Toxicity of diclofenac sodium salt after two weeks of daily intramuscular administration in cynomolgus monkeys.

IF 1.6 4区医学 Q4 TOXICOLOGY

Toxicological Research Pub Date : 2025-02-26 eCollection Date: 2025-05-01 DOI:10.1007/s43188-025-00281-4

Sieun Yoo, Jung-Ho Noh, Hong-Soo Lee, Sang-Hee Lee, Eunji Choi, Dong-Il Kim, Seung Eui Min, Kang-Hyun Han, Sang Kyum Kim

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Abstract

Diclofenac sodium salt (DSS) has been extensively studied in pharmacological research to better understand its pain relief and inflammation-reducing properties. However, it is crucial to evaluate the safety profile of this non-steroidal anti-inflammatory drug, particularly in nonhuman primates (NHPs), such as cynomolgus monkeys. Understanding the potential adverse effects and toxicity of DSS in NHP is critical for determining their overall safety and use in clinical settings. Further investigation into its toxicity to NHPs would provide valuable information for developing and using this drug in medical practice. Our aim was to evaluate the toxicity of DSS administered repeatedly to cynomolgus monkeys to identify its safety profile in NHPs. The general toxicity of DSS was established using a 2-week repeated-dose toxicity test. Twenty-four cynomolgus monkeys were intramuscularly injected with 0, 0.33, 1, and 3 mg/kg of DSS each day. This study assessed the potential adverse effects and toxicity of DSS in these monkeys, providing valuable data for understanding its safety in clinical settings. The 2-week repeated-dose toxicity study of DSS revealed no treatment-related changes in body weight, food consumption, ophthalmology, or general symptoms. Furthermore, no significant changes were observed in hematological, clinical chemistry, or urinalysis data. Histopathological examination revealed decreased cellularity (lymphocytes) in both the thymus and spleen (white pulp). The sternal bone marrow had a higher cell count than usual. Furthermore, mixed cell and mononuclear cell infiltration, inflammation, myofiber degeneration, and muscle fiber necrosis were observed at the injection site (skin), but these findings were not considered adverse effects. Notably, the no observed adverse effect level of DSS was estimated to be greater than 3 mg/kg in both males and females. Therefore, this study established a non-toxic dose of DSS, laying the groundwork for further nonclinical studies to assess the safety of DSS using NHP.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-025-00281-4.

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双氯芬酸钠对食蟹猴每日肌注两周后的毒性。

双氯芬酸钠盐（DSS）在药理学研究中得到了广泛的研究，以更好地了解其缓解疼痛和减少炎症的特性。然而，评估这种非甾体抗炎药的安全性是至关重要的，特别是在非人灵长类动物（NHPs）中，如食蟹猴。了解DSS在NHP中的潜在不良反应和毒性对于确定其在临床环境中的总体安全性和使用至关重要。进一步调查其对NHPs的毒性，将为该药物在医疗实践中的开发和使用提供有价值的信息。我们的目的是评估DSS反复给食蟹猴的毒性，以确定其在NHPs中的安全性。采用2周重复给药毒性试验确定DSS的一般毒性。24只食蟹猴每天肌肉注射0、0.33、1、3 mg/kg的DSS。本研究评估了DSS对这些猴子的潜在不良反应和毒性，为了解其在临床环境中的安全性提供了有价值的数据。为期2周的DSS重复剂量毒性研究显示，在体重、饮食、眼科或一般症状方面没有与治疗相关的变化。此外，在血液学、临床化学或尿液分析数据中没有观察到明显的变化。组织病理学检查显示胸腺和脾脏（白色髓）细胞（淋巴细胞）减少。胸骨骨髓细胞计数高于正常水平。此外，在注射部位（皮肤）观察到混合细胞和单核细胞浸润、炎症、肌纤维变性和肌纤维坏死，但这些发现不被认为是不良反应。值得注意的是，未观察到的DSS不良反应水平估计在男性和女性中均大于3 mg/kg。因此，本研究建立了DSS的无毒剂量，为进一步使用NHP评估DSS安全性的非临床研究奠定了基础。补充信息：在线版本包含补充资料，可在10.1007/s43188-025-00281-4获得。

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来源期刊

Toxicological Research TOXICOLOGY-

CiteScore

4.20

自引率

4.30%

发文量

期刊介绍： Toxicological Research is the official journal of the Korean Society of Toxicology. The journal covers all areas of Toxicological Research of chemicals, drugs and environmental agents affecting human and animals, which in turn impact public health. The journal’s mission is to disseminate scientific and technical information on diverse areas of toxicological research. Contributions by toxicologists, molecular biologists, geneticists, biochemists, pharmacologists, clinical researchers and epidemiologists with a global view on public health through toxicological research are welcome. Emphasis will be given to articles providing an understanding of the toxicological mechanisms affecting animal, human and public health. In the case of research articles using natural extracts, detailed information with respect to the origin, extraction method, chemical profiles, and characterization of standard compounds to ensure the reproducible pharmacological activity should be provided.