Efficacy of atropine sulfate/obidoxime chloride co-formulation against sarin exposure in guinea pigs.

Autor: Joosen MJA; TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, Rijswijk, the Netherlands. Electronic address: Marloes.joosen@tno.nl., Klaassen SD; TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, Rijswijk, the Netherlands., Verheij E; TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, Rijswijk, the Netherlands., van Groningen T; TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, Rijswijk, the Netherlands., Cornelissen AS; TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, Rijswijk, the Netherlands., Skiadopoulos MH; Emergent BioSolutions, Emergent Prod. Dev. Gaithersburg, 300 Professional Drive, Gaithersburg, MD, 20879, USA., Cochrane L; Emergent BioSolutions, Emergent Prod. Dev. Gaithersburg, 300 Professional Drive, Gaithersburg, MD, 20879, USA., Shearer JD; Emergent BioSolutions, Emergent Prod. Dev. Gaithersburg, 300 Professional Drive, Gaithersburg, MD, 20879, USA.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2018 Dec 25; Vol. 296, pp. 34-42. Date of Electronic Publication: 2018 Sep 12.
DOI: 10.1016/j.cbi.2018.09.004
Abstrakt: The efficacy and pharmacokinetics of the aqueous co-formulation contents of the Trobigard™ (atropine sulfate, obidoxime chloride) auto-injector were evaluated in a sarin exposed guinea pig model. Two subcutaneous (sc) sarin challenge doses were evaluated in guinea pigs instrumented with brain and heart electrodes for electroencephalogram (EEG) and electrocardiogram (ECG). Sarin challenge doses were chosen to reflect exposure subclasses with sublethal (moderate to severe clinical signs) and lethal consequences. The level of protection of intramuscular human equivalent doses of the co-formulation was defined by (1) the mitigation of signs and symptoms at a sublethal level and (2) the increase of survival time at the supralethal sarin dose levels. Pharmacokinetics of both atropine sulfate and obidoxime were proportional at 1 and 3 human equivalent doses, and only a small increase in heart rate was observed briefly as a side effect. At both sarin challenge doses, 54 μg/kg and 84 μg/kg, the co-formulation treatment was effective against sarin-induced effects. Survival rates were improved at both sarin challenge levels, whereas clinical signs and changes in EEG activity could not in all cases be effectively mitigated, in particular at the supralethal sarin challenge dose level. Reactivation of sarin inhibited cholinesterase was observed in blood, and higher brain cholinesterase activity levels were associated with a better clinical condition of the co-formulation treated animals. Although the results cannot be directly extrapolated to the human situation, pharmacokinetics and the effects over time related to plasma levels of therapeutics in a freely moving guinea pig could aid translational models and possibly improve prediction of efficacy in humans.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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