I. Overview of the development of marine drugs
At present, the research and development of marine natural products in the world is in the ascendant, and the United States, Japan and the member countries of Europe are at the forefront of this field. In the United States, the National Research Council and the National Cancer Institute spend more than $51 million each year on the research and development of marine drugs. In recent years, the research funds of marine drugs in the National Institutes of Health have increased to more than 11% of the total research funds, which is basically the same as that of synthetic drugs and plant drugs. The Japanese Marine Biotechnology Institute and the Japan Marine Science and Technology Center spend about $1 billion each year on marine drug development and research. The EU's Marine Sciencesand Technology (MAST) program spends about $1 billion each year on the development and research of marine drugs.
The screening of marine natural drugs began in the mid-1961s, and expanded to the screening of antiviral, immunosuppressive, cardiotonic and anti-inflammatory substances after the 1971s. In the 1981s, most of them were antibacterial and antifungal. With the research and application of new biotechnology, such as genetic engineering, cell engineering and enzyme engineering, the research and development of marine drugs have been further promoted. By the 1991s, marine biology had become a mature research discipline, which laid a good foundation for marine drug research. At present, the main research is anti-cardiovascular and cerebrovascular diseases and anti-AIDS. The results of biological activity screening show that about 21% of marine extracts or compounds show different degrees of activity. Among these compounds, there are not only various chemical structure types existing in terrestrial organisms, but also many special chemical structure types. Their specific chemical structures are unmatched by terrestrial natural active substances, which has become the basis for the development of new drugs.
China is one of the first countries to use marine life as medicine, and it has a clinical application history of more than 2,111 years. Since the founding of the People's Republic of China, the research on marine drugs in China has entered a new era. Since the proposal of "asking for drugs from the ocean" was put forward by the National Science and Technology Conference in 1978 and the strategic assumption of "developing marine lakes and marshes resources and establishing China blue pharmaceutical industry" was put forward later, the research on marine medicinal resources in China has had a certain foundation. Relevant data show that at present, five kinds of marine drugs in China have been approved for listing by the state: sodium alginate, glycosyl ester, tetrodotoxin, doxycycline and mannitol nicotinate; There are also 11 kinds of marine health products with the brand name of Jian.
II. Research and application of marine drugs
1. Antimicrobial drugs
The microorganisms that exist with marine organisms are a rich antibacterial treasure house. At present, fatty acids, acrylic acids, phenols, indoles and other compounds with antibacterial activity have been isolated from marine organisms, and a series of marine antibacterial drugs such as cephalosporins have been developed in China.
2. Antiviral drugs
Compounds with antiviral activity, such as terpenoids, nucleosides, alkaloids, polysaccharides and heterocyclic compounds, have been isolated, and products such as Zhenning injection and acidic extract from pearl shell have been listed on the domestic market.
3, anti-tumor drugs
The most promising anti-cancer drugs will come from the ocean, and marine anti-tumor active substances have always been the focus of marine drug research. At present, it has been found that at least 11% of marine biological extracts have anti-tumor activity, including nucleotides, amides, polyethers, macrolides and other compounds, among which cytarabine has formed drugs. Anti-tumor drugs being developed in China include chondroitin 6- sulfate, Haiyangbao capsule, debrominated sea rabbit toxin, ascidian A(B, C), Stichopus japonicus polysaccharide potassium injection and so on. At present, only 11 marine antineoplastic drugs have entered clinical research, and more are in preclinical research. "Haimo Zhixue Tablet" made from ink sac discarded during cuttlefish processing in Zhoushan City, Zhejiang Province is effective for various bleeding such as digestive tract, especially for women's functional uterine bleeding. The product is exported to Southeast Asian countries, but it has not been further studied. At present, it is found that squid ink has anti-tumor effect, and its mechanism of action has been studied a lot in China, and great progress has been made, and new discoveries have been made continuously, mainly focusing on immunity.
4. Anti-cardiovascular drugs
Many drugs have been developed for the prevention and treatment of cardiovascular diseases, such as terpenoids, polysaccharides, polyunsaturated fatty acids, peptides and nucleosides, all of which have the effects of inhibiting thrombosis and dilating blood vessels. There are more than 51 kinds of marine biotoxins, which not only have cardiotonic effects, but also have strong antihypertensive effects. At present, there are many studies on the antiarrhythmic effects of tetrodotoxin. In addition, Spirulina has good preventive and adjuvant therapeutic effects on hyperlipidemia and atherosclerosis.
