Since this century, artemisinin has dominated the treatment of malaria, delaying the invasion of human life by malaria. According to statistics, from 2000 to 2015, the incidence of malaria decreased by 38%, and the number of people who died of malaria decreased by 48%. Before artemisinin was introduced and promoted, about 400 million people worldwide contracted malaria each year, and at least 1 million people died from the disease. It can be said that artemisinin is a well-deserved "life-saving miracle drug".
As an important discoverer of artemisinin, Tu Youyou has recently attracted much attention from the outside world.
On June 16, Xinhua News Agency issued an article saying, "Tu Youyou's team will release major new breakthroughs in scientific research tomorrow." On the morning of June 17, the mystery was revealed: in view of the drug resistance problem of artemisinin in some parts of the world in recent years, Tu Youyou and his team have made new breakthroughs in "antimalarial mechanism research", "causes of drug resistance", "adjustment of treatment methods" and other aspects, and recently proposed practical treatment plans to deal with the problem of "artemisinin resistance".
According to Tu Youyou's answer: "The so-called 'artemisinin resistance' problem can be solved by appropriately extending the medication time or replacing the auxiliary drugs that have developed resistance in artemisinin combination therapy." ”
For a while, public opinion was in an uproar, and 9 artemisinin concept stocks also all rose, and Yuheng Pharmaceutical (002437. SZ) and Kunpharm Group (600422.SH) are sealed in the limit throughout the day.
Shortly after xinhua news agency released an interview, the surging news release at noon on June 17 pointed out that 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, pointed out that some views are in practice, but they are still in the early stages, and the final results should be based on clinical data.
<h1>How to deal with "artemisinin resistance"? </h1>
Behind the widespread discussion triggered by this report is the gradual emergence of the problem of artemisinin resistance.
WHO's latest World Malaria Report 2018 shows that global malaria control efforts have stagnated, the root cause is that malaria parasites have also become resistant to artemisinin-based antimalarial drugs, and a number of studies have shown that in Cambodia, Thailand, Myanmar, Vietnam and other countries in the Greater Mekong Subregion, the three-day cycle of artemisinin combination therapy ("artemisinin drugs" combined with "other antimalarial formulas") for malaria-infected people shows signs of slow clearance of malaria parasites, And develop resistance to artemisinin.
In this regard, Tu Youyou, Wang Jigang and others wrote in the New England Journal of Medicine on April 25 this year, "The Response Solution of Artemisinin Resistance", saying that "this phenomenon has sounded a wake-up call for us"; as early as December 2015, Tu Youyou also publicly stated that once artemisinin becomes resistant, it will take another ten years to study new drugs.
Why is there resistance? Drug resistance, also known as drug resistance, refers to the tolerance of microorganisms, parasites and tumor cells to the effects of chemotherapy drugs, once drug resistance is formed, the efficacy of chemical drugs will be greatly reduced.
Because of its unique pharmacological pathways and small toxic side effects, artemisinin has been highly regarded since its introduction in the 1970s; in 2001, the World Health Organization recommended artemisinin-based combination therapy (ACT therapy) as the preferred option for malaria in all malaria-based countries, and in 2010, about 180 million people treated with ACT worldwide had a cure rate of 97%.
But the long treatment cycle (40 years after the advent of artemisinin) is also enough for the malaria parasite to begin to "tolerate" - that is, when the "detection" of artemisinin is present, it temporarily goes into a dormant state, slowing down the metabolic rate and reducing the release of heme; after the artemisinin is ineffective, it will then carry out a "massacre" of red blood cells. In particular, the half-life of artemisinin in the human body is only 1-2 hours, while the clinically recommended course of artemisinin combination therapy is only 3 days, so the really efficient "insecticidal window" is only 4-8 hours.
Therefore, the problem of artemisinin resistance seems inevitable, so how to deal with it?
According to Tu Youyou et al., in "Stress Solutions for Artemisinin Resistance", artemisinin resistance is still manifested by delayed parasite clearance, and there is no evidence of a fully resistant phenotype. In addition, the existing public reports of artemisinin resistance are not actually resistance to artemisinin itself, but rather resistance to one or both combinations based on artemisinin derivatives;
The so-called "adjustment" is the adjunctive drug that has developed resistance in the aforementioned replacement combination therapy. However, public reports point out that research on complementary drugs that have developed resistance in the change of artemisinin in combination use is also ongoing, and it has not yet been determined which drug to replace. But the problem is that the drug development process is so fraught with so much uncertainty that the next generation of antimalarials that outperform artemisinin in terms of efficacy, safety, and resistance risk seem unlikely in the short term.
