CN102149377A - 决奈达隆在制备用于预防中风或短暂性缺血发作的药物中的用途 - Google Patents
决奈达隆在制备用于预防中风或短暂性缺血发作的药物中的用途 Download PDFInfo
- Publication number
- CN102149377A CN102149377A CN200980135272XA CN200980135272A CN102149377A CN 102149377 A CN102149377 A CN 102149377A CN 200980135272X A CN200980135272X A CN 200980135272XA CN 200980135272 A CN200980135272 A CN 200980135272A CN 102149377 A CN102149377 A CN 102149377A
- Authority
- CN
- China
- Prior art keywords
- dronedarone
- patient
- purposes
- apoplexy
- prevention
- 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.)
- Pending
Links
- 229960002084 dronedarone Drugs 0.000 title claims abstract description 64
- ZQTNQVWKHCQYLQ-UHFFFAOYSA-N dronedarone Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 ZQTNQVWKHCQYLQ-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 208000032109 Transient ischaemic attack Diseases 0.000 title claims abstract description 31
- 201000010875 transient cerebral ischemia Diseases 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 title claims abstract description 29
- 230000002265 prevention Effects 0.000 title claims abstract description 28
- 208000006011 Stroke Diseases 0.000 claims description 90
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 66
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 60
- 206010003662 Atrial flutter Diseases 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 24
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 20
- 208000005189 Embolism Diseases 0.000 claims description 11
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 6
- 230000000747 cardiac effect Effects 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 206010056370 Congestive cardiomyopathy Diseases 0.000 claims description 4
- 208000025747 Rheumatic disease Diseases 0.000 claims description 4
- 238000013155 cardiography Methods 0.000 claims description 4
- 208000018578 heart valve disease Diseases 0.000 claims description 4
- 210000005246 left atrium Anatomy 0.000 claims description 4
- 230000009885 systemic effect Effects 0.000 claims description 4
- 230000002861 ventricular Effects 0.000 claims description 4
- 208000019622 heart disease Diseases 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 208000002330 Congenital Heart Defects Diseases 0.000 claims description 2
- 201000010046 Dilated cardiomyopathy Diseases 0.000 claims description 2
- 208000003734 Supraventricular Tachycardia Diseases 0.000 claims description 2
- 208000001871 Tachycardia Diseases 0.000 claims description 2
- 208000028831 congenital heart disease Diseases 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 claims description 2
- 230000000552 rheumatic effect Effects 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- 208000003663 ventricular fibrillation Diseases 0.000 claims description 2
- 230000033764 rhythmic process Effects 0.000 description 31
- 229940068196 placebo Drugs 0.000 description 15
- 239000000902 placebo Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 9
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical group [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 8
