TW201010695A - Use of dronedarone for the preparation of a medicament for the prevention of stroke or transient ischemic attack - Google Patents
Use of dronedarone for the preparation of a medicament for the prevention of stroke or transient ischemic attack Download PDFInfo
- Publication number
- TW201010695A TW201010695A TW098126633A TW98126633A TW201010695A TW 201010695 A TW201010695 A TW 201010695A TW 098126633 A TW098126633 A TW 098126633A TW 98126633 A TW98126633 A TW 98126633A TW 201010695 A TW201010695 A TW 201010695A
- Authority
- TW
- Taiwan
- Prior art keywords
- stroke
- dronedarone
- medicament
- patients
- atrial
- Prior art date
Links
- 229960002084 dronedarone Drugs 0.000 title claims abstract description 42
- 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 42
- 239000003814 drug Substances 0.000 title claims abstract description 22
- 230000002265 prevention Effects 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 201000010875 transient cerebral ischemia Diseases 0.000 title abstract description 10
- 208000032109 Transient ischaemic attack Diseases 0.000 title abstract 2
- 208000006011 Stroke Diseases 0.000 claims description 79
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 47
- 206010003662 Atrial flutter Diseases 0.000 claims description 33
- 230000033764 rhythmic process Effects 0.000 claims description 31
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 19
- 230000001746 atrial effect Effects 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 230000000747 cardiac effect Effects 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000005189 Embolism Diseases 0.000 claims description 9
- 230000000302 ischemic effect Effects 0.000 claims description 9
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 230000036772 blood pressure Effects 0.000 claims description 5
- 238000002604 ultrasonography Methods 0.000 claims description 5
- 208000025747 Rheumatic disease Diseases 0.000 claims description 4
- 208000019622 heart disease Diseases 0.000 claims description 4
- 208000018578 heart valve disease Diseases 0.000 claims description 4
- 230000002861 ventricular Effects 0.000 claims description 4
- 206010056370 Congestive cardiomyopathy Diseases 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 231100000518 lethal Toxicity 0.000 claims description 3
- 230000001665 lethal effect Effects 0.000 claims description 3
- 230000000552 rheumatic effect Effects 0.000 claims description 3
- 230000009885 systemic effect Effects 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
- 208000028831 congenital heart disease Diseases 0.000 claims description 2
- 210000003709 heart valve Anatomy 0.000 claims description 2
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 claims description 2
