关键词： 4-Week repeated toxicity AAALAC, association for assessment and accreditation of laboratory animal care ALT, alanine aminotransferase AP, Alkaline phosphatase AST, aspartate aminotransferase AUC, area under the concentration-time curve BUN, blood urea nitrogen BW, body weight CAS, chemical abstracts service CL, clearance COX, cyclooxygenase CREA, creatine CRO, contract research organization CV, coefficients of variation Cmax, maximum plasma concentration DSS, diclofenac sodium salt Diclofenac sodium salt ECG, Electrocardiogram GI, gastrointestinal GLP, good laboratory practice H&E, hematoxylin and eosin HED, human effective dose HR, heart rate IACUC, institutional animal care and use committee Minipig NDA, new drug application NOAEL, No-observed-adverse-effect levels NSAIDs, nonsteroidal anti-inflammatory drugs No-observed-adverse-effect level RBC, red blood cell SD, standard deviation TK, toxicokinetics TP, total protein Tmax, time to maximum plasma concentration WBC, white blood cell aVF, augmented vector foot aVL, augmented vector left aVR, augmented vector right

来  源：   DOI：10.1016/j.toxrep.2021.02.022   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
Diclofenac sodium salt (DSS) is a widely used nonsteroidal anti-inflammatory drug. The present study was performed under good laboratory practice (GLP) regulations to investigate the toxicity of DSS after 4 weeks of repeated intramuscular administration at doses of 0, 2, 10, or 20 mg/kg/day in 32 minipigs and to evaluate the DSS effect following a 2-week recovery period. Dose-related clinical signs and alterations of hematological or clinical chemistry parameters, organ weight, and macroscopic as well as histopathological findings in hepatic, renal, gastrointestinal, skin and injection sites were observed in both sexes\' animals of the 10 or 20 mg/kg/day group. With the exception of the skin-related findings, most symptoms showed a tendency to resolve after the 2-week recovery period. The systemic exposure (AUClast) of DSS in plasma showed similar pattern to the increase rate of the dose and similar values between males and females except for the female 20 mg/kg dose group (56 %) on Day1. The systemic exposure showed a decreasing trend in the 10 or 20 mg/kg group after 4-week of repeated administration compared to Day1. The no-observed-adverse-effect level of DSS in this study was considered to be 2 mg/kg/day in both male and female minipigs.
摘要：
双氯芬酸钠盐（DSS）是一种广泛使用的非甾体抗炎药。本研究是在良好的实验室规范（GLP）规定下进行的，目的是在32只小型猪中以0、2、10或20mg/kg/天的剂量重复肌内给药4周后研究DSS的毒性，并评估2周恢复期后的DSS效果。剂量相关的临床体征和血液学或临床化学参数的改变，器官重量,肝脏的宏观和组织病理学发现，肾,胃肠,在10或20mg/kg/day组的两种性别动物中观察到皮肤和注射部位。除了与皮肤有关的发现,大多数症状在2周恢复期后有缓解的趋势.DSS在血浆中的全身暴露（AUClast）显示出与剂量增加速率相似的模式，男性和女性之间的值相似，除了在第1天的女性20mg/kg剂量组（56％）。与第1天相比，重复给药4周后，10或20mg/kg组的全身暴露呈下降趋势。在该研究中DSS的未观察到的不利影响水平在雄性和雌性小型猪中被认为是2mg/kg/天。
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