- 229960005260 amiodarone Drugs 0.000 description 8
- 230000002526 effect on cardiovascular system Effects 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 238000012545 processing Methods 0.000 description 8
- 230000003288 anthiarrhythmic effect Effects 0.000 description 7
- 239000003416 antiarrhythmic agent Substances 0.000 description 7
- 230000001709 ictal effect Effects 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- -1 hard or Gelseal Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 6
- 229960002370 sotalol Drugs 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 206010007559 Cardiac failure congestive Diseases 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 239000008119 colloidal silica Substances 0.000 description 4
- 238000011217 control strategy Methods 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000000302 ischemic effect Effects 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229960000502 poloxamer Drugs 0.000 description 4
- 229920001983 poloxamer Polymers 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 210000003437 trachea Anatomy 0.000 description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000002008 hemorrhagic effect Effects 0.000 description 3
- 229960001021 lactose monohydrate Drugs 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 230000002085 persistent effect Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 238000002679 ablation Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 235000021152 breakfast Nutrition 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 206010061592 cardiac fibrillation Diseases 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002600 fibrillogenic effect Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000002837 heart atrium Anatomy 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000759226 Homo sapiens Zinc finger protein 143 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 208000007542 Paresis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 102100023389 Zinc finger protein 143 Human genes 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000001466 anti-adreneric effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 238000013153 catheter ablation Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000008753 endothelial function Effects 0.000 description 1
- 230000007849 functional defect Effects 0.000 description 1
- 230000010247 heart contraction Effects 0.000 description 1
- 206010019465 hemiparesis Diseases 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000009251 neurologic dysfunction Effects 0.000 description 1
- 208000015015 neurological dysfunction Diseases 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- 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
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
Abstract
决奈达隆在制备用于预防中风或短暂性缺血发作的药物中的用途。
Description
本发明涉及决奈达隆(dronedarone)在制备用于预防中风(stroke)或短暂性缺血发作(transient ischemic attack)的药物中的用途。
2-正丁基-3-[4-(3-二-正丁基氨基丙氧基)苯甲酰基]-5-甲基磺酰胺基-苯并呋喃(2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamido-benzofuranne)或决奈达隆及其药学可接受盐记载于欧洲专利EP 0471609 B1。
决奈达隆是一种多通道阻断剂,影响钙、钾和钠通道,而且具有抗肾上腺素能特性。
