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

Toxicology. 2005 Mar 30;208(3):399-409. doi: 10.1016/j.tox.2004.12.001.

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Atropine / pharmacology
  • Chemical Warfare Agents / poisoning*
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Male
  • Neuroprotective Agents / pharmacokinetics*
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Organophosphate Poisoning*
  • Organophosphorus Compounds
  • Oximes
  • Pyridinium Compounds / pharmacokinetics*
  • Pyridinium Compounds / pharmacology
  • Pyridinium Compounds / therapeutic use
  • Soman / poisoning*
  • Swine
  • Time Factors

Substances

  • Chemical Warfare Agents
  • Neuroprotective Agents
  • Organophosphorus Compounds
  • Oximes
  • Pyridinium Compounds
  • Atropine
  • Soman
  • asoxime chloride
  • cyclohexyl methylphosphonofluoridate