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 b-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.

Identification of 2,2-Dimethylbutanoic Acid (HST5040), a Clinical Development Candidate for the Treatment of Propionic Acidemia and Methylmalonic Acidemia

“…Based on the absence of adverse effects, the NOAEL for HST5040A was 300 mg/kg/day, the highest dose level tested, which provided exposures well above those projected to occur at the clinical efficacious dose. Overall, these data are similar to previously reported preclinical safety data with this molecule. , Based on these data and the pharmacological activity in disease models, HST5040 was selected as a clinical development candidate for the treatment of PM and MMA.…”

“…Overall, these data are similar to previously reported preclinical safety data with this molecule. 31,32 Based on these data and the pharmacological activity in disease models, HST5040 was selected as a clinical development candidate for the treatment of PM and MMA.…”

Potential anti-genotoxic effect of sodium butyrate to modulate induction of DNA damage by tamoxifen citrate in rat bone marrow cells

“…In contrary to the previous studies, our findings demonstrated that administration of SB alone has altered bone marrow erythropoiesis based on the marked increase of PCEs percent in the bone marrow (3.39 ± 0.05 * ), that may be attributed to the increased ratio of the antiapoptotic proteins BCL-XL and MCL-1 to their proapoptotic partners BCL-XS and MCL-1SL, respectively, as demonstrated by Castaneda et al (2005), who found that SB induces erythroid cell progenitor survival and proliferation in vitro through BCLfamily antiapoptotic protein expression (Castaneda et al 2005). On the other hand, Terse et al showed that SB did not significantly change PCEs percentage, indicating that it did not change bone marrow erythropoiesis at the tested doses (6.25 and 12.5 mM) (Terse et al 2011). Anyway, the underlying mechanism of the observed hematologic effects at the dose tested is not completely understood.…”

STP Best Practices for Evaluating Clinical Pathology in Pharmaceutical Recovery Studies

“…A broad review of the literature suggested that clinical pathology is most often incorporated in the recovery groups to evaluate reversibility of organ dysfunction (such as renal, hematopoietic, immune, and endocrine systems), with fewer reports incorporating clinical pathology to monitor tissue injury (Abraham, Gottschalk, and Ungemach 2005;Boorman et al 1982;Henzen et al 2000;Derelanko et al 1985;Lefebvre et al 1984;Rouse et al 2011;Streck and Lockwood 1979;Terse et al 2011).…”

“…A large global retrospective analysis detailing general practices for use of recovery groups (Sewell et al 2014) provided recommendations for minimizing recovery animals where scientifically justified, including avoiding recovery phases in first in human (FIH)-enabling studies. A broad review of the literature suggested that clinical pathology is most often incorporated in the recovery groups to evaluate reversibility of organ dysfunction (such as renal, hematopoietic, immune, and endocrine systems), with fewer reports incorporating clinical pathology to monitor tissue injury (Abraham, Gottschalk, and Ungemach 2005;Boorman et al 1982;Henzen et al 2000;Derelanko et al 1985;Lefebvre et al 1984;Rouse et al 2011;Streck and Lockwood 1979;Terse et al 2011).…”