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The phamacokinetics of medical countermeasures against nerve agents

The phamacokinetics of medical countermeasures against nerve agents
The phamacokinetics of medical countermeasures against nerve agents
Nerve agents are organophosphorus compounds that irreversibly inhibit acetylcholinesterase, causing accumulation of the neurotransmitter acetylcholine and this excess leads to an overstimulation of acetylcholine receptors. Inhalation exposure to nerve agent can be lethal in minutes and conversely, skin exposure may be lethal over longer durations. Medical Countermeasures (MedCM) are fielded in response to the threat posed by nerve agents. MedCM with improved efficacy are being developed but the efficacy of these cannot be tested in humans, so their effectiveness is proven in animals. It is UK Government policy that all MedCM are licensed for human use.

The aim of this study was to test the hypothesis that the efficacy of MedCM against nerve agent exposure by different routes could be better understood and rationalised through knowledge of the MedCM pharmacokinetics (PK). The PK of MedCM was determined in naïve and nerve agent poisoned guinea pigs. PK interactions between individual MedCM drugs when administered in combination were also investigated. In silico simulations to predict the concentration-time profiles of different administration regimens of the MedCM were completed using the PK parameters determined in vivo. These simulations were used to design subsequent in vivo PK studies and to explain or predict the efficacy or lack thereof for the MedCM.

The PK data generated in this study are the first such data in conscious guinea pigs, the small animal species of choice for determination of MedCM efficacy. These data show how PK can improve the understanding of MedCM efficacy. PK studies such as those reported here should be integrated into the development programmes of future MedCM.
University of Southampton
Armstrong, Stuart
345fcac3-1a0f-4cb3-8692-f82e8204ff31
Armstrong, Stuart
345fcac3-1a0f-4cb3-8692-f82e8204ff31
Green, Chris
5ee106e6-0a6f-423f-91c6-66382323a2bc
Clough, Geraldine
9f19639e-a929-4976-ac35-259f9011c494

Armstrong, Stuart (2014) The phamacokinetics of medical countermeasures against nerve agents. University of Southampton, Doctoral Thesis, 330pp.

Record type: Thesis (Doctoral)

Abstract

Nerve agents are organophosphorus compounds that irreversibly inhibit acetylcholinesterase, causing accumulation of the neurotransmitter acetylcholine and this excess leads to an overstimulation of acetylcholine receptors. Inhalation exposure to nerve agent can be lethal in minutes and conversely, skin exposure may be lethal over longer durations. Medical Countermeasures (MedCM) are fielded in response to the threat posed by nerve agents. MedCM with improved efficacy are being developed but the efficacy of these cannot be tested in humans, so their effectiveness is proven in animals. It is UK Government policy that all MedCM are licensed for human use.

The aim of this study was to test the hypothesis that the efficacy of MedCM against nerve agent exposure by different routes could be better understood and rationalised through knowledge of the MedCM pharmacokinetics (PK). The PK of MedCM was determined in naïve and nerve agent poisoned guinea pigs. PK interactions between individual MedCM drugs when administered in combination were also investigated. In silico simulations to predict the concentration-time profiles of different administration regimens of the MedCM were completed using the PK parameters determined in vivo. These simulations were used to design subsequent in vivo PK studies and to explain or predict the efficacy or lack thereof for the MedCM.

The PK data generated in this study are the first such data in conscious guinea pigs, the small animal species of choice for determination of MedCM efficacy. These data show how PK can improve the understanding of MedCM efficacy. PK studies such as those reported here should be integrated into the development programmes of future MedCM.

Text
S J Armstrong Corrected Thesis - Version of Record
Available under License University of Southampton Thesis Licence.
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Published date: November 2014

Identifiers

Local EPrints ID: 434950
URI: http://eprints.soton.ac.uk/id/eprint/434950
PURE UUID: 31d0e97b-896e-43f2-a403-bd8d4ac84d85
ORCID for Geraldine Clough: ORCID iD orcid.org/0000-0002-6226-8964

Catalogue record

Date deposited: 17 Oct 2019 16:30
Last modified: 18 Oct 2019 00:37

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Contributors

Author: Stuart Armstrong
Thesis advisor: Chris Green
Thesis advisor: Geraldine Clough ORCID iD

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