Efficacy of atropine sulfate/obidoxime chloride co-formulation against sarin exposure in guinea pigs. (25th December 2018)

• Record Type: Journal Article
• Authors: Joosen, Marloes J.A.; Klaassen, Steven D.; Verheij, Elwin; van Groningen, Tomas; Cornelissen, Alex S.; Skiadopoulos, Mario H.; Cochrane, Laura; Shearer, Jeff D.
• Is Part Of: Chemico-biological interactions. Volume 296(2018)
• Page Start: 34
• Page End: 42
• Publication Date: 2018-12-25
• Subjects: Sarin -- Nerve agent -- Obidoxime -- Atropine sulfate -- EEG -- Autoinjector; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2018.09.004
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: 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. Highlights: Atropine/obidoxime pharmacokinetics were dose proportional and not affected by Sarin challenge. Survival rates were improved by atropine/obidoxime at two sarin challenge levels. Reactivation of sarin inhibited cholinesterase was observed in blood. Effective mitigation of CNS effects was only apparent at the lower sarin challenge. The primary benefit is a gain in time to allow for supportive treatment.