...... In the future, the innovation of new drug research and development will shift to six modes: one is to create a novel molecular structure type "NCE"-a breakthrough new drug research and development; Second, create a new drug "me-too"-research and development of imitation new drugs; Third, further research and development of known drugs-extending the research and development of new drugs; Fourth, apply modern biotechnology to develop a new biochemical drugs; 5. Pharmaceutical research and development of existing drugs-development of new products; Six, the application of modern new technology to carry out major technological innovation and technological transformation of the old product production process. Modern chemical research methods are more and more closely combined with various biotechnology, which has become the mainstream of marine drug research and development, and will be the main trend of marine drug research in the next few decades. (1) Studies on bioactive components from marine organisms 1. The discovery of marine natural bioactive components The study of marine natural bioactive components is the foundation and source of marine drug development. There are many kinds of marine life and many special secondary metabolites. However, at present, the discovery of active components in marine organisms is only in the initial stage, and the number of marine organisms that have been systematically studied in terms of chemical components is less than 1% of the total. There are still a large number of marine organisms that need systematic chemical composition research and activity screening. This study focuses on lower marine organisms, such as invertebrates. Marine natural active components are often complicated in chemical structure and have extremely low content. Using multi-target biological screening technology, it is a challenge for scientists to establish rapid and trace extraction, separation and structure determination methods and discover new bioactive components. 2. Structural optimization of marine natural active ingredients A large number of active natural ingredients have been found in marine organisms, some of which can directly enter the research and development of new drugs, but some have problems such as low activity or high toxicity. Therefore, it is necessary to further optimize the structure of these active components as lead compounds, such as structural modification and structural transformation, in order to obtain new chemical components with higher activity and less toxicity. 3. Solving the problem of drug sources Many marine natural active ingredients are low in content, and it is difficult to collect raw materials, which limits the clinical research and industrialization of this compound. Finding economic, artificial and environment-friendly drug sources has become an urgent task for marine drug development. Chemical synthesis is an important means to solve the problem of drug source. Many marine active natural products have been fully synthesized, such as COLEOPTERA lactone 1 and sphingosine B. Due to the complex structure of many components, it is difficult to synthesize completely and the cost is high, which makes it difficult to form industrialization. Through artificial propagation or simulating natural conditions for indoor propagation research, Stanford University in the United States successfully carried out laboratory propagation research on grass moss insects. The utilization of tissue cell culture and functional gene expression in Cologne is also a new development direction to solve the drug source problem. Many scientists are conducting beneficial exploration and in-depth research in this field, and the application of these biotechnology will surely show the broad prospects for the development of biological resources. (2) Exploring new marine biological resources. Marine biological resources are huge biological resources to be further developed. The diversity of environment determines the diversity of organisms and compounds. Exploring new marine biological resources has become an important development trend of marine drug research. 1. Marine microbial resources There are more than 1 10,000 species of marine microorganisms, and the diversity of secondary metabolites is unmatched by terrestrial microorganisms. However, there are only a few thousand kinds of marine microorganisms that can be cultured artificially, which is less than 1% of the total. Up to now, even fewer marine microorganisms have been isolated and cultured to separate metabolites. Because microorganisms can obtain a large number of fermentation products through fermentation engineering, the source of drugs is guaranteed. In addition, marine microorganisms may be the real producers of natural active substances in their hosts, which has important research value. 2. Rare marine living resources Marine animals and plants that grow in the deep sea, polar regions and inaccessible islands contain some special chemical components and functional genes. Large marine worms with special physiological functions were found on the seabed below 6000 meters. Bacteria still exist in seawater with a water temperature of 90 degrees Celsius. The study of these creatures will become a new direction. 3. Marine biological gene resources Marine biological active metabolites are obtained through the coding, regulation and expression of a single gene or genome. Obtaining these genes indicates that these compounds can be obtained. It is of great significance to carry out the research on marine medicinal gene resources for the research and development of new marine drugs. (1) Genetic resources of marine animals and plants: functional genes of active substances, such as active peptides and protein. (2) Marine microbial gene resources: marine environmental microbial genes and marine microbial genes. 