Universiẗat, Diss., 2004--München.

Chemical warfare agents including organophosphorus nerve agents (NA) continue to be a significant threat to both military and civilian populations. The current Canadian Armed Forces (CAF) treatment of NA poisoning includes administration of the oxime HI-6 (used to reactivate inhibited acetylcholinesterase) in combination with atropine contained in an autoinjector, with a benzodiazepine also being administered. Two salts of HI-6 are currently available: HI-6 2Cl (1-[[[4-(Aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyiminio)methyl] pyridinium dichloride (MW 376.22 g/mol) and HI-6 DMS (1-[[[4-(Aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyiminio)methyl] pyridinium dimethanesulfonate (MW 477.49 g/mol). Currently HI-6 is available to the Canadian Armed Forces under a special access program. In order to attain licensure of HI-6 numerous studies must be carried out in animal models to ensure its safety (tolerability and toxicity), efficacy and pharmacokinetics prior to human clinical trials. The present experiment aimed to determine and compare the pharmacokinetic parameters of HI-6 in two animal models under various conditions including: direct comparison of salts (HI-6 2Cl compared to HI-6 DMS), comparison of routes of administration (intramuscular compared to intravenous), comparison of effect of anaesthetic, comparison of different concentrations of HI-6, determination of the effect of atropine sulphate co-administration and evaluation of calculated pharmacokinetic parameters when infusing HI-6. Serial plasma samples were collected and HI-6 levels were quantified using a HPLC method. In all studies a significant difference was reported for absorption/distribution parameters when comparing salts. Additionally the absorption/distribution parameters when comparing routes of administration were significantly different however all other parameters were similar. Significant differences in calculated parameters were reported when examining the effect of anaesthetic on the pharmacokinetics of HI-6. Similar to previous ascending dose studies, differences were reported for the absorption/distribution kinetics. Co-administration of HI-6 with atropine sulphate did not have significant effect on the pharmacokinetics of HI-6. The determined pharmacokinetic values for both salts were accurate for the determination of an infusion rate to reach and maintain a target plasma concentration. Finally the calculated animal model pharmacokinetic data was compared to previously published human clinical trial data and the calculated pharmacokinetic values were found to be similar.

Reactivators of acetylcholinesterase inhibited by organophosphate inhibitors play an important role in organophosphate poisoning therapy. There are a large number of reactivators being tested for their ability of penetration through blood-brain barrier (BBB) nowadays. The main aim of this thesis is to test this ability in four well know reactivators {--} HI-6, K-027, K-074 and TO-032. The 5% lethal dose (LD50) {--} therapeutic dose - of each reactivator was i.m. (intramuscularly) applied to experimental animals (Wistar rats) into right posterior thighs. Then the animals were sacrificed and the blood (plasma) and brain were collected for HPLC analysis. Subsequently, brain and plasma were frozen at -80 °C and stored until the assay. The reactivator concentrations were measured in plasma and four parts of the brain {--} frontal cortex (FC), basal ganglia (BG), ponto-medullar part (PM) and cerebellum (Ce). There were five animals for each group used for the purpose of the experiment. The concentrations of reactivators in plasma and blood samples were measured using HPLC-UV/VIS methodology. HI-6 concentrations CFC were on the average 4.29% of Caverage in plasma, CBG were on the average 1.9% of Caverage in plasma, CPM were on the average 2.3% of Caverage in plasma, and CCe were on the average 1.85% of Caverage in plasma. These rates were counted from all concentrations within the scope of particular observed parts of the brain. All the other tested reactivators were not quantified in brain at all.