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  1. Article ; Online: Of Mice and Men: The Inter-individual Variability of the Brain's Response to Drugs.

    Löscher, Wolfgang

    eNeuro

    2024  Volume 11, Issue 2

    Abstract: Biological variation is ubiquitous in nature. Despite highly standardized breeding and husbandry under controlled environmental conditions, phenotypic diversity exists in laboratory mice and rats just as it does in humans. The resulting inter-individual ... ...

    Abstract Biological variation is ubiquitous in nature. Despite highly standardized breeding and husbandry under controlled environmental conditions, phenotypic diversity exists in laboratory mice and rats just as it does in humans. The resulting inter-individual variability affects various characteristics of animal disease models, including the responsiveness to drugs. Thus, the common practice of averaging data within an experimental group can lead to misinterpretations in neuroscience and other research fields. In this commentary, the impact of inter-individual variation in drug responsiveness is illustrated by examples from the testing of antiseizure medications in rodent temporal lobe epilepsy models. Individual mice and rats rendered epileptic by treatment according to standardized protocols fall into groups that either do or do not respond to antiseizure medications, thus mimicking the clinical situation in patients with epilepsy. Population responses are not normally distributed, and divergent responding is concealed in averages subjected to parametric statistical tests. Genetic, epigenetic, and environmental factors are believed to contribute to inter-individual variation in drug response but the specific molecular and physiological causes are not well understood. Being aware of inter-individual variability in rodents allows an improved interpretation of both behavioral phenotypes and drug effects in a pharmacological experiment.
    MeSH term(s) Mice ; Humans ; Rats ; Animals ; Epilepsy ; Epilepsy, Temporal Lobe ; Disease Models, Animal ; Brain
    Language English
    Publishing date 2024-02-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2800598-3
    ISSN 2373-2822 ; 2373-2822
    ISSN (online) 2373-2822
    ISSN 2373-2822
    DOI 10.1523/ENEURO.0518-23.2024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: On hidden factors and design-associated errors that may lead to data misinterpretation: An example from preclinical research on the potential seasonality of neonatal seizures.

    Löscher, Wolfgang

    Epilepsia

    2023  Volume 65, Issue 2, Page(s) 287–292

    Abstract: Unintentional misinterpretation of research in published biomedical reports that is not based on statistical flaws is often underrecognized, despite its possible impact on science, clinical practice, and public health. Important causes of such ... ...

    Abstract Unintentional misinterpretation of research in published biomedical reports that is not based on statistical flaws is often underrecognized, despite its possible impact on science, clinical practice, and public health. Important causes of such misinterpretation of scientific data, resulting in either false positive or false negative conclusions, include design-associated errors and hidden (or latent) variables that are not easily recognized during data analysis. Furthermore, cognitive biases, such as the inclination to seek patterns in data whether they exist or not, may lead to misinterpretation of data. Here, we give an example of these problems from hypothesis-driven research on the potential seasonality of neonatal seizures in a rat model of birth asphyxia. This commentary aims to raise awareness among the general scientific audience about the issues related to the presence of unintentional misinterpretation in published reports.
    MeSH term(s) Animals ; Rats ; Seizures ; Epilepsy ; Infant, Newborn, Diseases ; Asphyxia Neonatorum
    Language English
    Publishing date 2023-12-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 216382-2
    ISSN 1528-1167 ; 0013-9580
    ISSN (online) 1528-1167
    ISSN 0013-9580
    DOI 10.1111/epi.17840
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 517: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 475: Show issues

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  3. Article ; Online: Is the antiparasitic drug ivermectin a suitable candidate for the treatment of epilepsy?

    Löscher, Wolfgang

    Epilepsia

    2023  Volume 64, Issue 3, Page(s) 553–566

    Abstract: There are only a few drugs that can seriously lay claim to the title of "wonder drug," and ivermectin, the world's first endectocide and forerunner of a completely new class of antiparasitic agents, is among them. Ivermectin, a mixture of two macrolytic ... ...

