Title
Comparison of the therapeutic effects and pharmacokinetics of HI-6, HLo-7, HGG-12, HGG-42 and obidoxime following non-reactivatable acetylcholinesterase inhibition in rats
Author
van Helden, H.P.M.
van der Wiel, H.J.
Zijlstra, J.J.
Melchers, B.P.C.
Busker, R.W.
Publication year
1994
Abstract
The oximes HI-6, HLo-7, HGG-12, HGG-42 and obidoxime were used in a previously developed rat model to evaluate the therapeutic effects of oximes other than acetylcholinesterase (AChE) reactivation (so-called 'nonreactivating effects'). To test this anaesthetized, atropinized and artificially ventilated rats (n = 8 or 16) were poisoned with a three times LD50 dose of the potent AChE-inhibitor crotylsarin (CRS, i.v.). CRS-inhibited rat AChE dealkylates instantaneously, thereby excluding AChE reactivation by the oximes. Five minutes after poisoning the rats were treated (i.v.) with an oxime or saline and 10 min later artificial ventilation was terminated. Survival times were determined. Saline-treated animals died within 15 min. In comparison, treatment with HI-6, HLo-7, HGG-12, HGG42 or obidoxime resulted in a significant prolongation of survival time. In the groups treated with HLo-7, HI-6 or HGG-12, 12-37% of the animals survived more than 24 h. It was investigated whether differences in therapeutic effectiveness are caused by differences in pharmacokinetics of the oximes. The plasma half-lives of HI-6, HLo-7, HGG-12, HGG-42 and obidoxime amounted to 67, 63, 27, 55 and 179 min, respectively. At doses of 75 or 150 umol/kg, all oximes could be detected in brain and medulla oblongata in similar amounts (6-10 nmol/g tissue). In vitro, all oximes were effective in restoring failure of neuromuscular transmission (NMT) caused by CRS, albeit with varying potency. All oximes bound with affinities in the micromolar range to rat brain muscarinic receptors. The present results show that (1) prolongation of survival time following lethal intoxication with an organophosphate can be achieved by non-reactivating properties of the oximes and (2) the observed differences in a) pharmacokinetics, b) potency to restore NMT and c) affinity for muscarinic receptors of the various oximes do not correlate with the observed differences in therapeutic effectiveness. Therefore, it is concluded that the prolongation of survival must be due to as yet undefined effects in the brain.
Subject
Acetylcholinesterase
Crotylsarin
HGG-12
HGG-42
HI-6
HLo-7
Non-reactivating effects
Obidoxime
Organophosphate poisoning
Oximes
Pharmacokinetics survival
1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether
1 [2,4 bis(hydroxyiminomethyl)pyridinio] 1' (4 carbamoylpyridinio)dimethyl ether diiodide
[(3 benzoyl 1 pyridiniomethyl) (2 hydroxyiminomethyl 1 pyridiniomethyl)] ether
[(3 cyclohexylcarbonyl 1 pyridiniomethyl) (2 hydroxyiminomethyl 1 pyridiniomethyl)] ether
muscarinic receptor
obidoxime
organophosphate
oxime derivative
unclassified drug
animal experiment
animal model
article
cholinesterase inhibition
controlled study
enzyme reactivation
intoxication
intravenous drug administration
male
nonhuman
priority journal
rat
receptor affinity
survival time
Animal
Binding, Competitive
Brain
Cholinesterase Inhibitors
Cholinesterase Reactivators
Comparative Study
In Vitro
Male
Neuromuscular Junction
Obidoxime Chloride
Pyridines
Pyridinium Compounds
Quinuclidinyl Benzilate
Rats
Sarin
Support, Non-U.S. Gov't
Synaptic Transmission
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http://resolver.tudelft.nl/uuid:4ccb96e9-29df-4267-be5f-7b3813211531
DOI
https://doi.org/10.1007/s002040050061
TNO identifier
232477
ISSN
0340-5761
Source
Archives of Toxicology, 68 (68), 224-230
Bibliographical note
Correspondence Address: Van Helden, H.P.M.; TNO Medical Biological Laboratory, P.O. Box 5815, 2280 HV Rijswijk, Netherlands Chemicals/CAS: 1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether, 34433-31-3; 1 [2,4 bis(hydroxyiminomethyl)pyridinio] 1' (4 carbamoylpyridinio)dimethyl ether diiodide, 120103-35-7; [(3 benzoyl 1 pyridiniomethyl) (2 hydroxyiminomethyl 1 pyridiniomethyl)] ether, 65320-89-0; [(3 cyclohexylcarbonyl 1 pyridiniomethyl) (2 hydroxyiminomethyl 1 pyridiniomethyl)] ether, 65320-92-5; obidoxime, 114-90-9, 7683-36-5; Cholinesterase Inhibitors; Cholinesterase Reactivators; crotylsarin, 138780-00-4; HGG 12, 83972-73-0; HGG 42, 65320-92-5; HI 6, 34433-31-3; HLo 7, 120103-35-7; Obidoxime Chloride, 114-90-9; Pyridines; Pyridinium Compounds; Quinuclidinyl Benzilate, 6581-06-2; Sarin, 107-44-8
Document type
article