Synergistic polytherapy for the broad-spectrum treatment of chemically-induced seizures in rats.

Autor: Cornelissen AS; Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands; Predictive Pharmacology group, Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Gorlaeus Laboratory, Einsteinweg 55, 2333 CC Leiden, the Netherlands. Electronic address: alex.cornelissen@tno.nl., van den Berg RM; Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands., Klaassen SD; Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands., de Koning JC; Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands., Langenberg JP; Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands., de Lange ECM; Predictive Pharmacology group, Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Gorlaeus Laboratory, Einsteinweg 55, 2333 CC Leiden, the Netherlands., Joosen MJA; Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2024 Oct 29; Vol. 493, pp. 117137. Date of Electronic Publication: 2024 Oct 29.
DOI: 10.1016/j.taap.2024.117137
Abstrakt: Chemically-induced seizures, as a result of exposure to a neurotoxic compound, present a serious health concern. Compounds can elicit seizure activity through disruption of neuronal signaling by neurotransmitters, either by mimicking, modulating or antagonizing their action at the receptor or interfering with their metabolism. Benzodiazepines, such as diazepam and midazolam, and barbiturates are the mainstay of treatment of seizures. However, chemically-induced seizures are often persistent, requiring repeated treatment and increased doses of anticonvulsants, which in turn may lead to severe adverse effects such as respiratory depression. Here, we investigated the potential of rational polytherapy consisting of the benzodiazepine midazolam and the selective α 2 -adrenergic agonist dexmedetomidine as an improved, generically applicable anticonvulsant treatment regimen. Therapeutic efficacy was evaluated against two experimental paradigm compounds that induce persistent seizures in rats, the rodenticide TETS and the nerve agent soman. Following exposure, both TETS and soman elicited profound seizure activity and convulsions, associated with substantial mortality. Treatment with midazolam or dexmedetomidine alone provided no or limited suppression of seizure activity and improvement of survival at 4 h. Polytherapy consisting of midazolam and dexmedetomidine showed excellent anticonvulsant efficacy. Even at low doses, polytherapy showed a profound effect that lasted for the duration of the experiment. Analysis of the dose-response relationships confirmed presence of synergy. Administration of polytherapy in non-exposed animals did not indicate aggravation of adverse effects on respiration or heart rate. Even though more research is needed for the translation to clinical use, polytherapy consisting of midazolam and dexmedetomidine shows promise for the broad-spectrum treatment of (chemically-induced) seizures in emergency situations.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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