CN1230159C - 必需脂肪酸在预防心血管疾病中的应用 - Google Patents
必需脂肪酸在预防心血管疾病中的应用 Download PDFInfo
- Publication number
- CN1230159C CN1230159C CNB008050732A CN00805073A CN1230159C CN 1230159 C CN1230159 C CN 1230159C CN B008050732 A CNB008050732 A CN B008050732A CN 00805073 A CN00805073 A CN 00805073A CN 1230159 C CN1230159 C CN 1230159C
- Authority
- CN
- China
- Prior art keywords
- epa
- ethyl ester
- acid ethyl
- dha
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 235000004626 essential fatty acids Nutrition 0.000 title claims abstract description 18
- 230000002265 prevention Effects 0.000 title description 6
- 230000007211 cardiovascular event Effects 0.000 title 1
- MBMBGCFOFBJSGT-KUBAVDMBSA-N docosahexaenoic acid Natural products CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims abstract description 31
- 239000000203 mixture Substances 0.000 claims abstract description 24
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 19
- 206010042434 Sudden death Diseases 0.000 claims abstract description 11
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 235000020669 docosahexaenoic acid Nutrition 0.000 claims abstract 10
- 229940090949 docosahexaenoic acid Drugs 0.000 claims 9
- 235000020673 eicosapentaenoic acid Nutrition 0.000 abstract description 21
- 229920000064 Ethyl eicosapentaenoic acid Polymers 0.000 abstract description 14
- TYLNXKAVUJJPMU-DNKOKRCQSA-N Docosahexaenoic acid ethyl ester Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(=O)OCC TYLNXKAVUJJPMU-DNKOKRCQSA-N 0.000 abstract 2
- DVSZKTAMJJTWFG-UHFFFAOYSA-N docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCCC=CC=CC=CC=CC=CC=CC(O)=O DVSZKTAMJJTWFG-UHFFFAOYSA-N 0.000 description 21
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 20
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 20
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 20
- ITNKVODZACVXDS-YNUSHXQLSA-N ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate Chemical compound CCOC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC ITNKVODZACVXDS-YNUSHXQLSA-N 0.000 description 11
- 239000002775 capsule Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 6
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 5
- 208000024172 Cardiovascular disease Diseases 0.000 description 5
- 206010000891 acute myocardial infarction Diseases 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 3
- 206010061216 Infarction Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 235000021323 fish oil Nutrition 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 229960000984 tocofersolan Drugs 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 239000002076 α-tocopherol Substances 0.000 description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 101710186708 Agglutinin Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 101001000747 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 2A Proteins 0.000 description 1
