青蒿素面临抗药性 抗击疟疾亟需新药

China’s first Nobel Prize for physiology or medicine was 419 years in the making. Tu Youyou, an 85 year-old chemist, won last year’s prize for her work in the 1970s developing artemisinin as a malaria treatment.

中国获得首个诺贝尔生理学或医学奖(Nobel Prize)花了419年时间。去年，85岁的药学家屠呦呦因在上世纪70年代开发用来治疗疟疾的青蒿素(artemisinin)赢得诺贝尔奖。

She had been alerted to the potential of artemisinin — an extract from the sweet wormwood plant — after scouring Chinese literature in search of traditional herbal remedies for the disease.

她在翻阅治疗疟疾的传统中草药文献后注意到了青蒿素的潜在价值，青蒿素是从青蒿(Artemisia annua)中提炼出来的。

Records of sweet wormwood, or Artemisia annua, being used against malaria date back to at least 1596, when Li Shizhen, a Chinese medical scholar, suggested that it be given to patients as a tea.

用青蒿治疗疟疾的记录至少可追溯到1596年，当时中国医药学家李时珍建议，患者应把青蒿代茶饮。

It is still one of the main weapons in the world’s armoury against the disease. Treatment courses of artemisinin-based combination therapies increased from 11m in 2005 to 392m in 2013 as global health authorities put the drug at the centre of their fight against the mosquito-borne scourge.

它仍是全球治疗疟疾的主要武器之一。基于青蒿素的综合疗法的疗程从2005年的1100万个增至2013年的3.92亿个，全球医疗当局把这种药物推到抗击由蚊子传播的疟疾的风口浪尖。

Concern is growing, however, that four centuries after artemisinin’s first use, the parasites responsible for malaria may be starting to get the better of its ancient powers. Artemisinin-resistant strains were first detected eight years ago in western Cambodia. Cases have since been detected in Myanmar, Thailand, Vietnam and Laos.

然而，人们越来越担心，在首次使用青蒿素4个世纪后，引发疟疾的寄生虫可能正开始战胜古老力量。8年前，在柬埔寨西部首次发现了具有青蒿素抗药性的菌株。随后缅甸、泰国、越南和老挝也发现了类似的病例。

For global health leaders, the pattern is alarmingly similar to the way resistance to chloroquine, another malaria treatment, emerged in Southeast Asia in the 1950s and spread to Africa — where the large majority of cases occur.

对于全球公共卫生主管而言，这种现象与另一种抗疟药物氯奎(chloroquine)遭遇抗药性的经历有着惊人的相似性，上世纪50年代，氯奎抗药性在东南亚出现，然后蔓延至非洲，大部分疟疾病例出现在非洲。

“We see a little bit of history repeating itself,” says Thierry Diagana, head of the Novartis Institute for Tropical Diseases. “Artemisinin resistance has spread as far as the western border of Thailand and Cambodia. If it crosses into India it will become a much bigger challenge.”

“我们看到历史正在重演，”诺华热带疾病研究所(Novartis Institute for Tropical Diseases)负责人蒂埃里•迪亚贾纳(Thierry Diagana)表示，“青蒿素抗药性正蔓延到泰国和柬埔寨西部边境。如果它越过边境进入印度，那将变成一个严峻得多的挑战。”

Novartis, the Swiss pharmaceuticals group, commercialised artemisinin combination therapy in the 1990s. The group is among the leaders in the hunt for new drugs to replace artemisinin as its efficacy fades.

上世纪90年代，瑞士制药集团诺华将青蒿素综合疗法商业化。随着青蒿素药效减退，很多制药公司正在寻找替代青蒿素的新药，诺华是这项努力的领军者之一。

In 2014, the Novartis unit led by Dr Diagana demonstrated the first clinical proof-of-concept — a clinical trial showing that a drug works — for a new malaria treatment. The compound, codenamed KAE 609, works by interfering with the sodium concentration in both of the two parasites that cause the majority of cases. Plasmodium vivax is common in Asia and South America, while the more virulent Plasmodium falciparum is most prevalent in Africa. Importantly, KAE 609 also worked in people with artemisinin-resistant strains in Southeast Asia.

2014年，由迪亚贾纳博士领导的诺华热带疾病研究所展示了一种治疗疟疾的新药的首次临床概念验证（显示药物有效的临床试验）。这种复方药物的代号是KAE 609，它通过干扰引发大部分疟疾病例的两种寄生虫体内的纳浓度而起到治疗作用。间日疟原虫(Plasmodium vivax)在亚洲和南美较为普遍，而毒性更大的恶性疟原虫(Plasmodium falciparum)在非洲最为普遍。重要的是，KAE 609对于东南亚那些携带青蒿素抗药性菌株的人也有疗效。

Proof-of-concept data are expected soon on a second Novartis compound, known as KAF 156. It has shown promise against drug-resistant strains of both parasites as well as a further unique advantage. Unlike artemisinin-based therapies, KAF 156 acts against the parasites while still in the asymptomatic “liver stage” of the disease, before it has spread into the blood stream.

