Morita Junya, Izumi Tomoko, Ogawa Bunichiro, Ban Yoshiki, Takagi Hironori, Sasaki Minoru, Tsutsumi Shunsuke
Drug Safety, Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd.
J Toxicol Sci. 2017;42(1):31-42. doi: 10.2131/jts.42.31.
This study sought to clarify the effects of reduced feeding on physiological parameters in dogs to enable appropriate evaluations of the safety and toxicity of test compounds. We measured alkaline phosphatase isozymes and the circulating blood volume, as well as clinical signs, body weight, hematology, blood chemistry, electrocardiography, organ weight, and histopathology, in male beagle dogs fed a diet consisting of 300 g/day or 150 g/day for 4 weeks. There were no abnormal clinical signs in any of the dogs. In the 150-g/day feeding group, a decreased alkaline phosphatase 3 suggesting effects on the bone and a decreased circulating blood volume associated with body weight loss were observed. Additionally, the following changes were also observed in the 150-g/day group: a decrease in body weight; hematologic changes including decreases in white blood cells, neutrophils, red blood cells, hemoglobin, hematocrit and reticulocytes; blood chemical changes including decreases in aspartate aminotransferase, lactate dehydrogenase and calcium and an increase in the creatinine at week 1 or thereafter; electrocardiographic changes including a decrease in the heart rate, a prolonged QRS duration and the occurrence of a second-degree atrioventricular block at week 3 or thereafter; and pathological changes including decreases in the weights of the liver and thymus, a decrease in hepatocyte rarefaction, and thymic atrophy. These results provide useful information for assessing the safety of compounds in toxicological studies, enabling direct treatment effects and secondary changes caused by decreased food intake to be distinguished.
本研究旨在阐明减少喂食对犬生理参数的影响，以便能够对受试化合物的安全性和毒性进行适当评估。我们对雄性比格犬进行了为期4周的实验，分别给予每日300克或150克的饮食，测量了碱性磷酸酶同工酶、循环血量，以及临床体征、体重、血液学指标、血液生化指标、心电图、器官重量和组织病理学。所有犬均未出现异常临床体征。在每日150克喂食组中，观察到碱性磷酸酶3降低，提示对骨骼有影响，且循环血量减少与体重减轻相关。此外，在每日150克组中还观察到以下变化：体重下降；血液学变化，包括白细胞、中性粒细胞、红细胞、血红蛋白、血细胞比容和网织红细胞减少；血液生化变化，包括第1周或之后天冬氨酸转氨酶、乳酸脱氢酶和钙减少，肌酐增加；心电图变化，包括心率降低、QRS波时限延长以及第3周或之后出现二度房室传导阻滞；以及病理变化，包括肝脏和胸腺重量减轻、肝细胞稀疏减少和胸腺萎缩。这些结果为毒理学研究中评估化合物的安全性提供了有用信息，能够区分由食物摄入量减少引起的直接治疗效果和继发变化。