- 101001000734 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 2B Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 101710146024 Horcolin Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 101710189395 Lectin Proteins 0.000 description 1
- 101710179758 Mannose-specific lectin Proteins 0.000 description 1
- 101710150763 Mannose-specific lectin 1 Proteins 0.000 description 1
- 101710150745 Mannose-specific lectin 2 Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NCYSTSFUYSFMEO-OBLTVXDOSA-N PGI3 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C\C=C/CC)[C@H](O)C[C@@H]21 NCYSTSFUYSFMEO-OBLTVXDOSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000000910 agglutinin Substances 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- IXMINYBUNCWGER-UHFFFAOYSA-M sodium;4-propoxycarbonylphenolate Chemical compound [Na+].CCCOC(=O)C1=CC=C([O-])C=C1 IXMINYBUNCWGER-UHFFFAOYSA-M 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Fats And Perfumes (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及含有高含量二十碳五烯酸乙酯(EPA)或二十二碳六烯酸乙酯(DHA)或其高浓度混合物的必需脂肪酸在制备用于预防心肌梗死患者死亡的药物组合物中的应用，所述死亡特别是指由猝死所引起的死亡。
Description
本发明涉及含有来源于鱼油的必需脂肪酸乙酯的药物组合物、特别是含有以(20:5ω3)二十碳五烯酸(EPA)乙酯和(22:6ω3)二十二碳六烯酸(DHA)乙酯的高浓度混合物形式的必需脂肪酸乙酯的药物组合物在预防心血管疾病中的应用，尤其是用于预防在急性心肌梗死(AMI)住院期后幸存患者的死亡。
众所周知，鱼油中含有的必需脂肪酸对预防和治疗心血管疾病具有治疗学效果，例如能够用于治疗血栓形成、高胆固醇血症、动脉硬化、脑梗死和和高脂血症。
可以作为例子的参考文献例如美国专利US 5,502,077、US 5,656,667和US 5,689,594。
从上述现有技术中，已知特别是属于ω-3类的脂肪酸、更特别是(20:5ω3)二十碳五烯酸(EPA)和(22:6ω3)二十二碳六烯酸(DHA)能够用于治疗上述疾病。
诚然，EPA是PGI3和TxA3的前体物质，其具有预防血小板凝集作用和抗血栓作用，这是因为其能够抑制环氧合酶(类似于阿司匹林的作用)和/或与花生四烯酸竞争环氧合酶，结果导致PGE2和TxA2(二者是公知的血小板凝集素)的合成减少。
另一方面，DHA是人脑中脂类物质的重要组份，而且其还是血小板细胞的结构成分。该物质间接干预增加血小板的流动性，从而对于抗血栓活性有重要作用。
国际专利申请WO89/11521特别公开了从动物和/或植物油中得到高含量多不饱和脂肪酸的提取混合物的工业生产方法，其中所示不饱和脂肪酸包括EPA和DHA及它们的乙酯。该文献的内容在此引入作为参考。
据报道，按照WO89/11521所述方法得到的脂肪酸的混合物(尤其是EPA/DHA)对治疗心血管疾病特别有用。
然而，在心血管疾病预防方面，更特别是预防死亡(尤其是由猝死所引起的死亡，而猝死常常在患有心肌梗死的患者中发生，这是由于患者在第一次患有急性心肌梗死后会复发)方面，目前针对人的治疗尚不能令人满意。
因此，仍然需要具体用于预防这些疾病复发的有效药物。
因此，本发明的目的是含有高含量EPA-乙酯或DHA乙酯或其高浓度混合物的必需脂肪酸在制备用于预防死亡的药物中的应用，其中所述的死亡由例如心血管疾病，或者患有心肌梗死的患者猝死所引起。
因此，本发明一个优选方面涉及含有高含量EPA-乙酯或DHA乙酯或其高浓度混合物的必需脂肪酸在制备用于预防患心肌梗死的患者的猝死的药物中的应用。
为了便于描述，将“EPA乙酯”和“DHA乙酯”在此也写成“EPA”和“DHA”。
根据本发明，含有高含量EPA-乙酯或DHA-乙酯的必需脂肪酸优选含有大于25％重量(b.w)、特别是约60～约100％重量的所述酯。
这些化合物可以通过已知方法得到。
在含有高浓度EPA-乙酯和DHA-乙酯的混合物的必需脂肪酸中，优选地，EPA+DHA在该混合物中的含量大于25％重量、特别是约30～约100％重量、优选约85％重量。
在EPA/DHA混合物中，EPA的优选含量为约40～约60％重量，DHA的优选含量为约25至约45-50％。
在所有情况下，在这样的EPA/DHA混合物中，EPA/DHA的优选比例约为0.9-1.5。
药理学
本发明的治疗效果通过例如这样的事实所证明：在进行为期3.5年的临床试验中，通过该治疗观察到梗死后的死亡率有惊人的和明显的降低，其中临床试验所用标准如下：
1“对照组”接受通常用于梗死患者的标准治疗；
