In malaria-endemic countries, repeated intake of artemisinin-based combination therapies (ACTs) is rampant and driven by drug resistance, improper usage, and easy accessibility. Stress effects and potential liver toxicity due to the frequent therapeutic use of ACTs have not been extensively studied. Here, we investigated the effects of repeated treatment with standard doses of the commonly used ACTs artemether/lumefantrine (A/L) and artesunate-amodiaquine (A/A) on oxidative stress and liver function markers in male mice (BALB/c). Forty Five mice were divided into three groups: control, A/L, and A/A. The drugs were administered three days in a row per week, and the regimen was repeated every two weeks for a total of six cycles. The levels of oxidative stress and liver function markers were measured in both plasma and liver tissue after initial (baseline) and repeated exposures for the second, third, and sixth cycles. Exposure to A/L or A/A caused a significant (p < 0.001) increase in plasma malondialdehyde (MDA) levels after the first and repeated exposure periods. However, Hepatic MDA levels increased significantly (p < 0.01) only after the sixth exposure to A/A. Following either single or repeated exposure to A/L or A/A, plasma and liver glutathione peroxidase (GPx) and catalase (CAT) activities, plasma aspartate and alanine transaminase, alkaline phosphatase activity, and bilirubin levels increased, whereas total plasma protein levels decreased significantly (p < 0.001). Varying degrees of hepatocyte degeneration and blood vessel congestion were observed in liver tissues after a single or repeated treatment period. Irrespective of single or repeated exposure to therapeutic doses of A/L or A/A, plasma oxidative stress and liver damage were observed. However, long-term repeated A/A exposure can led to hepatic stress. Compensatory processes involving GPx and CAT activities may help reduce the observed stress.

中文翻译：

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基线和反复暴露于标准剂量的青蒿素联合疗法 (ACT) 会诱导小鼠氧化应激和肝损伤 (BALB/c)

在疟疾流行国家，重复服用基于青蒿素的联合疗法（ACT）十分猖獗，其原因是耐药性、使用不当和易于获取。由于频繁使用 ACT 进行治疗而产生的应激效应和潜在的肝毒性尚未得到广泛研究。在这里，我们研究了常用的 ACT 药物蒿甲醚/苯芴醇 (A/L) 和青蒿琥酯-阿莫地喹 (A/A) 重复治疗对雄性小鼠 (BALB/c) 氧化应激和肝功能标志物的影响。将 45 只小鼠分为三组：对照组、A/L 组和 A/A 组。每周连续给药三天，每两周重复一次该方案，总共六个周期。在初始（基线）和第二、第三和第六个周期的重复暴露后，测量血浆和肝组织中氧化应激和肝功能标志物的水平。首次和重复暴露后，暴露于 A/L 或 A/A 会导致血浆丙二醛 (MDA) 水平显着增加 (p < 0.001)。然而，仅在第六次暴露于 A/A 后，肝脏 MDA 水平才显着增加 (p < 0.01)。单次或重复接触 A/L 或 A/A 后，血浆和肝脏谷胱甘肽过氧化物酶 (GPx) 和过氧化氢酶 (CAT) 活性、血浆天冬氨酸和丙氨酸转氨酶、碱性磷酸酶活性和胆红素水平增加，而血浆总蛋白水平增加显着下降（p < 0.001）。单次或重复治疗后，肝组织出现不同程度的肝细胞变性和血管充血。无论单次或重复暴露于治疗剂量的 A/L 或 A/A，均观察到血浆氧化应激和肝损伤。然而，长期反复接触 A/A 会导致肝应激。涉及 GPx 和 CAT 活动的补偿过程可能有助于减少观察到的压力。