title: Treatment efficacy in a soman-poisoned guinea pig model: added value of physostigmine?
abstract: Current treatment of organophosphate poisoning is insufficient, and survivors may suffer from long-lasting adverse effects, such as cognitive deficits and sleep-wake disturbances. In the present study, we aimed at developing a guinea pig model to investigate the benefits of immediate and delayed stand-alone therapy on the development of clinical signs, EEG, heart rate, respiration and AChE activity in blood and brain after soman poisoning. The model allowed the determination of the therapeutic effects at the short-term of obidoxime, atropine and physostigmine. Obidoxime exerted the highest therapeutic efficacy at administration of the lowest dose (3.1 mg/kg i.m.), whereas two higher doses (9 and 18 mg/kg) were less effective on most parameters. Addition of atropine at 0.03 and 3 mg/kg (i.m.) to the treatment did not improve the therapeutic effects of obidoxime alone. Physostigmine (0.8 mg/kg im) at 1 min after poisoning increased mortality. Two lower doses (0.1 and 0.3 mg/kg i.m.) showed improvements on all parameters but respiration. The middle dose was most effective in preventing seizure development and therefore assessed as the most efficacious dose. Combined treatment of obidoxime and physostigmine shortened the duration of seizures, if present, from up to 80 min to ~10-15 min. In practice, treatment will be employed when toxic signs appear, with the presence of high levels of AChE inhibition in both blood and brain. Administration of physostigmine at that moment showed to be redundant or even harmful. Therefore, treatment of OP poisoning with a carbamate, such as physostigmine, should be carefully re-evaluated.
authors.affiliation: TNO Defence, Security and Safety, BU CBRN Protection, Rijswijk, The Netherlands. marloes.joosen@tno.nl
authors.forename: Marloes J A
authors.initials: MJ
authors.lastname: Joosen
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Herman P M
authors.initials: HP
authors.lastname: van Helden
mesh_terms: D000818:Animals; D001285:Atropine / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects; D002219:Carbamates / Q000627:therapeutic use*; D002619:Chemical Warfare Agents / Q000506:poisoning*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004569:Electroencephalography / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D023421:Models, Animal; D009768:Obidoxime Chloride / Q000494:pharmacology; D010276:Parasympatholytics / Q000627:therapeutic use; D010830:Physostigmine / Q000627:therapeutic use*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D012999:Soman / Q000506:poisoning*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D002219:Carbamates; D002619:Chemical Warfare Agents; D010276:Parasympatholytics; D009768:Obidoxime Chloride; D001285:Atropine; D012999:Soman; D010830:Physostigmine