WO2017129056A1 - 一种用于治疗心脑血管疾病的药物 - Google Patents

一种用于治疗心脑血管疾病的药物 Download PDF

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WO2017129056A1
WO2017129056A1 PCT/CN2017/071851 CN2017071851W WO2017129056A1 WO 2017129056 A1 WO2017129056 A1 WO 2017129056A1 CN 2017071851 W CN2017071851 W CN 2017071851W WO 2017129056 A1 WO2017129056 A1 WO 2017129056A1
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parts
glycoprotein
protein
cerebrovascular diseases
weight
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PCT/CN2017/071851
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English (en)
French (fr)
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徐宝贞
程潜
程龙
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徐宝贞
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Priority to US16/073,867 priority Critical patent/US10772932B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A61K36/03—Phaeophycota or phaeophyta (brown algae), e.g. Fucus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A61K36/04—Rhodophycota or rhodophyta (red algae), e.g. Porphyra
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A61K36/05—Chlorophycota or chlorophyta (green algae), e.g. Chlorella
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/19—Acanthaceae (Acanthus family)
    • A61K36/195—Strobilanthes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • A61K36/315—Isatis, e.g. Dyer's woad
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/704—Polygonum, e.g. knotweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/74—Rubiaceae (Madder family)
    • A61K36/748—Oldenlandia or Hedyotis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to a medicine for treating cardiovascular and cerebrovascular diseases, and belongs to the technical field of medicine.
  • Cardiovascular and cerebrovascular diseases are the general term for diseases of the heart and blood vessels of the heart. They refer to the ischemic or hemorrhagic diseases of the heart, brain and whole body tissues caused by hyperlipidemia, blood viscosity, atherosclerosis and hypertension. It is a common disease that seriously threatens the health of human beings, especially middle-aged and elderly people over 50 years old. Even with the most advanced and perfect treatment methods, more than 50% of survivors of cerebrovascular accidents can not fully take care of themselves. The number of people dying from cardiovascular and cerebrovascular diseases in the world is as high as 15 million, ranking first in all causes of death.
  • Patent: a traditional Chinese medicine composition for treating cardiovascular and cerebrovascular diseases CN201310297384.3 discloses a traditional Chinese medicine composition for treating cardiovascular and cerebrovascular diseases, belonging to the technical field of Chinese herbal medicine preparations, and the technical problem to be solved is to provide a convenient carrying and taking.
  • a traditional Chinese medicine composition for effectively treating cardiovascular and cerebrovascular diseases comprising the following raw materials by weight ratio: bezoar 0.04-0.07g, total ⁇ 0.5-1.5g , Sanqi 0.8-1.2g, antelope horn powder 0.05-0.15g, soil mites 1-4g, salvia miltiorrhiza 0.5-1.5g, spatholobus suberectus 0.8-1.6g; the invention is used for treating cardiovascular and cerebrovascular diseases, the medicament is small, The dosage is small, the side effects are small, and it is very convenient to carry and take.
  • the basic glucose derivative is selected from the group consisting of meglumine or glucosamine.
  • Patent: Use of low molecular weight fucoidan sulfate in the preparation of a medicament for treating cardiovascular and cerebrovascular diseases CN200610140395.0 discloses a low molecular weight fucoidan sulfate in the preparation of a medicament for treating cardiovascular and cerebrovascular diseases, especially ischemic cardiovascular and cerebrovascular diseases Use in.
  • the low molecular weight fucoidan sulfate in the present invention may be obtained by degrading fucoidan sulfate extracted from kelp, Fucus, Phyllostachys, kelp or cyanobacteria, preferably fucoidan sulfate extracted from kelp.
  • the ester is degraded and has a molecular weight of 8,000 to 100,000.
  • the present invention provides a medicine for treating cardiovascular and cerebrovascular diseases in order to solve the deficiencies in the prior art, so as to achieve the following Purpose of the invention:
  • the medicament of the present invention can effectively reduce the triglyceride and total cholesterol content of rats;
  • the drug of the invention can prolong the survival time of hypoxia in mice, and the survival time of hypoxia is 70-85 minutes;
  • the drug of the present invention has a good therapeutic effect on arrhythmia induced by aconitine, and the incidence of ventricular tachycardia (VT) is 9 after the administration of the drug of the present invention. /20-13/20, the incidence of ventricular fibrillation (VF) is 5/20-8/20, the rate of sinus rhythm recovery is 8/20-12/20, and the incidence of ventricular premature beats (VP) is 2.24. 3.59min;
  • the medicament of the invention has a good protective effect on rat myocardial ischemia induced by pituitrin.
  • the present invention adopts the following technical solutions:
  • a medicament for treating cardiovascular and cerebrovascular diseases characterized in that the medicament is a glycoprotein, or a mixture or polypeptide or protein of a polysaccharide and a protein; the glycoprotein comprises 1-99% sugar, 1-99% protein; The mixture of polysaccharide and protein, by weight, comprises 1-99% polysaccharide, 1-99% protein.
  • the glycoprotein has a molecular weight of 0.2-3000 kDa;
  • the drug is a marine algae glycoprotein.
  • the marine algae glycoprotein comprises, by weight, 1-99% sugar, 1-99% protein; a mixture of the marine algae polysaccharide and protein, including by weight, 1-99%, protein 1- 99%.
  • the marine algae glycoprotein has a molecular weight of 0.2-3000 kDa;
  • the polysaccharide and protein mixture has a molecular weight of 0.2-3000 kDa
  • the protein has a molecular weight of 0.2-3000 kDa.
  • the drug comprises, by weight, 1-99 parts of glycoprotein and 1-25 parts of glucuronic acid.
  • the drug comprises, by weight, 1-99 parts of marine algae glycoprotein and 1-26 parts of glucuronic acid.
  • the drug comprises, by weight, 1-99 parts of marine algae glycoprotein, 1-26 parts of glucuronic acid, and 2-13 parts of medlar.
  • the algae is one or more of cyanobacteria, green algae, red algae, gold algae, and brown algae.
  • the drug comprises, by weight, 1-99 parts of marine algae glycoprotein, 8-15 parts of medlar, 7-14 parts of Chixiaodou, and 1-15 parts of glucuronic acid.
  • the drug by weight, includes 1-99 parts of marine algae glycoprotein, 8-15 parts of medlar, 7-14 parts of Chixiaodou, and 8-13 parts of Hedyotis diffusa.
  • the drug by weight, includes 1-99% sugar and 1-99% protein.
  • the marine algae glycoprotein comprises, by weight, 1-99% sugar and 1-99% protein.
  • the drug of the present invention can effectively reduce triglyceride and total cholesterol in rats, and the triglyceride content of the rat is reduced to 0.78-1.14 mmol/L at the 4th week after administration, and the total cholesterol content is lowered. To 1.97-2.64 mmol/L.