2“治疗组”接受给予“对照组”的治疗和85％EPA+DHA(1克/天)。
3“治疗组”接受给予“对照组”的治疗和维生素E；和
4“治疗组”接受给予“对照组”的治疗和维生素E和85％EPA+DHA(1克/天)。
事实上，与“对照组”1相比，“治疗组”2的患者显示总死亡率有约20％的降低，由猝死引起的死亡率有约40％的降低，由其它心血管疾病引起的死亡率有显著降低。与“对照组”1相比，“治疗组”3没有明显的不同结果，与对照组相比，“治疗组”4显示总死亡率有约19％的降低，该结果类似于治疗组2所得到的结果。根据上述临床结果，本领域技术人员容易得出结论：本发明药物组合物的用途在人的治疗中确实能够用于预防患有心肌梗死的患者的死亡。
因此，本发明提供一种预防患心肌梗死后幸存患者死亡的方法，包括：对所述患者给药治疗有效量的含有必需脂肪酸的药物，其中所述必需脂肪酸含有高含量的EPA-乙酯或DHA-乙酯或其高浓度混合物。众所周知，猝死是心血管疾病患者死亡率的重要原因，在美国，猝死人数每年超过450,000例。
大约有80％这样的患者，特别是那些急性心肌梗死并且心室射出量低的幸存患者，他们发生猝死或再梗死的危险性非常高。
上述临床结果显示：本发明提供有价值的新治疗手段用于预防患者特别是急性心肌梗死的幸存者的猝死。
因此，作为一个优选方面，本发明还提供治疗心肌梗死后幸存的患者的猝死的方法，包括：对所述患者给药治疗有效量的含有必需脂肪酸的药物，其中所述必需脂肪酸含有高含量的EPA-乙酯或DHA-乙酯或其高浓度混合物。
本发明的必需脂肪酸含有高含量例如大约25％重量的EPA乙酯或DHA-乙酯或其混合物。然而，EPA-乙酯和DHA-乙酯优选以其混合物形式存在，在混合物中，EPA+DHA的含量高于25％重量、特别是约30～约100％重量，优选约85％重量。
基于上述得到的临床结果，根据本发明的优选方面，含有85％重量效价的EPA+DHA混合物的必需脂肪酸给药于患者的口服剂量为约0.7克～约1.5克/天，优选约1克/天。为了达到预期的血浓度，作为EPA+DHA混合物来说，该产品的量(或者单独EPA-乙酯的量或者单独DHA-乙酯的量)可以每天分次给药，或者地优选地单次给药。显然，内科医师可以通过对患者的年龄、体重和一般健康状况的判断来调整产品的给药量。
可以按照本领域已知的方法制备本发明的药物例如药物组合物形式的药物。优选的给药途径是口服，然而，还可以根据内科医师的判断以可替代的其它途径给药，例如胃肠外给药。
下列实施例举例说明优选的口服制剂，但这些实施例不以任何方式限制本发明。
明胶胶囊
按照已知的药物技术，制备含有下列组合物的胶囊，每个胶囊含有1g活性成分(EPA+DHA，85％效价)。
制剂1
EPA-乙酯 525毫克/胶囊
DHA-乙酯 315毫克/胶囊
d-α-生育酚 4IU/胶囊
明胶 246毫克/胶囊
甘油 118毫克/胶囊
氧化铁红 2.27毫克/胶囊
黄色氧化铁 1.27毫克/胶囊
制剂2
多不饱和脂肪酸乙酯 1000毫克
其中ω-3多不饱和酯
(二十碳五烯酸EPA、
二十二碳六烯酸DHA)
中乙基酯含量 850毫克
d-1-α-生育酚 0.3毫克
琥珀酸明胶(gelatin succinate) 233毫克
甘油 67毫克
对羟基苯甲酸钠 1.09毫克
对羟基苯甲酸丙酯钠 0.54毫克
Claims (8)
1、含有二十碳五烯酸乙酯和二十二碳六烯酸乙酯的混合物的必需脂肪酸在制备用于预防心肌梗死患者死亡的药物中的应用，在所述混合物中，二十碳五烯酸乙酯和二十二碳六烯酸乙酯的含量之和为25％重量～100％重量，该药物用于口服给药。
2、根据权利要求1的应用，其中所述药物用于预防由心肌梗死患者的猝死引起的死亡。
3、根据权利要求1或2的应用，其中二十碳五烯酸乙酯和二十二碳六烯酸乙酯在所述混合物中的含量之和为30％～100％重量。
4、根据权利要求1或2的应用，其中二十碳五烯酸乙酯和二十二碳六烯酸乙酯在所述混合物中的含量之和为85％重量。
5、根据权利要求4的应用，其中在所述二十碳五烯酸乙酯和二十二碳六烯酸乙酯混合物中，二十碳五烯酸乙酯/二十二碳六烯酸乙酯的比例为0.9-1.5。
6、含有二十碳五烯酸乙酯或二十二碳六烯酸乙酯的必需脂肪酸在制备用于预防心肌梗死患者死亡的药物中的应用，其中二十碳五烯酸乙酯或二十二碳六烯酸乙酯的含量为25％重量～100％重量，所述药物通过口服给药。
7、根据权利要求6的应用，其中所述药物用于预防由心肌梗死患者的猝死所引起的死亡。
8、根据权利要求6或7的应用，其中二十碳五烯酸乙酯或二十二碳六烯酸乙酯的含量为60～100％重量。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI99A000313 | 1999-02-17 | ||
| IT1999MI000313A IT1308613B1 (it) | 1999-02-17 | 1999-02-17 | Acidi grassi essenziali nella prevenzione di eventi cardiovascolari. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1343120A CN1343120A (zh) | 2002-04-03 |
| CN1230159C true CN1230159C (zh) | 2005-12-07 |
Family
ID=11381919
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB008050732A Expired - Lifetime CN1230159C (zh) | 1999-02-17 | 2000-02-07 | 必需脂肪酸在预防心血管疾病中的应用 |
Country Status (26)
| Country | Link |
|---|---|
| US (2) | US7462643B1 (zh) |
| EP (2) | EP1247523A1 (zh) |
| JP (2) | JP5441287B2 (zh) |
| KR (2) | KR20070098954A (zh) |
| CN (1) | CN1230159C (zh) |
| AT (1) | ATE216230T1 (zh) |
| AU (1) | AU775078B2 (zh) |
