Dose optimization of early high-dose valproic acid for neuroprotection in a swine cardiac arrest model.
Cardiac arrest
Histone acetylation
Pharmacodynamics biomarker
Pharmacokinetic
Swine model
Valproic acid
Journal
Resuscitation plus
ISSN: 2666-5204
Titre abrégé: Resusc Plus
Pays: Netherlands
ID NLM: 101774410
Informations de publication
Date de publication:
Historique:
received:
23
03
2020
revised:
01
05
2020
accepted:
11
05
2020
entrez:
5
7
2021
pubmed:
6
7
2021
medline:
6
7
2021
Statut:
epublish
Résumé
High-dose valproic acid (VPA) improves the survival and neurologic outcomes after asphyxial cardiac arrest (CA) in rats. We characterized the pharmacokinetics, pharmacodynamics, and safety of high-dose VPA in a swine CA model to advance clinical translation. After 8 min of untreated ventricular fibrillation CA, 20 male Yorkshire swine were resuscitated until return of spontaneous circulation (ROSC). They were block randomized to receive placebo, 75 mg/kg, 150 mg/kg, or 300 mg/kg VPA as 90-min intravenous infusion (n = 5/group) beginning at ROSC. Animals were monitored for 2 additional hours then euthanized. Experimental operators were blinded to treatments. The mean(SD) total CA duration was 14.8(1.2) minutes. 300 mg/kg VPA animals required more adrenaline to maintain mean arterial pressure ≥80 mmHg and had worse lactic acidosis. There was a strong linear correlation between plasma free VPA C Up to 150 mg/kg VPA can be safely tolerated as 90-min intravenous infusion in a swine CA model. High-dose VPA induced dose-dependent increases in brain histone H3 and H4 acetylation, which can be predicted by plasma free VPA C
Identifiants
pubmed: 34223294
doi: 10.1016/j.resplu.2020.100007
pii: S2666-5204(20)30007-2
pmc: PMC8244526
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100007Subventions
Organisme : NHLBI NIH HHS
ID : K12 HL133304
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133129
Pays : United States
Organisme : NHLBI NIH HHS
ID : R34 HL130738
Pays : United States
Organisme : NHLBI NIH HHS
ID : R44 HL091606
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2020 The Author(s).
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