  • the drug of the invention can prolong the survival time of hypoxia in mice, the survival time of hypoxia is 70-85 minutes, and the survival time of hypoxia in the control group is only 46.23 minutes.
  • the drug of the present invention has a good therapeutic effect on arrhythmia induced by aconitine, and the incidence of ventricular tachycardia (VT) is 9 after the administration of the drug of the present invention.
  • /20-13/20 the incidence of ventricular fibrillation (VF) is 5/20-8/20, the rate of sinus rhythm recovery is 8/20-12/20, and the incidence of ventricular premature beats (VP) is 2.24. 3.59min;
  • the incidence of ventricular tachycardia (VT) in the model group was 18/20, the incidence of ventricular fibrillation (VF) was 10/20, and the rate of sinus rhythm recovery was 6/20.
  • VP Ventricular premature beats (VP). The occurrence time was 1.22 min.
  • the drug of the invention has a good protective effect on rat myocardial ischemia induced by pituitrin, and the content of lactate dehydrogenase (LDH) in serum is 8725.23-9200.23 U/L, malondialdehyde (MDA) The content is 3.60-4.14 nmol/ml, and the superoxide dismutase (SOD) content is 80.04-83.15 U/ml.
  • LDH lactate dehydrogenase
  • MDA malondialdehyde
  • SOD superoxide dismutase
  • the glycoprotein of the invention has the advantages of improving microcirculation, dilating coronary artery, improving myocardial blood supply, increasing blood flow of brain and coronary artery, slowing heart rate, lowering myocardial oxygen consumption index and improving metabolism of blood myocardial, antithrombotic, and high Density lipoprotein, anti-angiogenesis and the role of reducing platelet aggregation, reducing the effect of blood total cholesterol, triglycerides.
  • Embodiment 1 A medicine for treating cardiovascular and cerebrovascular diseases
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein comprises, by weight, 1% sugar, 99% protein
  • the molecular weight is 0.2 kDa
  • the sugar is a polysaccharide
  • the marine algae is cyanobacteria
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Example 2 A drug for treating cardiovascular and cerebrovascular diseases
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein which comprises 5% sugar and 82% protein by weight
  • the molecular weight is 15kDa
  • the marine algae is: green algae;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Example 3 A drug for treating cardiovascular and cerebrovascular diseases
  • the drug is a marine algae glycoprotein
  • the marine algal glycoprotein comprises, by weight, 10% sugar, 75% protein,
  • the molecular weight is 5kDa
  • the marine algae is: cyanobacteria
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Embodiment 4 A medicine for treating cardiovascular and cerebrovascular diseases
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein comprises, by weight, 25% sugar, 70% protein,
  • the molecular weight is 100 kDa
  • the marine algae is: red algae;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Example 5 A drug for treating cardiovascular and cerebrovascular diseases
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein comprises, by weight, 41% sugar, 59% protein,
  • the molecular weight is 500kDa
  • the marine algae is: brown algae;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Example 6 A drug for treating cardiovascular and cerebrovascular diseases
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein by weight, comprises 99% sugar, 1% protein,
  • the molecular weight is 3000kDa
  • the marine algae is: gold algae;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • the glycoprotein described in the above Examples 1-6 further includes a pigment; the pigment is a natural pigment contained in the algae substance.
  • the drug is a glycoprotein
  • the glycoprotein by weight content, comprises 1-99% sugar, 1-99% protein
  • the molecular weight is 0.2-30000 kDa
  • the sugar is a polysaccharide
  • the drugs include synthetic glycoproteins and synthetic polysaccharides and proteins.
  • the protein comprises 20 amino acids and 8 synthetic amino acids
  • the preparation method of the medicine the glycoprotein is prepared into capsules, tablets and the like according to a conventional process; the mixture of the polysaccharide and the protein is formed into capsules, tablets and the like according to a conventional process.
  • mice SD rats, weighing 160-170 g;
  • High-fat diet formula: 0.5%-2% cholesterol, 5%-10% lard, 0.1% bile salt, 15% sucrose, 8% cooked soybean meal, 3% whole milk powder, the rest Basic feed composition.
  • Rats were randomly divided into 8 groups after entering the laboratory, namely normal control group, model control group, 1-6 groups of the present invention, 10 rats in each group, weighing and numbering;
  • the normal control group was fed with basic diet, model control group and the present invention group, fed with high fat diet, the experimental period was 4 weeks.
  • the content of triglyceride and cholesterol was detected weekly; after 4 weeks, the normal control group
  • the model control group was intragastrically administered with distilled water, and the present invention group 1-6, the drug of the present invention was administered at a dose of 3 g/day, gavage, 3 times a day for 3 consecutive days, and 4 weeks after the administration, the serum was detected.
  • Triglyceride and total cholesterol content are shown in Table 1.
  • Examples 1-6 were effective in reducing triglyceride and total cholesterol in rats at a dose of 3 g/day, 3 times a day, and at the 4th week after administration, the triglyceride content of the rats was reduced to 0.78-1.14 mmol. /L, the total cholesterol content was reduced to 1.97-2.64 mmol / L.
  • Examples 2 and 3 are preferred embodiments.
  • mice Seventy mice were randomly divided into 7 groups, 10 in each group, control group: 10 ml/kg physiological saline; groups 1-6 of the present invention (corresponding to Examples 1-6): feeding examples 1-6, respectively
  • the drug is administered at a dose of 3 g/day, 3 times a day; after 30 minutes, the mouse is placed in a 500 ml mill bottle (containing 3 g of sodium lime), coated with petrolatum, and dried.
  • Table 3 The effect of observing the time of death in mice on the hypoxia survival time of normal mice is shown in Table 3.
  • glycoproteins described in Examples 1-6 were able to prolong the hypoxic survival time of mice, the survival time was 70-85 minutes, and the survival time of the control group was only 46.23 minutes.
  • mice 140 healthy female Wistar rats were randomly divided into 7 groups, 20 in each group.
  • Model group equal volume of normal saline, groups 1-6 of the present invention (corresponding to Examples 1-6): Examples 1-6 were administered.
  • the drug was administered at a dose of 3 g/day, 3 times a day, 30 minutes later, anesthetized with 20% urethane (5 mg/kg), and the animal was fixed on the rat table, and with the BL-420 biological function test system. Connected, tracing electrocardiogram; after the rat electrocardiogram was stabilized, 0.04% aconitine 1ml/kg (40 ⁇ g/kg) was injected into the sublingual vein of the model group and the mice of the present invention, and the intraventricular premature beat (VP) was observed within 5s.
  • the drugs of Examples 1-6 have a good therapeutic effect on aconitine-induced arrhythmia in rats, and the drug of the present invention is fed.
