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Secret Maoist Chinese Operation Conquered Malaria

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Secret Maoist Chinese Operation Conquered Malaria — and Won a Nobel

10/07/2015 – Jia-Chen Fu, Emory University

http://www.scientificcomputing.com/articles/2015/10/secret-maoist-chinese-operation-conquered-malaria-%E2%80%94-and-won-nobel?et_cid=4866514&et_rid=535648082

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This photo taken September 23, 2011, and released by Xinhua News Agency on October 5, 2015, shows Chinese pharmacologist Tu Youyou posing with her trophy after winning the Lasker Award, a prestigious U.S. medical prize, in New York. Three scientists from Ireland, Japan and China won the 2015 Nobel Prize in medicine on October 5 for discovering drugs against malaria and other parasitic diseases that affect hundreds of millions of people every year. Tu was awarded the prize for discovering artemisinin, a drug that has helped significantly reduce the mortality rates of malaria patients. (Wang Chengyun/Xinhua via AP)

At the height of the Cultural Revolution, Project 523 — a covert operation launched by the Chinese government and headed by a young Chinese medical researcher by the name of Tu Youyou — discovered what has been the most powerful and effective antimalarial drug therapy to date.

Known in Chinese as qinghaosu and derived from the sweet wormwood (Artemisia annua L.), artemisinin was only one of several hundred substances Tu and her team of researchers culled from Chinese drugs and folk remedies and systematically tested in their search for a treatment to chloroquine-resistant malaria.

How Tu and her team discovered artemisinin tells us much about the continual Chinese effort to negotiate between traditional/modern and indigenous/foreign.

Indeed, contrary to popular assumptions that Maoist China was summarily against science and scientists, the Communist party-state needed the scientific elite for certain political and practical purposes.

Medicine, particularly when it also involved foreign relations, was one such area. In this case, it was the war in Vietnam and the scourge of malaria that led to the organization of Project 523.

North Vietnamese soldiers had to deal with disease as well as the enemy. manhhaiCC BY

North Vietnamese soldiers had to deal with disease

North Vietnamese soldiers had to deal with disease

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A request from Vietnam and a military answer

As fighting escalated between American and Vietnamese forces throughout the 1960s, malaria became the number one affliction compromising Vietnamese soldier health. The increasing number of chloroquine-resistant malaria cases in the civilian population further heightened North Vietnamese concern.

In 1964, the North Vietnamese government approached Chinese leader Mao Tse Tung and asked for Chinese assistance in combating malaria. Mao responded, “Solving your problem is the same as solving our own.”

From the beginning, Project 523, which was classified as a top-secret state mission, was under the direction of military authorities. Although civilian agencies were invited to collaborate in May 1967, military supervision highlighted the urgent nature of the research and protected it from adverse political winds.

The original three-year plan produced by the People’s Liberation Army Research Institute aimed tointegrate far and near, integrate Chinese and Western medicines, take Chinese drugs as its priority, emphasize innovation, unify plans, divide labor to work together.

The medical mission

Project 523 had three goals: the identification of new drug treatments for fighting chloroquine-resistant malaria, the development of long-term preventative measures against chloroquine-resistant malaria, and the development of mosquito repellents.

To achieve these ends, research on Chinese drugs and acupuncture was integral.

The decision to investigate Chinese drugs was not without precedent. Back in 1926, Chen Kehui and Carl Schmidt of the Peking Union Medical College published their original paper on ephedrine, derived from Chinese herb mahuang. It ignited a research fire in which more than 500 scientific papers on ephedrine (for relief for asthma) appeared around the world by 1929.

In the 1940s, state interest in the Chinese drug changshan and its antimalarial properties led to the establishment of a state-funded research institute and experimental farm in Sichuan province.

Project 523’s embrace of Chinese materia medica — the traditional body of knowledge about substances’ healing properties — is a more recent example of the efforts to “scientize” Chinese medicine through selective appropriation and detailed investigation.

Biomedical interest in Chinese drugs was not in itself new. But the institutional climate within which Project 523 investigators worked was different from earlier antimalarial research efforts. The Vietnam War had exacerbated an epidemiological crisis to which Maoist China responded with nationalist fervor by turning to its institutions of traditional Chinese medicine.

In the 1960s, such institutions were a mixing ground of specialists, many of whom possessed more than a passing familiarity with Chinese medicine and biomedicine. This ensured that qinghao research proceeded within a climate in which scientists, “who themselves had learnt the ways of appreciating traditional knowledge, worked side by side with historians of traditional medicine, who had textual learning.”

Tons of Artemisia annua are grown annually in China today. Novartis AGCC BY-NC-ND

Tons of Artemisia

Tons of Artemisia

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Tu Youyou’s story

Tu Youyou’s research fits within this Maoist story of medical systematization and standardization.