| BR (1) | BR0008153A (zh) |
| CA (1) | CA2362271C (zh) |
| CZ (1) | CZ301307B6 (zh) |
| DE (1) | DE60000133C5 (zh) |
| DK (1) | DK1152755T3 (zh) |
| EA (1) | EA004312B1 (zh) |
| ES (1) | ES2174814T3 (zh) |
| HK (1) | HK1044720B (zh) |
| HU (1) | HUP0200111A3 (zh) |
| ID (1) | ID30205A (zh) |
| IL (2) | IL144377A0 (zh) |
| IT (1) | IT1308613B1 (zh) |
| NO (1) | NO328797B1 (zh) |
| NZ (1) | NZ513093A (zh) |
| PL (1) | PL209078B1 (zh) |
| PT (1) | PT1152755E (zh) |
| SK (1) | SK286523B6 (zh) |
| WO (1) | WO2000048592A1 (zh) |
| ZA (1) | ZA200106029B (zh) |
Families Citing this family (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1308613B1 (it) * | 1999-02-17 | 2002-01-09 | Pharmacia & Upjohn Spa | Acidi grassi essenziali nella prevenzione di eventi cardiovascolari. |
| ITMI20010129A1 (it) | 2001-01-25 | 2002-07-25 | Pharmacia & Upjohn Spa | Acidi grassi essenziali nella terapia di insufficienza cardiaca e scompenso cardiaco |
| ITMI20012384A1 (it) * | 2001-11-12 | 2003-05-12 | Quatex Nv | Uso di acidi grassi poliinsaturi per la prevenzione primaria di eventi cardiovascolari maggiori |
| ITMI20020269A1 (it) * | 2002-02-12 | 2003-08-12 | Victorix Assets Ltd | Uso di steri etilici di acidi poliinsaturi omega-3 in pazienti con insufficienza cardiaca |
| GB0210212D0 (en) * | 2002-05-03 | 2002-06-12 | Univ Southampton | Effects of dietary N-3 and N-6 pufa intake on atheromatous plaque stability |
| US8729124B2 (en) | 2002-03-05 | 2014-05-20 | Pronova Biopharma Norge As | Use of EPA and DHA in secondary prevention |
| CA2485116C (en) | 2002-05-03 | 2013-02-05 | Pronova Biocare As | Use of epa and dha in secondary prevention |
| ITMI20022511A1 (it) * | 2002-11-26 | 2004-05-27 | Victorix Assets Ltd | Uso di composizioni farmaceutiche contenenti esteri etilici di acidi poliinsaturi omega-3 nella orevenzione della fibrillazione atriale. |
| ATE499146T1 (de) | 2005-03-11 | 2011-03-15 | Recon Oil Ind Private Ltd | Synergistisch hitzestabiles ölmedium mit eicosapentaensäure (epa) und docosahexaensäure (dha) |
| CA2570763C (en) * | 2005-07-08 | 2011-08-23 | Mochida Pharmaceutical Co., Ltd. | Composition for preventing onset of cardiovascular events |
| JP5134916B2 (ja) * | 2005-07-08 | 2013-01-30 | 持田製薬株式会社 | 心血管イベント発症予防用組成物 |
| WO2007071733A2 (en) * | 2005-12-21 | 2007-06-28 | Brudy Technology, S.L. | Use of dha, epa or dha-derived epa for treating a pathology associated with cellular oxidative damage |
| ES2277557B1 (es) | 2005-12-21 | 2008-07-01 | Proyecto Empresarial Brudy, S.L. | Utilizacion de acido docosahexaenoico para el tratamiento del daño celular oxidativo. |
| CN101365438A (zh) | 2006-02-07 | 2009-02-11 | 持田制药株式会社 | 预防中风复发的组合物 |
