Nandre Rahul M, Joshi Pramod S, Sutula Thomas P, Terse Pramod S
National Center for Advancing Translational Sciences, NIH, Rockville, MD, USA.
University of Wisconsin, Madison, WI, USA.
Int J Toxicol. 2025 Sep-Oct;44(5):407-414. doi: 10.1177/10915818251340393. Epub 2025 May 26.
2-Deoxy-D-Glucose (2-DG) has anticonvulsant and antiseizure effects in rodent models and is in the development phase for novel antiseizure treatment. To evaluate potential toxicity, Beagle dogs (five/sex/group) were orally gavaged with either vehicle (deionized water) or 2-DG (5, 30, and 90 mg/kg BID) for 28 days followed by a 14-day recovery period. The safety endpoints evaluated were mortality, clinical observations, body temperature, respiratory assessment, body weights, food consumption, ophthalmic examinations, electrocardiograph (ECG), blood pressure, cardiac biomarker (NT-proBNP), and pathology. Toxicokinetic analysis was conducted after the first dose on days 1 and 28. The dose formulation analysis confirmed that 2-DG concentrations were within 93%-107% of the target concentrations. There were no 2-DG associated effects observed in mortality, clinical signs, body temperature, respiratory parameters, body weights, food consumption, ophthalmic examination, ECG, blood pressure, and NT-proBNP. There was an increase (∼1.7X) in aspartate transaminase on day 29, while histopathological evaluation revealed hepatic cytoplasmic alterations in 2 of 6 dogs on day 29 and only in 1 of 4 dogs on day 43 at 90 mg/kg BID. These changes were considered non-adverse because of minimal severity, reversibility trend after recovery period and no correlative increase in alanine transaminase. Toxicokinetic evaluation revealed dose dependent increases in C of ∼7.8, 39.5, and 114 μg/mL, and AUCs of 12.2, 70.8, and 202 h*μg/mL at 5, 30, and 90 mg/kg, respectively with T of ∼0.5-0.9 h and T of ∼3.8-5.4 h. In conclusion, 90 mg/kg BID of 2-DG was considered as the No Observed Adverse Effect Level following 28-day administration in dogs.
2-脱氧-D-葡萄糖（2-DG）在啮齿动物模型中具有抗惊厥和抗癫痫发作的作用，目前正处于新型抗癫痫治疗的研发阶段。为评估其潜在毒性，对比格犬（每组雌雄各5只）进行为期28天的口服给药，分别给予赋形剂（去离子水）或2-DG（5、30和90mg/kg，每日两次），随后有14天的恢复期。评估的安全终点包括死亡率、临床观察、体温、呼吸评估、体重、食物摄入量、眼科检查、心电图（ECG）、血压、心脏生物标志物（NT-proBNP）和病理学。在第1天和第28天首次给药后进行毒代动力学分析。剂量配方分析证实2-DG浓度在目标浓度的93%-107%范围内。在死亡率、临床体征、体温、呼吸参数、体重、食物摄入量、眼科检查、ECG、血压和NT-proBNP方面未观察到与2-DG相关的影响。在第29天，天冬氨酸转氨酶有所升高（约1.7倍），而组织病理学评估显示，在每日两次给予90mg/kg剂量时，第29天6只犬中有2只出现肝细胞质改变，第43天4只犬中只有1只出现改变。由于严重程度轻微、恢复期后有可逆趋势且丙氨酸转氨酶没有相应升高，这些变化被认为无不良影响。毒代动力学评估显示，在5、30和90mg/kg剂量下，C分别约增加7.8、39.5和114μg/mL，AUC分别为12.2、70.8和202h*μg/mL，T约为0.5-0.9h，T约为3.8-5.4h。总之，在犬类中连续28天给予2-DG，90mg/kg每日两次被认为是未观察到不良反应水平。
