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Increasing oxime efficacy by blood-brain barrier modulation

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Author: Joosen, M.J.A. · Schans, M.J. van der · Dijk, C.G.M. van · Kuijpers, W.C. · Wortelboer, H.M. · Helden, H.P.M. van
Source:Toxicology Letters, 1, 206, 67-71
Identifier: 435959
doi: doi:10.1016/j.toxlet.2011.05.231
Keywords: 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 · Life · CBRN - CBRN Protection PHS - Pharmacokinetics & Human Studies · EELS - Earth, Environmental and Life Sciences


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.