5. digestive system drugs
starfish saponins and total saponins extracted from marine organisms have better healing effect on gastric ulcer than cimetidine. Chitosan derivatives have definite curative effect and high cure rate on gastric ulcer, and have entered clinical trials. Marine stomach medicine made from domestic pharmaceutical factories and traditional Chinese medicine has achieved good results in clinic.
6. Anti-inflammatory and analgesic drugs
Manoalide, an inhibitor of phosphatase A2, is the most striking active ingredient isolated from marine natural products, which has been used as a typical anti-inflammatory agent in clinical practice more than twenty years ago.
7. Urinary system drug
Fucoidan sulfate has the functions of anticoagulation, blood lipid lowering, thrombosis prevention, anti-tumor, microcirculation improvement, leukocyte inhibition, etc. It is clinically used to treat cardiovascular and renal vascular diseases, especially to improve renal function and creatinine clearance rate. First of all, it is used to treat chronic renal failure and uremia, which has obvious curative effect and no toxic and side effects. Now it has been approved to enter clinical research according to the national second-class new drug.
8. Development and utilization of marine non-edible resources
The development direction of marine drugs mainly focuses on non-edible resources, which are rich in species. According to the survey, there are more than one million species of molluscs, more than 1.11111 species of coelenterates, more than 1.1111 species of sponges, more than 6,111 species of echinoderms and more than 2,111 species of caudates. The development and utilization of marine non-edible resources is of great significance. Not only can we get special drugs from them, but the remaining protein and polysaccharide after the extraction of its active components can be used as food and additives, and some can be used as feed for redevelopment, so as to improve the utilization rate of resources and avoid competing with edible resources.
9. Development and utilization of traditional Chinese patent medicines and Chinese herbal medicines
Because of overfishing of marine biological resources, natural resources can't meet the growing needs. It is necessary to develop traditional marine aquaculture in a planned way, expand breeding varieties, increase drug sources, and make a series of marine Chinese patent medicines to promote sales and promote the development of marine aquaculture. Therefore, the development and research should focus on the combination of the advantages of marine medicinal resources and traditional Chinese medicine resources, excavate and sort out folk prescriptions, prescriptions and secret recipes with definite curative effects, match them with marine medicinal sources, strengthen scientific prescription, and make them into new dosage forms with convenient use. For example, it is a good example that the output value of soft capsules made of ancient Huoxiang Zhengqi water combined with marine medicine sources exceeds 111 million yuan. In recent years, the reports on the treatment of tumor and cardiovascular diseases with Chinese herbal medicines have multiplied. Among them, the common Chinese herbal medicines are seaweed, kelp, oyster, concha Haliotidis, cuttlefish bone, concha arcae, laver, sea cucumber, scallop, sea dragon, seahorse, mother of pearl, shark liver oil and shark cartilage, which should be well planned and rationally developed.
11, functional food
It is a hot spot to make marine functional food with unique flavor and remarkable health care function by deep processing the active ingredients in marine organisms, thus broadening the research field of marine drugs and having great practical significance. These active substances include chitin and its derivatives, fish oil health products, seaweed health products, concentrated hydrolyzed protein, taurine, vitamins, phospholipids, active polysaccharides, dietary fiber, mineral elements and so on.
Third, the key areas of marine drug research
(1), marine anticancer drug research. Marine anticancer drug research has always played a leading role in marine drug research. Scientists predict that the most promising anticancer drugs will come from the ocean. It has been found that at least 11% of marine biological extracts have anti-tumor activity. Every year, 1,511 marine products are isolated in the United States, and 1% of them have anticancer activity. At present, at least more than 11 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 taking them as precursors for structural transformation, and developing new high-efficiency and low-toxicity anticancer components will become the development trend of marine anticancer drug research.
(2), marine cardiovascular and cerebrovascular drugs research. At present, many drugs have been developed to effectively prevent and treat cardiovascular and cerebrovascular diseases, such as highly unsaturated fatty acids, which have the effects of inhibiting thrombosis and dilating blood vessels, and now many preparations have been used in clinic. More than 51 kinds of marine biotoxins not only have cardiotonic effect, but also have strong antihypertensive effect. At present, the anti-arrhythmia effect of tetrodotoxin is studied more. In addition, there are sodium alginate and spirulina, which have good preventive and adjuvant therapeutic effects on hyperlipidemia and atherosclerosis.
