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At least 343 records · Page 19Linked to original sources
PubMed1991

Therapy of organophosphate poisoning in the rat by direct effects of oximes unrelated to ChE reactivation.

Isolated rat diaphragm preparations treated with soman or with the irreversible and oxime resistant cholinesterase (ChE) inhibitor S27 showed a considerable recovery of neuromuscular transmission (NMT) during incubation with the (bis)pyridinium oximes HI-6, HGG-12, P2S and obidoxime. In the soman-treated preparations this NMT recovery was predominantly caused by reactivation of acetylcholinesterase (AChE) but in the S27-treated preparations it was caused by a direct (pharmacological) effect unrelated to enzyme reactivation. Atropinized rats were artificially ventilated after injection with 3 x LD50 soman for 3 h and then treated with HI-6, i.e. at a time when oxime reactivation of soman inhibited ChE is no longer possible. Nevertheless, these rats started to breathe spontaneously and 50-60% survived more than 24 h, whereas all control animals (saline instead of HI-6) died within 10 min after artificial ventilation was terminated. In such animals no significant reactivation of ChE activity at various time intervals following HI-6 treatment was found, either in the diaphragms or in the brains. There was a significant amount of NMT (50%) in vitro in diaphragms obtained from these animals. This NMT did not improve in vitro in the presence of HI-6 and was not inhibited by soman administered to the medium. It is concluded that in this case the NMT found was based on synaptic adaptation to the continued inhibition of ChE and that the survival of the animals might be due to a combination of this synaptic adaptation and central direct effects of HI-6.

Animals↗
PubMed2000

Synthesis and biological activity of conformationally controlled 2-PAM derivatives.

A series of conformationally controlled 2-PAM derivatives were prepared from 2-acetylpyridine and 2,3-pyrido[b]cycloalkenones in two steps and their reactivities towards parathion poisoned AChE were evaluated. The most planar 2,3-pyrido[b]cyclohexanone oxime methiodide showed an activity comparable to 2-PAM implying E-syn is that the most active conformation of 2-PAM in the biological system.

Acetylcholinesterase↗
PubMed1994

Reflex sympathetic dystrophy syndrome secondary to organophosphate intoxication induced neuropathy.

Reflex sympathetic dystrophy or Sudeck's atrophy is a syndrome that can usually be followed by a traumatic insult. This disorder is accompanied by signs and symptoms of vasomotor instability, trophic skin changes, and rapid development of bony demineralization. This report presents a case with reflex sympathetic dystrophy syndrome secondary to organophosphate intoxication induced neuropathy. The patient was threated with calcitonin well.

Action Potentials↗
PubMed2000

Compared efficacy of diazepam or avizafone to prevent soman-induced electroencephalographic disturbances and neuropathology in primates: relationship to plasmatic benzodiazepine pharmacokinetics.

We performed an experiment to characterize the toxicity of soman in cynomolgus monkeys in which organophosphorus intoxication was followed by treatment with either the current three-drug therapy atropine/pralidoxime/diazepam or a combination of atropine/pralidoxime/avizafone, avizafone being the water soluble prodrug of diazepam. Clinical, electrophysiological, and histological approaches were combined. When benzodiazepines were injected at the similar molar dose of 0.7 micromol/kg, the protection against soman toxicity was better with the atropine/ pralidoxime/diazepam combination than with the atropine/pralidoxime/avizafone one. Pharmacokinetic studies demonstrated that this difference of efficacy could be explained by a lower plasmatic load of diazepam obtained after injection of avizafone at 0.7 micromol/kg, compared to the administration of diazepam at the same molar dose. Moreover, after injection of avizafone, plasmatic levels of diazepam were achieved faster and declined more rapidly than after administration of diazepam. Compared to diazepam given at a dose of 0.7 micromol/kg, injection of 1 micromol avizafone/kg gave a similar plasmatic load of benzodiazepine, but with a lower time to maximum plasma concentration (tmax) and a higher maximum plasma concentration (Cmax) for plasmatic diazepam. We therefore went on to demonstrate that administration of the atropine/pralidoxime/avizafone combination at a dose 1 micromol benzodiazepine/kg to intoxicated monkeys afforded electrophysiological and histological protection similar to that obtained after administration of atropine/pralidoxime/diazepam at a dose of 0.7 micromol diazepam/kg. Reflections on the possible incorporation of avizafone in three-drug emergency treatment are presented.

Animals↗
PubMed2000

Effect of human plasma on the reactivation of sarin-inhibited human erythrocyte acetylcholinesterase.

The reactivation of organophosphate-inhibited acetylcholinesterase (AChE) by oximes inevitably results in the formation of highly reactive phosphoryloximes (POX), which are able to re-inhibit the enzyme. In this study, the dependence of POX formation on AChE concentration was investigated with sarin-inhibited human erythrocyte AChE (EryAChE). A marked dependence was found with obidoxime but not with the experimental oxime HI 6, suggesting great differences in the decomposition rates of the respective POXs. At a physiological erythrocyte content the reactivation of EryAChE was markedly affected by POX with obidoxime and pralidoxime (2-PAM) but not with the newer oximes HI 6 and HLö 7. Addition of extensively dialysed, sarin-treated human plasma reduced the reactivation by obidoxime and 2-PAM even more. Obidoxime and 2-PAM were superior to HI 6 and HLö 7 in reactivating butyrylcholinesterase (BChE). This effect was pronounced in diluted plasma, but was obscured in concentrated plasma, probably because of re-inhibition by the generated POX. Addition of native erythrocytes to sarin-treated plasma resulted in marked inhibition of EryAChE in the presence of obidoxime, suggesting a higher affinity of the POX for EryAChE. The results indicate that obidoxime and 2-PAM may reactivate sarin-inhibited AChE insufficiently due to re-inhibition by the POX formed. In addition, the re-inhibition of Ery-AChE may be aggravated by the POX that is produced during BChE reactivation. These reactions must be regarded as therapeutically detrimental and disqualify those oximes which are capable of forming stable POX by reactivation of BChE.

Acetylcholinesterase↗