Born in 1930, she was a medical student during the 1950s, when state efforts to make Chinese medicine scientific through the research and expertise of biomedical researchers were especially acute. She rose to the head of a malaria research group at the Beijing Academy of Traditional Chinese Medicine in 1969.

The group was composed of phytochemical researchers who studied the chemical compounds that occur naturally in plants and pharmacological researchers who focused on the science of drugs. They began with a list of over 2,000 Chinese herbal preparations, of which 640 preparations were found to have possible antimalarial activities. They worked steadily and obtained more than 380 extracts from some 200 Chinese herbs, which they then evaluated against a mouse model of malaria.

Of the 380+ extracts they had obtained, a qinghao (Artemisia annua L.) extract appeared promising, but inconsistently so. Faced with varying results, Tu and her team returned to the existing materia medica literature and reexamined each instance in which qinghao appeared in a traditional recipe.

Tu was drawn to one particular reference made by Ge Hong 葛洪 (284-363) in his fourth-century BC text, Emergency Prescriptions One Keeps Up One’s Sleeve. Ge Hong instructed: take a bunch of qing hao and two sheng [2 x 0.2 liter] of water for soaking it, wring it out to obtain the juice, and ingest it in its entirety.

Chinese woodcut portrait of Ge Hong. Gan Bozong via Wellcome ImagesCC BY

Chinese woodcut portrait of Ge Hong

Chinese woodcut portrait of Ge Hong

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In what can be characterized as her eureka moment, Tu had the idea that “the heating involved in the conventional extraction step we had used might have destroyed the active components, and that extraction at a lower temperature might be necessary to preserve antimalarial activity.” Herhunch proved correct; once they switched to a lower-temperature procedure, Tu and her team obtained much better and more consistent antimalarial activity with qinghao. By 1971, they had obtained a nontoxic and neutral extract that was called qinghaosu or artemisinin. It was 100 percent effective against malarial parasites in animal models.

Tu’s research has drawn accolades from the international scientific community, while also igniting adebate in the Chinese language media about the celebration of individual inventors over collective group efforts.

Tu Youyou poses with Chinese officials after the announcement of her Nobel Prize. China Daily China Daily Information Corp – CDIC/Reuters

This too, perhaps, may be part of the legacy of Maoist mass science, which demanded research that served practical needs and engaged the masses. Scientific achievement, while important, was not the be-all, end-all of scientific work. During the Cultural Revolution, it mattered that science proceed along revolutionary lines. It mattered that scientific advances resulted from collective endeavor and drew from popular sources. Does it still?

Jia-Chen Fu, Assistant Professor of Chinese, Emory University. This article was originally published on The Conversation. Read the original article.

The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine

Youyou Tu

Lasker~DeBakey Clinical Medical Research Award
© 2011 Nature America, Inc. All rights reserved.
1218 volume 17 | number 10 | october 2011 nature medicine

Youyou Tu is at the Qinghaosu Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
e-mail: youyoutu1930cn@yahoo.com.cn

Joseph Goldstein has written in this journal that creation (through invention) and revelation (through discovery) are two different routes to advancement in the biomedical sciences1. In my work as a phytochemist, particularly during the period from the late 1960s to the 1980s, I have been fortunate enough to travel both routes. I graduated from the Beijing Medical University School of Pharmacy in 1955. Since then, I have been involved in research on Chinese herbal medicine in the China Academy of Chinese Medical Sciences (previously known as the Academy of Traditional Chinese Medicine). From 1959 to 1962, I was released from work to participate in a training course in Chinese medicine that was especially designed for professionals with backgrounds in Western medicine. The 2.5-year training guided me to the wonderful treasure to be found in Chinese medicine and toward understanding the beauty in the philosophical thinking that underlies a holistic view of human beings and the universe.

Discovery of antimalarial effect of qinghao

Malaria, caused by Plasmodium falciparum, has been a life-threatening disease for thousands of years. After the failure of international attempts to eradicate malaria in the 1950s, the disease rebounded, largely due to the emergence of parasites resistant to the existing antimalarial drugs of the time, such as chloroquine. This created an urgent need for new antimalarial medicines. In 1967, a national project against malaria was set up in China under the leadership of the Project 523 office. My institute quickly became involved in the project and appointed me to be the head of a malaria research group comprising both phytochemical and pharmacological researchers. Our group of young investigators started working on the extraction and isolation of constituents with possible antimalarial activities from Chinese herbal materials. During the first stage of our work, we investigated more than 2,000 Chinese herb preparations and identified 640 hits that had possible antimalarial activities. More than 380 extracts obtained from ~200 Chinese herbs were evaluated against a mouse model of malaria. However, progress was not smooth, and no significant results emerged easily. The turning point came when an Artemisia annua L. extract showed a promising degree of inhibition against parasite growth. However, this observation was not reproducible in subsequent experiments and appeared to be contradictory to what was recorded in the literature. Seeking an explanation, we carried out an intensive review of the literature. The only reference relevant to use of qinghao (the Chinese name of Artemisia annua L.) for alleviating malaria symptoms appeared in Ge Hong’s A Handbook of Prescriptions for Emergencies: “A handful of qinghao immersed with 2 liters of water, wring out the juice and drink it all” (Fig. 1). This sentence gave me the idea that the heating involved in the conventional extraction step we had used might have destroyed the active components, and that extraction at a lower temperature might be necessary to preserve antimalarial activity. Indeed, we obtained much better activity after switching to a lower temperature procedure.

