title: Restoration of nerve agent inhibited muscle force production in human intercostal muscle strips with HI 6.
abstract: An important factor for successful therapy of poisoning with organophosphorus compounds (OP) is the rapid restoration of blocked respiratory muscle function. To achieve this goal, oximes are administered for reactivation of inhibited acetylcholinesterase (AChE). Unfortunately, clinically used oximes, e.g. obidoxime and pralidoxime, are of limited effectiveness in poisoning with different OP nerve agents requiring the search for alternative oximes, e.g. HI 6. In view of substantial species differences regarding reactivation properties of oximes, the effect of HI 6 was investigated with sarin, tabun and soman exposed human intercostal muscle. Muscle force production by indirect field stimulation and the activity of the human muscle AChE was assessed. 30 μM HI 6 resulted in an almost complete recovery of sarin blocked muscle force and in an increase of completely inhibited muscle AChE activity to approx. 30% of control. In soman or tabun exposed human intercostal muscle HI 6 (50 and 100 μM) had no effect on blocked muscle force or on inhibited human muscle AChE activity. In addition, HI 6 up to 1000 μM had no effect on soman blocked muscle force indicating that this oxime has no direct, pharmacological effect in human tissue. These results emphasize that sufficient reactivation of AChE is necessary for a beneficial therapeutic effect on nerve agent blocked neuromuscular transmission.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937 Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Seeger
authors.forename: K V
authors.initials: KV
authors.lastname: Niessen
authors.forename: P
authors.initials: P
authors.lastname: Langer
authors.forename: J
authors.initials: J
authors.lastname: Gerhardus
authors.forename: F
authors.initials: F
authors.lastname: Worek
authors.forename: H
authors.initials: H
authors.lastname: Friess
authors.forename: R
authors.initials: R
authors.lastname: Bumm
authors.forename: A L
authors.initials: AL
authors.lastname: Mihaljevic
authors.forename: H
authors.initials: H
authors.lastname: Thiermann
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000368:Aged; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004558:Electric Stimulation; D006801:Humans; D066298:In Vitro Techniques; D007366:Intercostal Muscles / Q000187:drug effects* / Q000201:enzymology; D053580:Muscle Strength / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects; D010755:Organophosphates / Q000633:toxicity; D010091:Oximes / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012524:Sarin / Q000633:toxicity; D012999:Soman / Q000633:toxicity
chemical_list: D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D012999:Soman; D012524:Sarin; D000110:Acetylcholinesterase; C022870:asoxime chloride; C009374:tabun