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Toxicol Appl Pharmacol. 2020 Apr 03;:114994
Authors: Cornelissen AS, Klaassen SD, van Groningen T, Bohnert S, Joosen MJA
Abstract
Anticholinergic treatment is key for effective medical treatment of nerve agent exposure. Atropine is included at a 2 mg intramuscular dose in so-called autoinjectors designed for self- and buddy-aid. As patient cohorts are not available, predicting and evaluating the efficacy of medical countermeasures relies on animal models. The use of atropine as a muscarinic antagonist is based on efficacy achieved in studies in a variety of species. The dose of atropine administered varies considerably across these studies. This is a complicating factor in the prediction of efficacy in the human situation, largely because atropine dosing also influences therapeutic efficacy of oximes and anticonvulsants generally part of the treatment administered. To improve translation of efficacy of dosing regimens, including pharmacokinetics and physiology provide a promising approach. In the current study, pharmacokinetics and physiological parameters obtained using EEG and ECG were assessed in naïve rats and in sarin-exposed rats for two anticholinergic drugs, atropine and scopolamine. The aim was to find a predictive parameter for therapeutic efficacy. Scopolamine and atropine showed a similar bioavailability, but brain levels reached were much higher for scopolamine. Scopolamine exhibited a dose-dependent loss of beta power in naïve animals, whereas atropine did not show any such central effect. This effect was correlated with an enhanced anticonvulsant effect of scopolamine compared to atropine. These findings show that an approach including pharmacokinetics and physiology could contribute to improved dose scaling across species and assessing the therapeutic potential of similar anticholinergic and anticonvulsant drugs against nerve agent poisoning.
PMID: 32251685 [PubMed - as supplied by publisher]
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