4. Marine natural product resources After decades of research, marine natural products have accumulated rich research data, providing scientific basis for the development of marine drugs. (1) We screened tens of thousands of marine natural products with multiple targets and new patterns, and found new activities. (two) to modify or transform the structure of the obtained marine natural products. (3) Using combinatorial chemistry or biosynthesis technology, more new compounds are derived and new active ingredients are screened out. 5. Marine traditional Chinese medicine resources Marine traditional Chinese medicine is an important part of the treasure house of traditional Chinese medicine and a summary of long-term folk experience in drug use. Modern clinical practice has proved that there are more than 1 10 kinds of marine drugs in herbal medicines of past dynasties, which are important resources for finding lead compounds and developing marine drugs. The development of new drugs of marine traditional Chinese medicine has the characteristics of strong pertinence, quick effect and short cycle. (3) Constructing a new biological screening technology targeting enzymes and receptors (1) Qualcomm screening. (2) Based on protein omics, the biological mechanism of these compounds was fully revealed by means of nuclear magnetic resonance, mass spectrometry, gene database and high column identification. (IV) Study on Marine Chemical Ecology Marine chemical ecology is to combine the chemical and ecological methods of marine natural products, explore the marine biochemical defense mechanism, trace back the biological sources and ecological functions of active natural products, and reveal the chemical nature of marine ecosystems. This paper studies the information transmission mode, chemical defense mechanism, relationship between organisms and food chain of active chemicals in marine ecological environment, and discusses the action mechanism of bioactive substances from the ecological macro perspective. At present, the United States, Japan and other developed countries are at the forefront in the development and research of marine drugs. In China, the research on marine drugs is still in the ascendant. From the investment of scientific research funds, we can see that the developed countries such as the United States attach importance to marine drug research: the National Research Council and the National Cancer Institute of the United States spend more than 50 million dollars each year on marine drug development and research; In recent years, the growth rate of NIH marine drug fund has reached more than 1 1%, which is basically the same as that of synthetic drugs and plant drugs. Japan Institute of Marine Biotechnology and Japan Marine Science and Technology Center spend about $654.38 billion annually on the development and research of marine drugs. The annual expenditure of the European Ocean Science and Technology Plan for the development and research of marine drugs is about $654.38 billion. The research and development of marine drugs has developed towards industrialization. The total value of global marine life 196913 billion USD, 1982 340 billion USD, 1992 670 billion USD, and about15 trillion USD in 2000. The research on marine natural products in China began in the 1970s and has a history of more than 30 years. Scholars such as Zeng have systematically studied the chemical constituents of corals in the South China Sea, and found a new type of bis 14 yuan cyclic tetraterpene in 1985. Since 1990s, the research on marine natural products has developed rapidly, and sponges, corals, echinoderms, liverworts, algae and marine microorganisms in China's oceans have been extensively studied. So far, it is estimated that more than 500 kinds of marine organisms have been studied, and about 50 invention patents have been applied. Many marine drugs have obtained new drug certificates or entered clinical research. The research on marine natural products, marine polysaccharides, marine microorganisms and marine biotechnology has become the four characteristics of marine drug research in China. With the rapid development of marine drugs, many provinces, cities and key universities have set up corresponding marine drug research institutions and academic groups, and hold various types of marine pharmacology seminars every year. The National Natural Science Foundation, the National "863" High-tech Research and Development Fund and key funds of various provinces and cities have all increased their funding for marine drugs year by year. Some colleges and universities have set up marine medicine majors to train marine medical professionals. At present, the whole country has gradually formed a systematic marine drug development system integrating teaching, scientific research and production. The research of marine drugs is in the ascendant, which makes this kind of research occupy an increasingly prominent position in the field of pharmaceutical research and biotechnology research in China. According to relevant data, at present, six kinds of marine drugs in China have been approved for listing by the state: sodium alginate, glycosyl ester, tetrodotoxin, squalene, doxycycline, mannitol nicotinate and so on. In addition, there are 10 kinds of marine health products with healthy brand names. There are chondroitin 6- sulfate, Haiyangbao capsule, debrominated sea rabbit toxin, sea squirt A(B, C), ground cheese ester, sea cucumber polysaccharide potassium injection, sea squirt, etc., but the long-term efficacy needs further observation and evaluation. In addition, a number of products to be declared as a new class of drugs have entered clinical research, such as "9 1 1", "D- polyglycerol ester" and "9 16", the national second-class new drug for treating renal failure. At present, the nine key areas of marine drug research are: 1. The research of marine anticancer drugs has always been the dominant one. Scientists predict that the most promising anticancer drugs will come from the ocean. It has been found that at least 10% of marine biological extracts have anti-tumor activity. 