  • the incidence of ventricular tachycardia (VT) was 9/20-13/20
  • the incidence of ventricular fibrillation (VF) was 5/20-8/20
  • the rate of sinus rhythm recovery was 8/20-12/20
  • the incidence of ventricular premature beats (VP) was 2.24-3.59min
  • the incidence of ventricular tachycardia (VT) in the model group was 18/20
  • the incidence of ventricular fibrillation (VF) was At 10/20
  • the sinus rhythm recovery rate was 6/20
  • the ventricular premature beat (VP) occurred at 1.22 min.
  • Example 2 and Example 3 are preferred embodiments.
  • 80 healthy Wistar rats were randomly divided into 8 groups: normal control group: equal volume of normal saline, (2) model group: equal volume of normal saline; group 1-6 of the invention (corresponding to examples 1-6) : administering the drug of Examples 1-6 of the present invention at a dose of 3 g/day, 3 times a day;
  • Rats were screened for the sensitivity of pituitary vasopressin on the day before the experiment.
  • the method was as follows: the rat sublingual injection of pituitrin 1 U/kg, observe the changes of electrocardiogram, and select for the vasopressin-sensitive rats. Experiment (T wave is obviously elevated, ST segment elevation exceeds 0.1 mV). Sensitive rats obtained by screening were used in the model group and the mistletoe group, and the experiment was started 24 hours later.
  • Normal control group administration of equal volume of normal saline
  • model group administration of equal volume of physiological saline
  • Groups 1-6 of the present invention administration of the drugs of Examples 1-6 of the present invention, The dose was 3g/day, 3 times a day; after 1 hour, 20% urethane (5ml/kg) was anesthetized by intraperitoneal injection.
  • the animal was fixed on the rat table and connected with the BL-420 biological function test system to record the electrocardiogram. .
  • normal saline was injected into the sublingual vein.
  • the rest of the sublingual vein was injected with 1 U/kg of pituitary.
  • the electrocardiogram changes were observed immediately and 1 min later.
  • the T wave and ST segment changes were used as indicators to determine the degree of myocardial ischemia and drug effects. 60 min, blood was taken from the posterior abdominal aorta, serum was separated, and serum lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA) levels were measured. LDH and MDA in myocardial ischemia rats were measured. The results of the influence of SOD are shown in Table 5.
  • the drugs described in Examples 1-6 have a good protective effect on rat myocardial ischemia induced by pituitrin.
  • the serum lactate dehydrogenase (LDH) content is 8725.23-9200.23 U/L
  • MDA malondialdehyde
  • SOD superoxide dismutase
  • Example 2 and Example 3 are preferred embodiments.
  • Embodiment 8 A medicine for treating cardiovascular and cerebrovascular diseases
  • the marine algae glycoprotein which comprises 5% sugar and 82% protein by weight
  • the molecular weight is 8kDa
  • the marine algae is: cyanobacteria
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Example 9 A drug for treating cardiovascular and cerebrovascular diseases
  • Embodiment 10 A medicine for treating cardiovascular and cerebrovascular diseases
  • Embodiment 11 A medicine for treating cardiovascular and cerebrovascular diseases
  • Embodiment 12 A medicament for treating cardiovascular and cerebrovascular diseases
  • the marine algal glycoprotein comprises, by weight, 10% sugar, 75% protein,
  • the molecular weight is 20kDa;
  • the marine algae is: spirulina
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Example 13 A drug for treating cardiovascular and cerebrovascular diseases
  • weight content it includes 29 parts of marine algae glycoprotein, 8 parts of glucuronic acid, and 5 parts of green barley.
  • Embodiment 14 A drug for treating cardiovascular and cerebrovascular diseases
  • Embodiment 15 A medicament for treating cardiovascular and cerebrovascular diseases
  • Example 7 Using the test method described in Example 7, the present invention is the drug described in Example 8 - Example 15, and the application effect is as follows:
  • Example 8-12 changing the ratio of marine algae glycoprotein to glucuronic acid, conducting experiments, obtaining Example 10 as a preferred embodiment;
  • Example 13 - Example 15 by changing marine algal glycoprotein, glucuronic acid, The weight ratio of the barley was obtained, and
  • Example 14 was obtained as a preferred embodiment.
  • Embodiment 16 A medicament for treating cardiovascular and cerebrovascular diseases
  • the marine algae glycoprotein comprises, by weight, 25% sugar, 70% protein,
  • the molecular weight is 8kDa
  • the marine algae is: hair dish;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Embodiment 17 A drug for treating cardiovascular and cerebrovascular diseases
  • the marine algae glycoprotein comprises, by weight, 25% sugar, 70% protein,
  • the molecular weight is 12kDa
  • the marine algae is: hair dish;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Embodiment 18 A medicament for treating cardiovascular and cerebrovascular diseases
  • weight content it includes 99 parts of marine algae glycoprotein, 15 parts of green barley, 14 parts of red bean, and 15 parts of glucuronic acid.
  • the marine algae glycoprotein comprises, by weight, 25% sugar, 70% protein,
  • the molecular weight is 60kDa;
  • the marine algae is: hair dish;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Embodiment 19 A medicine for treating cardiovascular and cerebrovascular diseases
  • weight content including 1 part of marine algae glycoprotein, 8 parts of green barley, 7 parts of red bean, and 8 parts of Hedyotis diffusa.
  • the marine algae glycoprotein comprises, by weight, 41% sugar, 59% protein,
  • the molecular weight is 8kDa
  • the marine algae is: Sargassum;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Embodiment 20 A medicine for treating cardiovascular and cerebrovascular diseases
  • weight it includes 39 parts of marine algae glycoprotein, 12 parts of green barley, 11 parts of red bean, and 10 parts of Hedyotis diffusa.
  • the marine algae glycoprotein comprises, by weight, 41% sugar, 59% protein,
  • the molecular weight is 20kDa;
  • the marine algae is: cyanobacteria
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Embodiment 21 A medicine for treating cardiovascular and cerebrovascular diseases
  • weight it includes 99 parts of marine algae glycoprotein, 15 parts of green barley, 14 parts of red bean, and 13 parts of Hedyotis diffusa.
  • the marine algae glycoprotein comprises, by weight, 41% sugar, 59% protein,
  • the molecular weight is 200kDa
  • the marine algae is: cyanobacteria
  • the sugar is a polysaccharide
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein comprises: arginine, lysine, serine, threonine;
  • Example 7 Using the test method described in Example 7, the present invention is the drug described in Example 16 to Example 21, and the application effect is as follows:
  • Example 16-18 experiments were carried out by changing marine algal glycoprotein, barley, red bean, glucuronic acid, and Example 17 was obtained as a preferred embodiment
  • Example 19 Example 21
  • Example 20 Example 20 was obtained as a preferred example.