(3), research on marine antibacterial and antiviral drugs. Microorganisms living with marine animals and plants 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 isolated from starfish and total saponin extracted from starfish can treat gastric ulcer, and the latter has stronger healing effect on gastric ulcer than cimetidine and carboxymethyl derivative of chitosan, with the trade name of "Weikean" capsule, which has definite curative effect and high cure rate, and has entered clinical research. Dalian Chinese Medicine Factory cooperated with traditional Chinese medicine to make "Ocean Stomach Medicine", which has achieved good results in clinical application.
(5), research on marine anti-inflammatory and analgesic drugs. Manoalide, the most striking active ingredient isolated from marine natural products, is a phosphatase A2 inhibitor, which has been used as a typical anti-inflammatory agent in clinical trials in the mid-1981s.
(6), drug research of marine urinary system. Fucoidan sulfate is a kind of water-soluble polysaccharide, which has the functions of anticoagulation, reducing blood lipid, preventing thrombosis, improving microcirculation, detoxicating, inhibiting white blood cells and resisting tumor. It is clinically used to treat cardiovascular and renal vascular diseases, especially to improve renal function and improve the creatinine clearance rate of renal spoils. It is first used at home and abroad to treat chronic renal failure and save uremia patients with obvious curative effect and no toxic side effects. At present, it has been approved to enter clinical research according to the national second-class new drug, with the trade name of "Shenhaikang".
(7), the study of marine immunity regulating drugs. Marine natural products are important sources of immunomodulators. Keratan with immunomodulatory activity is a kind of sulfated polysaccharide from macroalgae, which is widely used as immunosuppressant and modifier of cell response in renal 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 the survival and reproduction place of new species of microorganisms. From many new species of microorganisms, a series of highly effective antibacterial drugs can be cultivated. For example, Teleocidin from various Streptomyces is a strong antibacterial drug. Marine toxins are the fastest-growing field of 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 drugs in new 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, memory-losing amino acid shellfish poisoning, ester-soluble phenols and phosphate-containing complexes.
(9), research and development of marine functional food. 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.
It includes taurine, fish oil unsaturated fatty acids and phospholipids, chitin and chitosan, active polysaccharides, vitamins, dietary fiber, mineral elements and so on. The development trend of marine functional food is to research and develop new varieties of marine functional food with high-tech content, high function and high benefit by using multidisciplinary modern high-tech methods to preserve the natural characteristics and nutritional components of marine organisms as much as possible.
IV. Overview of overseas marine drugs research
The particularity of marine ecological environment leads to the biodiversity of marine drugs, which often contain strange and novel chemical substances with pharmacological specificity, high activity and diversity. Up to now, there are 22 categories, 1822 genera and 3118 species of marine life found in shallow sea, offshore and near islands and reefs.
The main biological types of marine drug research are: (1) seaweed, such as kelp, seaweed, seaweed, spirulina, Sargassum fusiforme, Sargassum thunbergii, etc. (2) Molluscs, such as oysters, pearls, octopus, concha Haliotidis, clams, etc.; (3) Arthropods, such as lobsters, prawns and hermit crabs; (4) echinoderms, such as sea cucumbers, sea urchins, starfish and petrels; (5) Chordata animals, such as seahorses, sea dragons, sea eels, hairtail, etc. (6) coelenterates, such as corals, jellyfish and pumice; (7) Microorganisms, such as sponges, sea squirts, bryozoa, microalgae, bacteria and fungi. Tropical and temperate marine life is the focus of research, among which marine invertebrates are the most fully studied.
with the continuous expansion of the research scope, the marine life involved has gradually expanded to resources that are difficult to obtain by conventional equipment and conditions such as the far sea, deep sea, polar regions, high temperature, cold and high pressure, and extreme environmental resources. At present, more than 21,111 kinds of marine natural products have been isolated from various marine organisms, and the newly discovered compounds are increasing at an average rate of 51% every four years. The structure of marine natural products covers most major structural types, including sugars, polysaccharides, amino acids, protein, inorganic salts, saponins, sterols, alkaloids, terpenoids, macrolides and nucleosides. The screening target is mainly used to treat cancer, cardiovascular and cerebrovascular diseases, viral infections (AIDS, etc.) and other difficult diseases that seriously endanger human health.
In recent years, a large number of patented marine natural products involving medicines, foods, functional foods, cosmetics, enzyme preparations and biological tools have appeared abroad. The pharmacological activities of marine active substances mainly include central nervous system function, antitumor function, antibacterial and antiviral function, cardiovascular and cerebrovascular system function, anti-inflammatory, analgesic, antioxidant, hypoglycemic and so on. Many compounds have potential for new drug development. The classic marine drugs that have been put into use in the world are cephalosporin and acesulfame.