Efficacy and pharmacokinetic/pharmacodynamic study of 1,1'-methylenebis{4-[(hydroxyimino)methyl] pyridinium} dimethanesulfonate in guinea pigs and rhesus macaques exposed to cyclosarin.
Male Hartley guinea pigs and male rhesus macaques were used to determine an efficacious dose of 1,1'-methylenebis{4-[(hydroxyimino)methyl] pyridinium} dimethanesulfonate (MMB4 DMS) that would result in 80% survival, 24 hours following a single exposure to cyclosarin (GF). The pharmacokinetic/pharmacodynamic relationship between acetylcholinesterase activity and MMB4 plasma concentrations relative to survival was evaluated. Guinea pigs and non-human primates (NHPs) were concurrently administered MMB4 DMS (guinea pigs: 0, 10, 30, or 40 mg/kg, intramuscular [IM] and NHPs: 0.1, 1, 5, 10, or 20 mg/kg, IM), atropine, and diazepam following a 3 × median lethal dose (LD50) GF challenge. Clinical observations were evaluated using a quality-of-life (QOL) scoring system. All GF-exposed animals exhibited typical signs of nerve agent poisoning immediately following challenge. In guinea pigs, 24-hour survival was 0%, 50%, 90%, and 90% for 0, 10, 30, and 40 mg/kg MMB4 DMS groups, respectively. In addition, nearly all animals surviving to 24 hours were clinically normal, with many in the 30 and 40 mg/kg MMB4 DMS dose group observed as normal by 4 hours post-challenge. In NHPs, survival was 100% for all treatment groups, with all animals noted as clinically normal by 48 hours. Following treatment with atropine/MMB4 DMS/diazepam, NHPs exhibited dose- and temporal-related decreases in incidence and duration of the clinical signs of toxicity. The QOL scores improved with increasing MMB4 DMS dose in both species. The estimated ED80s were 25.5 mg/kg MMB4 DMS (human equivalent dose [HED] of 5.5 mg/kg) and ≤ 0.1 mg/kg (HED of 0.03 mg/kg) in guinea pigs and NHPs, respectively.
Medical Chemical Defense, Battelle, 505 King Avenue, Columbus, OH 43201, USA. harvilchuckj@battelle.org
Jill A
JA
Harvilchuck
S Peter
SP
Hong
Jamie S
JS
Richey
Merrill R
MR
Osheroff
Jerry D
JD
Johnson
D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001285:Atropine / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D003975:Diazepam / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008253:Macaca mulatta; D008297:Male; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010091:Oximes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D010091:Oximes; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); D001285:Atropine; D003975:Diazepam; C053914:cyclohexyl methylphosphonofluoridate
MMB4 DMS; acetylcholinesterase; cyclosarin; guinea pig; monkey; organophosphate; pahrmacodynamic; pharmacokinetic