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 several nerve agents (tabun, sarin and soman) in mice with and without treatment. The addition of MB327 increased the therapeutic efficacy of atropine alone, and atropine in combination with an oxime, against all three nerve agents, although differences in the LD50 values only reached statistical significance for sarin. In conclusion, the addition of the compound MB327 to the standard antidotal treatment of acute poisonings with nerve agents was beneficial regardless of the chemical structure of the nerve agent, although at the dose employed, MB327 in combination with atropine, or atropine and an oxime, provided only a modest increase in protection ratio. These results from mice, and previous ones from guinea-pigs, provide consistent evidence for additional, albeit modest, efficacy resulting from the inclusion of the antinicotinic compound MB327 in standard antidotal therapy. Given the typically steep probit slope for the dose-lethality relationship for nerve agents, such modest increases in protection ratio could provide significant survival benefit.

• Klíčová slova
• Atropine, MB327, mice, nerve agents, oximes,
• MeSH
• antidota aplikace a dávkování   terapeutické užití   toxicita   MeSH
• atropin aplikace a dávkování   terapeutické užití   toxicita   MeSH
• inbrední kmeny myší MeSH
• kombinovaná farmakoterapie MeSH
• LD50 MeSH
• molekulární struktura MeSH
• nervová bojová látka otrava   MeSH
• otrava farmakoterapie   MeSH
• oximy aplikace a dávkování   terapeutické užití   toxicita   MeSH
• pyridinové sloučeniny aplikace a dávkování   chemická syntéza   terapeutické užití   toxicita   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antidota MeSH
• atropin MeSH
• MB327 MeSH Prohlížeč
• nervová bojová látka MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH

The therapeutic efficacy of treatments for acute intoxication with highly toxic organophosphorus compounds, called nerve agents, usually involves determination of LD50 values 24 h after nerve agent challenge without and with a single administration of the treatment. Herein, the LD50 values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated intoxication were investigated in mice for experimental end points of 6 and 24 h. The LD50 values of the nerve agents were evaluated by probit-logarithmical analysis of deaths within 6 and 24 h of i.m. challenge of the nerve agent at five different doses, using six mice per dose. The efficiency of atropine alone or atropine in combination with an oxime was practically the same at 6 and 24 h. The therapeutic efficacy of the higher dose of the antinicotinic compound MB327 was slightly higher at the 6 h end point compared to the 24 h end point for soman and tabun intoxication. A higher dose of MB327 increased the therapeutic efficacy of atropine alone for sarin, soman and tabun intoxication, and that of the standard antidotal treatment (atropine and oxime) for sarin and tabun intoxication. The therapeutic efficacy of MB327 was lower than the oxime-based antidotal treatment. To compare the 6 and 24 h end points, the influence of the experimental end point was not observed, with the exception of the higher dose of MB327. In addition, only a negligible beneficial impact of the compound MB327 was observed. Nevertheless, antinicotinics may offer an additional avenue for countering poisoning by nerve agents that are difficult to treat, and synthetic and biological studies towards the development of such novel drugs based on the core bispyridinium structure or other molecular scaffolds should continue.

• Klíčová slova
• MB327, atropine, mice, nerve agents, oximes,
• Publikační typ
• časopisecké články MeSH

