Wednesday, December 4, 2024 12/4/2024

Pediatric model for evaluation of effects of and therapies for high level organophosphate anticholinesterase poisoning.

Award Number: U01NS123255
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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Project Summary/Abstract Many of the organophosphate (OP) anticholinesterases, such as nerve agents, are highly toxic. Terrorist actions or accidents involving OPs could lead to mass casualties. The current therapy consists of the muscarinic receptor antagonist atropine and an oxime reactivator of the inhibited acetylcholinesterase (AChE) (2-PAM in the US). The current testing paradigms to identify improved medical countermeasures are largely from adult animals, and there is little information available on pediatric therapies. There is some information on the vulnerability of juvenile animals from the OP insecticide literature, which verifies that the juveniles are more sensitive to OPs. Thus, there is a need to have a pediatric testing paradigm available to investigate the efficacy and safety of new countermeasures to OP threats in juvenile animals. We have developed a testing paradigm in adult rats and have used it for several years to evaluate the efficacy of therapeutic countermeasures in adult rats using a nerve agent chemistry (nitrophenyl isopropyl methylphosphonate; NIMP, sarin surrogate) and an OP insecticide chemistry (paraoxon, active metabolite of parathion). The paradigm is particularly relevant to civilian casualties in that it introduces the antidotes at the time of appearance of signs of poisoning (typically about 30 minutes) which would be consistent with therapy in the field in a mass casualty situation. We have developed a platform of novel brain-penetrating oxime AChE reactivators that have shown impressive efficacy in adult rats; Oxime 20 is our lead candidate. We propose to evaluate this paradigm in juvenile rats (12 and 21 days, 3 and 7 year human equivalent) to verify the natural history of the toxidrome for these 2 OPs (i.e., dosage of OP, signs of toxicity, time to severe signs, time to death in lethal dose) (Aim 1a) and the efficacy of standard of care (atropine + 2-PAM or novel Oxime 20) (Aim 1b). The overarching goal of this supplement is to develop a pediatric testing paradigm for high dose poisoning by an OP anticholinesterase that will be useful for the development of new medical countermeasures suitable for infants and children.


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: 2024 ( Subtotal = $802,801 )
2024	2024	MISSISSIPPI STATE UNIVERSITY	245 BARR AVE	MISSISSIPPI STATE	MS	39762	OKTIBBEHA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	9/3/2024	SUPPLEMENT FOR EXPANSION	$145,499
2024	2024	MISSISSIPPI STATE UNIVERSITY	245 BARR AVE	MISSISSIPPI STATE	MS	39762	OKTIBBEHA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/6/2024	NON-COMPETING CONTINUATION	$657,302
2024	2023	MISSISSIPPI STATE UNIVERSITY	245 BARR AVE	MISSISSIPPI STATE	MS	39762	OKTIBBEHA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	8/20/2024	NON-COMPETING CONTINUATION	$0
2024	2023	MISSISSIPPI STATE UNIVERSITY	245 BARR AVE	MISSISSIPPI STATE	MS	39762	OKTIBBEHA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $802,801

Issue Date FY: 2023 ( Subtotal = $672,916 )
2023	2023	MISSISSIPPI STATE UNIVERSITY	245 BARR AVE MCARTHUR HALL	MISSISSIPPI STATE	MS	39762	OKTIBBEHA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/11/2023	NON-COMPETING CONTINUATION	$672,916
														Subtotal = $672,916

Issue Date FY: 2022 ( Subtotal = $688,206 )
2022	2022	MISSISSIPPI STATE UNIVERSITY	245 BARR AVE MCARTHUR HALL	MISSISSIPPI STATE	MS	39762	OKTIBBEHA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/6/2022	NON-COMPETING CONTINUATION	$688,206
														Subtotal = $688,206

Issue Date FY: 2021 ( Subtotal = $706,875 )
2021	2021	MISSISSIPPI STATE UNIVERSITY	245 BARR AVE MCARTHUR HALL	MISSISSIPPI STATE	MS	39762	OKTIBBEHA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/30/2021	NEW	$706,875
														Subtotal = $706,875

Grand Total All Awards = $2,870,798

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Pediatric model for evaluation of effects of and therapies for high level organophosphate anticholinesterase poisoning.

Award Number: U01NS123255

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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