  • Embodiment 22 A medicine for treating cardiovascular and cerebrovascular diseases
  • the glycoprotein is a marine algae glycoprotein
  • the marine algae glycoprotein which comprises 7% sugar and 80% protein by weight
  • the molecular weight is 8kDa
  • the marine algae is: yellow algae;
  • Example 23 A medicament for treating cardiovascular and cerebrovascular diseases
  • the glycoprotein is a marine algae glycoprotein
  • the marine algal glycoprotein comprises, by weight, 14% sugar, 72% protein,
  • the molecular weight is 22kDa
  • the marine algae is: spirulina
  • Embodiment 24 A medicament for treating cardiovascular and cerebrovascular diseases
  • the glycoprotein is a marine algae glycoprotein
  • the marine algal glycoprotein comprises, by weight, 18% sugar, 62% protein,
  • the molecular weight is 30kDa
  • the marine algae is: Candida albicans;
  • Embodiment 25 A medicament for treating cardiovascular and cerebrovascular diseases
  • the glycoprotein is a marine algae glycoprotein
  • the marine algae glycoprotein including 30% sugar and 55% protein, by weight
  • the molecular weight is 40kDa;
  • the marine algae is: Anabaena;
  • Embodiment 26 A method for preparing a medicament for treating cardiovascular and cerebrovascular diseases
  • Step 1 weighing
  • the Chinese medicine is pulverized into 100 mesh medicinal materials powder, 10 times the amount of 50% ethanol is added, and the control temperature is 60 ° C, 260 W micro Wave power, microwave wavelength of 130 mm, microwave radiation with a frequency of 1200 MHz for 5 min, filtration, collecting filtrate; separating the dregs, adding 12 volumes of clean water, controlling the temperature to 50 ° C, 200 W microwave power, microwave wavelength 140 mm , microwave irradiation at a frequency of 1250 MHz for 5 min, filtration, and collecting the filtrate;
  • the marine algae glycoprotein powder and the above traditional Chinese medicine powder are uniformly mixed; and the medicine is prepared into different dosage forms such as capsules and tablets.
  • Example 7 Using the test method described in Example 7, the present invention is the drug described in Example 22 to Example 25, and the application effect is as follows:
  • Example 8-22 drugs were clinically tested, 3 times a day, 1 g each time, and the results are as follows, see Table 18, Table 19.
  • the medicament of the present invention has a pH of between 5.3 and 9.8, preferably between 6.5 and 7.5.
  • the invention has been subjected to a large number of tests, and the invention has been carried out by performing a plurality of tests on a mixture of marine shells, bones of livestock and poultry, glycoprotein extracted from the skeleton of marine animals, and polysaccharides and proteins.
  • Embodiment 28 A medicine for treating cardiovascular and cerebrovascular diseases
  • the drug is a mixture of polysaccharides and proteins
  • the drug in parts by weight, comprises 1-99% polysaccharide, 1-99% protein;
  • the polysaccharide comprises: glucose, galactose, mannose, rhamnose;
  • the protein includes: arginine, lysine, serine, threonine.
  • the polysaccharide and protein mixture has a molecular weight of 0.2-3000 kDa
  • the protein has a molecular weight of 0.2-3000 kDa.
  • the pigment is a natural pigment contained in an algae substance
  • the algal protein may be phycocyanin, phycoerythrin or phycoerythrin.
  • the glycoproteins include synthetic glycoproteins and synthetic polysaccharides and proteins.