决奈达隆是一种抗心律不齐药,用于治疗具有心房纤颤或心房扑动历史的患者。
心房纤颤(AF)在北美影响约230万人而在欧盟影响约450万人,而且由于人口的老龄化,正在引起越来越多的公共健康关注。
AF指如下的状况,其中心脏上部的房室以不协调且无组织的方式跳动,导致非常不规则且快速的心律(即不规则地,不规则的心跳)。当血液被不完全地泵出心脏的房室时,它会汇合并凝结。如果血液凝块在心房中形成,离开心脏并阻塞脑中的动脉,那么导致中风。因此,约15%的中风源自AF。但是中风也能并发其它疾患,像例如高血压。还有,出血性中风可以是为预防形成血栓而医嘱用抗凝血药治疗的并发症,特别是在AF患者中。
短暂性缺血发作(TIA)是由脑区血供的短暂紊乱引起的,导致通常持续不到1小时,有时长达24小时的短暂神经学功能障碍;如果症状持续更长时间,那么它归类为中风。
短暂性缺血发作常常被视为中风逼近的警告。约三分之一有短暂性缺血发作的患者会有复发性短暂性缺血发作,而另三分之一会有永久性神经细胞消亡所致中风。
短暂性缺血发作的最常见原因是阻塞脑中动脉的栓子(血块)。这可能来自两条颈动脉之一中的动脉粥样硬化斑块或来自心脏,例如在心房纤颤的情况中。
最常见症状包括暂时性黑矇(目盲);失语(难以交谈);轻偏瘫(身体一侧的虚弱);身体一侧的感觉异常(麻木)。
AF随着年龄增长而越来越频繁,而且常常由年龄相关的心脏变化、肉体或心理压力、刺激心脏的药剂诸如咖啡因、或作为心血管病的结果而引起。预期数目会在下一个20年里加倍。在没有适宜管理的情况下,AF会导致严重的并发症,诸如中风和充血性心力衰竭。
由于大多数研究没有评估与心房纤颤有关并发症诸如中风,所以不知道抗心律不齐药对这些终点的影响(Cochrane Collaboration,The Cochrane Library,2008,2)。
另外,在AF患者中进行的包括抗心律不齐药的两项大型研究,AFFIRM(D.G.Wyse and al.,The New England Journal of Medecine,2002,vol.347,p.1825-1833)和AF-CHF(D.Roy and al.,The New England Journal of Medecine,2008,vol.358,p.2667-2677),没有显示心率和心律组之间中风率显著差异(心律组中推荐的抗心律不齐药主要是胺碘达隆(amiodarone))。
血栓栓塞事件(包括中风)是心房纤颤患者中的主要并发症。尚未完全了解这些血栓栓塞事件的病因。根据主要假说,心房纤颤导致心房中的血郁,这促进血块形成并由此引起血栓栓塞事件像中风,如果血块到达体循环的话。因此,认为预防心房纤颤或抗凝会预防血栓栓塞事件和中风。多项临床研究证实了恰当的抗凝能预防血栓栓塞事件,包括中风(Fuster et al.)。但是,所有使用抗心律不齐药的随机化临床试验都没有显示中风发生率的降低,尽管在心律控制或治疗组中有效维持窦性心律。例如,在AFFIRM试验中,Wyse等人比较了心律控制(63%胺碘达隆和41%索他洛尔是最常用的抗心律不齐药)与心率控制策略。如Wyse等人的论文的表3所示,与心率控制组(77/2027)相比,心律控制组(80/2033)中的中风或TIA的发生率是相似的,尽管5年后与心率控制组(35%)相比,心律控制组(63%)中有更多数目的患者处于窦性心律。
在STAF试验中,Carlsson等人比较了心律控制(42%胺碘达隆)与心率控制策略。如Carlsson等人的论文的表2所示,与心率控制组(1/100)相比,心律控制组中的中风或TIA发生率在数字上更高(5/100),尽管研究结束时与心率控制组相比,心律控制组中具有窦性心律的患者有高度显著的29%绝度增多。
在HOT CAFE中,Opolski等人比较了心率和心律控制策略。如Opolski等人的论文的表2所示,与心率控制组中的0/101相比,心律控制组中的3/104名患者在随访期间患有中风。
在J-RHYTHM试验中,Ogawa等人比较了心律控制(85%的患者服用I类抗心律不齐药)与心率控制策略。如Ogawa等人的论文的表3所示,与心率控制组(11/404)相比,心律控制组(9/419)中有症状的中风的发生率是相似的,尽管3年时与心率控制组相比,心律控制组中具有窦性心律的患者有高度显著的29%绝对增多。
在SAFE-T试验中,Singh等人在有持续性心房纤颤的患者的治疗中比较了胺碘达隆、索他洛尔(sotalol)和安慰剂。胺碘达隆和索他洛尔都比安慰剂显著更有效地延长距心房纤颤复发的时间(心律控制的一项广泛使用的测量)(P<0.001)。在意图治疗(intention-to-treat)分析中,胺碘达隆的效率是索他洛尔的六倍(P<0.001),而在依照实际接受治疗的分析中是四倍(P<0.001)。尽管有这种有效的心律控制,所有组在随访中的每100患者-年的中风数是相似的,胺碘达隆为2.06major,索他洛尔为2.71,而安慰剂为1.91,其中在安慰剂组中观察到最低心率,其具有最高心房纤颤复发率(根据第1866页最后一段底部计算)。
因此,根据本领域当前知识,施用药物来预防心房纤颤不能视为暗示预防中风。出乎意料地,决奈达隆在ATHENA试验(Hohnloser et al.)中证明了它降低中风发生率的能力。现在用决奈达隆看到的效果不是基于单独的心律控制,而是基于决奈达隆的独特特性组合,其包括但不限于:有效的心律控制,心率降低效应,血压降低效应,对内皮功能的直接效应等等。
发明人现在已经在临床上证明决奈达隆降低中风的发生,而其它抗心律不齐化合物没有证明这一点。
本发明的主题是决奈达隆或其药学可接受盐之一在制备用于预防中风或短暂性缺血发作(特别是在有心房纤颤或心房扑动历史的患者中)的药物中的用途。
本发明的主题还是决奈达隆或其药学可接受盐之一在制备用于预防中风(特别是在有心房纤颤或心房扑动历史的患者中)的药物中的用途。
脑循环功能不全(其是认知功能缓慢退化的一种慢性病)不同,中风是具有脑血管原因的一种急性或亚急性进展的神经学缺陷,通过脑血管中的紊乱所致症状持续超过24小时来定义或通过症状快速消失的患者中急性临床有关脑损害的成像来定义。
这可能是由于由血栓形成或栓塞引起的缺血(缺少血供),或是由于出血(R.L.Sacco et al.,Stroke,2006;vol.37p.577-617)。
中风能引起永久性神经学损伤或死亡。它是美国和欧洲成人残疾的首要原因。
中风的风险因子包括高龄、高血压、先前的中风或短暂性缺血发作(TIA)、糖尿病、高胆固醇、吸烟、心房纤颤、等。高血压是中风最重要的可改变风险因子。
中风的症状与短暂性缺血发作的症状相似,但是持续超过24小时。
主要的中风有缺血性或出血性中风。缺血性中风是更常见的,而且在有些情况中能变成出血性中风。
在一个实施方案中,本发明涉及决奈达隆或其药学可接受盐之一在制备用于预防缺血性中风(特别是在有心房纤颤或心房扑动历史的患者中)的药物中的用途。
更准确地说,本发明涉及决奈达隆或其药学可接受盐之一在制备用于在有心房纤颤或心房扑动历史的患者中预防约35%的中风或短暂性缺血发作的药物中的用途。
更准确地说,本发明涉及决奈达隆或其药学可接受盐之一在制备用于在有心房纤颤或心房扑动历史的患者中预防约35%的中风的药物中的用途。
在另一个实施方案中,本发明涉及决奈达隆或其药学可接受盐之一在制备用于预防致命中风的药物中的用途。
