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Abstract
Even if organophosphorus (OP) nerve agents were banned entirely, their presence would remain a problem as weapons of terror (like in Syria). Oxime antidotes currently used in medical practice still fall short of their therapeutic purpose, as they fail to fully restore the activity of cholinesterases, the main target for OPs. As orphan drugs, these antidotes are tested too seldom for anybody's benefit. Over the last few decades, search for improved reactivators has reached new levels, but the translation of data obtained in vitro to in vivo application is still a problem that hinders efficient therapy. In this study, we tested the strengths and weaknesses of extrapolating pyridinium oxime antidotes reactivation efficiency from in vitro to in vivo application. Our results show that this extrapolation is possible with well-determined kinetic constants, but that it also largely depends on oxime circulation time and its tissue-specific distribution. This suggests that pharmacokinetic studies should be planned at the early stages of antidote development. Special attention should also be given to improving oxime distribution throughout the organism to overcome this major constraint in improving overall OP therapy.
Highlights
Even if organophosphorus (OP) nerve agents were banned entirely, their presence would remain a problem as weapons of terror
The potential of the oximes used in medical practice today, such as 2-PAM, HI-6, and obidoxime, is limited primarily due to the very specific properties of each of the enzyme-OP conjugates [6,7,8,9]
Just as any other drug, oximes have to comply with a great number of requirements to be accepted for human use. Antidotes of this kind fall into the category of orphan drugs, which means that trials are seldom performed
Summary
Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning. Maja Katalinić, Nikolina Maček Hrvat, Jana Žďárová Karasová, Jan Misik, and Zrinka Kovarik. The potential of the oximes used in medical practice today, such as 2-PAM, HI-6, and obidoxime, is limited primarily due to the very specific properties of each of the enzyme-OP conjugates [6,7,8,9] With this in mind, we tested the strengths and weaknesses of extrapolating pyridinium oxime antidote results from in vitro to in vivo application. We focused on oxime distribution, elimination, and tissue-specific AChE reactivation capacity in rats exposed subcutaneously to a single sub-lethal dose of tabun (3/4 LD50) This route and dose were chosen to ensure toxic manifestations at all levels without loading the animals with excess poison (that would mask the effect of the oxime). Our oxime model should be specific to AChE reactivation [11], data obtained on BChE will give additional information for the extrapolation of in vitro pyridinium oxime efficiency to its efficiency in vivo
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