Increasing oxime efficacy by blood-brain barrier modulation.

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.

• Authors: Marloes J A Joosen, Marcel J van der Schans, Christian G M van Dijk, Willem C Kuijpers, Heleen M Wortelboer, Herman P M van Helden
• Journal: Toxicology letters (Toxicol Lett) Vol. 206 Issue 1 Pg. 67-71 (Sep 25 2011) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 21600273 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antidotes
• Chemical Warfare Agents
• Cholinesterase Inhibitors
• Oximes
• Pyridinium Compounds
• Quinolines
• Soman
• Cholinesterases
• asoxime chloride
• tariquidar

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• Animals
• Antidotes (pharmacokinetics, therapeutic use)
• Blood-Brain Barrier (drug effects, metabolism)
• Brain (drug effects, enzymology)
• Chemical Warfare Agents (toxicity)
• Cholinesterase Inhibitors (toxicity)
• Cholinesterases (metabolism)
• Electrophoresis, Capillary
• Male
• Microdialysis
• Oximes (blood, pharmacokinetics, therapeutic use)
• Pyridinium Compounds (blood, pharmacokinetics, therapeutic use)
• Quinolines (pharmacology)
• Rats
• Rats, Wistar
• Seizures (chemically induced)
• Soman (toxicity)