| ES2500063T3 (es) | 2006-05-31 | 2014-09-29 | Mochida Pharmaceutical Co., Ltd. | Composición para prevenir la aparición de acontecimiento cardiovascular en paciente con riesgo múltiple |
| US20090264520A1 (en) * | 2008-04-21 | 2009-10-22 | Asha Lipid Sciences, Inc. | Lipid-containing compositions and methods of use thereof |
| MX2011001419A (es) | 2008-08-07 | 2011-05-25 | Prodotti Antibiotici Spa | Tratamiento a largo plazo de deficiencia cardiaca sintomatica. |
| JPWO2010018856A1 (ja) * | 2008-08-13 | 2012-01-26 | 持田製薬株式会社 | カンナビノイド受容体関連疾患の予防／改善または治療剤 |
| EP2475309A4 (en) * | 2009-09-08 | 2015-07-29 | Atrium Medical Corp | HERNIAPFLASTER |
| RU2014146265A (ru) | 2009-12-30 | 2015-07-10 | Басф Фарма (Калланиш) Лимитед | Способ хроматографического разделения с псевдодвижущимся слоем |
| US8715648B2 (en) | 2011-02-16 | 2014-05-06 | Pivotal Therapeutics Inc. | Method for treating obesity with anti-obesity formulations and omega 3 fatty acids for the reduction of body weight in cardiovascular disease patients (CVD) and diabetics |
| US9119826B2 (en) | 2011-02-16 | 2015-09-01 | Pivotal Therapeutics, Inc. | Omega 3 fatty acid for use as a prescription medical food and omega 3 fatty acid diagniostic assay for the dietary management of cardiovascular patients with cardiovascular disease (CVD) who are deficient in blood EPA and DHA levels |
| US8952000B2 (en) | 2011-02-16 | 2015-02-10 | Pivotal Therapeutics Inc. | Cholesterol absorption inhibitor and omega 3 fatty acids for the reduction of cholesterol and for the prevention or reduction of cardiovascular, cardiac and vascular events |
| US8951514B2 (en) | 2011-02-16 | 2015-02-10 | Pivotal Therapeutics Inc. | Statin and omega 3 fatty acids for reduction of apolipoprotein-B levels |
| GB201111595D0 (en) | 2011-07-06 | 2011-08-24 | Equateq Ltd | Improved process |
| GB201111601D0 (en) | 2011-07-06 | 2011-08-24 | Equateq Ltd | New process |
| GB201111594D0 (en) | 2011-07-06 | 2011-08-24 | Equateq Ltd | New improved process |
| GB201111589D0 (en) | 2011-07-06 | 2011-08-24 | Equateq Ltd | New modified process |
| GB201111591D0 (en) | 2011-07-06 | 2011-08-24 | Equateq Ltd | Further new process |
| KR101681907B1 (ko) * | 2012-02-27 | 2016-12-12 | 주식회사 케어사이드 | 혈액 순환 촉진 및 피부 질환 개선용 조성물 |
| US9480651B2 (en) | 2012-03-30 | 2016-11-01 | Sancilio & Company, Inc. | Omega-3 fatty acid ester compositions unitary pharmaceutical dosage forms |
| US20160228397A1 (en) | 2012-03-30 | 2016-08-11 | Sancilio & Company, Inc. | Omega-3 fatty acid ester compositions |
| US10898458B2 (en) | 2012-03-30 | 2021-01-26 | Micelle Biopharma, Inc. | Self-micellizing fatty acids and fatty acid ester compositions and their use in the treatment of disease states |
| MY189576A (en) | 2012-03-30 | 2022-02-17 | Micelle Biopharma Inc | Omega-3 fatty acid ester compositions |
