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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2008-9-22
pubmed:abstractText
In search for more efficacious reactivators of acetylcholinesterase (AChE) inhibited by organophosphorus compounds, experimental K-oximes have been synthesized which show good in vitro efficacy. However, AChE inhibition by oximes themselves (as quantified by their intrinsic IC50) is the major cause of oxime toxicity and the dose-limiting factor. To assess K-oxime efficacy in vivo, the extent of protection from mortality induced by diisopropylfluorophosphate (DFP) was quantified by Cox survival analysis and compared with that of the clinically available oximes. Oximes were administered in an equitoxic dosage, i.e. half the LD01. Best protection was conferred by K-27, reducing the relative risk of death (RR) to 16% of control RR (P < or = 0.05), which was statistically significantly better (P < or = 0.05) than all other tested oximes, except obidoxime, K-53 and K-75. The efficacy of obidoxime (RR = 0.19), K-48 (RR = 0.28), K-53 (RR = 0.22), K-74 (RR = 0.38) and K-75 (RR = 0.29) was significantly (P < or = 0.05) better than that of 2-PAM (RR = 0.62) and K-113 (RR = 0.73). No significant protective effect was observed for K-107 and K-108. Our LD50 data show that K-107, K-108 and K-113 (which strongly inhibit AChE in vitro) are in vivo markedly more toxic than all other oximes tested and can therefore only be safely administered at a low dosage which is insufficient to protect from DFP-induced mortality. Dosage calculations based on in vitro IC50 measurements may therefore in future replace in vivo LD50 determinations, thereby reducing the number of animals required.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0260-437X
pubmed:author
pubmed:issnType
Print
pubmed:volume
28
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
920-8
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Eight new bispyridinium oximes in comparison with the conventional oximes pralidoxime and obidoxime: in vivo efficacy to protect from diisopropylfluorophosphate toxicity.
pubmed:affiliation
Department of Anatomy, FMHS, UAE University, Al Ain, United Arab Emirates.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't