Figure 1 A Handbook of Prescriptions for Emergencies by Ge Hong (284–346 CE). (a) Ming dynasty version (1574 CE) of the handbook. (b) “A handful of qinghao immersed with 2 liters of water, wring out the juice and drink it all” is printed in the fifth line from the right. (From volume 3.)

Beyond artemisinin Dihydroartemisinin was not initially considered a useful therapeutic agent by organic chemists because of concerns about its chemical stability. During evaluation of the artemisinin
covery of artemisinin was the first step in our advancement—the revelation. We then went on to experience the second step—creation— by turning the natural molecule into a drug. We had found that, in the genus Artemisia, only the species A. annua and its fresh leaves in the alabastrum stage contain abundant artemisinin. My team, however, used an Artemisia local to Beijing that contained relatively small amounts of the compound. For pharmaceutical production, we urgently required an Artemisia rich in artemisinin. The collaborators in the nationwide Project 523 found an A. annua L. native to the Sichuan province that met this requirement. The first formulation we tested in patients was tablets, which yielded unsatisfactory results. We found out in subsequent work that this was due to the poor disintegration of an inappropriately formulated tablet produced in an old compressing machine. We shifted to a new preparation—a capsule of pure artemisinin—that had satisfactory clinical efficacy. The road leading toward the creation of a new antimalarial drug opened again.

Spreading the word

In addition to problems of production and formulation, we also faced challenges regarding the dissemination of our findings to the world. The stereo-structure of artemisinin, a sesquiterpene lactone, was determined with the assistance of a team at the Institute of Biophysics, Chinese Academy of Sciences, in 1975. The structure (Fig. 3) was first published in 1977
commentary (ref. 2), and both the new molecule and the paper were immediately cited by the Chemical Abstracts Service in the same year. However, the prevailing environment in China at the time restrained the publication of any papers concerning qinghaosu, with the exception of several published in Chinese2–20. Fortunately, in 1979, the China National Committee of Science and Technology granted us a National Invention Certificate in recognition of the discovery of artemisinin and its antimalarial efficacy. In 1981, the fourth meeting of the Scientific Working Group on the Chemotherapy of Malaria, sponsored by the United Nations Development Programme, the World Bank and the World Health Organization (WHO), took place in Beijing (Fig. 4). During a special program for research and training in tropical diseases, a series of presentations on qinghaosu and its antimalarial properties elicited enthusiastic response. As the first speaker of the meeting, I presented our report “Studies on the Chemistry of Qinghaosu.” The studies disclosed on this presentation were then published in 1982 (ref. 10). The efficacy of artemisinin and its derivatives in treating several thousand patients infected with malaria in China attracted worldwide attention in the 1980s 21. We subsequently separated the extract into its acidic and neutral portions and, at long last, on 4 October 1971, we obtained a nontoxic, neutral extract that was 100% effective against parasitemia in mice infected with Plasmodium berghei and in monkeys infected with Plasmodium cynomolgi. This finding represented the breakthrough in the discovery of artemisinin.

From molecule to drug

During the Cultural Revolution, there were no practical ways to perform clinical trials of new drugs. So, in order to help patients with malaria, my colleagues and I bravely volunteered to be the first people to take the extract. After ascertaining that the extract was safe for human consumption, we went to the Hainan province to test its clinical efficacy, carrying out antimalarial trials with patients infected with both Plasmodium vivax and P. falciparum. These clinical trials produced encouraging results: patients treated with the extract experienced rapid disappearance of symptoms—namely fever and number of parasites in the blood—whereas patients receiving chloroquine did not. Encouraged by the clinical outcome, we moved on to investigate the isolation and purification of the active components from Artemisia (Fig. 2). In 1972, we identified a colorless, crystalline substance with a molecular weight of 282 Da, a molecular formula of C15H22O5, and a melting point of 156–157 °C as the active component of the extract. We named it qinghaosu (or artemisinin; su means “basic element” in Chinese).

Figure 2 Artemisia annua L. (a) A hand-colored drawing of qinghao in Bu Yi Lei Gong Pao Zhi Bian Lan (Ming Dynasty, 1591 CE). (b) Artemisia annua L. in the field.

