title: Restoration of soman-blocked neuromuscular transmission in human and rat muscle by the bispyridinium non-oxime MB327 in vitro.
abstract: The standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes is not sufficiently effective against all types of nerve agents. Alternative therapeutic strategies are required and bispyridinium non-oximes, acting as nicotinic antagonists, were identified as promising compounds. A previous study showed that the di(methanesulfonate) salt of the bispyridinium compound MB327 could restore soman-impaired neuromuscular function in vitro and improve survival of sarin, soman and tabun poisoned guinea pigs in vivo. Here, by using the indirect field stimulation technique, the ability of MB327 to counteract soman-impaired neuromuscular transmission was investigated in human intercostal muscle and rat diaphragm preparations. MB327 restored muscle force in a concentration-dependent manner in both species without reactivating soman-inhibited acetylcholinesterase. The therapeutic effect of MB327 could be washed out, indicating a direct effect at the nicotinic receptor level. Also the ability of MB327 to restore respiratory muscle function could be demonstrated for the first time in rat and human tissue. In combination with previous in vitro and in vivo findings MB327 may be considered a promising compound for the treatment of nerve agent poisoning and further studies are needed to identify optimized drug combinations, concentrations and dosing intervals to provide an effective therapy for OP poisoning.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Seeger
authors.forename: M
authors.initials: M
authors.lastname: Eichhorn
authors.forename: M
authors.initials: M
authors.lastname: Lindner
authors.forename: K V
authors.initials: KV
authors.lastname: Niessen
authors.forename: J E H
authors.initials: JE
authors.lastname: Tattersall
authors.forename: C M
authors.initials: CM
authors.lastname: Timperley
authors.forename: M
authors.initials: M
authors.lastname: Bird
authors.forename: A C
authors.initials: AC
authors.lastname: Green
authors.forename: H
authors.initials: H
authors.lastname: Thiermann
authors.forename: F
authors.initials: F
authors.lastname: Worek
mesh_terms: D000368:Aged; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007366:Intercostal Muscles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011726:Pyridinium Compounds / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012132:Respiratory Muscles / Q000187:drug effects / Q000378:metabolism; D012999:Soman / Q000633:toxicity*; D013045:Species Specificity
chemical_list: D000931:Antidotes; D002619:Chemical Warfare Agents; C571852:MB327; D011726:Pyridinium Compounds; D011978:Receptors, Nicotinic; D012999:Soman