致命中风定义为导致死亡的中风。
在另一个实施方案中,本发明涉及决奈达隆或其药学可接受盐之一在制备用于预防中风、急性冠状动脉综合征和死亡或心血管死亡的药物中的用途。
在另一个实施方案中,本发明涉及决奈达隆或其药学可接受盐之一在制备用于预防急性冠状动脉综合征(ACS)的药物中的用途。
中风、急性冠状动脉综合征和死亡或心血管死亡的复合终点是心血管结局试验中的一项经典结局测量,也称作MACE(主要不利心血管事件)终点。包括这项终点显示更宽的影响和发现与中风的相关性。
根据二者都是缺血事件的事实,ACS数据独自与中风有联系。
就临床研究而言,预防“中风、急性冠状动脉综合征和死亡或心血管死亡”构成称作复合标准或组合终点的。
上文的百分比对应于平均值。
在决奈达隆的药学可接受盐中,可提到盐酸盐。
所治疗的患者可以是有心房纤颤或心房扑动历史的患者。
表述“有心房纤颤或心房扑动历史”意味着患者先前表现过心房纤颤(AF)或心房扑动(AFL)的至少一种症状,而且在决奈达隆施用时可以处于窦性心律或处于心房纤颤或心房扑动。
还会规定,表述“有心房纤颤或心房扑动历史的患者”、“有心房纤颤或扑动历史或者有当前心房纤颤或扑动的患者”或“有心房纤颤或扑动最近历史或者有当前心房纤颤或扑动的患者”或“有发作性或持续性心房纤颤或扑动的患者”或“有发作性或持续性心房纤颤或扑动历史或者有当前发作性或持续性心房纤颤或扑动的患者”或“有发作性或持续性心房纤颤或扑动最近历史或者有当前发作性或持续性心房纤颤或扑动的患者”或“有发作性或间歇性心房纤颤或心房扑动和心房纤颤或心房扑动最近发作,处于窦性心律或会心脏复率的患者”或“有发作性或持续性心房纤颤或心房扑动和心房纤颤或心房扑动最近发作,处于窦性心律或会心脏复率的患者”意味着患者在过去呈现过一次或多次心房纤颤或扑动发作和/或在使用决奈达隆或其药学可接受盐时正在罹患心房纤颤或心房扑动。更具体地说,此表述意味着患者有开始治疗前的最后6个月内处于心房纤颤或扑动和窦性心律的记录。患者在启动决奈达隆或其药学可接受盐时可以处于窦性心律或处于心房纤颤或扑动。
还会规定,术语“持续性(persistent)”和“间歇性(intermittent)”是等同的。
处于“永久性心房纤颤或扑动”的患者指在施用决奈达隆或其药学可接受盐的整个期间所有预定ECG处于这种心律的患者。
在有心房纤颤或心房扑动最近历史或者有当前心房纤颤或心房扑动的患者中,可以提到有最近历史或者有当前非永久性心房纤颤或扑动的患者。
在本发明中,“心房纤颤”意味着心房纤颤和/或心房扑动。
在有心房纤颤或心房扑动历史的患者中,可以提到还有至少一项下述风险因子的患者:
-年龄值得注意地等于或超出70,或甚至超出75,
-高血压,
-糖尿病,
-在先脑血管意外或全身性栓塞,
-根据超声心动图显像,左心房直径大于或等于50mm,
-根据二维回波描记术,左心室射血分数小于40%。
在有心房纤颤或心房扑动历史的患者中,还可以提到有别的风险因子的患者,所述风险因子对应于至少一项下述疾病:
-高血压,
-结构性心脏病,
-心动过速,
-冠心病,
-非风湿性瓣膜心脏病,
-缺血性扩张型心肌病,
-AF/AFL消除(ablation)历史,例如导管消除(catheter ablation)或手术消除(surgical ablation),
-AF/AFL以外的室上性心动过速,
-心脏瓣膜手术历史,
-非缺血性扩张型心肌病,
-肥厚型心肌病,
-风湿性瓣膜心脏病,
-持续室性心动过速,
-先天性心脏病,
-AF/AFL以外原因的消除历史,例如导管消除,
-心室纤颤,
和/或至少一项选自下述的心脏装置:
-起搏器,
-植入式心复律器除颤器。
可以提到,充血性心力衰竭是结构性心脏病的一个亚组。
本发明的另一个目的是包含决奈达隆及其药学可接受盐之一作为活性要素(principle)的药物组合物。此药物组合物包含有效剂量的至少一种依照本发明的式(I)化合物、或其加成盐及其药学可接受盐、或其水合物或溶剂合物,及至少一种药学可接受赋形剂。所述赋形剂是依照想要的施用路径和药物形式在本领域技术人员知道的常规赋形剂中选择的。
在用于口服、舌下、皮下、肌肉内、静脉内、表面、局部、气管内、鼻内、经皮或直肠施用的依照本发明的药物组合物中,决奈达隆或其盐、溶剂合物或水合物之一可作为单式剂量形式(unitary dosage form)、与常规药学赋形剂混合,为预防或治疗上文所述病理状态而施用于动物和人类。适宜的单式剂量形式包括口服形式,诸如片剂、硬或软明胶胶囊剂、粉剂、颗粒剂和口服溶液或悬浮液、舌下、含服、气管内、眼内、鼻内形式,适应吸入、表面、经皮、皮下、肌肉内或静脉内投递的形式,直肠形式和植入物。对于表面应用,本发明的化合物可作为霜剂、凝胶剂、软膏剂或洗剂使用。
为了它的治疗用途,将决奈达隆及其药学可接受盐掺入药物组合物。
这些药物组合物含有有效剂量的至少决奈达隆或其药学可接受盐之一,及至少一种药学可接受赋形剂。
所述赋形剂是依照想要的施用路径和药物形式在本领域技术人员知道的常规赋形剂中选择的。
在用于口服、舌下、皮下、肌肉内、静脉内、表面、局部、气管内、鼻内、经皮或直肠施用的药物组合物中,决奈达隆或其药学可接受盐之一可作为单式剂量形式、与常规药学赋形剂混合而施用于处于上文所述疾病的动物和人类。
适宜的单式剂量形式包括口服形式,诸如片剂、硬或软明胶胶囊剂、粉剂、颗粒剂和口服溶液或悬浮液、舌下、含服、气管内、眼内、鼻内形式,通过吸入、表面、经皮、皮下、肌肉内或静脉内形式,直肠形式和植入物。对于表面应用,本发明的化合物可作为霜剂、凝胶剂、软膏剂或洗剂使用。
作为一个例子,决奈达隆或其药学可接受盐之一的片剂形式的单式剂量形式可包含下述组分:
组分 | mg |
决奈达隆盐酸盐(对应于400mg基药) | 426 |
甲羟丙基纤维素 | 21,1 |
乳糖单水合物 | 46,55 |
改性玉米淀粉 | 45,5 |
聚乙烯比咯烷酮 | 65 |
Poloxamer 407 | 40 |
无水胶体二氧化硅 | 2,6 |
硬脂酸镁 | 3,25 |
650 |
组分 | mg |
决奈达隆盐酸盐(对应于400mg基药) | 426 |
微晶纤维素 | 65 |
无水胶体二氧化硅 | 2,6 |
无水乳糖 | 42,65 |
聚乙烯比咯烷酮 | 13 |
Poloxamer 407 | 40 |
Macrogol 6000 | 57,5 |
硬脂酸镁 | 3,25 |
650 |
组分 | mg |
决奈达隆盐酸盐(对应于400mg基药) | 426 |
微晶纤维素 | 26 |
玉米淀粉 | 45,5 |
聚乙烯比咯烷酮 | 65 |
Poloxamer 407 | 40 |
无水胶体二氧化硅 | 3,25 |
硬脂酸镁 | 3,25 |
乳糖单水合物 | 41,65 |
650 |
组分 | mg |
决奈达隆盐酸盐(对应于400mg基药) | 213 |
微晶纤维素 | 13 |
玉米淀粉 | 22,75 |
聚乙烯比咯烷酮 | 32,5 |
Poloxamer 407 | 20 |
无水胶体二氧化硅 | 1,3 |
硬脂酸镁 | 1,625 |
乳糖单水合物 | 20,825 |
650 |
所述药物组合物可以与食物一起每天给予一次或两次。
每天口服施用的决奈达隆剂量可达到800mg,以一次或多次(例如一次或两次)摄入来服用。
