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
Life
CBRN - CBRN Protection PHS - Pharmacokinetics & Human Studies
EELS - Earth, Environmental and Life Sciences
HI6
Nerve agent
P-glycoprotein
Seizures
Tariquidar
1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether
Acetylcholinesterase
Atropine
Tariquidar
Animal experiment
Animal model
Article
Blood brain barrier
Blood level
Brain blood volume
Controlled study
Convulsion
Drug effect
Drug efficacy
Drug intoxication
Drug penetration
Male
Microdialysis
Modulation
Nerve agent poisoning
Nonhuman
Priority journal
Quantitative analysis
Rat
Seizure
Rattus
1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether, 34433-31-3
Acetylcholinesterase, 9000-81-1
Atropine, 51-55-8, 55-48-1
Tariquidar, 206873-63-4
Tradenames: hi 6, TNO; xr 9576, avaant
Manufacturers: 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