Figure 3 Artemisinin. (a) Molecular structure of artemisinin. (b) A three-dimensional model of artemisinin. Carbon atoms are represented by black balls, hydrogen atoms are blue and oxygen atoms are red. The Chinese characters underneath the model read Qinghaosu.

Figure 4 Delegates at the fourth meeting of the Scientific Working Group on the Chemotherapy of Malaria in Beijing in 1981. Professor Ji Zhongpu (center, first row), president of the Academy of Traditional Chinese Medicine, delivered the opening remarks to the meeting. The author is in the second row (fourth from the left).

In keeping with Goldstein’s view, we found that dihydroartemisinin was more stable and ten times more effective than artemisinin. More importantly, there was much less disease recurrence during treatment with this derivative. Adding a hydroxyl group to the molecule also introduced more opportunities for developing new artemisinin derivatives through esterification.

My group later developed dihydroartemisinin into a new medicine. Over the past decade, my colleagues and I have explored the use of artemisinin and dihydroartemisinin for the treatment of other diseases22–33.

The history of the discovery of qinghaosu and the knowledge we gained about the molecule and its derivatives during the course of our studies are summarized in the book Research on Qinghaosu and Its Derivatives (in Chinese)34. In 2005, the WHO announced a switch in strategy to artemisinin combination therapy (ACT). ACT is currently widely used, saving many lives, mostly those of children in Africa. The therapy markedly reduces the symptoms of malaria because of its antigametocyte activity.

Other gifts from Chinese medicine Artemisinin, with its unique sesquiterpene lactone created by phytochemical evolution, is a true gift from old Chinese medicine. The route to the discovery of artemisinin was short compared with those of many other phytochemical discoveries in drug development. But this is not the only instance in which the wisdom of Chinese medicine has borne fruit. Clinical studies in China have shown that arsenic, an ancient drug used in Chinese medicine, is an effective and relatively safe drug in the treatment of acute promyelocytic leukemia (APL)35. Arsenic trioxide now is considered the firstline treatment for APL, exerting its therapeutic effect by promoting the degradation of promyelocytic leukemia protein (PML), which drives the growth of APL cells36. Huperzine A, an effective agent for treatment of memory dysfunction, is a novel acetylcholinesterase inhibitor derived from the Chinese medicinal herb Huperzia serrata37, and a derivative of huperzine A is now undergoing clinical trails in Europe and the United States for the treatment of Alzheimer’s disease. However, the use of a single herb for the treatment of a specific disease is rare in Chinese medicine. Generally, the treatment is determined by a holistic characterization of the patient’s syndrome, and a prescription comprises a group of herbs specifically tailored to the syndrome. The rich correlations between syndromes and prescriptions have fueled the advancement of Chinese medicine for thousands of years.

Progress in the therapy of cardiovascular and cerebrovascular diseases has also received gifts from Chinese medicine. A key therapeutic concern for Chinese medicine is the principle of activating blood circulation to remove blood stasis, and there are several examples of this principle in action in Western medicine. Compounds derived from Chinese medicinal products—the molecules chuangxiongol and paeoniflorin—have been tested for their efficacy in preventing restenosis after percutaneous coronary intervention (PCI). A multicenter, randomized, double-blind, placebo-controlled trial (335 patients, 6 months) showed that restenosis rates were significantly reduced by the medicine as compared with the placebo (26.0% versus 47.2%)38. Evidence supporting the therapeutic value of related strategies from Chinese medicine aimed at activating blood circulation has been obtained in the treatment of ischemic diseases39 and in the management of myocardial ischemiareperfusion injury40–43. Also in relation to cardiovascular disease, a new discipline called biomechanopharmacology aims at combining the pharmacological effects of Chinese medicine with the biomechanical properties of flowing blood44. The joint application of exercise (to increase the shear stress of blood flow) with extracts from shenlian, another Chinese medicine, shows promise for the prevention of atherosclerosis45. And recent reports have begun to provide a glimpse into the molecular mechanisms that account for the effects of Chinese remedies. For example, a recent study identified a potential mechanism to account for the effect of salvianolic acid B, a compound from the root of Salvia miltiorrhiza, in combination with increased shear stress, on the functions of endothelial cells46. The examples cited here represent only a sliver of the gifts or potential gifts Chinese medicine has to offer. It is my dream that Chinese medicine will help us conquer life threatening diseases worldwide, and that people across the globe will enjoy its benefits for health promotion.

