青蒿素与疟疾:药物激活、作用机理及抗药性的研究进展

Artemisinin and malaria: Current understandings of drug activation, action, and resistance

如能及早确诊并合理救治,疟疾是可以通过抗疟药来治愈的.然而,抗药性疟原虫通常在一种新型药物的大规模使用后的数年内就会出现.随着疟原虫几乎对所有类型的抗疟药均产生了不同程度的抗性,青蒿素类药物联合疗法(ACTs)也由此成为治疗疟疾最重要的手段.不幸的是,已有报道称在东南亚地区采用青蒿素或ACTs治疗后出现了延迟原虫清除的现象,这也让研究者们对青蒿素及其衍生物治疗在未来发生完全失效的可能感到担忧.本文简要综述了青蒿素的药物激活、作用机理、药物靶点及可能的抗药性机制等研究的进展;对抗药性的定义、青蒿素组合用药中伴侣药物的选择,以及当前为消除疟疾采取全民用药的努力等问题作了讨论.与此相关的议题已有大量的研究和文献报道,由于篇幅有限未能逐一列举.此外,本文所讨论的某些问题仍存争议、还需深入的研究方能解答.

Malaria is a disease that can be cured with antimalarial drugs if treated early and appropriately. However, parasites resistant to a new drug generally emerge within a few years after large-scale applications. Artemisinin（ART or Qinghaosu） combination therapies（ACTs） have become the major treatments for malaria after the emergence of parasites resistant to almost all classes of antimalarial drugs. Parasites with delayed parasite clearance（DPC） after ART or ACT therapies have also been reported in Southeast Asia, raising concerns of total failure of ART and its derivatives. Many classes of antimalarial drugs have been introduced to successfully treat malaria infections, including chloroquine, piperaquine, primaquine, mefloquine（MQ）, pyrimethamine, sulfadoxine, ART and derivatives, etc. Regrettably, many of these drugs have been abandoned by many countries in malaria endemic regions due to the emergence of drug resistant parasites. According to World Health Organization, parasite responses to a drug can be classified into four categories（S, RI, RII, and RIII）： Sensitivity（S） to a drug is defined as clearance of asexual parasitemia within seven days of the first day of treatment without recrudescence; Resistance RI is defined as clearance of asexual parasitemia as in sensitive parasites, followed by recrudescence; RII resistance is indicated by marked reduction of asexual parasitemia, but no clearance; and RIII resistance shows no marked reduction of asexual parasitemia. Currently, RII and RIII resistance to chloroquine, pyrimethamine, and other drugs have been widely reported; but residence to ART remains largely at R1 level. ART resistance was initially defined as parasites with half parasite clearance time（PC1/2）5 h under a standard ART treatment regimen（three-day artesunate treatment at 2–4 mg kg-1 d-1）. A second measurement is in vitro ring survival assay（RSA） that was developed based on the observation that the ring stages of some parasite strains could survive a short period of ART treatment. Another indicator of increasing ART tolerance is the elevated rate of recrudescence after ART or ACT treatments. The generation of highly reactive radicals via endoperoxide cleavage is critical for ART activation. Both free ferrous iron and heme have been proposed to be the predominant iron sources for ART activation. The heme required for ART activation can be derived from the parasite＇s heme biosynthesis pathway at the early ring stage and/or from hemoglobin digestion at later stages. A large number of parasite molecules have been found to bind or interact with ART, most notably the Plasmodium falciparum ATPase 6（PfA TP6 or SERCA）, phosphatidylinositol-3-kinase（PfP I3K）, chloroquine resistance transporter（Pf CRT）, and multiple drug resistance 1（Pf MDR1）. Recently, a gene encoding a parasite Kelch protein（＂K13＂） with a six-blade propeller domain was identified as a potential molecular marker of ART resistance in vivo（DPC5 h） and in vitro（RSA）. Various antimalarial drugs such as meflouine and piperaquine have been used as partner drugs in ACTs. However, parasites resistant to these partner drugs have also been reported, which may explain the reported slow parasite clearance after ACT treatment. The success of ACTs in treating malaria infections has generated optimism and proposals for malaria eradication by mass drug administration（MDA）, and successes have been achieved from several studies. However, the impact of MDA on malaria transmission in the long term, especially in low-and moderate-transmission settings, and the potential consequences of developing drug resistance, requires careful evaluation. There are a large number of studies and publications on these related subjects, and it is impossible to include or cite all the publications in this review. Additionally, some of the issues discussed here are still being debated, requiring further investigation.