- 230000002085 persistent 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
- 206010047302 ventricular tachycardia Diseases 0.000 claims description 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims 1
- 206010008190 Cerebrovascular accident Diseases 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 150000003839 salts Chemical class 0.000 description 21
- CPKOXUVSOOKUDA-UHFFFAOYSA-N 1-bromo-5-fluoro-2-iodo-4-methylbenzene Chemical compound CC1=CC(I)=C(Br)C=C1F CPKOXUVSOOKUDA-UHFFFAOYSA-N 0.000 description 16
- 229960002919 dronedarone hydrochloride Drugs 0.000 description 16
- 229940068196 placebo Drugs 0.000 description 14
- 239000000902 placebo Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 208000024172 Cardiovascular disease Diseases 0.000 description 8
- 239000003416 antiarrhythmic agent Substances 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
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 208000007536 Thrombosis Diseases 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 239000002552 dosage form Substances 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
- 230000000699 topical effect Effects 0.000 description 6
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [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 5
- 206010007559 Cardiac failure congestive Diseases 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229960005260 amiodarone Drugs 0.000 description 5
- 230000002490 cerebral effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 208000032382 Ischaemic stroke Diseases 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 230000035807 sensation Effects 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001732 thrombotic effect Effects 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
- 229920002261 Corn starch Polymers 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910000420 cerium oxide Inorganic materials 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 230000007812 deficiency 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
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- -1 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoinyl]-5-methanesulfonylaminobenzoate Furan Chemical compound 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000002429 anti-coagulating effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 210000001367 artery Anatomy 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
- 206010008118 cerebral infarction Diseases 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000010586 diagram Methods 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
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 208000014001 urinary system disease Diseases 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000208340 Araliaceae Species 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
