Bispyridinium (oxime) compounds antagonize the “ganglion blocking” effect of pyridostigmine in isolated superior cervical ganglia of the rat

Schlagmann, Christel; Ulbrich, Hanna; Remien, Jörg

doi:10.1007/bf01977631

Cited by 5 publications

(2 citation statements)

References 20 publications

(24 reference statements)

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“…The experiments were performed on TE671 cell line, which is medulloblastoma cell line endogenously expressing human embryonic muscle-like acetylcholine receptor (Schoepfer et al 1988). Even though the cell line is of neuronal origin, rhabdomyosarcoma properties has been described too (Stratton et al 1989).…”

Section: In Vitro Measurement Of Direct Nicotinic Receptor Inhibitionmentioning

confidence: 99%

“…Antinicotinic action, which atropine lacks and which can prevent respiratory failure, has also been reported. Both neuromuscular blocking (Schlagmann et al 1990, Tattersall 1993, Chiou and Chang 1994 and ganglioblocking Tremblay 1979, Schlagmann et al 1990) types of antinicotinic action have been reported. However, the reported in vitro properties do not correlate with the antidotal observations in vivo.…”

Section: Introductionmentioning

confidence: 98%

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Oxime Reactivators and Their in Vivo and in Vitro Effects on Nicotinic Receptors

Soukup

Krůšek²,

Kaniakova³

et al. 2011

Physiol Res

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Current treatment of organophosphorus poisoning, resulting in overstimulation and desensitization of muscarinic and nicotinic receptors by acetylcholine (ACh), consists of the administration of atropine and oxime reactivators. However, no versatile oxime reactivator has been developed yet and some mortality still remains after application of standard atropine treatment, probably due to its lack of antinicotinic action. In our study, we focused on the interesting non-acetylcholinesterase property of oximes, i.e. antinicotinic effect of reactivators. Two standard reactivators (HI-6, obidoxime) and two new compounds (K027 and K203) were chosen for in vitro (patch clamp) and in vivo (nerve-evoked muscle contraction) testings. Both examinations showed antinicotinic effects of the reactivators. In vitro inhibition of acetylcholine-evoked currents by obidoxime, HI-6 and K203 was equivalent while K027 was less potent. Similar order of potency was observed by the in vivo examinations. We thus confirm previous in vitro results, which describe antinicotinic effects of oxime reactivators, and furthermore, we show in vivo antagonism of oxime reactivators exerted by the inhibition of ACh effect on the nicotinic receptor in the neuromuscular junction. Taking together, the effects of tested oxime reactivators indicate an antagonism on both embryonic and adult form of the muscle nicotinic receptors.

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Section: In Vitro Measurement Of Direct Nicotinic Receptor Inhibitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Oxime Reactivators and Their in Vivo and in Vitro Effects on Nicotinic Receptors

Soukup

Krůšek²,

Kaniakova³

et al. 2011

Physiol Res

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HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases

Eyer

Hagedorn²,

Klimmek

et al. 1992

Arch Toxicol

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HLö 7 dimethanesulfonate (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2,4-bis [(hydroxyimino)methyl]pyridinium dimethanesulfonate) is a broad-spectrum reactivator against highly toxic organophosphorus compounds. The compound was synthesized by a new route with the carcinogenic bis(chloromethyl)ether being substituted by the non-mutagenic bis(methylsulfonoxymethyl)ether. The very soluble dimethanesulfonate of obidoxime was also prepared by this way. HLö 7 dimethanesulfonate is the first water-soluble salt of HLö 7 that should be suitable for the wet/dry autoinjector technology, because aqueous solutions of HLö 7 are not very stable (calculated shelf-life 0.2 years when stored at 8 degrees C, 1 M solution, pH 2.5). The crystalline preparation contains 96% of the syn/syn-isomer, less than 2% of the syn/anti-isomer and some minor identified by-products. HLö 7 was very efficient in reactivating acetylcholinesterase (AChE) blocked by organophosphates as long as ageing did not prevent dephosphylation. HLö 7 was superior to HI 6 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2- [(hydroxyimino)methyl]pyridinium dichloride) in reactivating soman and sarin-inhibited AChE from erythrocytes, and literature data indicate that HLö 7 exceeds HI 6 by far in reactivating tabun-inhibited AChE. In atropine-protected, soman-poisoned mice HLö 7 was three times more potent than HI 6 (protective ratio 5 versus 2.5), and in sarin-poisoned mice HLö 7 was 10 times more potent than HI 6 (protective ratio 8 for both oximes). In atropine-protected guinea-pigs HLö 7 was less effective than HI 6 (protective ratio: 2.3 versus 5.2 for soman; 5.2 versus 6.8 for sarin; 4.3 versus 3.8 for tabun). The mean survival time of anaesthetized guinea-pigs exposed to 5 LD50 soman (6.3 min) was increased by atropine (27 min) and atropine + HLö (57 min). HLö 7 alone did not prolong the survival. The most impressive effect of HLö 7 was on respiration: 3 min after i.v. injection of HLö 7 and atropine, the depressed respiration increased rapidly to 60% of control and remained at that level during the observation period (60 min). With atropine alone, respiration recovered only slowly. Behavioural and physiologic parameters were determined in atropine-protected mice exposed to a sublethal soman dose. The running performance was significantly improved by HLö 7. Even central symptoms, e.g. hypothermia and convulsions, were decreased markedly by HLö 7 (evaluation 60 min after poisoning). The pharmacokinetic data for HLö 7 in male beagle dogs are similar to those of HI 6.(ABSTRACT TRUNCATED AT 400 WORDS)

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Oxime K203: a drug candidate for the treatment of tabun intoxication

et al. 2018

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Bispyridinium (oxime) compounds antagonize the “ganglion blocking” effect of pyridostigmine in isolated superior cervical ganglia of the rat

Cited by 5 publications

References 20 publications

Oxime Reactivators and Their in Vivo and in Vitro Effects on Nicotinic Receptors

Oxime Reactivators and Their in Vivo and in Vitro Effects on Nicotinic Receptors

HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases

Oxime K203: a drug candidate for the treatment of tabun intoxication

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