    Abstract There are only a few drugs that can seriously lay claim to the title of "wonder drug," and ivermectin, the world's first endectocide and forerunner of a completely new class of antiparasitic agents, is among them. Ivermectin, a mixture of two macrolytic lactone derivatives (avermectin B
    MeSH term(s) Antiparasitic Agents/chemistry ; Antiparasitic Agents/pharmacokinetics ; Antiparasitic Agents/therapeutic use ; Antiparasitic Agents/toxicity ; Ivermectin/chemistry ; Ivermectin/pharmacokinetics ; Ivermectin/therapeutic use ; Ivermectin/toxicity ; Epilepsy/drug therapy ; Humans ; Cysteine Loop Ligand-Gated Ion Channel Receptors/agonists ; Anticonvulsants/chemistry ; Anticonvulsants/pharmacokinetics ; Anticonvulsants/therapeutic use ; Anticonvulsants/toxicity ; Brain/metabolism ; Animals ; Mice
    Chemical Substances Antiparasitic Agents ; Ivermectin (70288-86-7) ; Cysteine Loop Ligand-Gated Ion Channel Receptors ; Anticonvulsants
    Language English
    Publishing date 2023-01-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 216382-2
    ISSN 1528-1167 ; 0013-9580
    ISSN (online) 1528-1167
    ISSN 0013-9580
    DOI 10.1111/epi.17511
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 517: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 475: Show issues

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  4. Book ; Online ; E-Book: Atlas of neuromuscular diseases

    Feldman, Eva L. / Russell, James W. / Löscher, Wolfgang / Grisold, Wolfgang / Meng, Stefan

    a practical guideline

    2021  

    Author's details Eva L. Feldman, James W. Russell, Wolfgang N. Löscher, Wolfgang Grisold, Stefan Meng
    Keywords Neuromuscular diseases-Atlases ; Electronic books
    Language English
    Size 1 Online-Ressource (xxiii, 353 Seiten), Illustrationen, Diagramme
    Edition Third edition
    Publisher Springer
    Publishing place Cham
    Publishing country Switzerland
    Document type Book ; Online ; E-Book
    Remark Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
    HBZ-ID HT021689159
    ISBN 978-3-030-63449-0 ; 9783030634483 ; 3-030-63449-3 ; 3030634485
    DOI 10.1007/978-3-030-63449-0
    Database ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

    Full text online

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  5. Article: Dogs as a Natural Animal Model of Epilepsy.

    Löscher, Wolfgang

    Frontiers in veterinary science

    2022  Volume 9, Page(s) 928009

    Abstract: Epilepsy is a common neurological disease in both humans and domestic dogs, making dogs an ideal translational model of epilepsy. In both species, epilepsy is a complex brain disease characterized by an enduring predisposition to generate spontaneous ... ...

    Abstract Epilepsy is a common neurological disease in both humans and domestic dogs, making dogs an ideal translational model of epilepsy. In both species, epilepsy is a complex brain disease characterized by an enduring predisposition to generate spontaneous recurrent epileptic seizures. Furthermore, as in humans, status epilepticus is one of the more common neurological emergencies in dogs with epilepsy. In both species, epilepsy is not a single disease but a group of disorders characterized by a broad array of clinical signs, age of onset, and underlying causes. Brain imaging suggests that the limbic system, including the hippocampus and cingulate gyrus, is often affected in canine epilepsy, which could explain the high incidence of comorbid behavioral problems such as anxiety and cognitive alterations. Resistance to antiseizure medications is a significant problem in both canine and human epilepsy, so dogs can be used to study mechanisms of drug resistance and develop novel therapeutic strategies to benefit both species. Importantly, dogs are large enough to accommodate intracranial EEG and responsive neurostimulation devices designed for humans. Studies in epileptic dogs with such devices have reported ictal and interictal events that are remarkably similar to those occurring in human epilepsy. Continuous (24/7) EEG recordings in a select group of epileptic dogs for >1 year have provided a rich dataset of unprecedented length for studying seizure periodicities and developing new methods for seizure forecasting. The data presented in this review substantiate that canine epilepsy is an excellent translational model for several facets of epilepsy research. Furthermore, several techniques of inducing seizures in laboratory dogs are discussed as related to therapeutic advances. Importantly, the development of vagus nerve stimulation as a novel therapy for drug-resistant epilepsy in people was based on a series of studies in dogs with induced seizures. Dogs with naturally occurring or induced seizures provide excellent large-animal models to bridge the translational gap between rodents and humans in the development of novel therapies. Furthermore, because the dog is not only a preclinical species for human medicine but also a potential patient and pet, research on this species serves both veterinary and human medicine.
    Language English
    Publishing date 2022-06-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2834243-4
    ISSN 2297-1769
    ISSN 2297-1769
    DOI 10.3389/fvets.2022.928009
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  6. Article ; Online: Steve Schachter - A role model as an Editor-in-Chief.

