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Artemisinin: "Chinese God Grass" refines the global antimalarial medicine

Artemisinin: "Chinese God Grass" refines the global antimalarial medicine

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The activated artemisinin can covalently bond with more than 100 malaria parasite proteins and alkylate them, destroying many life processes of malaria parasites, thereby killing the parasites.

Artemisinin: "Chinese God Grass" refines the global antimalarial medicine

This is a gift of Chinese medicine to the world, and it is also a vivid practice of Chinese medicine modernization.

Malaria is one of the important public health problems of global concern. Once, people talked about "malarial" discoloration. According to figures, there were about 400 million people infected with malaria every year around the world, and at least 1 million people died from the disease.

Since the advent of artemisinin in the 1970s, countless malaria patients have been cured. Artemisinin antimalarial drugs have become life-saving drugs in malaria-ridden areas.

The hardships behind it can only be experienced by those who have experienced it. Tu Youyou, as a lifelong researcher and chief researcher of the China Academy of Chinese Medical Sciences and director of the Artemisinin Research Center, feels deeper and pays more.

The discovery of artemisinin saved millions of lives. In 2015, Tu Youyou won the Nobel Prize in Physiology or Medicine; in 2017, he won the country's highest science and technology award; in 2019, he won the "Medal of the Republic". On the road of antimalarial drug research and development, she has quietly cultivated more than 40 spring and autumn. It is she who made the "small grass" Artemisia annua become the world-famous "Chinese god grass".

However, she always said: "On the battlefield of global malaria prevention and control, individual power is small. Only organized and targeted large teams can gradually defeat malaria."

Indeed, artemisinin is the result of the nationwide system. For more than 40 years, artemisinin, dihydroartemisinin, compound artemether, artemisinin piperaquine tablets... Artemisinin and its derivatives have been widely used in anti-malarial clinics, and they have gone abroad, eventually affecting The world.

After all the hardships, the effective components of Artemisia annua L

Tu Youyou was born in Ningbo, Zhejiang. At the age of 16, she had to interrupt her studies for two years because of tuberculosis. This raging illness also gave her a simple wish to "cure diseases and save people": the role of medicine is amazing. If I learn it, I can not only save myself from the pain, but also save more people.

On the eve of the university entrance examination in 1951, Tu Youyou reported to the Department of Pharmacy of Peking University School of Medicine. After graduating from university, she was assigned to the Institute of Chinese Materia Medica, Academy of Chinese Medicine. In 1959, she participated in the third phase of the "Traditional Chinese Medicine Research Institute's Western Medicine Leaving School of Traditional Chinese Medicine" organized by the former Ministry of Health. During the two-and-a-half years of full-time study, Tu Youyou not only mastered theoretical knowledge, but also participated in clinical studies, went to medicinal materials companies, and learned Chinese medicine identification and processing techniques. These experiences paved the way for her to find artemisinin in Chinese medicine.

At the end of January 1969, Tu Youyou, a 39-year-old former intern researcher at the Institute of Traditional Chinese Medicine of the Ministry of Health, suddenly received a secret task-the "523" task: as the research team leader, research and development of anti-malarial Chinese herbal medicine. It is the above experience that revealed her solid scientific research skills and was entrusted with important tasks.

After taking over the task, Tu Youyou read through ancient books, searched for prescriptions, visited old Chinese medicine practitioners, and copied the information on Chinese medicines verbatim. On the basis of bringing together more than 2,000 prescriptions for internal and external use including plants, animals, minerals, etc., the research team has compiled a "Malaria Single Verification Collection" with 640 traditional Chinese medicines. It is the collection and analysis of this information that formed the basis for the discovery of artemisinin.

By the beginning of September 1971, the research team had screened more than 200 samples of water extracts and alcohol extracts of more than 100 kinds of traditional Chinese medicines, but the results were disappointing.

"I also doubt if I took the wrong path, but I don't want to give up." Tu Youyou said, and had to go back and read the doctor's book.

From "Shen Nong's Materia Medica" to "Sheng Ji Zong Lu" to "Fenbrile Diseases"... Finally, the record of Artemisia annua antimalarial in Ge Hong's "Elbow Reserve Emergency Recipe", for the research team groping in the dark A gleam of light-"One hold of Artemisia annua, stain with two liters of water, squeeze the juice, and take it all."

Why did the ancients use "juice"? Did heating destroy the active ingredients in Artemisia annua? Tu Youyou decided to use ether with a boiling point of only 34.6°C to extract Artemisia annua. "We bought A. annua, soaked first, then wrapped the leaves and soaked in ether. It wasn't until the No. 191 extract that we really found the effective components." Tu Youyou said.

The experiment process is complicated and lengthy. On October 4, 1971, the animal anti-malarial experiment of the neutral extract of Artemisinin No. 191 was finally released-the inhibition rate of malaria parasite reached 100%.

Researchers tried the drug artemisinin finally came out

In March 1972, Tu Youyou reported at a meeting of the Nanjing Traditional Chinese Medicine Professional Group hosted by the "523" office that the neutral crude extract of artemisinin had an inhibition rate of 100% for mouse malaria and monkey malaria.

The "523" office requested that he had to go to the clinic in Hainan that year to see how the effect was.

In the pre-clinical test of extract No. 191, suspected side effects were found in the pathological sections of individual animals. Is it a problem with the animal itself, or is it caused by the drug? Colleagues engaged in toxicology and pharmacological experiments insist: Only after conducting follow-up animal experiments and ensuring safety can they go to the clinic.

