Organophosphorous Chemical Threat Agents (CTAs) are major risks for military and civilian population alike. CTAs exert their toxic effects by inhibiting acetylcholinesterase (AChE) leading to the accumulation of acetylcholine at synaptic and neuromuscular junctions leading to symptoms of acute CTA poisoning including salivation, lacrimation, defecation, muscular twitching, seizures/status epilepticus and ultimately rapid death due to respiratory failure. Available treatment for acute CTA poisoning includes combinations of: 1) oxime to reactivate the inhibited AChE;2) atropine to antagonize the action of excess acetylcholine formed at muscarinic receptors and 3) diazepam or midazolam to allosterically potentiate the action of inhibitory neurotransmitter -amino butyric acid (GABA) at GABAA receptors. The two major limitations of the current therapeutic strategies are: 1) poor blood-brain barrier (BBB) permeability of oximes and 2) resistance for reactivation of the CTA-inhibited AChE due to rapid 'aging'. Quick delivery of oximes to the brain is critical to reactivat the rapidly 'aging'AChE in the brain and protect the brain from acute and subsequent chronic injuries. Non-invasive intranasal nose-to-brain delivery offers faster delivery of therapeutics to the brain. The mechanism involves possible transport through the neuroepithelial cells of olfactory epithelium as well as through trigeminal nerve pathways. The major advantage of this approach is that charged molecules or even high molecular weight drugs which cannot bypass the BBB under physiological conditions can be successfully delivered to the brain. Efficiency of nose-to- brain delivery can be significantly improved by either making formulations such as mucoadhesive nanoemulsions of the drugs or by encapsulating the drugs in biodegradable nanoparticles. Our central hypothesis is that intranasal administration of therapeutic formulations of oxime, atropine and midazolam in a nanoemulsion form can rapidly deliver these drugs to the brain in addition to lungs and blood circulation to protect against CTAs at 30 min or later time points. Our long term objective is to establish the efficacy of intranasal brain deliver systems for use with chemical threat- related therapeutics, which can be of tremendous use in civilian mass casualty situations. The immediate goal is to develop the mucoadhesive nanoemulsion approach for this purpose and test them for effectiveness in a preclinical model system. Use of nanoemulsion technology for intranasal brain delivery of drugs is a highly innovative approach to bypass BBB and efforts along these lines are underway in many laboratories. The proposed intranasal brain delivery technique using nanoemulsion needs to be investigated for protection against CTAs or any other situations involving civilian mass casualty. The major advantages of the successful use of this non-invasive technology against CTAs are: 1) it can rapidly deliver oximes (which cannot cross the BBB under physiological conditions) to the brain in addition to lungs and blood to reactivate the inhibited AChE;and 2) it can be self administered immediately after exposure to prevent 'aging'of the inhibited AChE and its resistance for reactivation. The successful use of an intranasal brain delivery technology against chemical threat agents will open up its wider application in numerous other areas of clinical medicine and research.

Public Health Relevance

Organophosphorous compounds including chemical threat agents are one of the major terrorist-related problems for military and civilian population alike. Our long term objective is to establish the efficacy of intranasal brain delivery pathways for use with chemical threat-related therapeutics while the immediate goal is to develop the mucoadhesive nanoemulsion approach for this purpose and test them for effectiveness in selected preclinical model systems. The successful use of intranasal brain delivery technology against chemical threat agents will open up its wider application in a number of other areas of clinical medicine and research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS076448-02
Application #
8551756
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (55))
Program Officer
Yeung, David
Project Start
2012-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$375,214
Indirect Cost
$125,214
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817