- 208000017667 Chronic Disease Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 240000003473 Grevillea banksii Species 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000759226 Homo sapiens Zinc finger protein 143 Proteins 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
- 235000009421 Myristica fragrans Nutrition 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 208000007542 Paresis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 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
- 208000001871 Tachycardia Diseases 0.000 description 1
- 208000026723 Urinary tract disease Diseases 0.000 description 1
- 208000012931 Urologic disease Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 102100023389 Zinc finger protein 143 Human genes 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 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
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 208000029028 brain injury Diseases 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
- 239000002775 capsule Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008753 endothelial function Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 206010019465 hemiparesis Diseases 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- WLHQHAUOOXYABV-UHFFFAOYSA-N lornoxicam Chemical compound OC=1C=2SC(Cl)=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 WLHQHAUOOXYABV-UHFFFAOYSA-N 0.000 description 1
- 239000001115 mace Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000009251 neurologic dysfunction Effects 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 208000015015 neurological dysfunction Diseases 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 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
- 239000002243 precursor Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (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)
Description
201010695 六、發明說明: 【發明所屬之技術領域】 本發明係關於一種決奈達隆(DRONEDARONE)於製備用 於預防中風或暫時性腦缺血之藥劑之用途。 在歐洲專利第047160981號中有閣述2-正丁基_3-[4-(3-二-正丁基胺基丙氧基)苯曱醯基]_5_甲磺醯胺基·苯并呋喃 或決奈達隆及其醫藥上可接受鹽。 【先前技術】 ® 決奈達隆係一種可影響鈣、鉀以及鈉通道之多通道阻斷 劑’並具有抗腎上腺素的特性。 • 決奈達隆係一種抗心律不整藥劑,其用於治療具有心房 顫動或心房撲動病史的患者。 心房顫動(AF)在北美洲影響約230萬人口,並在歐盟中 影響著45〇萬人口,並且由於人口結構老化,而逐漸成為 公共健康關注話題。 φ AF係一種心臟上心室以不協調且紊亂的方式跳動之疾 病,其造成非常的不規則且過快的節律(例如不規則的心 律失常)。當血液沒有完全泵出心室時,其將鬱滞並凝結 成塊。如果血凝塊形成於心房中,流出心臟並且在大腦中 阻斷動脈,則造成中風。因此,約丨5%的中風的產生係由 AF引起。但中風亦可使其他疾病複雜化(例如高血壓)。腦 溢企中風亦可為一種因處方使用抗凝血劑治療以預防血栓 症(特別係有AF患者)之併發症。 暫時性腦缺血(TIA)係由大腦某一區域暫時性供血障礙 141672.doc 201010695 、^成短暫性神經功能障礙,其通常持續時間為一小 =乂内彳時達到24小時,如果症狀持續更長的時間則將 其歸類為中風。 暫時性腦缺血經常被認為係接近中風的前兆。大約三分 之出現暫時性腦缺金的患者會復發暫時性腦缺血(TIA) 另一刀之的中風係由永久性神經細胞喪失引起。 最常見的暫時性腦缺血原因為血栓(血凝塊)在大腦中堵 塞動脈。其可來源於兩大頸動脈之—中的動脈粥樣硬化斑 塊或來自心臟例如當發生心房顫動時。 最常見的症狀包括暫時性黑朦(失明)、失語(發音障 礙)、輕偏癱(身體的半邊虛弱)、身體半邊感覺異常(麻 木)。 AF的發生頻率隨著年齡的增長而增加,並且其經常由 心臟與年齡相關的變化、生理或心理壓力、刺激心臟的藥 劑(例如咖啡因)引起或者由心血管疾病引起。預期在接下 來的二十年裏該數目將倍增。如果沒有適當的處理,AF可 導致嚴重的併發症,例如中風及充血性心力衰竭。 由於大β卩伤研究並沒有評估與心房顏動相關聯的併發 症,如:中風,因此抗心律不整藥劑在該等終點上的效果 係未知(科克倫協作網路’科克倫知識庫(c〇chrane
