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阿贝西利致腹泻的机制尚未阐明。
详细信息
服用 阿贝西利 发生腹泻的机制尚不明确。根据非临床报道,在缺乏周期蛋白依赖性激酶(CDK)4、CDK6 和细胞周期蛋白 D 的小鼠模型中,未观察到对胃肠(GI)道的影响,并且在缺乏 CDK4 的成年小鼠中,未观察到对食管和肠道等组织的影响。1,2
在非临床毒性研究中,在服用 阿贝西利的大鼠肠道黏膜中观察到了隐窝细胞增生变化和绒毛萎缩等病理学发现。3Thibault 等人的稿件中提出的结论与礼来公司获得的 阿贝西利在大鼠、小鼠和狗的胃肠道形态变化数据部分一致。4这些发现与通常在细胞杀伤性抗癌剂或放射治疗中观察到的组织学发现不同,后者包括隐窝细胞坏死和微绒毛或肠道黏膜上皮脱落。5-8
上次审阅日期:2022年5月10日
参考文献
1. Sherr CJ, Roberts JM. Living with or without cyclins and cyclin-dependent kinases. Genes Dev. 2004;18:2699-2711. http://dx.doi.org/10.1101/gad.1256504
2. Barrière C, Santamaría D, Cerqueira A, et al. Mice thrive without Cdk4 and Cdk2. Mol Oncol. 2007;1(1):72-83. http://dx.doi.org/10.1016/j.molonc.2007.03.001
3. Thibault S, Hu W, Hirakawa B, et al. Intestinal toxicity in rats following administration of CDK4/6 inhibitors is independent of primary pharmacology. Mol Cancer Ther. 2019;18(2):257-266. http://dx.doi.org/10.1158/1535-7163.MCT-18-0734
4. Data on file, Eli Lilly and Company and/or one of its subsidiaries.
5. Slavin RE, Dias MA, Saral R. Cytosine arabinoside induced gastrointestinal toxic alterations in sequential chemotherapeutic protocols: a clinical-pathologic study of 33 patients. Cancer. 1978;42(4):1747-1759. https://doi.org/10.1002/1097-0142(197810)42:4<1747::aid-cncr2820420413>3.0.CO;2-T</::aid-cncr2820420413>
6. Khan SA, Wingard JR. Infection and mucosal injury in cancer treatment. J Natl Cancer Inst Monogr. 2001;2001(29):31-36. https://doi.org/10.1093/oxfordjournals.jncimonographs.a003437
7. Boussios S, Pentheroudakis G, Katsanos K, Pavlidis N. Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann Gastroenterol. 2012;25(2):106-118. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959393/
8. Stacey R, Green JT. Radiation-induced small bowel disease: latest developments and clinical guidance. Ther Adv Chronic Dis. 2014;5(1):15-29. https://doi.org/10.1177/2040622313510730