Behavioral and Environmental Health, School of Health Sciences, College of Public Service, Jackson State University, Jackson, MS, USA.
Med Sci Monit. 2013 Jul 15;19:579-83. doi: 10.12659/MSM.889033.
Mefloquine use has been linked to severe gastrointestinal and neuropsychiatric adverse effects, including cognitive disturbances, anxiety, depression, psychosis, and violence. The adverse effects of the drug are thought to result from the secondary consequences of hepatocellular injury; in fact, mefloquine is known to cause a transient, anicteric chemical hepatitis. However, the mechanism of mefloquine-associated liver damage and the associated neuropsychiatric and behavioral effects of the drug are not well understood. Mefloquine and other 8-amino-quinolines are the only antimalarial drugs that target the liver-stage malaria parasites, which selectively absorb vitamin A from the host. Vitamin A is also stored mainly in the liver, in potentially poisonous concentrations. These observations suggest that both the therapeutic effectiveness of mefloquine and its adverse effects are related to the ability of the 8-aminoquinolines to alter the metabolism of retinoids (vitamin A and its congeners). Several lines of evidence support the hypothesis that mefloquine neurotoxicity and other adverse effects reflect an endogenous form of hypervitaminosis A due to a process involving: mefloquine-induced dehydrogenase inhibition; the accumulation of retinoids in the liver; retinoid-induced hepatocellular damage; the spillage of stored retinoids into the circulation; and the transport of these compounds to the gut and brain in toxic concentrations. The retinoid hypothesis could be tested clinically by comparing cases of mefloquine toxicity and untreated controls in terms of retinoid profiles (retinol, retinyl esters, percent retinyl esters, and retinoic acid). Subject to such tests, retinoid profiling could provide an indicator for assessing mefloquine-associated adverse effects.
盐酸甲氟喹的使用与严重的胃肠道和神经精神不良影响有关，包括认知障碍、焦虑、抑郁、精神病和暴力。该药物的不良反应被认为是肝损伤的继发后果；事实上，已知盐酸甲氟喹会导致短暂的、无黄疸的化学性肝炎。然而，盐酸甲氟喹相关肝损伤的机制以及该药物相关的神经精神和行为影响尚不清楚。盐酸甲氟喹和其他 8-氨基喹啉类药物是唯一靶向肝期疟原虫的抗疟药物，后者从宿主中选择性吸收维生素 A。维生素 A 也主要储存在肝脏中，浓度可能有毒。这些观察结果表明，盐酸甲氟喹的治疗效果及其不良反应都与 8-氨基喹啉类药物改变类视黄醇（维生素 A 及其同系物）代谢的能力有关。有几条证据支持这样一种假设，即盐酸甲氟喹的神经毒性和其他不良反应反映了一种内源性的维生素 A 过多症，其涉及：盐酸甲氟喹诱导的脱氢酶抑制；肝脏中类视黄醇的积累；类视黄醇诱导的肝细胞损伤；储存的类视黄醇溢出到循环中；以及这些化合物以有毒浓度转运到肠道和大脑。可以通过比较盐酸甲氟喹毒性病例和未经治疗的对照病例的类视黄醇谱（视黄醇、视黄酯、视黄酯百分比和视黄酸），来对类视黄醇假说进行临床检验。在进行这些测试的前提下，类视黄醇分析可能为评估盐酸甲氟喹相关不良反应提供一个指标。