  • the drug of the invention has a non-toxic dose of 1.6 g/kg for oral administration for dogs for 12 weeks, which is equivalent to 50 times of the equivalent dose for humans, so the safety of the clinical test can be considered to be guaranteed.
  • the medicament of the present invention may also be a health care product or a food.

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Abstract

本发明提供了一种用于治疗心脑血管疾病的药物，所述药物包括海藻糖蛋白。

Description

一种用于治疗心脑血管疾病的药物 技术领域
本发明涉及一种用于治疗心脑血管疾病的药物，属于医药技术领域。
背景技术
心脑血管疾病就是心脏血管和脑血管的疾病统称，泛指由于高脂血症、血液黏稠、动脉粥样硬化、高血压等所导致的心脏、大脑及全身组织发生缺血性或出血性疾病，是一种严重威胁人类，特别是50岁以上中老年人健康的常见病，即使应用目前最先进、完善的治疗手段，仍可有50％以上的脑血管意外幸存者生活不能完全自理，全世界每年死于心脑血管疾病的人数高达1500万人，居各种死因首位。
目前市场上作为治疗心脑血管疾病的药物多为西药，都存在一定的不足，如容易产生耐药性，作为治疗心律失常的药物本身又能导致心律失常的产生，甚至有的药物具有较强的毒副作用。
专利：一种治疗心脑血管疾病的中药组合物CN201310297384.3公开了一种治疗心脑血管疾病的中药组合物，属于中草药制剂技术领域，所要解决的技术问题是提供一种携带、服用方便的有效治疗心脑血管疾病的中药组合物；采用的技术方案为：一种治疗心脑血管疾病的中药组合物，包括以下重量份配比的原料：牛黄0.04-0.07g，全蝎0.5-1.5g，三七0.8-1.2g，羚羊角粉0.05-0.15g，土鳖虫1-4g，丹参0.5-1.5g，鸡血藤0.8-1.6g；本发明用于治疗心脑血管疾病，药剂体积小、剂量小、副作用小，携带和服用都非常方便。
专利：治疗心脑血管疾病、肝脏疾病的丹参酚酸复合物及其应用、CN200510094596.7公开了：丹参酚酸和碱性氨基酸，或碱性葡萄糖衍生物组成复合物，对于心脑血管疾病、肝脏疾病的治疗具有协同作用；所述碱性氨基酸选自精氨酸、赖氨酸或组氨酸。所述碱性葡萄糖衍生物选自葡甲胺或氨基葡萄糖。
专利：低分子量褐藻多糖硫酸酯在制备治疗心脑血管疾病的药物中的用途CN200610140395.0公开了低分子量褐藻多糖硫酸酯在制备治疗心脑血管疾病，特别是缺血性心脑血管疾病的药物中的用途。本发明中的低分子量褐藻多糖硫酸酯可以是从海带、墨角藻、泡叶藻、昆布或绳藻中提取得到的褐藻多糖硫酸酯降解而得，优选为从海带中提取得到的褐藻多糖硫酸酯降解而得，分子量为8000～100000。
发明内容：
本发明为解决现有技术中存在的不足，提供一种用于治疗心脑血管疾病的药物，以实现以下 发明目的：
(1)本发明所述药物，能够有效降低大鼠的甘油三酯和总胆固醇含量；
(2)本发明所述药物，能够延长小鼠缺氧存活时间，缺氧存活时间达70-85分钟；
(3)本发明所述药物，对乌头碱诱发的大鼠心律失常有较好的治疗作用，喂食本发明药物后，注射乌头碱，室性心动过速(VT)的发生率为9/20-13/20，室颤(VF)的发生率为5/20-8/20，窦性节律恢复率为8/20-12/20，室性早搏(VP)的发生时间为2.24-3.59min；
(4)本发明所述药物，对垂体后叶素诱发大鼠心肌缺血具有较好的保护作用。
为解决以上技术问题，本发明采用如下技术方案：
一种用于治疗心脑血管的药物，其特征在于：所述药物为糖蛋白，或多糖和蛋白质的混合物或多肽或蛋白；所述糖蛋白包括糖1-99％，蛋白质1-99％；所述多糖和蛋白质的混合物，以重量含量计，包括多糖1-99％，蛋白质1-99％。所述糖蛋白，分子量为0.2-3000kDa；
以下是对上述技术方案的进一步改进：
所述药物为海洋藻类糖蛋白。
所述海洋藻类糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％；所述海洋藻类多糖和蛋白质的混合物，以重量含量计，包括多糖1-99％，蛋白质1-99％。
所述海洋藻类糖蛋白，分子量为0.2-3000kDa；
所述多糖和蛋白质的混合物，多糖的分子量为0.2-3000kDa，蛋白质的分子量为0.2-3000kDa。
所述药物，以重量含量计，包括糖蛋白1-99份、葡萄糖醛酸1-25份。
所述药物，以重量含量计，包括海洋藻类糖蛋白1-99份、葡萄糖醛酸1-26份。
所述药物，以重量含量计，包括海洋藻类糖蛋白1-99份、葡萄糖醛酸1-26份、青黛2-13份。
所述藻类为蓝藻、绿藻、红藻、金藻、褐藻中的一种或多种。
所述药物，以重量含量计，包括海洋藻类糖蛋白1-99份、青黛8-15份、赤小豆7-14份、葡萄糖醛酸1-15份。
所述药物，以重量含量计，包括海洋藻类糖蛋白1-99份、青黛8-15份、赤小豆7-14份、白花蛇舌草8-13份。
所述药物，以重量含量计，包括糖1-99％，蛋白质1-99％。
所述海洋藻类糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％。
相对现有技术，本发明的有益效果为：
(1)本发明所述药物，能够有效降低大鼠的甘油三酯和总胆固醇含量，给药后第4周，大鼠的甘油三酯含量降低至0.78-1.14mmol/L，总胆固醇含量降低至1.97-2.64mmol/L。
(2)本发明所述药物，能够延长小鼠缺氧存活时间，缺氧存活时间为70-85分钟，对照组缺氧存活时间仅为46.23分钟。
(3)本发明所述药物，对乌头碱诱发的大鼠心律失常有较好的治疗作用，喂食本发明药物后，注射乌头碱，室性心动过速(VT)的发生率为9/20-13/20，室颤(VF)的发生率为5/20-8/20，窦性节律恢复率为8/20-12/20，室性早搏(VP)的发生时间为2.24-3.59min；模型组室性心动过速(VT)的发生率为18/20，室颤(VF)的发生率为10/20，窦性节律恢复率为6/20，室性早搏(VP)的发生时间为1.22min。
(4)本发明所述药物，对垂体后叶素诱发大鼠心肌缺血具有较好的保护作用，血清中乳酸脱氢酶(LDH)含量为8725.23-9200.23U/L，丙二醛(MDA)含量为3.60-4.14nmol/ml，超氧化物歧化酶(SOD)含量为80.04-83.15U/ml。
(5)本发明糖蛋白具有改善微循环，扩张冠状动脉，改善心肌供血，增加脑和冠状动脉血流量，减慢心率，降低心肌耗氧指数而改善血心肌的代谢，抗血栓素，提高高密度脂蛋白、抗血管痉挛和降低血小板聚集的作用，降低血总胆固醇、甘油三酯的功效。
具体实施方式
以下对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
实施例1一种用于治疗心脑血管疾病的药物
所述药物，为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖1％，蛋白质99％；
分子量为0.2kDa；
所述糖为多糖；
所述海洋藻类为蓝藻；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例2一种用于治疗心脑血管疾病的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖5％，蛋白质82％，
分子量为15kDa；
所述海洋藻类为：绿藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例3一种用于治疗心脑血管疾病的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖10％，蛋白质75％，
