Research Project
8546071
DESCRIPTION (provided by applicant): The use of chemical antidotes is likely the first treatment for civilian and military-installation nerve agent (NA) casualties. These treatments would include the current standard of care (SOC) therapies (United States) of acetylcholine receptor blocker atropine, acetylcholinesterase (AChE) reactivator pralidoxime (2-[(hydroxyimino)methyl]-1-methylpyridinium, 2-PAM), and symptom modulator diazepam. From a single intramuscular (IM) dose these compounds do provide some immediate protection, but for persistent NAs (VX, VR) and pesticides (parathion- active derivative paraoxon, PX) and chlorpyrifos (Cpf)) the therapeutic regimen of continuous infusion of 2-PAM for up to 7 d may be required. 2-PAM however has other limitations as it does not cross the blood brain barrier (BBB) and therefore not available to reactivate poisoned brain AChE. The BBB is comprised of an endothelial cell layer that is nearly impenetrable to proteins and polar molecules. The Tokyo sarin attack in 1995 with 5500 casualties and immense impact on the emergency health services demonstrates the need for reactivators with improved pharmacokinetics, reduced toxicity, and the potential to cross the BBB for reducing treatment requirements in mass casualty situations. To this last point, glucose transporters (GLUTs) are present at high concentrations in the brain capillary epithelial cells and it has been demonstrated that glucose-drug conjugates can be transferred across the BBB by these transporters. We propose to exploit this by coupling broad spectrum reactivators (oximes) to glucose sites predicted by in silico modeling to not interfere with transport by the GLUT facilitative transporter.