ACKNOWLEDGMENTS I wish to express my heartfelt thanks to all my colleagues at the Academy of Traditional Chinese Medicine for their devotion to our work and for their exceptional contributions to the discovery and application of artemisinin and its derivatives. I thank my colleagues in the Shangdong Provincial Institute of Chinese Medicine, the Yunnan Provincial Institute of Materia Medica, the Institute of Biophysics and the Shanghai Institute of Organic Chemistry at the Chinese Academy of Sciences, Guangzhou University of Chinese Medicine and the Academy of Military Medical Sciences for their significant contributions to Project 523. I also would pay my respects to the leadership at the national Project 523 office and their sound efforts in organizing the malaria project activities.

COMPETING FINANCIAL INTERESTS The author declares no competing financial interests.

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Studies on the constituents of Artemisia annua L. and derivatives of artemisinin [in Chinese]. Zhongguo Zhong Yao Za Zhi 6, 31 (1981). 9. Tu, Y.Y. et al. Studies on the constituents of Artemisia annua L. (II). Planta Med. 44, 143–145 (1982). 10. Collaboration Research Group for Qinghaosu. Chemical studies on qinghaosu. J. Tradit. Chin. Med. 2, 3–8 (1982). 11. Xiao, Y.Q. & Tu, Y.Y. Isolation and identification of the lipophilic constituents from Artemisia anomala S. Moore [in Chinese]. Yao Xue Xue Bao 19, 909–913 (1984). 12. Tu, Y.Y., Yin, J.P., Ji, L., Huang, M.M. & Liang, X.T. Studies on the constituents of Artemisia annua L. (III) [in Chinese]. Chin. Tradit. Herbal Drugs 16, 200–201 (1985). 13. Wu, C.M. & Tu, Y.Y. Studies on the constituents of Artemisia apiacea Hance [in Chinese]. Chin. Tradit. Herbal Drugs 6, 2–3 (1985). 14. Tu, Y.Y., Zhu, Q.C. & Shen, X. Studies on the constituents of Young Artemisia annua L [in Chinese]. Zhongguo Zhong Yao Za Zhi 10, 419–420 (1985). 15. Wu, C.M. & Tu, Y.Y. Studies on the constituents of Artemisia gmelinii Web.exstechm [in Chinese]. Chin. Bull. Bot. 3, 34–37 (1985). 16. Wu, C.M. & Tu, Y.Y. Studies on the constituents of Artemisia argyi Levl et vant [in Chinese]. Zhongguo Zhong Yao Za Zhi. 10, 31–32 (1985). 17. Xiao, Y.Q. & Tu, Y.Y. Isolation and identification of the lipophilic constituents from Artemisia anomala S. Moore [in Chinese]. Acta Bot. Sin. 28, 307–310 (1986). 18. Tu, Y.Y. Study on authentic species of Chinese herbal drug winghao [in Chinese]. Bull. Chin. Mater. Med. 12, 2–5 (1987). 19. Yin, J.P. & Tu, Y.Y. Studies on the constituents of Artemisia eriopoda Bunge [in Chinese]. Chin. Tradit. Herbal Drugs 20, 149–150 (1989). 20. Gu, Y.C. & Tu, Y.Y. Studies on chemical constituents of Artemisia japonica Thunb [in Chinese]. Chin. Tradit. Herbal Drugs 24, 122–124 (1993). 21. Klayman, D.L. Qinghaosu (artemisinin): an antimalarial drug from China. Science 228, 1049–1055 (1985). 22. Sun, X.Z. et al. 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Immunopharmacol. 6, 1243–1250 (2006). 33. Zhang, D., Yang, L., Yang, L.X., Huang, M.M. & Tu, Y.Y. Determination of artemisinin, arteannuin B and artemisinic acid in Artemisia annua by HPLC-UVELSD [in Chinese]. Yao Xue Xue Bao 42, 978–981 (2007).
34. Qinghao Ji Qinghaosulei Yaowu (Artemisia annua L., Artemisinin and its Derivatives) [in Chinese] (ed. Tu, Y.Y.) (Publisher of Chemical Industry, Beijing, 2009). 35. Chen, G.Q. et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89, 3345–3353 (1997). 36. Zhang, X.W. et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 328, 240–243 (2010). 37. Tang, X.C. & Han, Y.F. Pharmacological profile of huperzine A, a novel acetylcholinesterase inhibitor from Chinese herb. CNS Drug Rev. 5, 281–300 (1999). 38. Chen, K.J. et al. XS0601 reduces the incidence of restenosis: a prospective study of 335 patients undergoing percutaneous coronary intervention in China. Chin. Med. J. 119, 6–13 (2006). 39. Gao, D. et al. The effect of Xuefu Zhuyu decoction on in vitro endothelial progenitor cell tube formation. Chin. J. Integr. Med. 16, 50–53 (2010). 40. Zhao, N. et al. Cardiotonic pills, a compound Chinese medicine, protects ischemia-reperfusion-induced microcirculatory disturbance and myocardial damage in rats. Am. J. Physiol. Heart Circ. Physiol. 298, H1166–H11176 (2010). 41. Xu, X.S. et al. The antioxidant Cerebralcare Granule attenuates cerebral microcirculatory disturbance during ischemia-reperfusion injury. Shock 32, 201–209 (2009). 42. Sun, K. et al. Cerebralcare Granule, a Chinese herb compound preparation, improves cerebral microcirculatory disorder and hippocampal CA1 neuron injury in gerbils after ischemia–reperfusion. J. Ethnopharmacol. 130, 398–406 (2010). 43. Han, J.Y. et al. Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion. Pharmacol. Ther. 117, 280–295 (2008). 44. Liao, F. et al. Biomechanopharmacology: a new borderline discipline. Trends Pharmacol. Sci. 27, 287–289 (2006). 45. You, Y. et al. Joint preventive effects of swimming and Shenlian extract on rat atherosclerosis. Clin. Hemorheol. Microcirc. 47, 187–198 (2011). 46. Xie, L.X. et al. The effect of salvianolic acid B combined with laminar shear stress on TNF-alpha-stimulated adhesion molecule expression in human aortic endothelial cells. Clin. Hemorheol. Microcirc. 44, 245–258 (2010).