Collaboration,The Cochrane Library),2008 2) 〇 此外,包括AF患者之抗心律不整藥劑之兩大研究, AFFIRM(D.G. Wyse等人,新英格蘭醫學雜誌(The New England Journal of Medicine),2002,第 347卷,^ 1825- 141672.doc 201010695 1833頁)與AF-CHF (D. Roy等人,新英格蘭醫學雜誌(The New England Journal of Medicine),2008,第 358 卷, 2667-2677頁),在心跳速率組與心跳節律組之間罹患中風 比例沒有顯示出顯著的差異(在節律組中建議使用的抗心 律不整藥劑主要為胺埃酮(amiodarone))。 在心房顫動患者中血栓性栓塞病例(包括中風)為主要併 發症。該等血栓性栓塞病例的病因學並沒有被完全瞭解。 根據主要假設心房顫動導致心房中血液淤滯,其促進血凝 塊形成,並引起血栓性栓塞病例(如果血凝塊到達體循環 會引起中風)。因此認為心房顫動的預防或抗凝血作用可 預防血栓性栓塞病例及中風的發生。大量臨床研究已經證 實適當的抗凝血作用可預防血栓性栓塞病例(包括中 風)(Fuster等人)。然而,儘管在節律控制或處理組有效地 維持竇性心律,使用抗心律不整藥劑之所有的隨機化臨床 試驗顯示中風的發生率並未減少。 g 例如,在AFFIRM試驗中,Wyse等人比較節律控制法 (63%胺碘酮與41%索他洛爾(sotalol)為最常用於抗心律不 整藥劑)與心跳速率控制法。如Wyse等人所著文章之表3所 示,當比較節律控制組(80/2033)與心跳速率控制組 (77/2027)時,其中風發生率或TIA近似,儘管5年後之節律 控制組(63%)比心跳速率控制組(35%)之竇性心律患者數量 更多。 在STAF試驗中,Carlsson等人比較節律控制法(42%胺碘 酮)與心跳速率控制法。如Carlsson等人所著文章之表2所 141672.doc 201010695 示,節律控制組(5/100)之中風發生率或TIA在數量上高於 心跳速率控制組(1A00),儘管在本研究結束時,節律=制 組之竇性心律患者比心跳速率控制組顯著地絕對增加 29% 〇 9 在HOT CAF6試驗中’ 〇p〇lski等人比較心跳速率控制法 與節律控制法。如Opolski等人所著文章之表2所示在節 律控制組追蹤罹患中風之患者為3/1〇4,相較於心跳速率 控制組之0/101。 在J-RHYTHM試驗+,〇gawa等人比較節律控制法⑻% 的患者接受第I類抗心律不整藥劑)與心跳速率控制法。如 〇g:wa等人所著文章之表3所示’心跳速率控制組⑴/4〇句 與節律控制組(9/419)之中風症狀發生率近似 制組在3年内羅患寶性心律之比例比心跳速率控 顯著地絕對增加29%。 在SAFEM驗中,如的等人在持續性心房顫動患者的 治療中比較胺碘酮、索他洛爾及安慰劑。在將時間延長至 心房顏動的復發時間(係—種廣泛用於測定節律控制之方 法),胺蛾酮與索他洛爾均比安慰劑顯著有效(ρ<〇 〇〇ι)。 在治療意願分析中’胺碘酮的效果係索他洛爾的六倍 (P<0·001)’並且在根據實際接受治療的分析中,胺峨明的 效果係索他洛爾的四倍(p<〇〇〇1)。儘管有該有效節律控 制,但在後續數年每_個患者中中風患者的數量在所: 2群中均近似,胺破網:2〇6(嚴重)、索他洛爾:2取 女慰劑· 1.91,其在安慰劑組觀察到最低心跳速率,但心 141672.doc 201010695 房顫動復發率最高(由第祕頁的上—段、落的頁腳計算)。 因此,根據相關技藝的最新認知,投與預防心房顫動之 藥劑並無法預防中風。出乎意料地,已經在a··試驗 (H〇hnl°ser等人)中有闡述,決奈達隆能夠減少中風的發生 率。目前所見的決奈達隆的效果不僅基於控制節律,而且 基於決奈達隆的特性之獨特组人 词竹.、豆σ,其包括(但不限制)有效 節律控制、減慢心率的效果、降低也壓的效果、直接影響 内皮功能的效果及其他效果。 本發明者現已在臨床上證明決奈達隆可減少中風的發 生,此點係其他抗心律不整化合物尚未證實者。 【發明内容】 本發明係關於一種以決奈達隆或其醫藥上可接受之一種 鹽於製備用於預防中風或暫時性腦缺血(特別係有心房顏 動或心房撲動病史的患者)之藥劑上之用途。 本發明亦關於一種以決奈達隆或其醫藥上可接受之一種 參 帛於製備用於預防中風(特別係有心房顏動或心房撲動病 史的患者)的藥劑上之用途。 對照於認知功能緩慢惡化之慢性疾病之腦供血不足中 風係急性或亞急性腦血管原因之神經機能缺損,其症狀之 定義為由於大腦血管障礙而使得症狀持續μ小時以上或之 =快速消失症狀的患者之急性臨床相關腦損傷之顯影: 這些可歸因於由血栓症或栓塞或出血引起的缺
—-Q \ V )(.L. Sacco 等人,中風(stroke),2006 .梦, ’弟37卷第 141672.doc 201010695 577-617頁)。 中風可引起永久性的神經損傷或死亡。在美國以及^ 洲,其為造成成年人失能的主要原因。 歐 中風的風險因素包括高齡、高血壓、早期曾中風或 性腦缺血(TIA)、糖尿病、高膽固醇、吸煙、 等。高血壓係中風之最重要可變風險因素。 中風症狀類似暫時性腦缺血,但其持續24小時以上。 主要的中風為缺血性或出血性的中風。缺血性中風較常 見且在某些情況下可變成出血性中風。 【實施方式】 在一項實施例中,本發明係關於一種以決奈達隆或其醫 藥上可接受之一種鹽於製備用於特別為有心房顫動或心房 撲動病史的患者預防缺血性中風之藥劑之用途。 更精確地說,本發明係關於一種以決奈達隆或其醫藥上 可接受之一種鹽於製備用於為有心房顫動或心房撲動病史 的患者預防約35%的中風或暫時性腦缺血藥劑之用途。 更精確地說,本發明係關於一種以決奈達隆或其醫藥上 可接受之一種鹽於製備用於為有心房顫動或心房撲動病史 的患者預防約35%的中風之藥劑之用途。 在另一實施例中,本發明係關於一種以決奈達隆或其醫 藥上可接受之一種鹽於製備用於預防致死性中風之藥劑之 用途。 致死性中風定義為導致死亡的中風。 