title: Continuous administration of low dose rates of physostigmine and hyoscine to guinea-pigs prevents the toxicity and reduces the incapacitation produced by soman poisoning.
abstract: A regime was developed, using mini-osmotic pumps, for the continuous subcutaneous administration of low doses of physostigmine (12.1, 9.7, 4.85 and 2.43 micrograms h-1), in combination with hyoscine (1.94 or 0.39 micrograms h-1), to guinea-pigs for up to 13 days. Physostigmine, in combination with hyoscine, inhibited plasma cholinesterase, and red blood cell and brain acetylcholinesterase, in a concentration-dependent manner, did not affect the normal growth rate of guinea-pigs, and produced no obvious signs of poisoning. A dose rate of 4.85 micrograms h-1 physostigmine and 1.94 micrograms h-1 hyoscine was required to inhibit red cell acetylcholinesterase by 30% and brain acetylcholinesterase by 5-15%, with an accompanying plasma hyoscine concentration of 700-850 pg mL-1. There was an apparent decline in red cell acetylcholinesterase activity during the 13 days. Hyoscine levels were higher in the cholinergic-rich areas of the brain than in the plasma. Continuous pretreatment (1 or 6 days) with physostigmine (4.84 micrograms h-1) and hyoscine (1.94 micrograms h-1) provided complete protection against the lethal effects, and minimized the incapacitation and weight loss produced by soman at a dose equivalent to the LD99 value. Following soman challenge, guinea-pigs exhibited early signs of soman poisoning, but generally these signs of poisoning were minimal by 1-2 h. Extending the pretreatment time to 13 days protected 75% of the guinea-pigs against the lethal effects of soman poisoning. Red cell acetylcholinesterase activity, 24 h after soman poisoning, was higher following continuous pretreatment with physostigmine and hyoscine than after acute treatment with atropine.
authors.affiliation: Chemical and Biological Defence Establishment, Salisbury, Wiltshire, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Wetherell
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000097:blood; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004912:Erythrocytes / Q000201:enzymology; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D015918:Infusion Pumps, Implantable; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000201:enzymology; D008636:Mesencephalon / Q000187:drug effects / Q000201:enzymology; D009995:Osmosis; D010830:Physostigmine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011041:Poisoning / Q000401:mortality / Q000517:prevention & control; D012601:Scopolamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012999:Soman / Q000506:poisoning*
chemical_list: D002800:Cholinesterase Inhibitors; D012999:Soman; D010830:Physostigmine; D012601:Scopolamine; D000110:Acetylcholinesterase