title: The pharmacokinetics and pharmacodynamics of two HI-6 salts in swine and efficacy in the treatment of GF and soman poisoning.
abstract: Anesthetized pigs were injected i.m. with 500 mg HI-6 dichloride (HI-6 2Cl) (1-[[[4-(aminocarbonyl)-pyridinio]methoxy]methyl]-2[(hydroxyimino)methyl]pyridinium dichloride; CAS 34433-31-3)) or the molar equivalent of HI-6 dimethanesulphonate (HI-6 DMS) 633 mg. Plasma HI-6 concentrations were measured by HPLC (1, 3, 5, 10, 15, 30, 60 min and every 30 min until 4h or 6h following the i.v. or i.m. dose respectively) while a variety of physiological responses were continuously examined. HI-6 (500 mg 2Cl or 633 mg DMS) resulted in an identical pharmacokinetic profile unaffected by atropine co-administration. Neither HI-6 salt resulted in clinically significant changes in cardiovascular or respiratory function. HI-6 DMS (1899 mg i.v.) resulted in plasma HI-6 concentrations about 10 times higher than measured following i.m. 500 mg 2Cl or 633 mg DMS and resulted in small transitory effect on mean arterial pressure. Atropine plus HI-6 DMS (1-9 mg/kg or 127-172 mg/kg i.m.) protected up to 100% of guinea pigs exposed to 5 x LD50 of GF (cyclohexyl methyl phosphonoflouridate) or soman (pinacolyl methylphosphonofluoridate) (GD) respectively. The results suggest that the two HI-6 salts have a similar pharmacokinetic profile while HI-6 DMS appears extremely safe and effective against nerve agents and may be as suitable for human use.
authors.affiliation: Chemical Biological Defence Section, Defence Research and Development Canada-Suffield, Box 4000, Medicine Hat Alberta, Alta., Canada T1A 8K6. paul.lundy@drdc-rddc.gc.ca
authors.forename: Paul M
authors.initials: PM
authors.lastname: Lundy
authors.forename: Ira
authors.initials: I
authors.lastname: Hill
authors.forename: Pierre
authors.initials: P
authors.lastname: Lecavalier
authors.forename: Murray G
authors.initials: MG
authors.lastname: Hamilton
authors.forename: Cory
authors.initials: C
authors.lastname: Vair
authors.forename: Corey
authors.initials: C
authors.lastname: Davidson
authors.forename: Kendal L
authors.initials: KL
authors.lastname: Weatherby
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Berger
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000506:poisoning*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D018696:Neuroprotective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D012999:Soman / Q000506:poisoning*; D013552:Swine; D013997:Time Factors
chemical_list: D002619:Chemical Warfare Agents; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; D012999:Soman; C022870:asoxime chloride; C053914:cyclohexyl methylphosphonofluoridate