| EP2897595B1 (en) * | 2012-09-24 | 2020-06-03 | Aker Biomarine Antarctic As | Omega -3 compositions |
| GB201300354D0 (en) | 2013-01-09 | 2013-02-20 | Basf Pharma Callanish Ltd | Multi-step separation process |
| US9428711B2 (en) | 2013-05-07 | 2016-08-30 | Groupe Novasep | Chromatographic process for the production of highly purified polyunsaturated fatty acids |
| US8802880B1 (en) | 2013-05-07 | 2014-08-12 | Group Novasep | Chromatographic process for the production of highly purified polyunsaturated fatty acids |
| EP3118186B1 (fr) | 2013-12-11 | 2022-02-09 | Novasep Process | Installation chromatographique de production d acides gras polyinsatures |
| BR112016015718B1 (pt) | 2014-01-07 | 2021-12-07 | Novasep Process Solutions | Processo de purificação de aminoácidos aromáticos |
| PL237374B1 (pl) * | 2017-11-10 | 2021-04-06 | Lambdafin Spolka Z Ograniczona Odpowiedzialnoscia | Kompozycja farmaceutyczna zawierająca mieszaninę estru etylowego kwasu eikozapentaenowego i estru etylowego kwasu dokozaheksaenowego oraz jej zastosowanie |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6034156A (ja) * | 1983-08-08 | 1985-02-21 | Hayashibara Biochem Lab Inc | エイコサペンタエン酸包接化合物及びこれを含有した飲食物 |
| US4526902A (en) * | 1983-10-24 | 1985-07-02 | Century Laboratories, Inc. | Combined fatty acid composition for treatment or prophylaxis of thrombo-embolic conditions |
| NO157302C (no) | 1985-12-19 | 1988-02-24 | Norsk Hydro As | Fremgangsmaate for fremstilling av et fiskeoljekonsentrat. |
| US4920098A (en) | 1986-09-17 | 1990-04-24 | Baxter International Inc. | Nutritional support or therapy for individuals at risk or under treatment for atherosclerotic vascular, cardiovascular, and/or thrombotic diseases |
| IT1205043B (it) | 1987-05-28 | 1989-03-10 | Innova Di Ridolfi Flora & C S | Procedimento per l'estrazione di esteri di acidi grassi poliinsaturi da olii di pesce e composizioni farmaceutiche e dietetiche contenenti detti esteri |
| GB2218984B (en) | 1988-05-27 | 1992-09-23 | Renafield Limited | Process for preparing high-concentration mixtures of polyunsaturated fatty acids & their esters and their prophylactic or therapeutic uses |
| GB8819110D0 (en) * | 1988-08-11 | 1988-09-14 | Norsk Hydro As | Antihypertensive drug & method for production |
| US5059622A (en) * | 1989-08-29 | 1991-10-22 | Biosyn, Inc. | Method for reducing blood pressure levels in hypertensive persons |
| JP2893866B2 (ja) | 1990-05-25 | 1999-05-24 | 日本油脂株式会社 | 抗不整脈薬 |
| US5324323A (en) | 1992-09-09 | 1994-06-28 | Telectronics Pacing Systems, Inc. | Multiple channel cardiosynchronous myoplasty apparatus |
| US5208236A (en) | 1992-09-23 | 1993-05-04 | Schering Corporation | N-(acylaminomethyl)glutaryl amino acids and use |