 

A race against RESISTANCE

Several African nations could strike a major blow against malaria by sacrificing the efficacy of some older drugs. Can they make it work?

BY AMY MAXMEN

It is September in southeastern Mali, and Louka Coulibaly is standing in the shade of a squat, concrete building, giving instructions to a dozen men and women perched on a wobbly wooden bench. Coulibaly, a local medical supervisor, hands out nylon backpacks, each filled with bags of pills, plastic cups and a porcelain mortar and pestle that the women pause to admire. By noon, the men and women are packing up and heading back to their respective villages on foot, bicycle and motorcycle.

The following day, they and about 1,400 other health workers throughout the region will set up shop in public spaces: under the shade of mango trees, in one-room schools, at market stands and in district health centres. They will mix and mash the pills with the mortar and pestle, dissolve them in water in a cup, and hand the bitter dandelion-coloured liquid to about 164,000 children.

The effort is part of a broad campaign to prevent malaria by providing African children with drugs usually used to treat the disease. Nearly 1.2 million healthy children from parts of Mali, Togo, Chad, Niger, Nigeria and Senegal received these drugs during the rainy season — from around July to November — when malaria usually ravages the population. The countries’ governments are deploying this intervention — known as seasonal malaria chemoprevention, or SMC — with financial support from the United States, the United Nations and the medical aid organization Médecins sans Frontières (MSF), also called Doctors Without Borders. Next year, many plan to expand the campaigns, and other countries hope to launch their own, encouraged by
recommendations from the World Health Organization (WHO).

Preventive use of anti-malarial drugs is not new: tourists routinely swallow them when travelling. But public-health officials have long instructed people living in regions where the disease is endemic to refrain from taking drugs prophylactically, in part because of concerns that the parasite that causes malaria will develop resistance when many people take the medicine on a long-term basis.

That risk has not disappeared. In fact, scientists fully expect SMC to encourage widespread drug resistance. No one knows when, exactly, but it could happen within as few as five years. Until then, SMC has the power to prevent 8.8 million cases and 80,000 deaths each year if implemented in regions with high rates of seasonal malaria. That is considered a powerful enough benefit to justify losing the drugs. “Life is a risk,” says Coulibaly, a Malian hired by MSF to train local health workers. “And if you don’t take risks, you don’t win.”

The project is designed to forestall drug resistance as long as possible, and to work in concert with mosquito nets and other preventive methods. Supporters hope that the combination will significantly suppress malaria, so that even if resistance eventually spreads, the caseload should be smaller and manageable with other treatments. But SMC will not be as successful if funding and infrastructure falter — and so far, programmes have had a shaky start. Still, advocates say that the challenges can be overcome.

WHEN INTENTIONS BACKFIRE

Previous attempts at large-scale malaria chemo prevention offer lessons on what not to do. In the 1950s, David Clyde, a malaria researcher with the British Colonial Medical Service, administered the drug pyrimethamine to villagers in Tanzania. At the time, pyrimethamine had a strong track record of clearing the parasite. But with any drug, there is a slim chance that some strains of parasite will be resistant and will survive to infect others — a chance that increases when many people take the medicine in an area where the parasites are abundant and circulate year-round.

Clyde’s experiment drove this concept home: malaria rates dropped at first, but after five months, 37% of infections in the village no longer responded to the drug1. Eight years later, pyrimethamine resistance had spread: up to 40% of infections within 25 kilometres of the original intervention site were unresponsive.