在另一實施例中’本發明係關於一種以決奈達隆或其醫 141672.doc 201010695 藥上可接受之-種鹽於製備用於預防中風、急性冠狀動脈 症候群以及死亡或心血管疾病死亡之藥劑之用途。 在另:r把例中’本發明係關於一種以決奈達隆或其醫 藥上可接受之-種鹽於製備用於預防急性冠狀動脈症候群 (ACS)之藥劑之用途。 中風、急性冠狀動脈症候群及死亡或心、血管疾病死亡的 複合終點為在心血管疾病結果試驗中典型的測量結果,亦 ❹稱作MACE(嚴重不良心血管病例)終點。該終點包括的内 谷闡述了中風的更廣泛的影響及相關的發現。 . ACS上的數據僅與巾風有關聯,事實上二者都係缺血性 病例。 就臨床研究而言,「中風、急性冠狀動脈症候群以及死 亡或心血管疾病死亡」的預防構成所謂的綜合標準或組合 終點。 以上百分比相當於平均值。 φ 決奈達隆之醫藥上可接受鹽中可提及鹽酸鹽。 所治療的患者可為有心房顫動或心房撲動病史的患者。 該表達法《有心房顫動或心房撲動病史》意指患者先前 患過至少一次明顯的心房顫動或心房撲動症狀,並且其在 服用決奈達隆時可呈竇性心律或心房顫動或者心房撲動。 亦將詳述表達法「有心房顫動或心房撲動病史之患 者」、「有心房顫動或心房撲動病史或目前罹患該病之患 者」或者「近期有心房顫動或心房撲動病史或目前罹患該 病之患者」或者「有突發性或永久性心房顗動或心房撲動 141672.doc 201010695 之患者」或者「有突發性或永久性心房顫動或心房撲動病 史或目前罹患該病之患者」或者「最近曾突發性或永久性 心房顫動或心房撲動病史或目前罹患該病之患者」或者 「羅患突發性或間歇性^房顏動或心房撲動並在最近期曾 發作心房顏動或心房撲動之患者,其患有竇性心律或需要 心搏復蘇」或者「有突發性或間歇性心房顫動或心房撲動 並在最近曾發作心房顫動或心房撲動之患者,其患有竇性 心律或需要心搏復蘇」意指患者過去曾發作一次或更多次 〜房顏動或心房撲動及/或在使用決奈達隆及其醫藥上可 接受鹽期間正罹患心房顫動或心房撲動。更特定言之,該 表達法意指患者在開始治療之前最近6個月内既有心房顫 動或心房撲動又有竇性心律的記錄。患者可在開始接受決 奈達隆及其醫藥上可接受鹽時為竇性心律或者心房顫動或 心房撲動。 亦將指明術語「永久性」與「間歇性」係相等。 「永久性心房顫動或心房撲動」患者在整個服用決奈達 隆及其醫藥上可接受鹽的期間具有在該節律所有應有的心 電圖。 在近期有心房顫動或心房撲動病史或目前罹患該病之患 者中’可提及近期有非永久性心房顏動或心房撲動病史或 目前罹患該病之患者。 在本發明中,「心房顫動」意指心房顏動及/或心房撲 動。 在有心房顫動或心房撲動病史之患者中,可提及進一步 141672.doc -10- 201010695 具有至少一種以下風險因素之患者: -年齡,明顯大於或等於70歲,或者甚至大於75歲, -面血壓’ -糖尿病^ -早期曾罹患腦血管意外或全身性栓塞, -由心臟超音波測量,左心房直徑大於或等於5 0 mm, -由二維心電圖測量,左心室射出分率小於40%。 在有心房顫動或心房撲動病史之患者中,亦可述及具有 相當於至少一種以下疾病之其他風險因素之患者: -尚血壓’ -結構性心臟病, -心動過速, -冠心病, •非風濕性心瓣膜病, -缺血性擴張心肌病, φ - AF/AFL的燒灼史,例如心導管燒灼或手術燒灼, -非AF/AFL之室上性心動過速, -心臟瓣膜手術病史, - -非缺血性擴張心肌病, -肥厚型心肌病, -風濕性心瓣膜病, -持續心室性心搏過速, -先天性心臟病, -其他非AF/AFL原因之燒灼,例如心導管燒灼, 141672.doc -11 - 201010695 •心室顫動, 及/或選自如下之至少_種心臟裝置: -心律調節器, -植入式心搏復蘇除顫器。 可提及充血性心臟病作為結構性心臟病之子群。 、本=明另—主題為—種醫藥組合物,其包含作為有效组 ^有:達隆或其醫藥上可接受之—種鹽。該醫藥組合物 ==之至少根據本發明之決奈達隆,或其加成鹽 與醫藥上可接受之鹽、或其水合物或溶劑化物及至少一 種醫藥上可接受賦形劑。該等賦形劑根據所需藥劑劑型及 給藥途徑’在熟悉此項技術者已知之常見賦形劑中選擇。 在用於經口、舌下、皮下、肌内、靜脈内、表面、局 部、氣管内、鼻内、穿皮或直腸給藥之本發明藥劑組合物 中,決奈達隆或其鹽、溶劑化物或水合物之—種可呈單位 形式給藥,其與常用之藥劑賦形劑形成混合物給藥於動物 及人類,用於預防或治療上述病變。適當之單位劑型包括 口服形式(例如藥m㈣膠囊、粉末、顆粒及口服 之溶液或懸浮液)、舌下、經頰、氣管内、眼内及鼻内給 藥方式、藉由吸入給藥的形式、表面給藥方式、穿皮式給 藥方式、皮下、肌内或靜脈内給藥方式、直腸給藥方式及 植入物。對於表面施用時,根據本發明化合物可呈乳霜、 凝膠、軟膏或洗液使用。 用於醫療上時,決奈達隆及其醫藥上可接受鹽係、併入醫 藥組合物中。 141672.doc •12- 201010695 該等醫藥組合物包括有效劑量之至少決奈達隆或其醫藥 上可接受之一種鹽及至少一種醫藥上可接受賦形劑。 該等賦形劑根據所需醫藥劑型及給藥途徑,在熟悉此項 技術者已知之常見賦形劑中選擇。 在用於經口、舌下、皮下、肌内、靜脈内、表面、局 部、氣管内、鼻内、穿皮或直腸給藥之本發明藥劑組合物 中,決奈達隆或其鹽、溶劑化物或水合物之一種可呈單位 劑型給藥,其與常用之藥劑賦形劑形成混合物給藥於動物 ® 及人類,用於預防或治療上述病變。 適當之單位劑型包括口服形式(例如藥片、硬或軟明膠 囊、粉末、顆粒及口服之溶液或懸浮液)、舌下、經頰、 氣管内、眼内及鼻内給藥方式、藉由吸入給藥的形式、表 面給藥方式、穿皮式給藥方式、皮下、肌内或靜脈内給藥 方式、直腸給藥方式及植入物。對於表面施用時,根據本 發明化合物可呈乳霜、凝膠、軟膏或洗液使用。 Φ 作為實例之呈藥片形式之決奈達隆或其醫藥可接受之鹽 之單位劑型可以包含以下成分: 成份 mg 決奈達隆鹽酸鹽(相當於400 mg鹼型) 426 甲基羥丙基纖維素 21.1 乳糖單水合物 46.55 改質玉米玉米澱粉 45.5 聚乙烯吡咯烷酮 65 泊洛沙姆(Poloxamer)407 40 無水膠態氧化矽 2.6 硬脂酸鎂 3.25 650 141672.doc -13· 201010695 成份 mg 決奈達隆鹽酸鹽(相當於400 mg鹼型) 426 微晶纖維素 65 無水膠態氧化矽 2.6 無水乳糖 42.65 聚乙烯吡咯烷酮 13 泊洛沙姆(P〇l〇xamer)407 40 聚乙二醇(Macrogol)6000 57.5 硬脂酸鎂 3.25 650 成份 mg 決奈達隆鹽酸鹽(相當於400 mg鹼型) 426 微晶纖維素 26 玉米澱粉 45.5 聚乙烯吡咯烷酮 65 泊洛沙姆(P〇l〇xamer)407 40 無水膠態氧化矽 3.25 硬脂酸鎂 3.25 乳糖單水合物 41.65 650 成份 mg 決奈達隆鹽酸鹽(相當於400 mg鹼型) 213 微晶纖維素 13 玉米澱粉 22.75 聚乙烯吡咯烷酮 32.5 泊洛沙姆(Pol〇xamer)407 20 無水膠態氧化石夕 1.3 硬脂酸鎂 1.625 乳糖單水合物 20.825 650 隨食物一天投與一次或兩次該醫藥組合物。 每曰經口投與之決奈達隆劑量可達800 mg,服用一次或 多次,例如一次或兩次。 141672.doc -14- 201010695 更明確言之,投與之決夺诖 建隆劑量可隨食物一起服用。