| KR950704259A (ko) | 1992-12-11 | 1995-11-17 | 베르너 발데크 | 치환된 벤즈아제피논(Substituted Benzazepinone) |
| CN1082909A (zh) * | 1993-01-03 | 1994-03-02 | 潘玉珍 | 精制二十二碳六烯酸乙酯复合溶栓、抗痴呆药剂 |
| JPH07118229A (ja) | 1993-10-19 | 1995-05-09 | Fujisawa Pharmaceut Co Ltd | 尿素誘導体およびその製造法 |
| US5760081A (en) * | 1994-05-10 | 1998-06-02 | The General Hospital Corporation | Omega 3 fatty acids in the prevention of ventricular fibrillation |
| JPH0812581A (ja) | 1994-06-30 | 1996-01-16 | Fujirebio Inc | 虚血性心疾患治療剤 |
| IT1274734B (it) | 1994-08-25 | 1997-07-24 | Prospa Bv | Composizioni farmaceutiche contenenti acidi grassi poliinsaturi, loro esteri o sali, unitamente a vitamine o provitamine antiossidanti |
| MY118354A (en) | 1995-05-01 | 2004-10-30 | Scarista Ltd | 1,3-propane diol derivatives as bioactive compounds |
| IT1277953B1 (it) | 1995-12-21 | 1997-11-12 | Sigma Tau Ind Farmaceuti | Composizione farmaceutica contenente l-carnitina o una alcanoil l- carnitina e un acido poliinsaturo della serie 3-omega utile per |
| US6333447B1 (en) | 1996-03-29 | 2001-12-25 | The General Hospital Corporation | Transgenic model of heart failure |
| US5861399A (en) | 1996-07-17 | 1999-01-19 | Heart Care Partners | Methods and compositions for the rapid and enduring relief of inadequate myocardial function |
| ATE347606T1 (de) | 1996-09-05 | 2006-12-15 | Univ California | Gentherapie für kongestives herzversagen |
| US6313167B1 (en) | 1997-06-16 | 2001-11-06 | Nippon Suisan Kaisha Ltd. | Composition having capability of removing risk factor during exercise |
| IT1308613B1 (it) * | 1999-02-17 | 2002-01-09 | Pharmacia & Upjohn Spa | Acidi grassi essenziali nella prevenzione di eventi cardiovascolari. |
| EP1130027A1 (de) | 2000-02-29 | 2001-09-05 | Aventis Pharma Deutschland GmbH | Memno-Peptide, Verfahren zu ihrer Herstellung und Verwendung derselben |
-
1999
- 1999-02-17 IT IT1999MI000313A patent/IT1308613B1/it active
-
2000
- 2000-02-07 EP EP20020076100 patent/EP1247523A1/en not_active Withdrawn
- 2000-02-07 PT PT00907510T patent/PT1152755E/pt unknown
- 2000-02-07 EA EA200100895A patent/EA004312B1/ru not_active IP Right Cessation
- 2000-02-07 SK SK1080-2001A patent/SK286523B6/sk not_active IP Right Cessation
- 2000-02-07 DE DE60000133.4T patent/DE60000133C5/de not_active Expired - Lifetime
- 2000-02-07 KR KR1020077019755A patent/KR20070098954A/ko not_active Application Discontinuation
- 2000-02-07 KR KR1020017010387A patent/KR100823051B1/ko active IP Right Review Request
- 2000-02-07 DK DK00907510T patent/DK1152755T3/da active
- 2000-02-07 JP JP2000599384A patent/JP5441287B2/ja not_active Expired - Lifetime
- 2000-02-07 NZ NZ513093A patent/NZ513093A/xx not_active IP Right Cessation
