Toxicity of Hydroxyurea in Rats and Dogs
| Autor: | Robert Austin-LaFrance, Lindsay Tomlinson, Lori A. Reed, Carrie A. Northcott, Wenhu Huang, Bradley E. Enerson, Daniel Morton, Scott H. Schelling, John M. Marcek |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Pathology Blood Pressure Toxicology Pathology and Forensic Medicine Rats Sprague-Dawley Dogs Bone Marrow Internal medicine Toxicity Tests medicine Animals Hydroxyurea Kinase activity Molecular Biology Thrombocytosis business.industry Myocardium Stomach Heart Cell Biology medicine.disease Rats Dose–response relationship Blood pressure Endocrinology medicine.anatomical_structure Toxicity Female Lymph Bone marrow business |
| Zdroj: | Toxicologic Pathology. 43:498-512 |
| ISSN: | 1533-1601 0192-6233 |
| Popis: | The toxicity of hydroxyurea, a treatment for specific neoplasms, sickle-cell disease, polycythemia, and thrombocytosis that kills cells in mitosis, was assessed in repeat-dose, oral gavage studies in rats and dogs and a cardiovascular study in telemetered dogs. Hydroxyurea produced hematopoietic, lymphoid, cardiovascular, and gastrointestinal toxicity with steep dose response curves. In rats dosed for 10 days, 50 mg/kg/day was tolerated; 500 mg/kg/day produced decreased body weight gain; decreased circulating leukocytes, erythrocytes, and platelets; decreased cellularity of thymus, lymph nodes, and bone marrow; and epithelial degeneration and/or dysplasia of the stomach and small intestine; 1,500 mg/kg/day resulted in deaths on day 5. In dogs, a single dose at ≥250 mg/kg caused prostration leading to unscheduled euthanasia. Dogs administered 50 mg/kg/day for 1 month had decreased circulating leukocytes, erythrocytes, and platelets; increased bone marrow cellularity with decreased maturing granulocytes; increased creatinine kinase activity; and increased iron pigment in bone marrow and hepatic sinusoidal cells. In telemetered dogs, doses ≥15 mg/kg decreased systolic blood pressure (BP); 50 mg/kg increased diastolic BP, heart rate, and change in blood pressure over time (+d P/d t), and decreased QT and PR intervals and maximum left ventricular systolic and end diastolic pressures with measures returning to control levels within 24 hr. |
| Databáze: | OpenAIRE |
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