Evaluation of chronic toxicity of cyclocreatine in beagle dogs after oral gavage administration for up to 23 weeks.

Autor: Wallery JJ; Battelle, Columbus, OH, USA., Kale VP; Battelle, Columbus, OH, USA. Electronic address: vkale02@amgen.com., Novak J; Battelle, Columbus, OH, USA., Gibbs S; Battelle, Columbus, OH, USA., Do MT; Lumos Pharma, Austin, TX, USA., McKew JC; Lumos Pharma, Austin, TX, USA., Terse PS; National Center for Advancing Translational Sciences, National Institute of Health, Bethesda, MD, USA. Electronic address: tersep@mail.nih.gov.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2021 Nov 01; Vol. 430, pp. 115680. Date of Electronic Publication: 2021 Aug 17.
DOI: 10.1016/j.taap.2021.115680
Abstrakt: Cyclocreatine (LUM-001) was evaluated for chronic toxicity (23 weeks) in beagle dogs to support clinical development in patients with creatine transporter deficiency (CTD) disorder. Deionized water (vehicle control) or cyclocreatine was administered by oral gavage twice daily (12 ± 1 h apart) at 20, 40 and 75 mg/kg/dose followed by a recovery period. Due to severe toxicity, the study was terminated earlier than the planned 39 weeks of dosing. Animals in the 20, 40 and 75 mg/kg/dose groups completed 160, 106, and 55 days of dosing, respectively, followed by 30, 55 and 106 days of a recovery period, respectively. Three (25%), 7 (58%), and 7 (58%) animals were euthanized and/or found dead in the 40, 80, and 150 mg/kg/day dose groups, respectively. Clinical signs observed were inappetence, frequent emesis, stool abnormalities, weight loss, lethargy and respiratory distress. Histopathological evaluation revealed congestion, edema, cellular infiltration, fibrin, and/or hemorrhage in the lungs of all dose groups. Additionally, animals in all cyclocreatine treatment groups had perinuclear cytoplasmic vacuoles in the heart, kidneys, skeletal and smooth muscles. After the recovery period, the vacuoles were still observed in the cardiac and renal tissues. Cyclocreatine was absorbed rapidly with mean T max within 1 to 2 h and half-life ranged between 2.17 and 2.79 h on Day 1, however, on the final day of dosing, it ranged between 5.80 and 8.77 h (males) and 10.3 to 13.1 h (females). To conclude, in this study the lungs, kidneys, heart, skeletal and smooth muscles were identified as the target organs of cyclocreatine toxicity in beagle dogs.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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