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Improved standard of care reactivaters and facilitative transport into the centra

Award Number: U01NS083448
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Improved standard of care reactivaters and facilitative transport into the centra - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$468,195 )
2023	2017	W4D7 USA MED RES INST CHEM DEF	EDGEWOOD AREA	ABERDEEN PROVING GROU	MD	21010		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	10/1/2022	NON-COMPETING CONTINUATION	-$468,195
														Subtotal = -$468,195

Issue Date FY: 2022 ( Subtotal = -$541,096 )
2022	2017	W4D7 USA MED RES INST CHEM DEF	EDGEWOOD AREA	ABERDEEN PROVING GROU	MD	21010		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	10/1/2021	NON-COMPETING CONTINUATION	-$541,096
														Subtotal = -$541,096

Issue Date FY: 2018 ( Subtotal = -$278,616 )
2018	2013	ARMY, UNITED STATES DEPARTMENT OF THE	E2900 RICKETTS POINT RD	ABERDEEN PROVING GROUND	MD	21010	HARFORD	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/30/2018	NEW	-$278,616
														Subtotal = -$278,616

Issue Date FY: 2017 ( Subtotal = $468,195 )
2017	2017	ARMY, UNITED STATES DEPARTMENT OF THE	BLDG 3100 3100 RICKETTS POINT RD	ABER PROV GRD	MD	21010	HARFORD	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/14/2017	NON-COMPETING CONTINUATION	$468,195
														Subtotal = $468,195

Issue Date FY: 2016 ( Subtotal = $541,096 )
2016	2016	US ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE	3100 RICKETTS POINT ROAD	ABERDEEN PROVING GROUND	MD	21010	HARFORD	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/19/2016	EXTENSION WITH OR WITHOUT FUNDS	$541,096
														Subtotal = $541,096

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2013	US ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE	3100 RICKETTS POINT ROAD	ABERDEEN PROVING GROUND	MD	21010	HARFORD	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/1/2015	NEW	$560,156
2015	2013	US ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE	3100 RICKETTS POINT ROAD	ABERDEEN PROVING GROUND	MD	21010	HARFORD	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/27/2015	NEW	-$560,156
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2013	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/14/2014	NEW	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $560,156 )
2013	2013	Dept of Defense Def Fin Acct Svc	6760 East Irvington Place	DENVER	CO	80279		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/1/2013	NEW	$560,156
														Subtotal = $560,156

Grand Total All Awards = $281,540

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Improved standard of care reactivaters and facilitative transport into the centra

Award Number: U01NS083448

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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