Evaluation of chronic toxicity of cyclocreatine in beagle dogs after oral gavage administration for up to 23 weeks
| Autor: | Jeffrey J. Wallery, Pramod S. Terse, Joseph Novak, John C. McKew, Seth Gibbs, Vijay P. Kale, Minh-Ha T Do |
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| Rok vydání: | 2021 |
| Předmět: |
Lung Diseases
Male Time Factors Administration Oral Physiology Kidney Toxicology Risk Assessment Beagle Article Lethargy Dogs Weight loss Edema medicine Animals Muscle Skeletal Toxicity Tests Chronic Lung Chronic toxicity Pharmacology No-Observed-Adverse-Effect Level Dose-Response Relationship Drug Respiratory distress business.industry Myocardium Muscle Smooth medicine.disease Toxicokinetics Cellular infiltration Creatinine Vacuoles Toxicity Female medicine.symptom business Half-Life |
| Zdroj: | Toxicol Appl Pharmacol |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2021.115680 |
| Popis: | 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 hours 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 hours and half-life ranged between 2.17 to 2.79 hours on Day 1, however, on the final day of dosing, it ranged between 5.80 to 8.77 hours (males) and 10.3 to 13.1 hours (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. |
| Databáze: | OpenAIRE |
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