分子量为5kDa；
所述海洋藻类为：蓝藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例4一种用于治疗心脑血管疾病的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖25％，蛋白质70％，
分子量为100kDa；
所述海洋藻类为：红藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例5一种用于治疗心脑血管疾病的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖41％，蛋白质59％，
分子量为500kDa；
所述海洋藻类为：褐藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例6一种用于治疗心脑血管疾病的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖99％，蛋白质1％，
分子量为3000kDa；
所述海洋藻类为：金藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
上述实施例1-6所述的糖蛋白，还包括色素；所述色素为藻类物质中含有的天然色素。
对上述实施例1-6进行概括为：
一种用于治疗心脑血管的药物
所述药物，为糖蛋白；
所述糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％；
分子量为0.2-30000kDa；
所述糖为多糖；
所述药物，包括合成糖蛋白及合成多糖和蛋白质。
所述蛋白包括20种氨基酸和8种人工合成氨基酸；
所述药物的制备方法：糖蛋白按照常规工艺制成胶囊、片剂等；多糖和蛋白的混合物按照常规工艺制成胶囊、片剂等。
实施例7所述药物在治疗心脑血管疾病中的应用
(1)本发明药物对大鼠模型血脂的影响
实验动物：SD大鼠，体重160-170g；
高脂饲料配方：由0.5％-2％的胆固醇、5％-10％的猪油、0.1％的胆盐、15％的蔗糖、8％的熟大豆粉、3％的全脂奶粉，其余为基础饲料组成。
实验方法：
大鼠进实验室后随机分为8组，即正常对照组、模型对照组、本发明组1-6，每组10只，称重并编号；
正常对照组饲以基础饲料，模型对照组和本发明组，饲以高脂饲料，实验周期为4周，实验过程中，每周检测甘油三脂和胆固醇的含量；4周后，正常对照组、模型对照组灌胃给予蒸馏水，本发明组1-6，给予本发明所述药物，剂量为3g/天，灌胃，每天3次，连续3天，给药后第4周，检测血清中甘油三酯和总胆固醇含量；结果见表1。
表1本发明药物对大鼠模型血脂的影响
Figure PCTCN2017071851-appb-000001
实施例1-6能够有效降低大鼠的甘油三酯和总胆固醇含量，剂量为3g/天，一天3次时，给药后第4周，大鼠的甘油三酯含量降低至0.78-1.14mmol/L，总胆固醇含量降低至1.97-2.64mmol/L。实施例2和3是优选实施例。
表2本发明糖蛋白不同剂量对大鼠模型血脂的影响
Figure PCTCN2017071851-appb-000002
(2)对小鼠缺氧存活时间的影响：
取小鼠70只，随机分为7组，每组10只，对照组：10ml/kg生理盐水；本发明组1-6(对应于实施例1-6)：分别喂食实施例1-6所述的药物，剂量为3g/天，一天3次；30分钟后将小鼠放入500ml磨口瓶中(含3g钠石灰)，涂凡士林后，盖干。观察小鼠死亡时间，对正常小鼠缺氧存活时间的影响结果见表3。
表3
组别 存活时间(分)
对照组 46.23±11.57
实施例1 75±11.26
实施例2 80±11.27
实施例3 85±14.56
实施例4 77±13.12
实施例5 75±10.89
实施例6 70±12.45
实施例1-6所述糖蛋白，能够延长小鼠缺氧存活时间，存活时间为70-85分钟，对照组存活时间仅为46.23分钟。
(3)对乌头碱诱发的大鼠心律失常的影响：
健康雌性Wistar大鼠140只，随机分为7组，每组20只，模型组：给予等容积生理盐水、本发明组1-6(对应于实施例1-6)：给予实施例1-6所述药物，剂量为3g/天，每天3次，30分钟后用20％乌拉坦(5mg/kg)腹腔注射麻醉，将动物仰位固定在鼠台上，并与BL-420生物机能实验系统相连，描记心电图；大鼠心电图稳定后，对模型组和本发明组小鼠舌下静脉注射0.04％乌头碱1ml/kg(40μg/kg)，5s内注完，观测室性早搏(VP)的发生时间，并统计室性心动过速(VT)、室颤(VF)的发生率和窦性节律恢复率。对乌头碱诱发的大鼠心律失常的影响结果见表4。
表4
Figure PCTCN2017071851-appb-000003
实施例1-6所述药物，对乌头碱诱发的大鼠心律失常有较好的治疗作用，喂食本发明药物 后，注射乌头碱，室性心动过速(VT)的发生率为9/20-13/20，室颤(VF)的发生率为5/20-8/20，窦性节律恢复率为8/20-12/20，室性早搏(VP)的发生时间为2.24-3.59min；模型组室性心动过速(VT)的发生率为18/20，室颤(VF)的发生率为10/20，窦性节律恢复率为6/20，室性早搏(VP)的发生时间为1.22min。
实施例2和实施例3是优选实施例。
(4)对垂体后叶素诱发大鼠心肌缺血的保护作用
健康Wistar大鼠80只，随机分为8组：正常对照组：给予等容积生理盐水、(2)模型组：给予等容积生理盐水；本发明组1-6(对应于实施例1-6)：给予本发明实施例1-6所述药物，剂量为3g/天，一天3次；
实验前一日进行大鼠对垂体后叶素敏感性筛选实验，方法是：大鼠舌下静脉注射垂体后叶素1U/kg，观察心电图变化情况，选取对垂体后叶素敏感大鼠用于实验(T波明显抬高，ST段抬高超过0.1mV)。将筛选获得的敏感大鼠用于模型组和槲寄生组，24h后开始实验。
正常对照组：给予等容积生理盐水、(2)模型组：给予等容积生理盐水；本发明组1-6(对应于实施例1-6)：给予本发明实施例1-6所述药物，剂量为3g/天，一天3次；1小时后用20％乌拉坦(5ml/kg)腹腔注射麻醉，将动物仰位固定在鼠台上，并与BL-420生物机能实验系统相连，描记心电图。正常对照组舌下静脉注射生理盐水，其余组舌下静脉注射垂体后叶素1U/kg后，分别于即刻、1min后观察心电图变化。以T波和ST段改变为指标，判断心肌缺血程度和药物作用。60min，后腹主动脉取血，离心分离血清，测定血清中乳酸脱氢酶(LDH)、超氧化物歧化酶(SOD)、丙二醛(MDA)含量，对心肌缺血大鼠LDH、MDA、SOD的影响结果见表5。
表5
组别 LDH(U/L) MDA(nmol/ml) SOD(U/ml)
正常对照组 7503.45±1345.58 2.74±0.67 96.58±9.78
模型组 11825.47±1218.41 4.97±0.86 72.15±8.97
实施例1 9150.57±1147.56 4.05±0.94 80.04±9.54
实施例2 8826.13±1245.07 3.69±0.72 82.45±8.53
实施例3 8725.23±1319.73 3.60±0.68 83.15±8.67
实施例4 9000.14±1348.06 3.85±1.10 81.64±9.43
实施例5 9100.49±1254.16 3.97±0.73 81.56±8.15
实施例6 9200.23±1378.58 4.14±0.79 80.79±8.59
实施例1-6所述药物，对垂体后叶素诱发大鼠心肌缺血具有较好的保护作用，血清中乳酸脱氢酶(LDH)含量为8725.23-9200.23U/L，丙二醛(MDA)含量为3.60-4.14nmol/ml，超氧化物歧化酶(SOD)含量为80.04-83.15U/ml。实施例2和实施例3是优选实施例。
实施例8一种用于治疗心脑血管疾病的药物
以重量含量计，包括海洋藻类糖蛋白1份、葡萄糖醛酸1份。
所述海洋藻类糖蛋白，以重量含量计，包括糖5％，蛋白质82％，
分子量为8kDa；
