The pharmacokinetics and pharmacodynamics of two HI-6 salts in swine and efficacy in the treatment of GF and soman poisoning

• Published in: Toxicology (Amsterdam) 2005-03, Vol.208 (3), p.399-409
• Main Authors: Lundy, Paul M., Hill, Ira, Lecavalier, Pierre, Hamilton, Murray G., Vair, Cory, Davidson, Corey, Weatherby, Kendal L., Berger, Bradley J.
• Format: Article
• Language: English
• Subjects: Animals; Atropine - pharmacology; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Chemical Warfare Agents - poisoning; Dose-Response Relationship, Drug; Gas, fumes; Guinea Pigs; Male; Medical sciences; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Organophosphate nerve agents; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Oximes (HI-6); Pharmacodynamics; Pharmacokinetics; Protective ratio; Pyridinium Compounds - pharmacokinetics; Pyridinium Compounds - pharmacology; Pyridinium Compounds - therapeutic use; Soman - poisoning; Swine; Time Factors; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2004.12.001

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 4 h or 6 h 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 × LD 50 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.