    Löscher, Wolfgang

    Epilepsy & behavior : E&B

    2022  , Page(s) 108696

    Language English
    Publishing date 2022-04-16
    Publishing country United States
    Document type Letter
    ZDB-ID 2010587-3
    ISSN 1525-5069 ; 1525-5050
    ISSN (online) 1525-5069
    ISSN 1525-5050
    DOI 10.1016/j.yebeh.2022.108696
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5289: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  7. Article: Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy.

    Löscher, Wolfgang

    Frontiers in pharmacology

    2021  Volume 12, Page(s) 730257

    Abstract: Rationally designed multi-target drugs (also termed multimodal drugs, network therapeutics, or designed multiple ligands) have emerged as an attractive drug discovery paradigm in the last 10-20 years, as potential therapeutic solutions for diseases of ... ...

    Abstract Rationally designed multi-target drugs (also termed multimodal drugs, network therapeutics, or designed multiple ligands) have emerged as an attractive drug discovery paradigm in the last 10-20 years, as potential therapeutic solutions for diseases of complex etiology and diseases with significant drug-resistance problems. Such agents that modulate multiple targets simultaneously are developed with the aim of enhancing efficacy or improving safety relative to drugs that address only a single target or to combinations of single-target drugs. Although this strategy has been proposed for epilepsy therapy >25 years ago, to my knowledge, only one antiseizure medication (ASM), padsevonil, has been intentionally developed as a single molecular entity that could target two different mechanisms. This novel drug exhibited promising effects in numerous preclinical models of difficult-to-treat seizures. However, in a recent randomized placebo-controlled phase IIb add-on trial in treatment-resistant focal epilepsy patients, padsevonil did not separate from placebo in its primary endpoints. At about the same time, a novel ASM, cenobamate, exhibited efficacy in several randomized controlled trials in such patients that far surpassed the efficacy of any other of the newer ASMs. Yet, cenobamate was discovered purely by phenotype-based screening and its presumed dual mechanism of action was only described recently. In this review, I will survey the efficacy of single-target vs. multi-target drugs vs. combinations of drugs with multiple targets in the treatment and prevention of epilepsy. Most clinically approved ASMs already act at multiple targets, but it will be important to identify and validate new target combinations that are more effective in drug-resistant epilepsy and eventually may prevent the development or progression of epilepsy.
    Language English
    Publishing date 2021-10-27
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2021.730257
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  8. Book ; Conference proceedings: New horizons in the development of antiepileptic drugs

    Löscher, Wolfgang

    papers presented at the Workshop [on New Horizons in the Development of Antiepileptic Drugs] ... in Philadelphia, USA on November 28 - 29, 2001

    (Epilepsy research ; 50,1/2 : Special issue)

    2002  

    Institution Workshop on New Horizons in the Development of Antiepileptic Drugs
    Author's details guest eds.: Wolfgang Löscher
    Series title Epilepsy research ; 50,1/2 : Special issue
    Collection
    Language English
    Size S. 1- 220 : Ill., graph. Darst.
    Publisher Elsevier
    Publishing place Amsterdam u.a.
    Publishing country Netherlands
    Document type Book ; Conference proceedings
    HBZ-ID HT013449380
    Database Catalogue ZB MED Medicine, Health

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    In stock of ZB MED Cologne/Königswinter

    Shelf markLoan statusLocation
    Zs A 2193 -50- not available for loan Zeitschriften-Lesesaal

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  9. Article: Epilepsy and Alterations of the Blood-Brain Barrier: Cause or Consequence of Epileptic Seizures or Both?