所述海洋藻类为：蓝藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例9一种用于治疗心脑血管疾病的药物
同实施例8，只改变海洋藻类糖蛋白和葡萄糖醛酸的配比，改变为：
以重量含量计，包括海洋藻类糖蛋白29份、葡萄糖醛酸7份。
实施例10一种用于治疗心脑血管疾病的药物
同实施例8，只改变海洋藻类糖蛋白和葡萄糖醛酸的配比，改变为：
以重量含量计，包括海洋藻类糖蛋白55份、葡萄糖醛酸16份。
实施例11一种用于治疗心脑血管疾病的药物
同实施例8，只改变海洋藻类糖蛋白和葡萄糖醛酸的配比，改变为：
以重量含量计，包括海洋藻类糖蛋白99份、葡萄糖醛酸26份。
实施例12一种用于治疗心脑血管疾病的药物
以重量含量计，包括海洋藻类糖蛋白1份、葡萄糖醛酸1份、青黛2份。
所述海洋藻类糖蛋白，以重量含量计，包括糖10％，蛋白质75％，
分子量为20kDa；
所述海洋藻类为：螺旋藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例13一种用于治疗心脑血管疾病的药物
同实施例12，只改变海洋藻类糖蛋白、葡萄糖醛酸、青黛的重量配比，改变为：
以重量含量计，包括海洋藻类糖蛋白29份、葡萄糖醛酸8份、青黛5份。
实施例14一种用于治疗心脑血管疾病的药物
同实施例12，只改变海洋藻类糖蛋白、葡萄糖醛酸、青黛的重量配比，改变为：
以重量含量计，海洋藻类糖蛋白60份、葡萄糖醛酸18份、青黛9份。
实施例15一种用于治疗心脑血管疾病的药物
同实施例12，只改变海洋藻类糖蛋白、葡萄糖醛酸、青黛的重量配比，改变为：
以重量含量计，海洋藻类糖蛋白99份、葡萄糖醛酸26份、青黛13份。
上述实施例8-实施例15所述药物在治疗心脑血管疾病中的应用：
采用实施例7所述的试验方法，本发明组为实施例8-实施例15所述药物，应用效果如下：
表6本发明药物对大鼠模型血脂的影响
Figure PCTCN2017071851-appb-000004
表7本发明药物对小鼠缺氧存活时间的影响
组别 存活时间(分)
对照组 46.23±11.57
实施例8 85±11.26
实施例9 87±12.27
实施例10 108±13.56
实施例11 88±12.12
实施例12 88±11.89
实施例13 90±12.41
实施例14 105±12.25
实施例15 92±12.30
表8本发明药物对乌头碱诱发的大鼠心律失常的影响：
Figure PCTCN2017071851-appb-000005
表9本发明药物对垂体后叶素诱发大鼠心肌缺血的保护作用
组别 LDH(U/L) MDA(nmol/ml) SOD(U/ml)
正常对照组 7503.45±1345.58 2.74±0.67 96.58±9.78
模型组 11825.47±1218.41 4.97±0.86 72.15±8.97
实施例8 8850.57±1142.56 3.55±0.94 82.04±9.54
实施例9 8726.13±1235.07 3.49±0.72 82.45±8.53
实施例10 7900.23±1359.73 3.20±0.68 90.15±8.67
实施例11 8800.14±1318.06 3.58±1.10 82.64±9.43
实施例12 9100.49±1204.16 3.67±0.73 82.56±8.15
实施例13 8920.23±1332.28 3.80±0.71 80.29±8.35
实施例14 7800.23±1352.57 3.14±0.70 90.79±8.29
实施例15 9100.23±1348.58 3.74±0.75 80.72±8.31
实施例8-12，改变海洋藻类糖蛋白和葡萄糖醛酸的配比，进行实验，得到实施例10为优选实施例；实施例13-实施例15，通过改变海洋藻类糖蛋白、葡萄糖醛酸、青黛的重量配比，得到实施例14为优选实施例。
实施例16一种用于治疗心脑血管疾病的药物
以重量含量计，包括海洋藻类糖蛋白1份、青黛8份、赤小豆7份、葡萄糖醛酸1份。
所述海洋藻类糖蛋白，以重量含量计，包括糖25％，蛋白质70％，
分子量为8kDa；
所述海洋藻类为：头发菜；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例17一种用于治疗心脑血管疾病的药物
以重量含量计，包括海洋藻类糖蛋白45份、青黛11份、赤小豆9份、葡萄糖醛酸7份。
所述海洋藻类糖蛋白，以重量含量计，包括糖25％，蛋白质70％，
分子量为12kDa；
所述海洋藻类为：头发菜；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例18一种用于治疗心脑血管疾病的药物
以重量含量计，包括海洋藻类糖蛋白99份、青黛15份、赤小豆14份、葡萄糖醛酸15份。
所述海洋藻类糖蛋白，以重量含量计，包括糖25％，蛋白质70％，
分子量为60kDa；
所述海洋藻类为：头发菜；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例19一种用于治疗心脑血管疾病的药物
以重量含量计，包括海洋藻类糖蛋白1份、青黛8份、赤小豆7份、白花蛇舌草8份。
所述海洋藻类糖蛋白，以重量含量计，包括糖41％，蛋白质59％，
分子量为8kDa；
所述海洋藻类为：马尾藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例20一种用于治疗心脑血管疾病的药物
以重量含量计，包括海洋藻类糖蛋白39份、青黛12份、赤小豆11份、白花蛇舌草10份。
所述海洋藻类糖蛋白，以重量含量计，包括糖41％，蛋白质59％，
分子量为20kDa；
所述海洋藻类为：蓝藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
实施例21一种用于治疗心脑血管疾病的药物
以重量含量计，包括海洋藻类糖蛋白99份、青黛15份、赤小豆14份、白花蛇舌草13份。
所述海洋藻类糖蛋白，以重量含量计，包括糖41％，蛋白质59％，
分子量为200kDa；
所述海洋藻类为：蓝藻；
所述糖，为多糖；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸；
上述实施例16-实施例21所述药物在治疗心脑血管疾病中的应用：
采用实施例7所述的试验方法，本发明组为实施例16-实施例21所述药物，应用效果如下：
表10本发明药物对大鼠模型血脂的影响
Figure PCTCN2017071851-appb-000006
表11本发明药物对小鼠缺氧存活时间的影响
组别 存活时间(分)
对照组 46.23±11.57
实施例16 90±11.76
实施例17 120±12.17
实施例18 91±13.46
实施例19 92±12.32
实施例20 119±11.99
实施例21 91±12.11
表12本发明药物对乌头碱诱发的大鼠心律失常的影响：
Figure PCTCN2017071851-appb-000007
表13本发明药物对垂体后叶素诱发大鼠心肌缺血的保护作用
组别 LDH(U/L) MDA(nmol/ml) SOD(U/ml)
正常对照组 7503.45±1345.58 2.74±0.67 96.58±9.78
模型组 11825.47±1218.41 4.97±0.86 72.15±8.97
实施例16 8650.57±1142.56 3.50±0.94 84.04±9.54
实施例17 7500.13±1230.07 2.78±0.72 96.45±8.23
实施例18 8550.23±1309.73 3.30±0.68 84.15±8.27
实施例19 8700.14±1328.06 3.48±0.80 82.64±9.03
实施例20 7400.49±1284.16 2.76±0.63 96.56±8.35
实施例21 8820.23±1302.28 3.60±0.61 82.29±8.31
实施例16-18，通过改变海洋藻类糖蛋白、青黛、赤小豆、葡萄糖醛酸进行实验，得到实施例17为优选实施例；