- 2000-02-07 CN CNB008050732A patent/CN1230159C/zh not_active Expired - Lifetime
- 2000-02-07 EP EP00907510A patent/EP1152755B1/en not_active Expired - Lifetime
- 2000-02-07 US US09/869,333 patent/US7462643B1/en not_active Expired - Fee Related
- 2000-02-07 CZ CZ20012947A patent/CZ301307B6/cs not_active IP Right Cessation
- 2000-02-07 HU HU0200111A patent/HUP0200111A3/hu unknown
- 2000-02-07 AT AT00907510T patent/ATE216230T1/de active
- 2000-02-07 PL PL350851A patent/PL209078B1/pl unknown
- 2000-02-07 WO PCT/EP2000/000957 patent/WO2000048592A1/en not_active Application Discontinuation
- 2000-02-07 AU AU29075/00A patent/AU775078B2/en not_active Expired
- 2000-02-07 IL IL14437700A patent/IL144377A0/xx active IP Right Grant
- 2000-02-07 ID IDW00200101999A patent/ID30205A/id unknown
- 2000-02-07 ES ES00907510T patent/ES2174814T3/es not_active Expired - Lifetime
- 2000-02-07 CA CA002362271A patent/CA2362271C/en not_active Expired - Lifetime
- 2000-02-07 BR BR0008153-1A patent/BR0008153A/pt not_active Application Discontinuation
-
2001
- 2001-07-17 IL IL144377A patent/IL144377A/en not_active IP Right Cessation
- 2001-07-23 ZA ZA200106029A patent/ZA200106029B/en unknown
- 2001-08-14 NO NO20013938A patent/NO328797B1/no not_active IP Right Cessation
-
2002
- 2002-08-29 HK HK02106382.1A patent/HK1044720B/zh not_active IP Right Cessation
-
2008
- 2008-08-15 US US12/192,627 patent/US20090018193A1/en not_active Abandoned
-
2010
- 2010-01-07 JP JP2010014742A patent/JP2010116414A/ja active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1230159C (zh) | 必需脂肪酸在预防心血管疾病中的应用 | |
| JP5228185B2 (ja) | 心臓血管疾患、関節炎、皮膚ガン、糖尿病、月経前症候群および経皮送達の予防および／または治療のためのオキアミおよび／または海洋生物の抽出物 | |
| CN1109543C (zh) | 包括二十碳五烯酸和/或十八碳四烯酸的药物制剂 | |
| EP1912638B1 (en) | Composition of n-3 fatty acids having high concentration of epa and/or dha and containing n-6 fatty acids | |
| CN1756545A (zh) | ω－3－脂肪酸在治疗糖尿病患者中的应用 | |
| US4970076A (en) | Fatty acid composition | |
| JP2775627B2 (ja) | 治療用組成物 | |
| US8461141B2 (en) | Preventive or therapeutic drug for Alzheimer-type dementia | |
| JP2574153B2 (ja) | ガン治療用薬剤 | |
| EP0087865B1 (en) | Pharmaceutical composition | |
| US20040235948A1 (en) | Treatment of diabetic patients with omega-3-fatty acids | |
| JP5952556B2 (ja) | 褥瘡治療剤 | |
| AU2005244483B2 (en) | Essential fatty acids in the prevention and/or treatment of depression in patients with coronary heart or artery disease | |
| JPH01156922A (ja) | 悩疾患治療用薬剤の製造方法と治療用化合物 | |
| MXPA01008213A (en) | Essential fatty acids in the prevention of cardiovascular events |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CX01 | Expiry of patent term |
Granted publication date: 20051207 |
|
| CX01 | Expiry of patent term |