It should be noted in particular that the pharmacological path of artemisinin is that when the malaria parasite destroys red blood cells in the human body, it will release extremely high concentrations of heme, heme can activate artemisinin, once activated, artemisinin will alkylation of many proteins and heme of the parasite, and heme alkylation can also inhibit the detoxification process of heme. Wang Jigang et al. argue that this unique mechanism of activation and broad targeting suggests that mutations in a single protein target are unlikely to cause drug resistance.
<h1>Other "wonderful uses" of artemisinin: the treatment of lupus erythematosus</h1>
In addition to antimalarial agents, artemisinin is also constantly trying to "expand the indications".
It is reported that in addition to the research launched by Tu Youyou's team on the possible resistance mechanism of artemisinin, a number of studies on artemisinin drugs in the treatment of lupus erythematosus, tumors, leukemia, rheumatoid arthritis, multiple sclerosis, and allergic diseases are being carried out successively.
According to public information, Tu Youyou's research group successfully synthesized the first artemisinin reduced derivative - dihydroartemisin in 1973, which can be used to treat the immune disease lupus erythematosus; in 2016, the dihydroartemisin treatment project for lupus erythematosus passed the CFDA approval and obtained drug clinical trial approval, and the Institute of Chinese Medicine of the Chinese Academy of Sciences signed a contract with Kunpharm Group to conduct clinical trials, and the first phase of clinical trials was officially launched in May last year.
Xue Qiao, medical manager of Kunpharm Group, said in an interview with The Paper that the phase I clinical trial involved a total of 120 samples, which were jointly carried out by 15 leading units across the country, including Peking Union Medical College Hospital, Peking University First Hospital, and the Affiliated Hospital of Inner Mongolia Medical University. It is reported that about 500 Chinese and foreign patients signed up for the clinical trial, and the first batch of volunteer patients have been enrolled in the trial, and the volunteer patients have not had unexpected adverse events.
We know that as malaria infection rates continue to decline in most areas, so does the sale of artemisinin products. Taking Kunpharm Group as an example, in 2018, the company's antimalarial products achieved operating income of 693 million yuan, down 35.66% year-on-year. In particular, China's artemisinin industry is still relatively inferior in the world. Statistics have shown that China's share of the global artemisinin market is less than 10%, accounting for a large number of multinational pharmaceutical companies such as Novartis and Sanofi and generic pharmaceutical companies in India.
For domestic enterprises producing artemisinin products, it is undoubtedly a better choice to achieve performance progress in the sales of artemisinin products and open up new indications. Among them, lupus erythematosus is an indication for the current commercialization path is relatively clear.
The clinical manifestations of lupus erythematosus (LE) are complex and diverse, initially involving only 1 to 2 systems, manifested as mild arthritis, rash, occult nephritis, thrombocytopenic purpura, etc., some patients are stable in a subclinical state or mild LE for a long time; some patients can suddenly change from mild to severe LE, and more from mild to gradually appear multisystem damage; there are also some people who affect multiple systems when they develop the disease, and lupus crisis occurs, resulting in kidney failure, resulting in death.
With regard to the treatment of systemic lupus erythematosus, drugs are the first choice. However, only 5 drug indications for systemic lupus erythematosus have been approved worldwide, including hormones, aspirin, hydroxychloroquine, belimab, and leflunomide. Most of them can only delay the progression of systemic lupus erythematosus and cannot be cured (except for bailizumab); however, some experts have pointed out that there is no clear evidence that bailimonab can be compared with classical immunosuppressants such as cyclophosphamide and mycophenolate mofetil in the treatment of severe cases, and it is not yet available in China and is expensive.
The exploration of new therapeutic drugs has also become the consensus of the international pharmaceutical community, and it is reported that there are currently 410 clinical studies on lupus treatment registered by the NIH. Dihydroartemisinin is one of the important ones, in addition to baletinib, rituximab, ascecipr, western logging monoclonal antibody, abascipit, epa jewelry monoclonal antibody and so on.
It is obvious that the demand market for lupus erythematosus indications is undoubtedly huge, there are millions of patients in China alone, and the future commercialization path is very clear. In the case of bailizumab, the drug was widely sought after as soon as it was launched, with sales of 306 million euros in 2016. If artemisinin has made new progress in this research, it is bound to expand the sales market of artemisinin.
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