更明確言之,決奈達隆之I 母曰經口投與劑量可達800 mg ’隨餐食服用兩次。 每曰經口投與決奈達隆劑量之頻率可以每天兩次,隨早 餐及晚餐服用。 更明確言之,兩次攝入量可包含相同量之決奈達隆。
在特疋情形下’可能適合採用較高或較低劑量;此等劑 量係包含於本發明範圍内。根據慣例,適合於每一患者之 劑量係經由醫師根據投與途徑、患者之體重、疾病、身體 表面積、心輸出量及反應而確定。 本發明亦關於一種預防中風之方法,其包括將有效劑量 之至少決奈達隆或其一種醫藥上可接受鹽投與患者。 本發明係由上述資料參考下圖加以說明: 圖1表示根據30個月的治療分析第一次中風或TIA時間之 Kaplan Meier累積發病曲線。 圖2表示根據30個月的治療分析第一次中風時間之 Kaplan Meier累積發病曲線。 ' 在預期的多國性雙盲隨機多中心,以安慰劑為對照組的 平行組試驗期間,由決奈達隆鹽酸鹽提供決奈達隆及其醫 藥上可接受鹽相較於安慰劑在預防中風上之功效。 I·患者 患者在招募時必須具有心房纖維性顫動或心房撲動病史 及/或可能為正常竇性心律或患有心房纖維性顫動或撲 動。 141672.doc -15- 201010695 考慮合乎以下合格標準之來招募患者: 合格標準: 1)須表現一種以下風險因素: -齡等於或大於70歲, -血壓(服用至少兩種不同分類之抗高血壓藥), _尿病, -中風(暫時性腦缺血性病例《完全腦中風)或全 栓塞病史, ’ -心臟超音波測量’左心房直徑大於或等於π·, -二維心電圖測量,左心室射出分率小於4〇〇/。; 或 _齡等於或大於70歲,或甚至大於7S歲,可能與至 少一種以下風險因素組合·· 〇血壓(服用至少兩種不同分類之抗高血壓藥), 〇尿病, 〇中風(暫時性腦缺血性病例或完全腦中風)或全 身性栓塞病史, 〇心臟超音波測量,左心房直徑大於或等於5〇 mm » 〇二維心電圖測量,左心室射出分率小於40% ; 2) 可獲得過去6個月内之心電圖,並顯示患者過去或現 在有心房顫動/撲動, 3) 可取得過去6個月内之心電圖,並顯示患者過去或現 在患有竇性心律。 141672.doc -16 - 201010695 Η·持續時間及治療 取試驗藥劑治療單位(相當於4〇〇 mg鹼型之安慰劑或決 奈達隆鹽酸鹽)’使每一患者在早上早餐期間或早餐之後 不久服用藥片’及在晚上晚餐期間或晚餐之後不久服用藥 片。 。治療持續時間係取決於試驗中每一患者之招募時間且可 能介於12個月至3 0個月之間。 III·結果 e 使用非參數的Kaplan-Meier評估計算結果。 用於評估危險比之Cox's比例風險模式也稱為相對危險 性。 相對危險性(RR)為決奈達隆處理組患者罹患中風(或者 暫時性腦缺血(TIA))之風險與安慰劑處理組患者罹患中風 (或者暫時性腦缺血(TIA))之風險之間之比例。 計算病例減少百分比如下: ❹ x=l-RR。 關於預防中風或暫時性颺缺血(TIA)之結果 試驗包括之4628名患者中,有2301名患者屬於決奈達隆 -鹽酸鹽處理組。 ,相較於決奈達隆鹽酸鹽處理組中出現52例中風病例,安 慰劑組中記錄到80例。 計算相對危險性等於0.65,亦即罹患中風或暫時性腦缺 血(TIA)的相對危險減少35%。 圖1顯示決奈達隆之效果發生較早並隨時間提高。 141672.doc Λη 201010695 闍於預防中風之結果 試驗包括之4628名患者中,有2301名患者·屬於決奈達隆 鹽酸鹽處理組。 相較於決奈達隆鹽酸鹽處理組中出現45例中風病例,安 慰劑組中記錄到70例。 計算相對危險性等於0.65,亦即患中風的相對危險減少 3 5%。 圖2顯示決奈達隆之效果發生較早並隨時間提高。 _於預防缺血性中風之結果 ® 試驗包括之4628名患者中,有2301名患者屬於決奈達降 鹽酸鹽處理組。 相較於決奈達隆鹽酸鹽處理組中出現33例中風病例,安 慰劑組中記錄到49例。 計算相對危險性等於0.68,亦即患腦缺血性中風的相對 危險減少32%。 關於預防致死性中風之結果 試驗包括之4628名患者中,有2301名患者屬於決奈達隆 ® 鹽酸鹽處理組。 相較於決奈達隆鹽酸鹽處理組中出現丨丨例致死性中風病 例’安慰劑組中記錄到丨8例。 計算相對危險性等於〇,62,亦即罹患致死性中風的相對 危險減少38%。 關於預防中風、急性冠狀動腺症候群(ACS)或死亡之結果 試驗包括之4628名患者中,有2301名患者屬於決奈達隆 141672.doc -18- 201010695 鹽酸鹽處理組。 相較於決奈達隆鹽酸鹽處理組中出現196例,安慰劑組 中δ己錄到262例。 計算相對危險性等於0·68,亦即患中風、急性冠狀動脈 症候群(ACS)或死亡的相對危險減少25%。 關於預防中風、急性冠狀動肤症候鮮(ACS)或心血管疾病 死亡之結果 試驗包括之4628名患者中,有23 01名患者屬於決奈達隆 鹽酸鹽處理組。 相較於決奈達隆鹽酸鹽處理組中出現147例,安慰劑組 中記錄到216例。 計算相對危險性等於0.68 ,亦即患中風、急性冠狀動脈 症候群(ACS)或心血管疾病死亡的相對危險減少32%。 Μ於預防因急性冠狀動脈症候群(ACS)而需住院治療心血 管疾病之結果 試驗包括之4628名患者中,有23 01名患者屬於決奈達隆 鹽酸鹽處理組。 相較於決奈達隆鹽酸鹽處理組中出現ACS有62例,安慰 劑組中記錄到ACS有89例。 計算相對危險性等於0.70,亦即因罹患急性冠狀動脈症 候群(ACS)而需住院治療心血管疾病的相對危險減少 3 0%。 