实施例19-实施例21，通过改变海洋藻类糖蛋白、青黛、赤小豆、白花蛇舌草进行实验，得到实施例20为优选实施例。
实施例22一种用于治疗心脑血管疾病的药物
以重量份计，包括以下组分：
海洋藻类糖蛋白70份、苏木5份、三棱7份、草决明6份、独一味5份、半边莲10份；
所述糖蛋白为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖7％，蛋白质80％，
分子量为8kDa；
所述海洋藻类为：黄群藻；
实施例23一种用于治疗心脑血管疾病的药物
以重量份计，包括以下组分：
海洋藻类糖蛋白80份、牛黄6份、水红花子9份、泽泻5份、延胡索4份、扶桑花6份；
所述糖蛋白为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖14％，蛋白质72％，
分子量为22kDa；
所述海洋藻类为：扁藻；
实施例24一种用于治疗心脑血管疾病的药物
以重量份计，包括以下组分：
海洋藻类糖蛋白85份、赤芍11份、斑蝥5份、何首乌6份、冬凌草8份、大蓟6份；
所述糖蛋白为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖18％，蛋白质62％，
分子量为30kDa；
所述海洋藻类为：念珠藻；
实施例25一种用于治疗心脑血管疾病的药物
以重量份计，包括以下组分：
海洋藻类糖蛋白70份、绿茶6份、莪术5份、蒲黄3份、瓜子金4份、瞿麦8份；
所述糖蛋白为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量含量计，包括糖30％，蛋白质55％，
分子量为40kDa；
所述海洋藻类为：鱼腥藻；
实施例26一种用于治疗心脑血管疾病的药物的制备方法
步骤1、称量
按照配方称量海洋藻类糖蛋白和各中药成分；
步骤2、中药的浸提
(1)清洗
将各中药成分，用清水冲洗，去处杂质；
(2)粉碎、微波萃取
将中药粉碎处理成100目药材粉末，加入10倍量50％乙醇，控制温度为60℃，以260W微 波功率、微波波长为130毫米，频率为1200兆赫的微波辐射5min，过滤，收集滤液；分离药渣，加入12倍体积的清水，控制温度为50℃，以200W微波功率、微波波长为140毫米，频率为1250兆赫的微波辐射5min，过滤，收集滤液；
合并两次的滤液；喷雾干燥，制备中药粉末；
所述喷雾干燥，将上述合并两次的滤液，经过0.45μm微孔滤膜过滤，得续滤液，所得续滤液经蠕动泵导入Büchi290小型喷雾干燥器的双流向螺旋式喷嘴，控制进口温度为125℃，进料速度为3mL/min，喷雾干燥。
步骤3、加入海洋藻类糖蛋白
海洋藻类糖蛋白粉末和上述中药粉末，混合均匀；制备成胶囊、片剂等不同剂型的药物。
上述实施例22-实施例25所述药物在治疗心脑血管疾病中的应用：
采用实施例7所述的试验方法，本发明组为实施例22-实施例25所述药物，应用效果如下：
表14本发明药物对大鼠模型血脂的影响
Figure PCTCN2017071851-appb-000008
表15本发明药物对小鼠缺氧存活时间的影响
组别 存活时间(分)
对照组 46.23±11.57
实施例22 110±11.76
实施例23 109±12.17
实施例24 108±13.46
实施例25 112±12.32
表16本发明药物对乌头碱诱发的大鼠心律失常的影响：
Figure PCTCN2017071851-appb-000009
表17本发明药物对垂体后叶素诱发大鼠心肌缺血的保护作用
组别 LDH(U/L) MDA(nmol/ml) SOD(U/ml)
正常对照组 7503.45±1345.58 2.74±0.67 96.58±9.78
模型组 11825.47±1218.41 4.97±0.86 72.15±7.97
实施例22 7650.57±1142.56 3.00±0.94 94.04±7.54
实施例23 7700.13±1230.07 2.88±0.72 93.45±7.23
实施例24 7850.23±1309.73 2.98±0.68 94.15±7.27
实施例25 8000.14±1328.06 3.12±0.80 92.64±8.03
实施例27本发明所述药物破除血管血栓的效果
本发明实施例8-22药物进行临床试验，每日3次，每次1g，结果如下，见表18、表19。
表18
Figure PCTCN2017071851-appb-000010
表19
Figure PCTCN2017071851-appb-000011
本发明所述药物，pH为5.3-9.8之间，优选为6.5-7.5之间。
本发明经过大量试验，我们采取了海洋贝壳类、畜禽类的骨头、海洋动物的骨架中提取的糖蛋白及多糖、蛋白的混合物进行多次试验，也能实现本发明的发明目的。
实施例28一种用于治疗心脑血管疾病的药物
所述药物，为多糖、蛋白质的混合物；
所述药物，以重量份计，包括多糖1-99％、蛋白质1-99％；
所述多糖，包括：葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：精氨酸、赖氨酸、丝氨酸、苏氨酸。
所述多糖和蛋白质的混合物，多糖的分子量为0.2-3000kDa，蛋白质的分子量为0.2-3000kDa。
所述多糖和蛋白的混合物，进一步为藻类多糖和藻类蛋白的混合物；
所述藻类多糖和藻类蛋白的混合物，还包括色素；
所述色素为藻类物质中含有的天然色素；
所述藻类蛋白可以是藻蓝蛋白、藻红蛋白或藻黄色蛋白。
所述糖蛋白包括合成糖蛋白及合成多糖、蛋白。
本发明所述药物对犬经口给药12周无毒性反应剂量为1.6g/kg，相当于人用等效剂量的50倍，故可认为临床试验的安全性可以得到保障。
本发明所述药物，还可以是保健品或食品。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (10)

  1. 一种用于治疗心脑血管疾病的药物，其特征在于：所述药物为糖蛋白或多糖和蛋白质的混合物或多肽或蛋白。
  2. 根据权利要求1所述的一种用于治疗心脑血管疾病的药物，其特征在于：所述药物为海洋藻类糖蛋白。
  3. 根据权利要求2所述的一种用于治疗心脑血管疾病的药物，其特征在于：所述糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％；所述海洋藻类糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％；所述多糖和蛋白质的混合物，以重量含量计，包括糖1-99％，蛋白质1-99％。
  4. 根据权利要求2所述的一种用于治疗心脑血管疾病的药物，其特征在于：所述糖蛋白，分子量为0.2-3000kDa；所述海洋藻类糖蛋白，分子量为0.2-3000kDa；所述多糖和蛋白质的混合物，多糖的分子量为0.2-3000kDa，蛋白质的分子量为0.2-3000kDa。
  5. 根据权利要求2所述的一种用于治疗心脑血管疾病的药物，其特征在于：以重量含量计，包括糖蛋白1-99份、葡萄糖醛酸1-26份。
  6. 根据权利要求2所述的一种用于治疗心脑血管疾病的药物，其特征在于：以重量含量计，包括糖蛋白1-99份、葡萄糖醛酸1-26份、青黛2-13份。
  7. 根据权利要求2所述的一种用于治疗心脑血管疾病的药物，其特征在于：所述藻类为蓝藻、绿藻、红藻、金藻、褐藻中的一种或多种。
  8. 根据权利要求1所述的一种用于治疗心脑血管疾病的药物，其特征在于：以重量含量计，包括糖蛋白1-99份、青黛8-15份、赤小豆7-14份、葡萄糖醛酸1-15份。
  9. 根据权利要求1所述的一种用于治疗心脑血管疾病的药物，其特征在于：以重量含量计，包括糖蛋白1-99份、青黛8-15份、赤小豆7-14份、白花蛇舌草8-13份。
  10. 根据权利要求5-9任一项所述的一种用于治疗心脑血管疾病的药物，其特征在于：所述糖蛋白、海洋藻类糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％。
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