Translational Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Chugai Research Institute for Medical Science, Inc., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Exp Anim. 2024 Feb 14;73(1):73-82. doi: 10.1538/expanim.23-0017. Epub 2023 Aug 29.
Animals frequently eat less after a test-article treatment in nonclinical toxicological studies, and it can be difficult to distinguish test article-derived toxicities from secondary changes related to this reduced food intake. Therefore, in this study, we restricted the food intake of cynomolgus monkeys (Cambodian, male, n=2 or 3, 48 ± 3 months old) to 25% of the control for two weeks and evaluated the effects on toxicological parameters (general conditions, body weight, electrocardiography, urinalysis, hematology, blood chemistry, bone marrow analysis, pathological examination). After 2 weeks, the monkeys exhibited decreases in bone marrow erythropoiesis (e.g., decreases in reticulocytes and bone marrow erythrocytes), as well as glycogenesis induction (e.g., increase in aspartate aminotransferase (AST)) and malnutrition (e.g., decrease in triglyceride and systemic adipocytes atrophy). Additionally, histopathological analysis revealed granuloma and inflammatory cell infiltration in coronary fat, which had never been found in previous food restriction studies using other animal species. These findings will enable researchers to more accurately evaluate the toxicological risks of test articles that simultaneously induce food intake reduction.
在非临床毒理学研究中，动物在接受试验性药物治疗后通常会减少进食量，并且很难将药物引起的毒性与因进食量减少导致的继发性变化区分开来。因此，在本研究中，我们将食蟹猴（柬埔寨，雄性，n=2 或 3，48 ± 3 月龄）的食物摄入量限制为对照组的 25%，持续两周，并评估了其对毒理学参数（一般状况、体重、心电图、尿液分析、血液学、血液化学、骨髓分析、病理学检查）的影响。两周后，猴子出现骨髓红细胞生成减少（例如网织红细胞和骨髓红细胞减少）、糖生成诱导（例如天门冬氨酸氨基转移酶（AST）增加）和营养不良（例如甘油三酯减少和全身脂肪细胞萎缩）。此外，组织病理学分析显示冠状脂肪中存在肉芽肿和炎症细胞浸润，这在以前使用其他动物物种进行的食物限制研究中从未发现过。这些发现将使研究人员能够更准确地评估同时引起进食量减少的试验性药物的毒理学风险。