關於預防已具有其他風險因素例如CHADS2分數、CHF、 高血廑、年齡、耱尿病、過去曹中風或TIA之患者中風 141672.doc -19- 201010695 結果 "_III"丨丨丨·_丨丨丨_1 1 0.1 決奈逮隆 較佳 1.0 特徵 CHAD52分數 Ν RRE96%GQ >-2 CHF 1S39 1.29 ㈣ 2m 否 3283 α.77ΐ〇4β;1^4] 是 高血壓 136S 047[α.26;0.90] 否 633 0.68[0.22;2.09] 是 年齡 3995 0.84 {QMtQMSi *n 2m 0.74|0.45;1.19J >75 糖尿病 192S 0,S3[0.29^97] 否 3683 »4S 0JS4PL42;1 删 是 中風 ίΤΙΛ 0.S410^1^1.332 否 4012 0.69 是 616 0.50 IQMitm 0.49 有慰劑 較佳 CHADS2分數之計算法為對AF患者每出現以下一項都給 一分:充企性心力衰竭、高jk壓、75歲或者大於75歲以及 糖尿病,而具有中風病史或出現中風風險特徵之TIA則給2 分。CHADS2分數越高中風危險越大。Gage BF, van Wairaven C, Pearce L, Hart RG, Koudstaal PJ, Boode BS, Petersen P.之選擇用於抗凝療法之心房顫動患者:服_用阿 司匹林的患者之中風危險群(Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin) ° 2004發行;110:2287-92 【圖式簡單說明】 圖1表示根據30個月的治療分析第一次中風或TIA時間之 141672.doc -20- 201010695
Kaplan Meier累積發病曲線。 圖2表示根據30個月的治療分析第一次中風時間之 Kaplan Meier累積發病曲線。
141672.doc -21 -
Claims (1)
- 201010695 七、申請專利範圍: 1· 一種以決奈達隆於製備用於預防中風或暫時性 藥劑之用途。 、 2. 如睛求項1之用途,其用於製備用於預防中風之藥劑。 3. 如請求項1之用途,其用於製備用於預防約35%中風之藥 劑。 、 4. ❹5. 如請求項1之用途,其用於製備用於預防急性冠狀動脈 症候群之藥劑。 如請求項1之用途,其用於製備用於預防致死性中風之 藥劑。 6·如請求項1至5中任一項之用途,其中該預防法係提供給 過去或者現在患有心房顫動或心房撲動之患者。 7·如請求項1至5中任一項之用途,其特徵為該等患者具有 至少一種以下風險因素: 年齡,两血壓, 糖尿病, 早期腦血管意外或全身性栓塞, 由心臟超音波測量,左心房直徑大於或等於5〇 mm, 由二維心臟超音波測量,左心室射出分率小於4〇%。 8·如請求項1至5中任一項之用途,其特徵為該等患者具有 其他風險因素,該等風險因素相當於以下至少一種疾 病· 高血壓, 141672.doc 201010695 結構性心臟病, 心動過速, 冠心病’ 非風濕性心瓣膜病, 缺血性擴張心肌病’ 用於AF/AFL之燒灼, 非AF/AFL之室上性心動過速, 心臟瓣膜手術病史, 非缺血性擴張心肌病, 肥厚型心肌病, 風濕性心瓣膜病, 持續心室性心搏過速, 先天性心臟病, 非AF/AFL原因之燒灼, 心室顫動, 及/或選自如下之至少一種心臟裝置: 心律調節器, 植入式心搏復蘇除顫器。 9.如請求項1至5中任一項之用途,其特徵在於當經口投與 藥劑時,決奈達隆日劑量可達800 mg。 141672.doc -2-
Applications Claiming Priority (2)
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 |
US8780308P | 2008-08-11 | 2008-08-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201010695A true TW201010695A (en) | 2010-03-16 |
Family
ID=40149599
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW098126633A TW201010695A (en) | 2008-08-07 | 2009-08-06 | Use of dronedarone for the preparation of a medicament for the prevention of stroke or transient ischemic attack |
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 |
---|---|---|---|---|
JP2011518785A (ja) * | 2008-04-17 | 2011-06-30 | サノフイ−アベンテイス | 心血管入院または死亡の予防に用いる薬剤を調製するためのドロネダロンの使用 |
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 |
AR081392A1 (es) * | 2010-05-13 | 2012-08-29 | Sanofi Aventis | Uso de dronedarona para la preparacion de un medicamento para la prevencion de hospitalizaciones cardiovasculares o muerte o sucesos cardiovasculares en pacientes con fibrilacion auricular permanente |
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 |
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 |
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 PE PE2011000135A patent/PE20110706A1/es not_active Application Discontinuation
- 2009-08-03 WO PCT/IB2009/006831 patent/WO2010015939A1/en active Application Filing
- 2009-08-03 CA CA2733149A patent/CA2733149A1/en not_active Abandoned