预计诺华的第二种复方药物（名为KAF 156）的概念验证数据将很快出炉。它有望抵御两种寄生虫的抗药菌株，并具有另一种独特优势。与基于青蒿素的疗法不同，KAF 156可以在疟疾的无症状“肝脏期”、在疾病蔓延到血流之前杀灭寄生虫。

This would enable it not only to treat sufferers at malaria’s earliest stage — the disease can remain dormant in the liver for months after infection — but also prevent them passing on the parasite to mosquitoes for further transmission.

这令其不仅能够治疗处于疟疾最早期的患者（在感染后，这种疾病可以在肝脏中潜伏数月之久），而且还能阻止患者将这种寄生虫传递到蚊子身上进一步传播。

The positive early data must be replicated in larger studies if KAE 609 and KAF 156 are to satisfy regulators. Dr Diagana says Novartis aims to have at least one of them on the market by 2021.

要让KAE 609和KAF 156获得监管机构的批准，积极的早期数据必须在更大规模的研究中得到验证。迪亚贾纳博士表示，诺华计划最迟在2021年至少向市场投放其中一种药物。

The Novartis compounds are among the most promising of over 50 antimalarial products being developed in partnership with the Medicines for Malaria Venture (MMV). Donors including the Bill & Melinda Gates Foundation, the UK Department for International Development and the Wellcome Trust have pledged $865m to the non-profit organisation since it was set up in 1999.

诺华公司的这两种复方药物列在与“疟疾药品事业会”(Medicines for Malaria Venture，简称MMV)合作开发的50多种最有希望的疟疾药品中。自这家非盈利组织1999年成立以来，捐款者已捐款8.65亿美元，包括比尔及梅琳达·盖茨基金会(Bill & Melinda Gates Foundation)、英国国际发展部(UK Department for International Development)以及维康信托基金会(Wellcome Trust)。

However, that is small compared with the billions of dollars invested by the pharmaceuticals industry in more commercially attractive disease areas such as cancer, and progress is slow. It typically takes about 10 years to get a new drug from early stage development to market and less than 10 per cent of candidates make it all the way.

然而，与制药行业投入癌症等更具商业吸引力的疾病领域的巨额资金相比，这些捐赠规模较小，而且进展缓慢。一种新药从初期研发到推向市场一般耗时10年左右，同时只有不到10%的候选新药会成功推向市场。

The MMV is not relying solely on big pharmaceuticals groups. It has also awarded research grants for academics to pursue assets from its so-called Malaria Box of compounds that have shown potential against the disease but have lacked funding for development.

疟疾药品事业会并不单单依赖大型制药公司。它还向学者们提供研究补助，支持他们研究所谓的“疟疾信息库”(Malaria Box)中的化合物，这些化合物已显示出治疗疟疾的潜力，但缺乏开发资金。

Back in China, last year’s Nobel Prize for Ms Tu — she is neither a doctor nor professor — has stirred pride but also surprise that she received little previous recognition in her own country. The official Xinhua news agency said that the four-decade gap between her discovery and the award showed that “science is never about instant success.”

回到中国，去年颁给屠呦呦的诺贝尔奖（她既不是医师也不是教授）激起了中国人的骄傲，但也让人意外，因为她之前在国内没有得到什么认可。官方的新华社表示，从发现青蒿素到获得诺奖经历了40年时间，表明科学不能急功近利。

The spread of artemisinin-resistant malaria is adding urgency to the search for a fresh generation of drugs. In her Nobel lecture in Stockholm in December, Ms Tu issued a “severe warning” over the looming threat to the drug she helped discover.

具有青蒿素抗药性的疟疾的蔓延给寻找新一代药物增添了紧迫感。在去年12月在斯德哥尔摩诺贝尔奖颁奖典礼上演讲时，屠呦呦对她帮助发现的这种药物面临的威胁发出了“严重警告”。

Dr Diagana says that Novartis and its partners are moving as fast as possible. “It’s a good time for malaria drug discovery,” he says. “But we need to make progress quickly so we can avoid another global failure like we had with chloroquine.”

迪亚贾纳博士表示，诺华及其合作伙伴正尽快采取行动。“现在是发现治疗疟疾药物的好时机，”他表示，“但我们需要快速取得进展，使我们能够避免当年氯奎那样的全球失败。”