Department of Internal Medicine, Mae Sot General Hospital, Tak, Thailand.
N Engl J Med. 2012 Apr 5;366(14):1298-309. doi: 10.1056/NEJMoa1007125.
Pyronaridine-artesunate is an artemisinin-based combination therapy under evaluation for the treatment of Plasmodium falciparum and P. vivax malaria.
We conducted a phase 3, open-label, multicenter, noninferiority trial that included 1271 patients between 3 and 60 years of age from Asia (81.3%) or Africa (18.7%) with microscopically confirmed, uncomplicated P. falciparum malaria. Patients underwent randomization for treatment with a fixed-dose combination of 180 mg of pyronaridine and 60 mg of artesunate or with 250 mg of mefloquine plus 100 mg of artesunate. Doses were calculated according to body weight and administered once daily for 3 days.
Pyronaridine-artesunate was noninferior to mefloquine plus artesunate for the primary outcome: adequate clinical and parasitologic response in the per-protocol population on day 28, corrected for reinfection with the use of polymerase-chain-reaction (PCR) genotyping. For this outcome, efficacy in the group receiving pyronaridine-artesunate was 99.2% (743 of 749 patients; 95% confidence interval [CI], 98.3 to 99.7) and that in the group receiving mefloquine plus artesunate was 97.8% (360 of 368 patients; 95% CI, 95.8 to 99.1), with a treatment difference of 1.4 percentage points (95% CI, 0.0 to 3.5; P=0.05). In the intention-to-treat population, efficacy on day 42 in the group receiving pyronaridine-artesunate was 83.1% (705 of 848 patients; 95% CI, 80.4 to 85.6) and that in the group receiving mefloquine plus artesunate was 83.9% (355 of 423 patients; 95% CI, 80.1 to 87.3). In Cambodia, where there were 211 study patients, the median parasite clearance time was prolonged for both treatments: 64 hours versus 16.0 to 38.9 hours in other countries (P<0.001, on the basis of Kaplan-Meier estimates). Kaplan-Meier estimates of the recrudescence rate in the intention-to-treat population in Cambodia until day 42 were higher with pyronaridine-artesunate than with mefloquine plus artesunate (10.2% [95% CI, 5.4 to 18.6] vs. 0%; P=0.04 as calculated with the log-rank test), but similar for the other countries combined (4.7% [95% CI, 3.3 to 6.7] and 2.8% [95% CI, 1.5 to 5.3], respectively; P=0.24). Elevated levels of aminotransferases were observed in those receiving pyronaridine-artesunate. Two patients receiving mefloquine plus artesunate had seizures.
Fixed-dose pyronaridine-artesunate was efficacious in the treatment of uncomplicated P. falciparum malaria. In Cambodia, extended parasite clearance times were suggestive of in vivo resistance to artemisinin. (Funded by Shin Poong Pharmaceutical Company and the Medicines for Malaria Venture; ClinicalTrials.gov number, NCT00403260.).
派隆那林-青蒿琥酯是一种青蒿素类复方疗法，正在评估用于治疗恶性疟原虫和间日疟原虫疟疾。
我们进行了一项 3 期、开放性、多中心、非劣效性试验，包括来自亚洲（81.3%）或非洲（18.7%）的 1271 名年龄在 3 至 60 岁之间、经显微镜确认的无并发症恶性疟原虫疟疾患者。患者随机分为接受固定剂量的派隆那林 180mg 和青蒿琥酯 60mg 或接受 250mg 甲氟喹和 100mg 青蒿琥酯治疗的两组。根据体重计算剂量，并每日 1 次给药 3 天。
派隆那林-青蒿琥酯在主要结局方面不劣于甲氟喹-青蒿琥酯：28 天时按聚合酶链反应（PCR）基因分型校正再感染的方案，符合方案人群的充分临床和寄生虫学应答。在接受派隆那林-青蒿琥酯治疗的组中，疗效为 99.2%（749 例中的 743 例；95%置信区间[CI]，98.3 至 99.7），接受甲氟喹-青蒿琥酯治疗的组中为 97.8%（368 例中的 360 例；95%CI，95.8 至 99.1），治疗差异为 1.4 个百分点（95%CI，0.0 至 3.5；P=0.05）。在意向治疗人群中，接受派隆那林-青蒿琥酯治疗的组在第 42 天的疗效为 83.1%（848 例中的 705 例；95%CI，80.4 至 85.6），接受甲氟喹-青蒿琥酯治疗的组为 83.9%（423 例中的 355 例；95%CI，80.1 至 87.3）。在柬埔寨有 211 例研究患者，两种治疗的寄生虫清除时间均延长：64 小时与其他国家的 16.0 至 38.9 小时（基于 Kaplan-Meier 估计，P<0.001）。在柬埔寨直至第 42 天的意向治疗人群中，派隆那林-青蒿琥酯的复燃率的 Kaplan-Meier 估计值高于甲氟喹-青蒿琥酯（10.2%[95%CI，5.4 至 18.6]与 0%；对数秩检验计算的 P=0.04），但在其他国家的合并数据中相似（分别为 4.7%[95%CI，3.3 至 6.7]和 2.8%[95%CI，1.5 至 5.3]；P=0.24）。接受派隆那林-青蒿琥酯治疗的患者中观察到氨基转移酶水平升高。有 2 名接受甲氟喹-青蒿琥酯治疗的患者发生癫痫发作。
固定剂量的派隆那林-青蒿琥酯对治疗无并发症恶性疟原虫疟疾有效。在柬埔寨，寄生虫清除时间延长提示存在对青蒿素的体内耐药性。（由 Shin Poong 制药公司和疟疾药物倡议资助；临床试验注册编号，NCT00403260。）
