目的 參考小兒消積止咳口服液的臨床用量，探討4個臨床療程（20 d）下，該品對幼齡小鼠潛在的毒性表現(xiàn)和受累的毒靶器官；以探索方中檳榔和檳榔堿對兒童臨床用藥風(fēng)險的影響。方法 根據(jù)產(chǎn)品說明書、臨床應(yīng)用情況和檳榔及檳榔堿毒理學(xué)研究報道，選擇幼齡小鼠分別給予小兒消積止咳口服液（4.29、17.16 g·kg^-1）、檳榔浸膏（0.24、0.96 g·kg^-1）、檳榔堿（0.49、5.46 mg·kg^-1）ig給藥20 d后，觀察小鼠一般情況及體質(zhì)量變化，檢測血清中丙氨酸氨基轉(zhuǎn)移酶（ALT）、天冬氨酸氨基轉(zhuǎn)移酶（AST）、乳酸脫氫酶（LDH）、尿素氮（BUN）、肌酐（Cr）水平，病理學(xué)觀察肝、腎、心、脾組織病理變化，用免疫組化方法分析心肌細(xì)胞凋亡蛋白的表達(dá)情況。結(jié)果 小兒消積止咳口服液、檳榔浸膏及檳榔堿各劑量組對小鼠體質(zhì)量增長沒有顯著影響；與對照組相比，肝、腎功能相關(guān)的血液生化學(xué)指標(biāo)無顯著差異，大體解剖及蘇木精-伊紅（HE）染色顯示各給藥組肝、腎、心、脾等臟器未見明顯的組織病理學(xué)改變，心肌細(xì)胞凋亡相關(guān)蛋白Bcl-2相關(guān)X蛋白（Bax）、半胱氨酸蛋白酶-8（Caspase-8）、消皮素D（GSDMD）表達(dá)量均未見顯著升高。結(jié)論 小兒消積止咳口服液、組方中的檳榔及所含成分檳榔堿對幼齡小鼠在臨床用量范圍內(nèi)、經(jīng)4倍給藥療程連續(xù)給藥，均未造成明確的毒性，表明小兒消積止咳口服液臨床應(yīng)用風(fēng)險可控。

Objective Based on the administration of Xiaoer Xiaoji Zhike Oral Liquid under four clinical procedures (20 d), to investigate its potential toxicity and target organs of toxicity in juvenile mice. Further to anticipate the clinical risks of Arecae Semen and arecoline in children. Methods According to the instructions and available studies, juvenile mice were ig given Xiaoer Xiaoji Zhike Oral Liquid (4.29, 17.16 g·kg^-1), Bing Lang Jin Gao (0.24, 0.96 g·kg^-1), and arecoline (0.49, 5.46 mg·kg^-1) for 20 d. The body weight of mice, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), urea nitrogen (BUN), creatinine (Cr) were observed. Histopathology of the liver, kidney, heart, and spleen detected by HE staining. Finally, cardiomyocyte apoptosis proteins were detected by immunohistochemistry. Results The body weight of mice was not significantly affected after the administration of Xiaoer Xiaoji Zhike Oral Liquid, Bing Lang Jin Gao and arecoline. There were no remarkable differences in blood biochemical indices related to liver and kidney function compared to the control group. No obvious histopathological changes were observed in organs such as liver, kidney, heart and spleen. Bcl-2-related X protein (Bax), caspase-8 , and gasdermin D (GSDMD) were not significantly altered. Conclusion Within the clinical dosage range and after a fourfold administration course, neither of Xiaoer Xiaoji Zhike Oral Liquid, and it contained arecae semen and arecoline have posed toxic side effects in juvenile mice, demonstrating that the risk of the clinical application of Xiaoer Xiaoji Zhike Oral Liquid is controlled.

R965.3

國家重點研發(fā)計劃項目（2022YFC3502100）;高等醫(yī)學(xué)研究院前沿學(xué)科發(fā)展基金項目（GYY2023QY01）;小兒消積止咳口服液上市后再評價研究項目（1520019015）