The design of MB327, a bispyridinium compound that ameliorates the nicotinic effects of acute organophosphorus nerve agent (NA) intoxication, followed an observation made by the German pharmacologist Klaus Schoene in the 1970s, who noted therapeutic activity in bispyridinium molecules missing the usual oxime group, CHNOH. Some of these compounds protected mice against soman. One structurally related to obidoxime called HY10 had this action. Its oxime moieties were capped by tert-butyl groups: CH=NOtBu. We modified HY10 by changing the bridge between the pyridinium units from a dimethylene ether to a trimethylene group (CH2OCH2 → CH2CH2CH2) and prepared a novel relative of trimedoxime, called LB1, whose synthesis and stereochemistry are described. Unlike obidoxime or trimedoxime, LB1 because of its capped oxime groups, cannot directly reactivate NA inhibited acetylcholinesterase. Its antidotal activity in mice is now reported. The therapeutic efficacy of LB1, atropine alone, atropine with LB1, atropine with an oxime (HI-6, obidoxime or trimedoxime), and atropine with an oxime and LB1, was studied by determining the LD50 values of the NAs soman, sarin, or tabun in mice treated with these compounds or mixtures. LB1 exceeded MB327 in toxicity and its activity was insufficient for a useful addition to the current standard antidotal treatment (protective ratio data are compared to those of MB327). Although this study produced largely negative biological results, the therapeutically beneficial mechanism of the effective bispyridinium non-oxime analogues is unclear, and has been demonstrated only in vivo. The present study points out directions in structural optimisation unlikely to yield the desired therapeutic outcomes and provides a literature review that could promote creative thinking for the design of widely-desirable non-oxime therapeutics for anticholinesterase inhibitors.

• Klíčová slova
• Bispyridinium, LB1, Mechanism, Mice, Nerve agent, Pyridinecarboxaldoxime,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota * chemická syntéza   chemie   farmakologie   terapeutické užití   MeSH
• atropin terapeutické užití   farmakologie   MeSH
• cholinesterasové inhibitory toxicita   MeSH
• myši MeSH
• nervová bojová látka * toxicita   MeSH
• organofosforové sloučeniny * toxicita   MeSH
• oximy chemie   MeSH
• pyridinové sloučeniny * chemická syntéza   chemie   terapeutické užití   farmakologie   MeSH
• soman toxicita   MeSH
• trimedoxim chemie   chemická syntéza   farmakologie   terapeutické užití   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota * MeSH
• atropin MeSH
• cholinesterasové inhibitory MeSH
• MB327 MeSH Prohlížeč
• nervová bojová látka * MeSH
• organofosforové sloučeniny * MeSH
• oximy MeSH
• pyridinové sloučeniny * MeSH
• soman MeSH
• trimedoxim MeSH

Therapeutic efficacy of antidotal treatment of acute poisoning by nerve agents is generally assessed by the evaluation of LD50 values of nerve agents over 24 h following poisoning without or with a single administration of antidotal treatment. In this study, LD50 values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated poisoning were evaluated in mice for two experimental end points - 6 h and 24 h. While the efficacy of atropine or oxime-based antidotal treatment was the same regardless of the experimental end point, the therapeutic efficacy of all three newly developed bispyridinium non-oxime compounds (MB408, MB442, and MB444) was mostly slightly higher at the 6 h end point compared to the 24 h end point, although the therapeutic efficacy of MB compounds was not superior to oxime-based antidotal treatment. These 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. It is suggested that the disparity may be due to pharmacokinetic differences between the two animal species.

• Klíčová slova
• MB compounds, Nerve agents, atropine, mice, oximes,
• MeSH
• antidota farmakologie   MeSH
• časové faktory MeSH
• chemické bojové látky toxicita   MeSH
• LD50 MeSH
• myši MeSH
• nikotinoví antagonisté farmakologie   MeSH
• organofosfáty toxicita   MeSH
• organofosforové sloučeniny toxicita   MeSH
• otrava organofosfáty farmakoterapie   etiologie   MeSH
• oximy farmakologie   MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• sarin toxicita   MeSH
• soman toxicita   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• antidota MeSH
• chemické bojové látky MeSH
• cyclohexyl methylphosphonofluoridate MeSH Prohlížeč
• MB408 MeSH Prohlížeč
• MB442 MeSH Prohlížeč
• MB444 MeSH Prohlížeč
• nikotinoví antagonisté MeSH
• organofosfáty MeSH
• organofosforové sloučeniny MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy MeSH
• sarin MeSH
• soman MeSH
• tabun MeSH Prohlížeč