Print Email Facebook Twitter Increasing oxime efficacy by blood-brain barrier modulation Title Increasing oxime efficacy by blood-brain barrier modulation Author Joosen, M.J.A. van der Schans, M.J. van Dijk, C.G.M. Kuijpers, W.C. Wortelboer, H.M. van Helden, H.P.M. Publication year 2011 Abstract One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood-brain barrier (BBB), whereas nerve agents easily do. Increasing the concentration of oximes in the brain, would therefore provide an attractive approach to improve medical countermeasures. An explanation for limited penetration might be that oximes are substrates for the active P-glycoprotein (Pgp) efflux transporter located in the BBB.Using quantitative brain microdialysis in rats, the effect of i.v. injected tariquidar, a non-competitive, specific Pgp-inhibitor, on HI-6 levels in blood and brain was investigated. It appeared that tariquidar enhanced HI-6 levels in the brain approximately 2-fold during the first hour after HI-6 administration, whereas plasma levels did not differ between the treatment groups. A subsequent proof-of-concept study in rats showed that soman-induced seizures and convulsions were prevented almost completely when they were, in addition to HI-6 and atropine, pretreated with tariquidar. Moreover, twice as much AChE activity was present in their brains as compared to control rats.These results in rats indicate that modulation of the BBB by a drug like tariquidar, which is non-toxic by itself, is of great value in enhancing the efficacy of oximes. © 2011 Elsevier Ireland Ltd. Subject LifeCBRN - CBRN Protection PHS - Pharmacokinetics & Human StudiesEELS - Earth, Environmental and Life SciencesHI6Nerve agentP-glycoproteinSeizuresTariquidar1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl etherAcetylcholinesteraseAtropineTariquidarAnimal experimentAnimal modelArticleBlood brain barrierBlood levelBrain blood volumeControlled studyConvulsionDrug effectDrug efficacyDrug intoxicationDrug penetrationMaleMicrodialysisModulationNerve agent poisoningNonhumanPriority journalQuantitative analysisRatSeizureRattus1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether, 34433-31-3Acetylcholinesterase, 9000-81-1Atropine, 51-55-8, 55-48-1Tariquidar, 206873-63-4Tradenames: hi 6, TNO; xr 9576, avaantManufacturers: TNO; avaant To reference this document use: http://resolver.tudelft.nl/uuid:13c5876c-1cda-4bf6-9d49-2a09a93cf9c9 DOI https://doi.org/10.1016/j.toxlet.2011.05.231 TNO identifier 435959 ISSN 0378-4274 Source Toxicology Letters, 206 (1), 67-71 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.