GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility.

GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility. Research Abstract Details 

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GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility. Abstract Text:

Paul Goldsmith,Zoe Golder,Julia Hunt,Stephane Berghmans,Derek Jones,James P Stables,Lauren Murphree,Diane Howden,Paul E Newton,Frances M Richards,

BACKGROUND/AIMS: GBR12909 has been reported to possess anticonvulsant activity with focal brain perfusion to the hippocampus of pilocarpine, although an earlier publication suggested any anticonvulsant effects were only mild. Here we further explored the anticonvulsant potential of GBR12909 with a suite of anticonvulsant assays in both zebrafish and mammals and then explored whether it possessed any QT effects which might limit clinical utility. METHODS: We assessed the anticonvulsant effects of GBR12909 in zebrafish pentylenetetrazole (PTZ), mammalian maximal electroshock and PTZ models of generalized epilepsy and a rodent hippocampal kindling model. Cardiac effects were assessed in zebrafish and man. RESULTS: GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy. However, phase 1 human data indicated potential QT effects. Subsequent testing in a zebrafish QT assay confirmed marked arrhythmogenic potential. CONCLUSION: Further clinical development of GBR12909 in epilepsy was considered inappropriate because of insufficient window between the therapeutic effects and the cardiac arrhythmia problems identified in zebrafish assays. Any further development based on this mechanism of action should avoid the GBR12909 chemical scaffold, or involve structure-activity dissociation of its neurological and cardiac effects.

GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility. Publishing Authors By Initials

P Goldsmith,Z Golder,J Hunt,S Berghmans,D Jones,JP Stables,L Murphree,D Howden,PE Newton,FM Richards,

For similar animals: chordata: vertebrates: fishes: cypriniformes: cyprinidae: zebrafish research abstracts see: animals: chordata: vertebrates: fishes: cypriniformes: cyprinidae: zebrafish research

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GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Pharmacology

VOLUME: 79

Page Numbers: 250-8

Journal Abbreviation: Pharmacology

ISSN: 0031-7012

DAY: 27

MONTH: 04

YEAR: 2007

GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility. Information

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LANGUAGE: eng

NlmUniqueID: 152016

GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility. Keywords Mesh Terms:

KEYWORDS: Zebrafish

MESH TERMS: pharmacology

Chemical & Substance for Abstract: GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility. Information

Substance Name: vanoxerine

Registry Number: 67469-78-7

Grant and Affiliation Information for GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility.

AFFILIATION: DanioLabs Ltd., Cambridge, UK. paul.goldsmith@daniolabs.com

Country: Switzerland

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MEDLINETA: Pharmacology

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