更具体地说,施用的决奈达隆剂量可以与食物一起服用。
更具体地说,每天口服施用的决奈达隆剂量可达到800mg,与进餐一起以两次摄入来服用。
每天口服施用的决奈达隆剂量可以与进餐一起以每天两次的速率来服用,例如与早餐和晚餐一起。
更具体地说,两次摄入可包含相同量的决奈达隆。
在具体的案例中,更高或更低的剂量可能是合适的;这些剂量包含在本发明的范围内。依照常规实践,适合于每位患者的剂量是由内科医师根据患者的施用路径、体重、疾病、体表、心排血量和响应确定的。
本发明还涉及一种预防中风的方法,其包括对患者施用有效剂量的至少决奈达隆或其药学可接受盐之一。
本发明以上文数据例示并参照下述附图:
图1呈现依照30个月的治疗中分析(on-treatment analysis)距第一次中风或TIA的时间的Kaplan Meier累积发生率曲线。
图2呈现依照30个月的治疗中分析距第一次中风的时间的Kaplan Meier累积发生率曲线。
与安慰剂相比,决奈达隆及其药学可接受盐用于预防中风的功效是由一项前瞻性、多国、双盲、随机化、多中心、以安慰剂为对照、平行组试验期间经决奈达隆盐酸盐提供的。
I.患者的选择
符合条件的患者有心房纤颤或心房扑动历史和/或可以在募集时处于正常窦性心律或处于心房纤颤或扑动。
患者的募集在进行时考虑了下述选择标准:
选择标准:
1)必须存在下述风险因子之一:
-年龄等于或大于70岁,
-高血压(服用至少两种不同类别的抗高血压药),
-糖尿病,
-脑中风(cerebral stroke)(瞬时缺血事件或完全脑中风(completed cerebral stroke))或全身性栓塞历史,
-根据超声心动图显像的测量,左心房直径大于或等于50mm,
-根据二维回波描记术的测量,左心室射血分数小于40%;
或
-年龄等于或超出70,或甚至超出75,可能与至少一项下述风险因子组合:
○高血压(服用至少两种不同类别的抗高血压药),
○糖尿病,
○脑中风(瞬时缺血事件或完全脑中风)或全身性栓塞历史,
○根据超声心动图显像的测量,左心房直径大于或等于50mm,
○根据二维回波描记术的测量,左心室射血分数小于40%;
2)可得到最近六个月内的一张心电图,显示患者曾经或现在处于心房纤颤/扑动,
3)可得到最近六个月内的一张心电图,显示患者曾经或现在处于窦性心律。
II.持续时间和处理
研究药物处理单位(安慰剂或决奈达隆盐酸盐,对应于400mg基药)是这样的,每位患者在上午在早餐期间或之后不久服用一片药,并在晚上在晚餐期间或之后不久服用一片药。
处理持续时间取决于试验中每位患者的募集时间,而且可以由12个月至30个月构成。
III.结果
使用非参数Kaplan-Meier估值计算结果。
使用Cox氏比例风险模型来估算危害比,也称作相对危险度。
相对风险度(RR)指用决奈达隆处理的患者具有中风(或短暂性缺血发作(TIA))的风险与用安慰剂处理的患者具有中风(或短暂性缺血发作(TIA))的风险之间的比。
如下计算事件降低百分比:
x=1-RR。
涉及预防中风或短暂性缺血发作(TIA)的结果
在试验中所包括的4628名患者中,2301人是用决奈达隆盐酸盐处理的组的一部分。
在安慰剂组中报告了80例中风或TIA事件,而在用决奈达隆盐酸盐处理的组中报告了52例中风或TIA事件。
计算相对风险度等于0.65,即中风或TIA的相对风险降低35%。
图1显示了决奈达隆的效果在早期发生,而且随时间增强。
涉及预防中风的结果
在试验中所包括的4628名患者中,2301人是用决奈达隆盐酸盐处理的组的一部分。
在安慰剂组中报告了70例中风事件,而在用决奈达隆盐酸盐处理的组中报告了45例中风事件。
计算相对风险度等于0.65,即中风的相对风险降低35%。
图2显示了决奈达隆的效果在早期发生,而且随时间增强。
涉及预防缺血性中风的结果
在试验中所包括的4628名患者中,2301人是用决奈达隆盐酸盐处理的组的一部分。
在安慰剂组中报告了49例中风事件,而在用决奈达隆盐酸盐处理的组中报告了33例中风事件。
计算相对风险度等于0.68,即缺血性中风的相对风险降低32%。
涉及预防致命中风的结果
在试验中所包括的4628名患者中,2301人是用决奈达隆盐酸盐处理的组的一部分。
在安慰剂组中报告了18例致命中风事件,而在用决奈达隆盐酸盐处理的组中报告了11例致命中风事件。
计算相对风险度等于0.62,即致命中风的相对风险降低38%。
涉及预防中风、急性冠状动脉综合征(ACS)或死亡的结果
在试验中所包括的4628名患者中,2301人是用决奈达隆盐酸盐处理的组的一部分。
在安慰剂组中报告了262例事件,而在用决奈达隆盐酸盐处理的组中报告了196例事件。
计算相对风险度等于0.68,即中风、急性冠状动脉综合征(ACS)或死亡的相对风险降低25%。
涉及预防中风、急性冠状动脉综合征(ACS)或心血管死亡的结果
在试验中所包括的4628名患者中,2301人是用决奈达隆盐酸盐处理的组的一部分。
在安慰剂组中报告了216例事件,而在用决奈达隆盐酸盐处理的组中报告了147例事件。
计算相对风险度等于0.68,即中风、急性冠状动脉综合征(ACS)或心血管死亡的相对风险降低32%。
涉及预防因急性冠状动脉综合征(ACS)而入心血管病房的结果
在试验中所包括的4628名患者中,2301人是用决奈达隆盐酸盐处理的组的一部分。
在安慰剂组中报告了89例ACS事件,而在用决奈达隆盐酸盐处理的组中报告了62例ACS事件。
计算相对风险度等于0.70,即因急性冠状动脉综合征而入心血管病房的相对风险降低30%。
涉及为有别的风险因子(诸如CHADS2得分、CHF、高血压、年龄、糖尿病、
先前中风或TIA)的患者预防中风的结果
CHADS2得分通过给充血性心力衰竭、高血压、年龄75岁或更老、和糖尿病的存在各赋值1点及通过给中风或TIA历史赋值2点来计算,所述CHADS2得分表征AF患者中的中风风险。CHADS2得分越高,则中风风险越高。Gage BF1 van Walraven C,Pearce L,Hart RG,Koudstaal PJ,Boode BS,Petersen P.Selecting patients with atrial fibrillation for anticoagulation:stroke risk stratification in patients taking aspirin.Circulation 2004;110:2287-92。
Claims (10)
1.决奈达隆在制备用于预防中风或短暂性缺血发作的药物中的用途。
2.依照权利要求1的在制备用于预防中风的药物中的用途。
3.依照权利要求1的在制备用于预防约35%的中风的药物中的用途。
4.依照权利要求1的在制备用于预防急性冠状动脉综合征的药物中的用途。
5.依照权利要求1的在制备用于预防致命中风的药物中的用途。
6.依照权利要求1至5任一项的用途,其中所述预防提供给有心房纤颤或心房扑动历史或当前心房纤颤或心房扑动的患者。
7.依照前述权利要求任一项的用途,其特征在于患者有至少一项下述风险因子:
-年龄,
-高血压,
-糖尿病,
-在先脑血管意外或全身性栓塞,
-根据超声心动图显像,左心房直径大于或等于50mm,
-根据二维超声心动图显像,左心室射血分数小于40%。
8.依照前述权利要求任一项的用途,其特征在于患者有别的风险因子,其对应于至少一项下述疾病:
-高血压,
