US Army Medical Material Development Activity, Ft Detrick, MD, USA.
Malar J. 2012 Aug 1;11:255. doi: 10.1186/1475-2875-11-255.
Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Research (WRAIR) has been developing a novel good manufacturing practice (GMP) injection of AS, which was approved by the US FDA for investigational drug use and distribution by the CDC.
Tolerability and pharmacokinetics of current GMP intravenous AS, as an anti-malarial agent, were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusion in 24 healthy subjects (divided into three groups) in the Phase 1 clinical trial study.
Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment. After intravenous injection, parent drug rapidly declined and was converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15-0.23 hr for AS and 1.23-1.63 hr for DHA, but the peak concentration (C(max)) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and C(max) values of AS and DHA were increased proportionally to the AS climbing multiple doses.
The safety of injectable AS, even at the highest dose of 8 mg/kg increases the probability of therapeutic success of the drug even in patients with large variability of parasitaemia.
每年有超过 100 万人死于重症疟疾，其中大多数是五岁以下的儿童，且生活在撒哈拉以南非洲地区。2006 年，世卫组织建议将注射用青蒿琥酯（AS）作为重症疟疾的初始治疗药物。沃尔特·里德陆军研究所（WRAIR）一直在开发一种新型符合良好生产规范（GMP）的 AS 注射液，该注射液已获得美国食品和药物管理局（FDA）批准用于研究性药物使用和疾病控制中心（CDC）分发。
在一项 1 期临床试验研究中，24 名健康受试者（分为 3 组）连续 3 天每日接受 2、4 和 8mg/kg 的递增剂量，2 分钟输注，评估作为抗疟药物的现行 GMP 静脉注射用 AS 的耐受性和药代动力学。
结果显示，没有任何不良事件随剂量增加而增加。药物浓度在 3 天的治疗过程中没有累积，也没有下降。静脉注射后，母体药物迅速下降，并转化为双氢青蒿素（DHA），总体平均消除半衰期范围为 0.15-0.23 小时，AS 为 1.23-1.63 小时，但 AS 的峰值浓度（C(max)）远高于 DHA，范围为 3.08-3.78 倍。此外，AS 和 DHA 的 AUC 和 C(max)值与 AS 递增剂量成正比增加。
即使在最高剂量 8mg/kg 下，注射用 AS 的安全性也增加了药物治疗成功的可能性，即使在寄生虫血症变异性较大的患者中也是如此。