"I am the team leader, and I am responsible for the first test of the drug!" In order not to miss the clinical observation season that year, Tu Youyou submitted a voluntary test report to the leader. In July 1972, Tu Youyou and three other scientific researchers were admitted to Beijing Dongzhimen Hospital. After a week of testing and observation, the extract was not found to have obvious toxic and side effects on the human body.

With the ether neutral extract of Artemisia annua, Tu Youyou and others went to the Changjiang area of ​​Hainan for clinical verification. The results show that the drug has a certain effect on vivax malaria and falciparum malaria in local, low malaria areas, and foreign populations, especially for 11 patients with vivax malaria, with an effective rate of 100%.

Subsequently, the first task of the research group was to find the effective ingredients in the neutral extract of artemisinin as soon as possible. In November 1972, based on the pretreatment of the chromatographic column by the team member Ni Muyun, Zhong Yurong used silica gel column to separate and eluted with petroleum ether and ethyl acetate-petroleum ether, and finally obtained the effective monomer artemisinin with antimalarial effect. . Artemisinin was born.

"Obtaining effective ingredients is only the first step, and clinical trials must be carried out before application. This requires a large amount of artemisinin." Jiang Tingliang, a member of the research team, recalled that the research team was "initiated by local methods": using 7 water tanks used by ordinary people. As a conventional extraction container in the laboratory, it is filled with ether, and the A. annua is soaked in it for extraction.

The equipment is simple, there is no ventilation system, and no protective equipment. In addition to dizziness and swelling, the researchers also have symptoms such as nose bleeding and skin allergies. Tu Youyou also developed toxic hepatitis.

However, they did not stop at artemisinin. In 1973, the research team also discovered for the first time an artemisinin derivative with better curative effect—dihydroartemisinin. This is another important contribution made by Tu Youyou and his research team to China and the world.

Artemisinin antimalarial drugs are the result of the nationwide system, the crystallization of collectivism, and a masterpiece of independent innovation. Tu Youyou often emphasized that honor belongs to everyone in the scientific research team and belongs to the group of Chinese scientists.

After nearly half a century, artemisinin research continues to move forward

Nowadays, it has been nearly half a century since artemisinin was discovered. Artemisinin and its derivatives have entered the international antimalarial clinic and become the first-line antimalarial drugs in the world.

Needless to say, artemisinin has contributed to the global malaria prevention and treatment, but its underlying mechanism for the treatment of malaria is still unclear. In particular, the resistance of artemisinin is an issue that Tu Youyou has always been concerned about, and it is also the biggest challenge facing the global fight against malaria.

Fortunately, on June 17, 2019, Tu Youyou team announced that its artemisinin resistance research has made phased progress. Wang Jigang, a member of Tu Youyou’s team and a researcher at the Artemisinin Research Center of the Chinese Academy of Chinese Medical Sciences, used chemical biology methods to study the process of heme activating artemisinin and found that the activated artemisinin can covalently covalently with more than 100 proteins of Plasmodium Bonds and alkylates them, destroying many life processes of the malaria parasite, thereby killing the parasite. This heme-activated multi-target theory has been recognized by the international antimalarial community, and is of great significance for revealing the deep-seated mechanism of artemisinin antimalarial, drug resistance, and promoting more effective clinical medications.

According to Wang Jigang, according to research, the half-life of artemisinin in the human body is very short, only 1 to 2 hours, while the clinically recommended artemisinin combination therapy course is 3 days. The really effective insecticidal window of artemisinin is only limited. To 8 hours. The existing drug-resistant strains make full use of the short half-life of artemisinin to change the life cycle or temporarily enter a dormant state to avoid the sensitive insecticidal period. At the same time, the malaria parasite can also develop significant resistance to the adjuvant drug "anti-malarial formula" in the artemisinin combination therapy, making the artemisinin combination therapy "failure".

In response to this, the team proposed a new treatment plan: one is to appropriately extend the medication time from 3 days to 5 or 7 days; the second is to replace the adjuvant drugs that have developed resistance in the artemisinin combination therapy. "In the foreseeable future, continuing to rationally and strategically apply artemisinin combination therapy (ACT) is the best solution to treatment failure, and it may be the only solution." Wang Jigang emphasized.

In addition to the anti-malarial research of artemisinin, the team also paid close attention to the anti-cancer effects of artemisinin. The anti-cancer mechanism of artemisinin is similar to the anti-malarial mechanism, that is, compared with normal body cells, the synthesis of heme in tumor cells is more vigorous, which activates artemisinin or its derivatives, and then activates the artemisinin It kills tumor cells in a multi-target manner. However, team members said that the anti-cancer effect of artemisinin is still in the basic research stage, and its effectiveness does not mean that it can be made into medicine. Whether artemisinin can become an anticancer drug requires a lot of follow-up research work.

Then there is the concern about artemisinin-based drugs in the treatment of lupus erythematosus. Dihydroartemisinin has a unique effect on the treatment of lupus erythematosus with high variability. Phase II clinical trials have been carried out. Tests have shown that artemisinin has an effective trend in the treatment of lupus erythematosus. In this regard, team members also said that the mechanism of action of dihydroartemisinin in the treatment of lupus erythematosus remains to be further studied.



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AboutMicro News: Artemisinin: "Chinese God Grass" refines the global antimalarial medicine
Artemisinin: "Chinese God Grass" refines the global antimalarial medicine
Artemisinin: "Chinese God Grass" refines the global antimalarial medicine
AboutMicro News
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