title: Physostigmine and hyoscine improves protection against the lethal and incapacitating effects of nerve agent poisoning in the guinea-pig.
abstract: This study is drawn from a work programme aimed at developing improved medical counter measures for nerve agent poisoning. Guinea-pigs were administered pyridostigmine (5.1 microg/h) or physostigmine (4.7 microg/h) and hyoscine (1.94 microg/h) for 6 days via a subcutaneously implanted mini osmotic pump. Pyridostigmine inhibited red cell acetylcholinesterase (AChE) by 44.2 +/- 2.7% and plasma cholinesterase (ChE) by 29.9 +/- 1.8%. Physostigmine and hyoscine inhibited red cell AChE by 18.7 +/- 3.7% and plasma ChE by 44.1 +/- 3.1%. On day 6, animals were challenged with a lethal dose of tabun (GA; 125 microg/kg), sarin (GB; 51.2 microg/kg), soman (GD; 31.2 microg/kg), GF (50 microg/kg) or VX (11.25 microg/kg) administered by the subcutaneous route. Animals were closely observed for signs of poisoning. The time to the onset of signs of poisoning was similar for all the agents except for VX, which showed a delay compared to the other agents. Following pretreatment with either pyridostigmine or physostigmine and hyoscine most animals survived for 2-3 h following nerve agent administration. In contrast, only physostigmine and hyoscine prevented or reduced the duration of the signs of incapacitation and the temperature drop produced by all the agents. Pyridostigmine-pretreated animals showed little or no recovery from incapacitation prior to death. Physostigmine and hyoscine pretreatment provided statistically (P < 0.05) better protection against GB, GD and VX lethality (24 h) than pyridostigmine pretreatment and better protection against GA and GF lethality.
authors.affiliation: Biomedical Sciences Department, Salisbury, Wilts, UK. jrwetherell@dstl.gov.uk
authors.forename: Janet
authors.initials: J
authors.lastname: Wetherell
authors.forename: Tracey
authors.initials: T
authors.lastname: Hall
authors.forename: Sarah
authors.initials: S
authors.lastname: Passingham
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002802:Cholinesterases / Q000097:blood; D004343:Drug Implants; D006168:Guinea Pigs; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage / Q000633:toxicity; D010830:Physostigmine / Q000494:pharmacology*; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D012601:Scopolamine / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002802:Cholinesterases; D004343:Drug Implants; D018727:Muscarinic Antagonists; D009946:Organothiophosphorus Compounds; D010830:Physostigmine; D011729:Pyridostigmine Bromide; D012601:Scopolamine; C009680:VX-agent