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dc.contributor.advisorMikler, John R.en_US
dc.creatorBohnert, Saraen_US
dc.date.accessioned2014-11-04T06:41:15Z
dc.date.available2014-11-04T06:41:15Z
dc.date.created2014-07en_US
dc.date.issued2014-08-13en_US
dc.date.submittedJuly 2014en_US
dc.identifier.urihttp://hdl.handle.net/10388/ETD-2014-07-1597en_US
dc.description.abstractChemical 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.en_US
dc.language.isoengen_US
dc.subjectOximeen_US
dc.subjectHI-6en_US
dc.subjectAtropine Sulphateen_US
dc.subjectPharmacokineticsen_US
dc.subjectOrganophosphatesen_US
dc.subjectNerve Agentsen_US
dc.titleThe oxime HI-6 : Determination of the pharmacokinetics and the effect of atropine co-administration in guinea pigs and domestic swineen_US
thesis.degree.departmentPharmacologyen_US
thesis.degree.disciplinePharmacologyen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelMastersen_US
thesis.degree.nameMaster of Science (M.Sc.)en_US
dc.type.materialtexten_US
dc.type.genreThesisen_US
dc.contributor.committeeMemberGopalakrishnan, Venkaten_US
dc.contributor.committeeMemberTaghibiglou, Changizen_US
dc.contributor.committeeMemberDesai, Kashen_US


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