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• W2010210144 abstract "There is acute concern that nerve agents (ie, sarin, soman, tabun, and VX) might be used on civilian and military populations. Standard treatment protocols for nerve-agent poisoning advise supportive measures, combined with the antidotal use of a cholinesterase reactivator (pralidoxime), atropine, and diazepam for seizures. In animals, however, the effectiveness of atropine for high doses of nerve agents is doubtful, probably because of atropine's weak effects on the central nervous system. Furthermore, there is substantial animal evidence that addition of a more centrally acting anticholinergic agent could improve survival and decrease morbidity after nerve-agent toxic effects. My co-workers and I have shown that the centrally active anticholinergic drug, Hyoscine, alone and in combination with the non-centrally acting anticholinergic agent, hyoscine methylnitrate, is significantly more effective than atropine in preventing the lethal effects of physostigmine in Swiss Webster mice. Physostigmine is a reversible centrally acting cholinesterase inhibitor which can serve as a prototypical nerve agent.1Janowsky DS Drennan M Berkowitz A Turken A Risch SC Antagonism of physostigmine-induced lethality by a combination of scopolamine and methscopolamine.Acta Pharmacol Toxicol (Copenh). 1985; 56: 154-157Crossref PubMed Scopus (7) Google Scholar, 2Janowsky DS Drennan M Berkowitz A Turken A Risch SC Comparative effects of scopolamine and atropine in preventing cholinesterase inhibitor induced lethality.Mil Med. 1985; 150: 693-695PubMed Google Scholar For low doses of physostigmine, pretreatment with subcutaneous atropine, or Hyoscine, or hyoscine methylnitrate are all roughly equally effective in preventing physostigmine-induced death.1Janowsky DS Drennan M Berkowitz A Turken A Risch SC Antagonism of physostigmine-induced lethality by a combination of scopolamine and methscopolamine.Acta Pharmacol Toxicol (Copenh). 1985; 56: 154-157Crossref PubMed Scopus (7) Google Scholar, 2Janowsky DS Drennan M Berkowitz A Turken A Risch SC Comparative effects of scopolamine and atropine in preventing cholinesterase inhibitor induced lethality.Mil Med. 1985; 150: 693-695PubMed Google Scholar However, at supralethal doses of physostigmine, Hyoscine was much more effective than hyoscine methyl-nitrate and atropine, respectively, and a combination of hyoscine methylnitrate plus Hyoscine was even more effective than Hyoscine alone in preventing death (table).TableEffects of atropine, Hyoscine, and Hyoscine plus Hyoscine methonitrate on survival after physostigmine poisoning in Swiss Webster miceSurvival by physostigmine dose (%)0·75 mg/kg2·25 mg/kg3·0 mg/kg6·0 mg/kgAntidote doseSaline17000Hyoscine 0·025 mg/kg86900Hyoscine 0·025 mg/kg + hyoscine····60*p<0·001.43†p<0·01.methylnitrate 3 mg/kgHyoscine 0·1 mg/kg100625750Hyoscine 0·1 mg/kg + hyoscine methylnitrate 3 mg/kg····8493‡p<0·05.Hyoscine 0·2 mg/kg100906671Hyoscine 0·2 mg/kg + hyoscine methylnitrate 3 mg/kg····9385Atropine 0·025 mg/kg640····Atropine 0·1 mg/kg10010‡p<0·05.····Atropine 0·2 mg/kg10018‡p<0·05.····p values calculated by comparing variables with equivalent Hyoscine doses.* p<0·001.† p<0·01.‡ p<0·05. Open table in a new tab p values calculated by comparing variables with equivalent Hyoscine doses. Consistent with our results, workers in many animal studies done before and after our work have shown better effectiveness of hyoscine, tri-hexyphenidyl, biperiden, and other centrally acting anticholinergic agents than for atropine in antagonising nerve-agent-induced seizures and death.3Philippens IH Melchers BP Olivier B Bruijnzeel PL Scopolamine augments the efficacy of physostigmine against soman poisoning in guinea pigs.Pharmacol Biochem Behav. 2000; 65: 175-182Crossref PubMed Scopus (42) Google Scholar, 4McDonough Jr, JH Zoeffel LD McMonagle J Copeland TL Smith CD Anticonvulsant treatment of nerve agent seizures: anticholinergic drugs versus diazepam in soman-intoxicated guinea pigs.Epilepsy Res. 2000; 38: 1-14Crossref PubMed Scopus (134) Google Scholar Most of those studies included pretreatment with carbamates (physo-stigmine, pyridostigmine), atropine, or both, and post-treatment with choline-sterase reactivators, atropine, or both. Paralleling these animal studies,1Janowsky DS Drennan M Berkowitz A Turken A Risch SC Antagonism of physostigmine-induced lethality by a combination of scopolamine and methscopolamine.Acta Pharmacol Toxicol (Copenh). 1985; 56: 154-157Crossref PubMed Scopus (7) Google Scholar, 2Janowsky DS Drennan M Berkowitz A Turken A Risch SC Comparative effects of scopolamine and atropine in preventing cholinesterase inhibitor induced lethality.Mil Med. 1985; 150: 693-695PubMed Google Scholar, 3Philippens IH Melchers BP Olivier B Bruijnzeel PL Scopolamine augments the efficacy of physostigmine against soman poisoning in guinea pigs.Pharmacol Biochem Behav. 2000; 65: 175-182Crossref PubMed Scopus (42) Google Scholar, 4McDonough Jr, JH Zoeffel LD McMonagle J Copeland TL Smith CD Anticonvulsant treatment of nerve agent seizures: anticholinergic drugs versus diazepam in soman-intoxicated guinea pigs.Epilepsy Res. 2000; 38: 1-14Crossref PubMed Scopus (134) Google Scholar My coworkers and I5Janowsky D Risch SC Ziegler M Gillin JC Antagonistic effects of scopolamine and atropine on the physostigmine response in man.Mil Med. 1987; 152: 579-581PubMed Google Scholar have shown in human beings that Hyoscine (0·5 mg intramuscular), by contrast with hyoscine methylnitrate (0·75 mg intramuscular) and atropine (1·0 mg. intramuscular), effectively blocks the behavioural (anergia, fatigue, and depression), cardiovascular (increased blood pressure and pulse rate), and endocrinological (increased cortisol, epinephrine, prolactin, adrenocortico-tropic hormone, and β-endorphin) effects of low-dose intravenous physo-stigmine (0·022 mg/kg). There may, therefore, be an effective way of treating nerve-agent poisoning with a combination of central and peripheral anticholinergic agents, along with standard treatments. Although centrally acting anticholinergic drugs have unique side-effects, including causing disorientation, confusion, and hallucinations, their use may be lifesaving." @default.
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• W2010210144 title "Central anticholinergics to treat nerve-agent poisoning" @default.
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