Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
PLoS One. 2011;6(5):e19283. doi: 10.1371/journal.pone.0019283. Epub 2011 May 13.
The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia.
Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days.
143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/µL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×10(9)/L) by Day 14 and resulted in the arm being halted early.
There is no pharmacodynamic benefit of increasing the daily dose of AS (4 mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy.
ClinicalTrials.gov NCT00722150.
青蒿素耐药性的出现引发了人们的担忧，即这种最有效的抗疟药物可能受到威胁。目前推荐的青蒿琥酯（AS）日剂量为 4 毫克/公斤，并与一种联合抗疟药物一起使用 3 天。本研究调查了不同 AS 剂量对柬埔寨西部已知青蒿素耐药地区疟疾患者的临床和寄生虫学反应的影响。
将患有无并发症恶性疟原虫疟疾的成年患者随机分为三组，接受为期 7 天的 AS 单药治疗方案：2、4 或 6 毫克/公斤/天（总剂量 14、28 和 42 毫克/公斤）。在 7 天的住院期间和第 42 天的每周随访期间收集临床、寄生虫学、药代动力学和体外药物敏感性数据。
共纳入 143 例患者（n=75、40 和 28 例分别接受 AS 2、4 和 6 毫克/公斤/天）。尽管几乎一半的患者在第 3 天仍有寄生虫血症，但所有治疗组在第 42 天的治愈率均很高。增加 AS 剂量对中位寄生虫清除时间、中位寄生虫清除率或第 3 天仍有寄生虫血症的患者比例均无影响。然而，在使用的最低剂量（2 毫克/公斤/天）中，寄生虫血症>10,000/µL 的患者的中位（IQR）寄生虫清除时间长于寄生虫血症<10,000/µL 的患者（63（48-75）比 84（66-96）小时，p<0.0001）。高剂量组有 19%的患者在第 14 天发生中性粒细胞减少症（绝对中性粒细胞计数<1.0×10(9)/L），导致该组提前停止。
只要联合药物保持高疗效，目前推荐用于治疗无并发症疟疾的短程联合治疗的 AS（4 毫克/公斤/天）日剂量增加没有药效学益处，即使在出现青蒿素耐药性的地区也是如此。
ClinicalTrials.gov NCT00722150。
