title: Short-term toxicity study of ST-20 (NSC-741804) by oral gavage in Sprague-Dawley rats.
abstract: 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.
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20852, USA. tersep@mail.nih.gov
authors.forename: Pramod S
authors.initials: PS
authors.lastname: Terse
authors.forename: Jerry D
authors.initials: JD
authors.lastname: Johnson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hawk
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Ritchie
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: Daphne Y
authors.initials: DY
authors.lastname: Vasconcelos
authors.forename: Denise A
authors.initials: DA
authors.lastname: Contos
authors.forename: Susan P
authors.initials: SP
authors.lastname: Perrine
authors.forename: James O
authors.initials: JO
authors.lastname: Peggins
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Tomaszewski
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D002087:Butyrates / Q000494:pharmacology / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D005260:Female; D007668:Kidney / Q000187:drug effects*; D007958:Leukocyte Count; D016014:Linear Models; D008099:Liver / Q000187:drug effects*; D008297:Male; D015162:Micronucleus Tests; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012156:Reticulocytes / Q000187:drug effects*; D023382:Toxicity Tests, Acute / Q000379:methods*
chemical_list: D002087:Butyrates; C074677:2,2-dimethylbutyric acid