1 0,500 marine products are isolated in the United States every year, and 1% has anticancer activity. At present, at least 10 marine anticancer drugs have entered the clinical or preclinical research stage. Expanding the activity screening of marine organisms, continuing to search for high-efficiency anticancer compounds, directly using them in clinic or as precursors of structural transformation, and developing new high-efficiency and low-toxicity anticancer components will become the development trend of marine anticancer drug research. 2. Research on marine cardiovascular and cerebrovascular drugs At present, many drugs that can effectively prevent and treat cardiovascular and cerebrovascular diseases have been developed, such as highly unsaturated fatty acids, which can inhibit thrombosis and dilate blood vessels. Now, many preparations have been used in clinic. More than 50 kinds of marine biotoxins not only have cardiotonic effect, but also have strong antihypertensive effect. At present, there are many studies on the antiarrhythmic effect of tetrodotoxin. In addition, there are sodium alginate and spirulina, which have good preventive and adjuvant therapeutic effects on hyperlipidemia and atherosclerosis. 3. Study on Marine Antibacterial and Antiviral Drugs; Marine flora and fauna microorganisms are rich in antibacterial resources. Japanese scholars have found that about 27% of marine microorganisms have antibacterial activity. 4. Research on drugs of marine digestive system. For example, starfish saponin separated from starfish and total saponin extracted from starfish can treat gastric ulcer. The latter has stronger healing effect on gastric ulcer than carboxymethyl derivatives of cimetidine and chitosan, and its trade name is "Weikean" capsule, which has definite curative effect and high cure rate and has entered clinical research. Dalian Chinese Medicine Factory cooperated with Chinese medicine to make "Ocean Stomach Medicine", which achieved good results in clinical application. 5. Research on marine anti-inflammatory and analgesic drugs. Manoalide is the most significant active ingredient isolated from marine natural products, and it is a phosphatase A2 inhibitor, which has been used as a typical anti-inflammatory agent in clinical trials in the mid-1980s. 6, marine urinary system drug research. Fucoidan sulfate is a kind of water-soluble polysaccharide, which has the functions of anticoagulation, blood lipid reduction, antithrombosis, microcirculation improvement, detoxification, leukocyte inhibition and anti-tumor. Clinically, it is used to treat cardiovascular and cerebrovascular diseases, especially to improve renal function and increase the creatinine clearance rate of renal spoils. For the first time at home and abroad, it is used to treat chronic renal failure and save uremia patients, with remarkable curative effect and no toxic and side effects. At present, it has entered the clinical research according to the second-class new drug approved by the state, and the trade name is "Shenhaikang". 7. Research on marine immunomodulatory drugs. Marine natural products are important sources of immunomodulators. Keratin is a kind of sulfated polysaccharide from macroalgae, which has immunomodulatory activity and is widely used as immunosuppressant and cell response regulator in kidney transplantation. 8. Research on other marine drugs. Other researches such as nervous system drugs and antiallergic drugs have also made great achievements. The ocean is a place for the survival and reproduction of new species of microorganisms. A series of highly effective antibacterial drugs can be cultivated from many new microbial species. For example, Teleocidin from various Streptomyces is a strong antibacterial drug. Marine toxins are the fastest growing field in marine biological research, and most of them have unique chemical structures. Because many highly toxic toxins are based on their highly specific effects on biological nervous system or cardiovascular system, these toxins and their mechanisms of action are important guiding compounds and clues for discovering new drugs for nervous system or cardiovascular system, and can also be used as the basis for finding new pesticides. The chemical structures of marine toxins found at present can be roughly divided into polyether compounds, nitrogen-containing compounds, hypoglycemic lipids, amnesiac amino acid shellfish poisoning, ester-soluble phenols and phosphorus-containing complexes. 9. Research and development of marine functional food Functional food is known as "2 1 century food", which represents the new trend of contemporary food development. The physiological regulation function of functional food is because it contains a variety of physiologically active substances, which is incomparable to terrestrial organisms. How to use the active ingredients in marine organisms for deep processing to make marine functional food with unique flavor and remarkable health care effect is an important research field at present. The development trend of marine functional food, including taurine, fish oil unsaturated fatty acids and phospholipids, chitin and chitosan, active polysaccharides, vitamins, dietary fiber and mineral elements, is aimed at common diseases, frequently-occurring diseases and difficult diseases of different groups of people, and uses multidisciplinary modern high-tech methods to research and develop new varieties of marine functional food with high technology content, high function and high benefit. In 2004, it was confirmed that Merck could restore the risk of celebrex myocardial infarction caused by Vioxx Pfizer globally. On September 30th, Merck, an American pharmaceutical company, announced that it would withdraw