsy.

Indexed as

AdolescentAdultAgedAnticonvulsantsBiotransformationBlood-Brain BarrierBrainChildChild, PreschoolCytochrome P-450 CYP3AEpilepsyFemaleHumansMaleMembrane Transport ProteinsMiddle AgedAnticonvulsantsCytochrome P-450 CYP3AMembrane Transport ProteinsReceptors, Cytoplasmic and NuclearTight Junction ProteinsAntiepileptic drugsBlood-brain barrierCytochrome P450Multiple drug transportersNuclear receptorsPharmacoresistant epilepsy

Identifiers

PMID31243719
PMCPMC6854685
OpenAlexW2954062726

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.