Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA.
Toxicology. 2011 Jan 11;279(1-3):1-9. doi: 10.1016/j.tox.2010.09.005. Epub 2010 Sep 21.
Studies with laboratory animals have demonstrated fatal neurotoxicity that is associated with administration of artemether (AM) and arteether (AE) intramuscularly or artelinic acid (AL) orally. Toxicokinetic studies showed oil-soluble artemisinins form a depot at the intramuscular injection sites, which is associated with fascia inflammation in muscles. Oral administration of AL induces a gastrointestinal toxicity that is linked with delayed gastric emptying. These effects suggest that the exposure time of artemisinins was extended due to drug accumulation in blood, and this in turn resulted in neurotoxicity. In the present report, the drug exposure time with a neurotoxic outcome (neurotoxic exposure time) was evaluated as a predictor of neurotoxicity in vivo. The neurotoxic exposure time represents a total time spent above a lowest observed neurotoxic effect levels (LONEL) in plasma. The dose of AE required to induce minimal neurotoxicity requires a 2-3 fold longer exposure time in rhesus monkeys (179.5 h) than in rats (67.1 h) and dogs (103.7 h) by using a daily dose of 6-12.5 mg/kg for 7-28 days, indicating that the safe dosing duration in monkeys should be longer than 7 days under the exposure. The neurotoxic exposure time of artemisinins could be longer in humans as the comparison of monkeys to humans is likely more relevant than from rodents or dogs. Oral AL required much longer exposure times (8-fold) than intramuscular AE to induce neurotoxicity, suggesting that water-soluble artemisinins appear to be much safer than oil-soluble artemisinins. Due to lower doses (2-4 mg/kg) used with current artemisinins and the more rare use of AE in treating humans the exposure time is much shorter in humans. Therefore, the current regimen of 3-5 days dosing duration should be quite safe. These findings support a recently published WHO guide for malaria treatment with artemisinin regimens, such as artemisinin-based combination therapies and injectable artesunate, to avoid neurotoxicity.
动物实验研究表明，青蒿琥酯（AM）和蒿甲醚（AE）肌肉注射或 artelinic 酸（AL）口服会导致致命的神经毒性。毒代动力学研究表明，油溶性青蒿素在肌肉内注射部位形成一个储库，这与肌肉中的筋膜炎症有关。AL 的口服给药会引起胃肠道毒性，这与胃排空延迟有关。这些作用表明，由于药物在血液中的积累，青蒿素的暴露时间延长，进而导致神经毒性。在本报告中，将具有神经毒性结果的药物暴露时间（神经毒性暴露时间）评估为体内神经毒性的预测指标。神经毒性暴露时间代表在血浆中低于最低观察到的神经毒性效应水平（LONEL）之上的总时间。用 6-12.5 mg/kg 的日剂量连续给药 7-28 天，AE 引起最小神经毒性所需的剂量是大鼠（67.1 h）和狗（103.7 h）的 2-3 倍，这表明猴子的安全给药持续时间应长于 7 天。由于与猴子相比，将啮齿动物或狗与人进行比较可能更相关，因此青蒿素类药物的神经毒性暴露时间可能在人类中更长。口服 AL 引起神经毒性所需的暴露时间比肌肉注射 AE 长 8 倍，这表明水溶性青蒿素类药物似乎比油溶性青蒿素类药物安全得多。由于目前使用的青蒿素类药物剂量较低（2-4mg/kg），并且 AE 治疗人类的使用频率较低，因此人类的暴露时间要短得多。因此，目前 3-5 天的给药持续时间方案应该是非常安全的。这些发现支持了世界卫生组织最近发布的抗疟治疗用青蒿素类药物方案指南，如青蒿琥酯联合疗法和注射用青蒿琥酯，以避免神经毒性。