The 1960s brought more lessons — this time, when scientists tried adding the drug chloroquine to table salt. Clinical trials had shown2 that the salt drastically lowered malaria rates. But when the tactic was scaled up and the salt was distributed to markets in Guyana and Brazil, people consumed only what met their tastes. Others opted for untreated salt when they could, because the chloroquine made their skin itch. As a result, many people carried sub-therapeutic levels of the drug — not enough to reduce the malaria burden, but enough to promote resistance. “The salt campaigns were a disaster,” says Christopher Plowe, a malariologist at the University of Maryland School of Medicine in Baltimore.

Governments and aid organizations mostly shelved chemoprevention programmes after that, but resistance continued to grow — albeit slowly — as people used drugs to treat malaria infections. Between 1960 and 2000, chloroquine resistance crept around the globe and the malaria death toll steadily rose. That trend started to reverse around 2005, after the widespread adoption of the drug artemisinin, derived from Chinese sweet wormwood (Artemisia annua). Today, artemisinin-based drugs are the gold standard for treating malaria.

SECOND CHANCE

Alassane Dicko, a malariologist at the University of Bamako in Mali, was a graduate student in Plowe’s laboratory in 2001, when he started to think seriously about reviving chemoprevention. As a child, Dicko had lost his older brother and his best friend to malaria. Later, as a medical student working in hospitals, he was distraught at the number of children he saw dying. “You really feel it,” he says. “If we want to do anything for this country in terms of health, we need to stop malaria first.”

Dicko suggested that older antimalarials might be repurposed for prevention in places where resistance to them is not yet widespread. By using drugs seasonally, only in uninfected children and in combination rather than alone, he hoped to avoid some of the mistakes of the past. With drug combinations, parasites need to acquire several mutations to survive. These mutations usually come at a cost to the parasite, so removing the selective pressure of the drugs during the dry season would give parasites still sensitive to the treatment a chance to outcompete resistant ones.

Dicko proposed using a mixture of sulphadoxine and pyrimethamine called SP, which was known to be relatively safe over the long term. In 2002, his team treated 130 children with SP for two months in a placebo-controlled trial in Mali3. The treatment reduced malaria by 68%.

Other West African scientists followed the study. Among them was Badara Cissé, a Senegalese researcher then pursuing his doctorate with malariologist Brian Greenwood at the London School of Hygiene and Tropical Medicine. Greenwood had been considering chemoprevention since the 1980s, and he and Cissé immediately grasped the potential in Dicko’s approach. In 2004, they began a trial in Senegal to test three monthly doses of SP plus artesunate, an artemisinin derivative. Compared with the placebo group, nearly nine out of ten malaria cases were averted4.

With a US$4.5-million grant from the Bill & Melinda Gates Foundation in 2008, Cissé and his colleagues launched an as-yet-unpublished, 3-year clinical trial to study SP with another drug, amodiaquine (to preserve the efficacy of artemisinin). They treated nearly 200,000 children under 10 years old and found that they had 83% fewer cases of malaria than controls, says Cissé. Smaller trials in other African nations reported similar findings. These are impressive numbers, especially given how recalcitrant malaria has been to preventive measures. No vaccine has ever proved fully effective against the disease, for example. And the one that is closest to approval — RTS,S — has shown disappointing results in ongoing clinical trials, with less than a 50% reduction in cases (see Nature 502, 271–272; 2013).

RESISTING THE CRITICS

SMC raised some concerns that slowed its adoption. Some health officials suggested that natural, partial immunity to the parasite — built up as a child survives multiple bouts of malaria — would be compromised. Others fretted about the potential side effects of taking the drugs regularly. But the loudest complaints were about losing the drugs to resistance.

In a cramped office in a makeshift building at the University of Dakar, Cissé explains how he was frustrated by the deliberations among public-health officials as malaria waged war on Senegal’s children. He slumps in a chair that seems much too small for him and asks, “Isn’t it selfish to sit in our offices with air conditioning, saying that we should save these drugs?” He recalls a single night, 20 years ago, when he watched five children die of malaria. There was nothing he could do to save them. “If this happened to you, you would not be debating about the fear of losing a drug,” he says.

In 2012, SMC finally won over most officials. The Cochrane Collaboration — an international group based in Melbourne, Australia, that specializes in evidence assessment — analysed results from trials in Senegal, Mali, Burkina Faso, Ghana and Gambia, and concluded5 that SMC could prevent more than three-quarters of malaria cases in places where the disease struck seasonally. In the trials, the signs of side effects, resistance and reduced immunity were all minimal. According to another report6, nearly 21 million children in these regions stood to gain from SMC each year. And prevention is cheaper than treatment. Each month, chemoprevention costs $1.50 per child, which pales in comparison to the costs of travel and medical care for a child who falls ill. In November 2012, the WHO published SMC-implementation guidelines that enabled countries to apply for funds from international organizations7.

