Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910, USA.
Malar J. 2011 Jul 29;10:212. doi: 10.1186/1475-2875-10-212.
Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns.
In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans.
The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies.
Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.
替法诺喹是一种 8-氨基喹啉，正在开发用于根治（消除血期和肝期）间日疟原虫。在单药治疗期间，该化合物表现出寄生虫和发热清除时间缓慢，葡萄糖-6-磷酸脱氢酶（G6PD）缺乏的毒性是一个关注点。与其他抗疟药物联合使用可能会减轻这些担忧。
2005 年，替法诺喹联合治疗对感染印度起源恒河猴的间日疟原虫的根治疗效进行了研究。在第一队列中，两组猴子接受了为期三天的替法诺喹治疗方案，剂量不同，单独和联合使用为期三天的氯喹方案，以确定最小治愈剂量（MCD）。在第二队列中，比较了为期一天的替法诺喹-甲氟喹方案与由 MCD 的替法诺喹与氯喹或青蒿琥酯-甲氟喹组成的两个为期三天的方案在六只猴子中的根治疗效。在最后一个队列中，在奎宁预处理消除无性期寄生虫后，六只猴子中的 MCD 替法诺喹单独和联合氯喹对休眠子的疗效进行了研究。通过 LC-MS 测定替法诺喹、氯喹和去乙基氯喹的血浆浓度，以便将药物剂量与人类临床使用的剂量进行比较。
根治联合治疗方案所需的替法诺喹总 MCD 比单药治疗低十倍（1.8 mg/kg 对 18 mg/kg）。该方案（1.8 mg/kg）与单药治疗或奎宁预处理消除无性期寄生虫后与氯喹联合治疗同样有效。相同剂量（1.8 mg/kg）与青蒿琥酯-甲氟喹联合具有根治作用。替法诺喹与甲氟喹联合也具有根治作用。替法诺喹单药治疗根治的 MCD（18 mg/kg）似乎与人类 600-1200 mg 剂量的生物学等效。在与血液裂殖体药物联合使用时（1.8 mg/kg），最大观察到的血浆浓度明显低于（20-84 对 550-1100 ng/ml），而在临床研究中使用 1200 mg 时。
如果替法诺喹与有效血裂体药物联合使用，与之前研究相比，用于治疗间日疟原虫休眠子的临床剂量可能降低十倍。