    Löscher, Wolfgang

    Handbook of experimental pharmacology

    2020  Volume 273, Page(s) 331–350

    Abstract: The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid, thereby preserving a narrow and stable ... ...

    Abstract The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid, thereby preserving a narrow and stable homeostatic control of the neuronal environment. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types within the "neurovascular unit" including astrocytes and pericytes. In addition to the morphological characteristics of the BBB, various specific transport systems, enzymes, and receptors regulate the molecular and cellular traffic across the barrier. Furthermore, the intact BBB prevents many macromolecules and immune cells from entering the brain. This changes dramatically following epileptogenic brain insults; such insults, among other BBB alterations, lead to albumin extravasation and diapedesis of leukocytes from blood into brain parenchyma, inducing or contributing to epileptogenesis, which finally leads to development of spontaneous recurrent seizures and epilepsy. Furthermore, seizures themselves may cause BBB disruption with albumin extravasation, which has been shown to be associated with activation of astrocytes, activation of innate immune systems, and modifications of neuronal networks. However, seizure-induced BBB disruption is not necessarily associated with enhanced drug penetration into the brain, because the BBB expression of multidrug efflux transporters such as P-glycoprotein increases, most likely as a "second line defense" mechanism to protect the brain from drug toxicity. Hopefully, a better understanding of the complex BBB alterations in response to seizures and epilepsy can lead to novel therapeutic intervention to prevent epileptogenesis and the development of other detrimental sequelae of brain injury.
    MeSH term(s) Albumins/metabolism ; Albumins/therapeutic use ; Blood-Brain Barrier/metabolism ; Endothelial Cells/metabolism ; Epilepsy/etiology ; Humans ; Seizures/etiology ; Seizures/metabolism
    Chemical Substances Albumins
    Language English
    Publishing date 2020-11-01
    Publishing country Germany
    Document type Journal Article
    ISSN 0171-2004
    ISSN 0171-2004
    DOI 10.1007/164_2020_406
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    Sign. bis Bd. 125 (1997): 1982 A 2146: Show issues
     danach: Sign. bei den Einzelbänden: Show issues

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  10. Article ; Online: Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments.

    Löscher, Wolfgang / White, H Steve

    Cells

    2023  Volume 12, Issue 9

    Abstract: In the last 30 years, over 20 new anti-seizure medicines (ASMs) have been introduced into the market for the treatment of epilepsy using well-established preclinical seizure and epilepsy models. Despite this success, approximately 20-30% of patients with ...

    Abstract In the last 30 years, over 20 new anti-seizure medicines (ASMs) have been introduced into the market for the treatment of epilepsy using well-established preclinical seizure and epilepsy models. Despite this success, approximately 20-30% of patients with epilepsy have drug-resistant epilepsy (DRE). The current approach to ASM discovery for DRE relies largely on drug testing in various preclinical model systems that display varying degrees of ASM drug resistance. In recent years, attempts have been made to include more etiologically relevant models in the preclinical evaluation of a new investigational drug. Such models have played an important role in advancing a greater understanding of DRE at a mechanistic level and for hypothesis testing as new experimental evidence becomes available. This review provides a critical discussion of the pharmacology of models of adult focal epilepsy that allow for the selection of ASM responders and nonresponders and those models that display a pharmacoresistance per se to two or more ASMs. In addition, the pharmacology of animal models of major genetic epilepsies is discussed. Importantly, in addition to testing chemical compounds, several of the models discussed here can be used to evaluate other potential therapies for epilepsy such as neurostimulation, dietary treatments, gene therapy, or cell transplantation. This review also discusses the challenges associated with identifying novel therapies in the absence of a greater understanding of the mechanisms that contribute to DRE. Finally, this review discusses the lessons learned from the profile of the recently approved highly efficacious and broad-spectrum ASM cenobamate.
    MeSH term(s) Animals ; Anticonvulsants/pharmacology ; Anticonvulsants/therapeutic use ; Epilepsy/drug therapy ; Disease Models, Animal ; Treatment Outcome ; Drug Resistance
    Chemical Substances Anticonvulsants
    Language English
    Publishing date 2023-04-24
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells12091233
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