-结构性心脏病,
-心动过速,
-冠心病,
-非风湿性瓣膜心脏病,
-缺血性扩张型心肌病,
-AF/AFL消除,
-AF/AFL以外的室上性心动过速,
-心脏瓣膜手术历史,
-非缺血性扩张型心肌病,
-肥厚型心肌病,
-风湿性瓣膜心脏病,
-持续室性心动过速,
-先天性心脏病,
-AF/AFL以外原因的消除,
-心室纤颤,
-和/或至少一项选自下述的心脏装置:
-起搏器,
-植入式心复律器除颤器。
9.依照前述权利要求任一项的用途,其特征在于决奈达隆用于口服施用时的日剂量可达到800mg。
10.预防中风的方法,其包括给患者施用有效剂量的至少决奈达隆或其药学可接受盐之一。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08290761A EP2153830A1 (en) | 2008-08-07 | 2008-08-07 | Use of dronedarone for the preparation of a medicament intended for the prevention of stroke or transient ischemic attack |
EP08290761.9 | 2008-08-07 | ||
US8780308P | 2008-08-11 | 2008-08-11 | |
US61/087,803 | 2008-08-11 | ||
PCT/IB2009/006831 WO2010015939A1 (en) | 2008-08-07 | 2009-08-03 | Use of dronedarone for the preparation of a medicament for the prevention of stroke or transient ischemic attack |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102149377A true CN102149377A (zh) | 2011-08-10 |
Family
ID=40149599
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200980135272XA Pending CN102149377A (zh) | 2008-08-07 | 2009-08-03 | 决奈达隆在制备用于预防中风或短暂性缺血发作的药物中的用途 |
Country Status (24)
Country | Link |
---|---|
US (1) | US20110230552A1 (zh) |
EP (2) | EP2153830A1 (zh) |
JP (1) | JP2011529958A (zh) |
KR (1) | KR20110042344A (zh) |
CN (1) | CN102149377A (zh) |
AR (1) | AR073265A1 (zh) |
AU (1) | AU2009278864A1 (zh) |
BR (1) | BRPI0917569A2 (zh) |
CA (1) | CA2733149A1 (zh) |
CL (1) | CL2011000268A1 (zh) |
CO (1) | CO6351721A2 (zh) |
CR (1) | CR20110061A (zh) |
DO (1) | DOP2011000043A (zh) |
EA (1) | EA201170301A1 (zh) |
EC (1) | ECSP11010811A (zh) |
IL (1) | IL211098A0 (zh) |
MA (1) | MA32602B1 (zh) |
MX (1) | MX2011001461A (zh) |
NI (1) | NI201100034A (zh) |
PE (1) | PE20110706A1 (zh) |
SV (1) | SV2011003827A (zh) |
TW (1) | TW201010695A (zh) |
UY (1) | UY32040A (zh) |
WO (1) | WO2010015939A1 (zh) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2280701A2 (en) * | 2008-04-17 | 2011-02-09 | Sanofi-Aventis | Use of dronedarone for the preparation of a medicament for use in the prevention of cardiovascular hospitalization or of mortality |
FR2930149B1 (fr) * | 2008-04-17 | 2011-02-18 | Sanofi Aventis | Association de dronedarone avec au moins un diuretique, son application en therapeutique |
EP2116239A1 (en) * | 2008-04-29 | 2009-11-11 | Sanofi-Aventis | Method for managing the risks associated with an increase in serum creatinine during dronedarone treatment |
EP2387996A1 (en) * | 2010-05-17 | 2011-11-23 | Sanofi | Use of dronedarone for the preparation of a medicament for the prevention of cardiovascular events in patients with permanent atrial fibrillation |
TW201200131A (en) * | 2010-05-13 | 2012-01-01 | Sanofi Aventis | Use of dronedarone for the preparation of a medicament for the prevention of cardiovacular hospitalizations or death or cardiovascular events in patients with premanent atrial fibrillation |
EP2387997A1 (en) * | 2010-05-18 | 2011-11-23 | Sanofi | Use of dronedarone for the preparation of a medicament for the prevention of cardiovascular events in patients who developed permanent atrial fibrillation throughout the period the dronedarone is administered |