SLOW START

Implementation has been a challenge, however. Mamadou Lamine Diouf, the drug-procurement manager for Senegal’s National Malaria Control Program, says that the rollout there was supposed to reach nearly 600,000 children each month, starting in July and August. But he and the US agency footing the bill for the medicine had underestimated how much time it would take to get these older drugs manufactured anew and assessed by various organizations. By early November, health workers had managed to reach only 53,000 children. “We are learning by doing,” says Diouf. “Now we know that if we don’t master this long supply chain, nothing will be possible.”

Drug delays set back chemo prevention pilots in northern Nigeria by a month. Togo’s campaign did not start until September. Burkina Faso’s project failed to launch when funds came up short. And the size of Mali’s intended intervention dropped after a coup d’état and an invasion by al-Qaeda affiliates last year sent the nation into disarray.

Still, with the lessons learned, supporters say that they will be better prepared next year (see ‘A million ounces of prevention’). In March, some countries plan to apply for funding from the Global Fund to Fight AIDS, Tuberculosis and Malaria. Scott Filler, a disease coordinator at the Global Fund, which is based in Geneva, Switzerland, says, “There are not many things that can prevent malaria in 75% of children, so we will fully support it when countries come to us.”

A MILLION OUNCES OF PREVENTION

By November 2013, seasonal malaria chemoprevention (SMC) reached almost 1.2 million children in areas that receive at least 60% of their annual rainfall in the rainy season. If SMC were scaled up to cover all areas where it might be effective, it could reach 25 million children and prevent an estimated 80,000 deaths each year.

Areas where more than 60% of annual rainfall falls in the rainy season

Mali  344,00

Niger 230,00

Chad 274,000

Nigeria 190,000

Senegal 53,000

Togo 88,000

Plan to implement SMC in 2014
Implemented SMC by November 2013, with number of children treated

As the programmes continue, researchers will keep watch to see if resistance to the drugs mounts. Randomly selected people who come to hospitals to be treated for malaria in Mali, Chad and Niger will have a spot of their blood smeared on filter paper, placed in a ziplock bag and shipped to a laboratory in Bamako, where Dicko and his colleagues will look for mutations associated with resistance to SP and amodiaquine. The University of Dakar will conduct similar tests.

For the campaigns to have a long-lasting effect, chemoprevention must work faster than the parasites acquire resistance. Supporters hope that the treatments will destroy most malaria parasites over the next several years, driving down infection rates and keeping them down even when resistance begins to spread.

Ramanan Laxminarayan, director of the Center for Disease Dynamics, Economics and Policy, a health-policy think tank in Washington DC, is sceptical. He predicts that imperfect implementation will prevent campaigns from having the benefits seen in clinical trials, and that the disease will bounce back in the end. Importantly, says Paul Milligan, a malaria researcher at the London School of Hygiene and Tropical Medicine, funding agencies must support follow-up evaluations to catch unintended effects such as increased vulnerability to malaria in children who outgrow the interventions. Plowe adds: “If we just roll this out without surveillance, we risk repeating all of the mistakes made in the past.”

Yet surveillance and drug resistance mean little to the mothers who congregate in a small village in the Koutiala region of Mali just after sunrise in September. Awa Damale, 25 years old and clad in an embroidered aqua dress and matching headscarf, arrives by donkey cart with her four children and two from another family. Five of the children swallow their medicine, but one of Damale’s sons has felt ill this week. He tests positive for malaria and gets a referral to the nearest clinic. SMC is for prevention only.

The boy’s illness may be a sign that the drugs he took last month are not 100% effective — or that he did not swallow all of the medicine — but his condition does not dampen Damale’s enthusiasm. It is the first time this year that one of her children has had malaria. Before the intervention, she constantly juggled working on the farm with caring for sick children. She does not want to hear about the possibility of the programme drying up or the drugs losing potency years down the road. Most of her children are healthy now, and that is what matters most. ■

SEE EDITORIAL P.165

Amy Maxmen is a freelance science journalist in New York City. Travel for this story was paid for by a grant from the Pulitzer Center on Crisis Reporting in Washington DC.
1. Plowe, C. V. Trans. R. Soc. Trop. Med. Hyg. 103, S11– S14 (2009). 2. Giglioli, G., Rutten, F. J. & Ramjattan, S. Bull. World Health Org. 36, 283–301 (1967). 3. Dicko, A. et al. Malar. J. 7, 123 (2008). 4. Cissé, B. et al. Lancet 367, 659–667 (2006). 5. Meremikwu, M. M., Donegan, S., Sinclair, D., Esu, E. & Oringanje, C. Cochrane Database Systematic Rev. 2012 http://dx.doi.org/10.1002/14651858. CD003756.pub4 (2012). 6. Cairns, M. et al. Nature Commun. 3, 881 (2012). 7. World Health Organization Seasonal malaria chemoprevention with sulfadoxine-pyrimethamine plus amodiaquine in children: A field guide (2012).

 

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