Evaluation of the benefit of the bispyridinium compound MB327 for the antidotal treatment of nerve agent-poisoned mice

@article{Kassa2016EvaluationOT,
  title={Evaluation of the benefit of the bispyridinium compound MB327 for the antidotal treatment of nerve agent-poisoned mice},
  author={J. Kassa and M. Pohanka and C. Timperley and M. Bird and A. C. Green and J. Tattersall},
  journal={Toxicology Mechanisms and Methods},
  year={2016},
  volume={26},
  pages={334 - 339}
}
Abstract The potency of the bispyridinium non-oxime compound MB327 [1,1′-(propane-1,3-diyl)bis(4-tert-butylpyridinium) diiodide] to increase the therapeutic efficacy of the standard antidotal treatment (atropine in combination with an oxime) of acute poisoning with organophosphorus nerve agents was studied in vivo. The therapeutic efficacy of atropine alone – or atropine in combination with an oxime, MB327, or both an oxime and MB237 – was evaluated by the determination of LD50 values of… Expand
Evaluation of the Influence of Three Newly Developed Bispyridinium Anti‐nicotinic Compounds (MB408, MB442, MB444) on the Efficacy of Antidotal Treatment of Nerve Agent Poisoning in Mice
TLDR
The addition of bispyridinium non‐oximes to the standard antidotal treatment of acute poisoning with tabun was beneficial regardless of the chosen non-oxime, but only slightly beneficial in the case of soman poisoning. Expand
Some benefit from non-oximes MB408, MB442 and MB444 in combination with the oximes HI-6 or obidoxime and atropine in antidoting sarin or cyclosarin poisoned mice.
TLDR
The addition of MB compounds to the standard antidotal treatment of acute nerve agent poisoning was beneficial for the antidotalreatment of sarin or cyclosarin poisoning, although their benefit at 24 h after poisoning was not significant, with the exception of the higher dose of MB444 against Cyclosarin. Expand
Influence of experimental end point on the therapeutic efficacy of the antinicotinic compounds MB408, MB442 and MB444 in treating nerve agent poisoned mice – a comparison with oxime-based treatment
TLDR
Results contrast with a study in guinea-pigs using a structurally-related compound, MB327, which showed a striking increase in protection at 6 h compared to 24’h, and it is suggested that the disparity may be due to pharmacokinetic differences between the two animal species. Expand
In silico and in vitro evaluation of two novel oximes (K378 and K727) in comparison to K-27 and pralidoxime against paraoxon-ethyl intoxication
TLDR
It is concluded that the novel oximes K378 and K727 are unlikely to be clinically useful and allow avoidance of unnecessary in vivo animal work and contribute to the reduction of laboratory animal use. Expand
Reactivation potency of two novel oximes (K456 and K733) against paraoxon-inhibited acetyl and butyrylcholinesterase: In silico and in vitro models.
TLDR
Both in vitro and in silico studies conclude that K456 and K733 are unlikely to be used as reactivators of paraoxon-inhibited AChE or BChE. Expand
Electrophysiological investigation of the effect of structurally different bispyridinium non-oxime compounds on human α7-nicotinic acetylcholine receptor activity-An in vitro structure-activity analysis.
TLDR
The electrophysiological properties of the human nAChR subtype α7 (hα7-nAChRs) and the functional effect of the 4-tert-butyl bispyridinium (BP) compound MB327 and of a series of novel substituted bispyrsinium compounds on the receptors are investigated by an automated patch clamp technique. Expand
Counteracting desensitization of human α7-nicotinic acetylcholine receptors with bispyridinium compounds as an approach against organophosphorus poisoning.
TLDR
Identification of more potent compounds able to restore nAChR function in OP intoxication is needed for development of a putative efficient antidote. Expand
Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning
TLDR
New therapeutic approaches for pre‐ and post‐exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Expand

References

SHOWING 1-10 OF 44 REFERENCES
Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig.
TLDR
MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision. Expand
Review of Oximes in the Antidotal Treatment of Poisoning by Organophosphorus Nerve Agents
  • J. Kassa
  • Chemistry, Medicine
  • Journal of toxicology. Clinical toxicology
  • 2002
TLDR
The H oximes appear to be very promising antidotes against nerve agents because they are able to protect experimental animals from toxic effects and improve survival of animals poisoned with supralethal doses. Expand
Antidotal treatment of GF-agent intoxication in mice with bispyridinium oximes.
TLDR
HS-6, K033 and BI-6 as well as obidoxime were comparably effective antidotes against GF-agent intoxication and their therapeutic ratios were similar. Expand
Two possibilities how to increase the efficacy of antidotal treatment of nerve agent poisonings.
TLDR
The review describes the evaluation of the potency of newly developed oximes or combinations of oximes to reactivate nerve agent-inhibited acetylcholinesterase and to counteract the acute toxicity of nerve agents in comparison with single commonly used oxime. Expand
Structure-activity relationship and efficacy of pyridinium oximes in the treatment of poisoning with organophosphorus compounds: a review of recent data.
  • M. Jokanović
  • Chemistry, Medicine
  • Current topics in medicinal chemistry
  • 2012
TLDR
The latest data on structure-activity relationship of pyridinium oximes including their efficacy in treatment of poisoning with organophosphorus compounds are reviewed. Expand
Affinities of bispyridinium non-oxime compounds to [(3)H]epibatidine binding sites of Torpedo californica nicotinic acetylcholine receptors depend on linker length.
TLDR
A homologous series of unsubstituting and 4-tert-butyl-substituted bispyridinium compounds with different alkane linker lengths was investigated in competition binding experiments and it was demonstrated that divalent cations increased the affinity of [(3)H]epibatidine. Expand
Interaction of bispyridinium compounds with the orthosteric binding site of human α7 and Torpedo californica nicotinic acetylcholine receptors (nAChRs).
TLDR
The results of the present study do not indicate a correlation between the affinity to the orthosteric binding site and the functional improvement of neuromuscular transmission and it is assumed that other mechanisms contribute to the therapeutic effect of the tested compounds. Expand
Direct reaction of oximes with sarin, soman, or tabun in vitro
TLDR
The maximal reaction velocities reveal that the detoxification of the nerve agents by direct reaction with oximes and the subsequent decomposition of the phosphonyl oxime in vivo do not substantially contribute to the therapeutic effect of these antidotes. Expand
Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes.
TLDR
There is obviously no direct structure-activity relationship for the various interactions of human AChE, OPs and oximes, indicating the superior inhibitory potency of organophosphonates. Expand
Neuroprotective efficacy of newly developed oximes in comparison with currently available oximes in tabun-poisoned rats
The ability of two newly developed oximes (K361, K378) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the oxime K203 and trimedoxime using a functional observationalExpand
...
1
2
3
4
5
...