Li Q G, Mog S R, Si Y Z, Kyle D E, Gettayacamin M, Milhous W K
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500, USA.
Am J Trop Med Hyg. 2002 May;66(5):516-25. doi: 10.4269/ajtmh.2002.66.516.
The neurotoxicity of beta-arteether (AE) is related to drug accumulation in blood due to slow and prolonged absorption from the intramuscular injection sites. In this efficacy and toxicity study of AE, the traditional sesame oil vehicle was replaced with cremophore to decrease the accumulation and toxicity of AE. Dihydroartemisinin (DQHS), a more toxic and active metabolite of AE, was also analyzed. When administered at a daily dosage of 25 mg/kg for seven days, blood accumulation of AE with sesame oil (AESO) was used had a 7.5-fold higher area under the curve (AUC) (on last versus first day dosing), while AE with cremophore (AECM) had only a 1.8-fold higher AUC. Although the accumulation of AECM was greatly reduced, its total exposure level (46.29 microg x h/ml) was 2.7-fold higher than with AESO (16.92 microg x h/ml) due to a higher bioavailability of AECM (74.5%) compared with AESO (20.3%). Total exposure time (calculated at over the minimal detected neurotoxicity level of 41.32 ng/ml) of AECM was 103 hours during the whole treatment period (192 hours), which was more than one-third (37%) less than with AESO (162 hours). Similar pharmacokinetic results were also shown with the active metabolite, DQHS. Anorexia and gastrointestinal toxicity with AESO were significantly more severe than with AECM (P < 0.001). Histopathologic examination of the brain demonstrated neurotoxic changes; the AESO rat group was significantly more severe than the AECM rat group. The brain injury scores with AECM were mild to moderate (2.3-3.0), and with AESO they were moderate to severe (3.0-4.7) on day 7 and day 10, respectively. In addition, the results of a 50% cure dose (CD50) against Plasmodium berghei in mice were 34.1 mg/kg for AESO and 14.2 mg/kg for AECM, indicating a significant higher efficacy was found in the AECM animals. Toxicity and efficacy of DQHS were also dependent on its exposure time and level, which was the same as its parent drug (AE). In conclusion, following the seven-day treatment in rats, AE and DQHS exposure time and level varied based on the vehicle used. The extension of drug exposure time and the low peak level of AE and DQHS were more associated with severe neurotoxicity and lower antimalarial efficacy, whereas the high level and short exposure time of AE and DQHS resulted in higher efficacy and milder toxicity.
蒿甲醚（AE）的神经毒性与肌肉注射部位吸收缓慢且持久导致药物在血液中蓄积有关。在这项蒿甲醚的疗效和毒性研究中，用聚氧乙烯蓖麻油取代了传统的芝麻油载体，以减少蒿甲醚的蓄积和毒性。还分析了蒿甲醚毒性更强且更具活性的代谢产物双氢青蒿素（DQHS）。当以25mg/kg的日剂量给药7天时，使用芝麻油的蒿甲醚（AESO）的血药蓄积曲线下面积（AUC）（末次给药日与首次给药日相比）高7.5倍，而使用聚氧乙烯蓖麻油的蒿甲醚（AECM）的AUC仅高1.8倍。尽管AECM的蓄积大幅减少，但由于AECM的生物利用度（74.5%）高于AESO（20.3%），其总暴露水平（46.29μg·h/ml）比AESO（16.92μg·h/ml）高2.7倍。在整个治疗期（192小时）内，AECM的总暴露时间（按超过最低检测神经毒性水平41.32ng/ml计算）为103小时，比AESO（162小时）少三分之一以上（37%）。活性代谢产物DQHS也显示出类似的药代动力学结果。AESO导致的厌食和胃肠道毒性明显比AECM严重（P<0.001）。脑组织病理检查显示有神经毒性改变；AESO大鼠组比AECM大鼠组严重得多。第7天和第10天时，AECM组的脑损伤评分为轻度至中度（2.3 - 3.0），AESO组则为中度至重度（3.0 - 4.7）。此外，对小鼠伯氏疟原虫的50%治愈剂量（CD50）结果显示，AESO为34.1mg/kg，AECM为14.2mg/kg，表明AECM组动物的疗效明显更高。DQHS的毒性和疗效也取决于其暴露时间和水平，这与其母体药物（AE）相同。总之，在大鼠进行7天治疗后，AE和DQHS的暴露时间和水平因所用载体而异。药物暴露时间延长以及AE和DQHS的低峰值水平与严重神经毒性和较低抗疟疗效更相关，而AE和DQHS的高水平和短暴露时间则导致更高疗效和更轻毒性。
