Dow G, Bauman R, Caridha D, Cabezas M, Du F, Gomez-Lobo R, Park M, Smith K, Cannard K
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, USA.
Antimicrob Agents Chemother. 2006 Mar;50(3):1045-53. doi: 10.1128/AAC.50.3.1045-1053.2006.
Mefloquine is one of the drugs approved by the FDA for malaria chemoprophylaxis. Mefloquine is also approved for the treatment of malaria and is widely used for this purpose in combination with artesunate. However, the clinical utility of the compound has been compromised by reports of adverse neurological effects in some patients. In the present study, the potential neurological effects of mefloquine were investigated with six 7-week-old female rats given a single oral dose of the compound. Potential mefloquine-induced neurological effects were monitored using a standard functional observational battery, automated open field tests, automated spontaneous activity monitoring, a beam traverse task, and histopathology. Plasma mefloquine concentrations were determined 72 h after dosing by using liquid chromatography-mass spectrometry. Mefloquine induced dose-related changes in endpoints associated with spontaneous activity and impairment of motor function and caused degeneration of specific brain stem nuclei (nucleus gracilis). Increased spontaneous motor activity was observed only during the rats' normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders. The threshold dose for many of these effects was 187 mg/kg of body weight. This dose yielded plasma mefloquine concentrations after 72 h that are similar to those observed in humans after the treatment dose. Collectively, these data suggest that there may be a biological basis for some of the clinical neurological effects associated with mefloquine.
甲氟喹是美国食品药品监督管理局（FDA）批准用于疟疾化学预防的药物之一。甲氟喹也被批准用于治疗疟疾，并广泛用于与青蒿琥酯联合治疗疟疾。然而，该化合物的临床应用因一些患者出现不良神经效应的报告而受到影响。在本研究中，对6只7周龄雌性大鼠单次口服该化合物，研究甲氟喹的潜在神经效应。使用标准功能观察组合、自动旷场试验、自动自发活动监测、横梁穿越任务和组织病理学监测甲氟喹可能引起的神经效应。给药72小时后，采用液相色谱-质谱法测定血浆中甲氟喹的浓度。甲氟喹引起与自发活动和运动功能损害相关的终点指标出现剂量相关变化，并导致特定脑干核（薄束核）变性。仅在大鼠正常睡眠阶段观察到自发运动活动增加，提示与甲氟喹引起的睡眠障碍有关。许多这些效应的阈剂量为187mg/kg体重。该剂量在72小时后产生的血浆甲氟喹浓度与人类治疗剂量后观察到的浓度相似。总体而言，这些数据表明，与甲氟喹相关的一些临床神经效应可能存在生物学基础。
