Short-term Toxicity Study of ST-20 (NSC-741804) by Oral Gavage in Sprague-Dawley Rats

• Published in: Toxicologic pathology 2011-06, Vol.39 (4), p.614-622
• Main Authors: Terse, Pramod S., Johnson, Jerry D., Hawk, Michael A., Ritchie, Glenn D., Ryan, Michael J., Vasconcelos, Daphne Y., Contos, Denise A., Perrine, Susan P., Peggins, James O., Tomaszewski, Joseph E.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Anemias. Hemoglobinopathies; Animals; Biological and medical sciences; Body Weight; Butyrates - pharmacology; Butyrates - toxicity; Diseases of red blood cells; Dose-Response Relationship, Drug; Erythrocyte Count; Female; Hematologic and hematopoietic diseases; Kidney - drug effects; Leukocyte Count; Linear Models; Liver - drug effects; Male; Medical sciences; Micronucleus Tests; No-Observed-Adverse-Effect Level; Organ Size - drug effects; Rats; Rats, Sprague-Dawley; Reticulocytes - drug effects; Toxicity Tests, Acute - methods; Toxicology
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623311406933

ST-20 (sodium 2,2-dimethylbutyrate) is a potential therapeutic agent for treatment of β-thalassemia and sickle cell disease. A subchronic oral toxicity study was conducted in Sprague-Dawley rats (10/sex/dose) at gavage dosages of 0 (vehicle control), 200, 600, or 1,000 mg/kg, once daily for up to 15 days followed by a 14-day recovery. Ataxia (females), rough coat/thin appearance (males), and decreased body weights were observed at 1,000 mg/kg. Functional observational battery (FOB) deficits were observed more frequently in females and included decreased body tone, rectal temperature, emotional reactivity, neuromotor-neuromuscular activity (as exhibited by a deficit in visual/tactile placing accuracy, ataxia, hind limb dragging, and decreased grip strength), and rearing. ST-20 caused a decrease in WBC/RBC counts and RBC parameters; increase in reticulocytes and red cell inclusion bodies; decrease in total protein, globulin, and glucose; and increase in AG ratio. Micronucleated polychromatic erythrocytes of the bone marrow increased significantly in males at 1,000 mg/kg. Mean liver and kidney weights increased, and hepatocellular hypertrophy was observed in males at 1,000 mg/kg. Toxicologic findings were fully recovered during the 14-day recovery period. In conclusion, the no-observed adverse effect level for FOB and general toxicity was 200 mg/kg following gavage administration of ST-20 for up to 15 consecutive days.