US8602215B2 (en) | 2010-06-30 | 2013-12-10 | Sanofi | Methods for reducing the risk of an adverse dronedarone/beta-blockers interaction in a patient suffering from atrial fibrillation |
WO2013024411A1 (en) | 2011-08-12 | 2013-02-21 | Lupin Limited | Co-milled formulation of dronedarone |
US10603316B2 (en) * | 2013-08-21 | 2020-03-31 | Morehouse School Of Medicine | Composition and methods for preventing or reducing the incidence of transient ischemic attacks |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9009389D0 (en) * | 1990-04-26 | 1990-06-20 | Smith Kline French Lab | Treatment |
FR2665444B1 (fr) | 1990-08-06 | 1992-11-27 | Sanofi Sa | Derives d'amino-benzofuranne, benzothiophene ou indole, leur procede de preparation ainsi que les compositions les contenant. |
-
2008
- 2008-08-07 EP EP08290761A patent/EP2153830A1/en not_active Withdrawn
-
2009
- 2009-08-03 EP EP09786247A patent/EP2326324A1/en not_active Withdrawn
- 2009-08-03 WO PCT/IB2009/006831 patent/WO2010015939A1/en active Application Filing
- 2009-08-03 KR KR1020117005222A patent/KR20110042344A/ko not_active Application Discontinuation
- 2009-08-03 AU AU2009278864A patent/AU2009278864A1/en not_active Abandoned
- 2009-08-03 JP JP2011521656A patent/JP2011529958A/ja not_active Withdrawn
- 2009-08-03 EA EA201170301A patent/EA201170301A1/ru unknown
- 2009-08-03 CN CN200980135272XA patent/CN102149377A/zh active Pending
- 2009-08-03 BR BRPI0917569A patent/BRPI0917569A2/pt not_active IP Right Cessation
- 2009-08-03 MX MX2011001461A patent/MX2011001461A/es not_active Application Discontinuation
- 2009-08-03 CA CA2733149A patent/CA2733149A1/en not_active Abandoned
- 2009-08-03 PE PE2011000135A patent/PE20110706A1/es not_active Application Discontinuation
- 2009-08-06 TW TW098126633A patent/TW201010695A/zh unknown
- 2009-08-06 AR ARP090103009A patent/AR073265A1/es unknown
- 2009-08-07 UY UY0001032040A patent/UY32040A/es not_active Application Discontinuation
-
2011
- 2011-02-02 CR CR20110061A patent/CR20110061A/es not_active Application Discontinuation
- 2011-02-03 DO DO2011000043A patent/DOP2011000043A/es unknown
- 2011-02-04 EC EC2011010811A patent/ECSP11010811A/es unknown
- 2011-02-04 US US13/020,889 patent/US20110230552A1/en not_active Abandoned
- 2011-02-04 SV SV2011003827A patent/SV2011003827A/es unknown
- 2011-02-06 IL IL211098A patent/IL211098A0/en unknown
- 2011-02-07 CO CO11013463A patent/CO6351721A2/es not_active Application Discontinuation
- 2011-02-07 NI NI201100034A patent/NI201100034A/es unknown
- 2011-02-07 CL CL2011000268A patent/CL2011000268A1/es unknown
- 2011-03-01 MA MA33659A patent/MA32602B1/fr unknown
Also Published As
Publication number | Publication date |
---|---|
NI201100034A (es) | 2011-10-20 |
PE20110706A1 (es) | 2011-10-11 |
US20110230552A1 (en) | 2011-09-22 |
AR073265A1 (es) | 2010-10-28 |
JP2011529958A (ja) | 2011-12-15 |
UY32040A (es) | 2010-03-26 |
MA32602B1 (fr) | 2011-09-01 |
TW201010695A (en) | 2010-03-16 |
IL211098A0 (en) | 2011-04-28 |
CL2011000268A1 (es) | 2011-07-29 |
WO2010015939A1 (en) | 2010-02-11 |
ECSP11010811A (es) | 2011-03-31 |
SV2011003827A (es) | 2011-04-29 |