its blockbuster drug Cox-2 inhibitor Vioxx from the global market. Merck made this decision based on a study that found that Vioxx can double the risk of heart attack and stroke. Two months later, on the morning of 12 and 17, Pfizer released a research result of the National Cancer Institute of the United States. The study found that the use of 400 mg and 800 mg celebrex increased the incidence of heart disease and stroke by 2.5% compared with the placebo control group, so the study was suspended. However, Pfizer has no plans to recall celebrex. Comments: Since Merck recovered Vioxx, the future development of Cox-2 inhibitor market has become a concern. At present, about 2 million people around the world are using Vioxx. Since the drug was well received by 1999, the cumulative number of users has reached 84 million. In 2003, global sales reached $2.55 billion. Products that are not yet on the market will be subject to stricter FDA review, including Novartis's Prexige(lumiracoxib) and Merck's other product, Arcoxia(etoricoxib). It is very likely that FDA will require these products to have a clinical study of cardiovascular adverse reactions for 18 months before they are approved for marketing. The launch of new products will undoubtedly be greatly affected. Therefore, how to fill the $2.5 billion market vacancy left by Wanluo is a difficult problem to ponder. If Wanluo continues to lead the market, the compound growth rate of Cox-2 inhibitors (mainly celebrex, Wanluo, mobike, Bextra, Dynastat, Arcoxia and Prexige) will reach 2.8% in 2004-20 10, and the market scale in 2065 438+00 is expected to exceed 9 billion dollars. As a result of re-forecasting, this figure has shrunk to $7.056 billion, and the average annual growth rate from 2004 to 20 10 has also become -0.4%. In this process, some patients who have used Vioxx will bid farewell to COX-2 inhibitor products, the price increase of Bextra will be smaller, and the pace of listing of new COX-2 inhibitors will also slow down. For celebrex, the news that the risk of myocardial infarction was confirmed was a blow. Even though the only thing that can show that celebrex's heart disease is not as serious as Wanwan's and the risk may be lower, all this seems to be enough to sentence celebrex to death. Bush's re-election is good for the pharmaceutical industry. 1On October 3rd, Bush was re-elected as President of the United States. According to insiders, since * * * and the Party's policies are more friendly to large pharmaceutical companies, Bush's re-election will benefit them. After the news came out, the American Express Biotech Stock Index rose 2.8%, and the Nasdaq Biotech Stock Index rose 2.6%. When the new york stock market finally closed, from a fundamental point of view, the major pharmaceutical stocks only rose moderately. Wyeth Pharmaceuticals opened up 6.7% and closed down to 3.7%; Pfizer opened 5.6% higher and closed down 3 percentage points; Schering-Plough opened up 4.4% and closed down 2.2%. Merck, Johnson & Johnson and Abbott closed up 4%, 2.4% and 3% respectively. Comments: For the pharmaceutical industry and investors who invest in Pfizer and other companies, Bush's successful re-election is undoubtedly the biggest good news, because if he is the president of Keridan, the pharmaceutical industry will face stricter price restrictions. To this end, the Consumer Association warned that Bush's re-election is bad news for ordinary Americans. Industry analysts in the pharmaceutical industry believe that Bush's re-election and the strengthening of the party's power in Congress will prevent the government from immediately restricting prescription drugs, and the pharmaceutical industry will still follow the free market system. However, the Bush administration will increase the import of cheap drugs during its term of office, but only in Canada. Of course, importing drugs from Canada will not affect the pharmaceutical industry in the United States, because the number of drugs imported from Canada will not exceed 10% of the sales of drugs in the United States, and the Medical Modernization Act signed by Bush in February 2003 prohibits the price discount of drugs imported from Canada. As for the medical insurance industry, all walks of life regard the soaring medical insurance cost as the biggest problem, but the proposal put forward by the Bush administration is to reduce the increase of medical insurance cost for companies and individuals. This year, each employer will increase the medical insurance cost for a family of four in the United States by nearly $7,300 on average, and a single family will increase by $3 137 on average, and the related insurance premium will also increase by double digits. The Bush administration will promote a health care bill that is beneficial to owners and their employees, and hopes that Congress will give low-income families a direct medical insurance subsidy of $65,438+$0,000. This will benefit many companies and individuals. Sanofi's Acquisition of Aventis on April 26th, Sanofi's St. Delaborg Pharmaceutical Factory finally successfully acquired Aventis Pharmaceuticals, and the price was about 65,438+04% (about 69 euros per share) higher than its original bid in 10, with a total purchase amount of 55 billion euros. The acquisition war that lasted for more than three months ended and the third largest pharmaceutical company in the world was born. New head, Francois? De Heck (the current CEO of Sanofi Saint-Draborg) painted a beautiful blueprint for the future development of the new company: in view of the advantages of the two companies in cardiovascular and oncology fields, these two sectors alone will create sales of $37 billion for the new company in 2008. It is predicted that the new company will surpass GlaxoSmithKline in annual sales of US$ 46.3 billion in 2008 and become the second largest pharmaceutical company in the world after Pfizer. ………………