EP2153830A1 (en) | 2010-02-17 |
CO6351721A2 (es) | 2011-12-20 |
MX2011001461A (es) | 2011-03-29 |
BRPI0917569A2 (pt) | 2019-09-24 |
EA201170301A1 (ru) | 2012-01-30 |
CA2733149A1 (en) | 2010-02-11 |
AU2009278864A1 (en) | 2010-02-11 |
EP2326324A1 (en) | 2011-06-01 |
KR20110042344A (ko) | 2011-04-26 |
DOP2011000043A (es) | 2011-03-15 |
CR20110061A (es) | 2011-04-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102149377A (zh) | 决奈达隆在制备用于预防中风或短暂性缺血发作的药物中的用途 | |
CN102056603A (zh) | 决奈达隆用于预防持续性心房纤颤 | |
JP7525868B2 (ja) | アルカリ性化剤による血液浄化 | |
CA2564025A1 (en) | A method for the treatment or prevention of cardiac hypertrophy | |
RU2760304C2 (ru) | Фармацевтические составы с отсроченным высвобождением, содержащие вальпроевую кислоту, и их применение | |
JP2013544870A (ja) | 肝障害のリスク管理に使用する薬剤の調製のためのドロネダロンの使用 | |
US10596151B2 (en) | Methods and pharmaceutical compositions for reducing arterial stiffness with a combination of a therapeutic agent blocking the angiotensin receptor and a therapeutic agent inhibiting the NEP enzyme | |
JP2001089382A (ja) | 早期血管再生及び低分子量ヘパリン投与による不安定冠動脈疾患の治療方法 | |
US20240277670A1 (en) | Safe use of mmp-12 inhibitor | |
JP2020520938A (ja) | Dglaを含む薬学的組成物およびその使用 | |
JP2005531492A (ja) | 高リスク患者のii型糖尿病を低減させる方法 | |
TW201206423A (en) | Use of dronedarone for the preparation of a medicament for use in the prevention of cardiovascular hospitalization or of mortality in patients having a first recurrence of atrial fibrillation or atrial flutter | |
JP2004339218A (ja) | 有機化合物の使用 | |
Munger et al. | Invasive pharmacodynamic characterization of combined ibopamine and calcium blocker therapy for heart failure | |
EP2387997A1 (en) | Use of dronedarone for the preparation of a medicament for the prevention of cardiovascular events in patients who developed permanent atrial fibrillation throughout the period the dronedarone is administered | |
KR20220168172A (ko) | 1-(3-시아노-1-아이소프로필-인돌-5-일)피라졸-4-카르복실산을 포함하는 약학적 조성물 | |
EP2387996A1 (en) | Use of dronedarone for the preparation of a medicament for the prevention of cardiovascular events in patients with permanent atrial fibrillation | |
WO2023200738A1 (en) | Combination treatment of dilated cardiomyopathy comprising a tyrosine kinase inhibitor and a statin | |
Komatsu et al. | Long-term efficacy of combination therapy with anti-arrhythmic agents and pravastatin in patients with paroxysmal atrial fibrillation | |
TWI462923B (zh) | Kmup-3之心肌梗塞疾患用途 | |
UA146879U (uk) | Фармацевтична композиція | |
UA146876U (uk) | Фармацевтична композиція | |
TW201200131A (en) | Use of dronedarone for the preparation of a medicament for the prevention of cardiovacular hospitalizations or death or cardiovascular events in patients with premanent atrial fibrillation | |
Nikolaeva et al. | Results of the Cardiological Study Invest: A New Word in the Therapy of Patients with Hypertension | |
KR20090042976A (ko) | 글루코즈 수준을 저하시키는 방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1158984 Country of ref document: HK |
|
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110810 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1158984 Country of ref document: HK |