- 2009-08-03 BR BRPI0917569A patent/BRPI0917569A2/pt not_active IP Right Cessation
- 2009-08-03 EP EP09786247A patent/EP2326324A1/en not_active Withdrawn
- 2009-08-03 MX MX2011001461A patent/MX2011001461A/es not_active Application Discontinuation
- 2009-08-03 AU AU2009278864A patent/AU2009278864A1/en not_active Abandoned
- 2009-08-03 KR KR1020117005222A patent/KR20110042344A/ko not_active Application Discontinuation
- 2009-08-03 EA EA201170301A patent/EA201170301A1/ru unknown
- 2009-08-03 CN CN200980135272XA patent/CN102149377A/zh active Pending
- 2009-08-03 JP JP2011521656A patent/JP2011529958A/ja not_active Withdrawn
- 2009-08-06 AR ARP090103009A patent/AR073265A1/es unknown
- 2009-08-06 TW TW098126633A patent/TW201010695A/zh 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 CL CL2011000268A patent/CL2011000268A1/es unknown
- 2011-02-07 NI NI201100034A patent/NI201100034A/es unknown
- 2011-02-07 CO CO11013463A patent/CO6351721A2/es not_active Application Discontinuation
- 2011-03-01 MA MA33659A patent/MA32602B1/fr unknown
Also Published As
Publication number | Publication date |
---|---|
ECSP11010811A (es) | 2011-03-31 |
WO2010015939A1 (en) | 2010-02-11 |
IL211098A0 (en) | 2011-04-28 |
CR20110061A (es) | 2011-04-04 |
EP2326324A1 (en) | 2011-06-01 |
CA2733149A1 (en) | 2010-02-11 |
MA32602B1 (fr) | 2011-09-01 |
NI201100034A (es) | 2011-10-20 |
PE20110706A1 (es) | 2011-10-11 |
EP2153830A1 (en) | 2010-02-17 |
EA201170301A1 (ru) | 2012-01-30 |
BRPI0917569A2 (pt) | 2019-09-24 |
MX2011001461A (es) | 2011-03-29 |
AU2009278864A1 (en) | 2010-02-11 |
KR20110042344A (ko) | 2011-04-26 |
CO6351721A2 (es) | 2011-12-20 |
AR073265A1 (es) | 2010-10-28 |
JP2011529958A (ja) | 2011-12-15 |
CN102149377A (zh) | 2011-08-10 |
SV2011003827A (es) | 2011-04-29 |
US20110230552A1 (en) | 2011-09-22 |
CL2011000268A1 (es) | 2011-07-29 |
DOP2011000043A (es) | 2011-03-15 |
UY32040A (es) | 2010-03-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW201010695A (en) | Use of dronedarone for the preparation of a medicament for the prevention of stroke or transient ischemic attack | |
TWI519298B (zh) | 決奈達隆(dronedarone)於製備用於預防心血管疾病住院或死亡之藥劑之用途 | |
US20110166220A1 (en) | Dronedarone for the prevention of permanent atrial fibrillation | |
JP2011518147A (ja) | 血中カリウム濃度を調節する薬剤を調製するためのドロネダロンまたは医薬的に許容されるこの塩の使用 | |
US20110166221A1 (en) | Use of dronedarone for the preparation of a medicament for use in the prevention of cardioversion | |
TW200951117A (en) | Combination of dronedarone with at least one diuretic, therapeutic application thereof | |
Kes et al. | Treatment of mild-to-moderate hypertension with calcium channel blockers: a multicentre comparison of once-daily nifedipine GITS with once-daily amlodipine | |
JP2015515971A (ja) | うつ病を治療するためのトラマドール | |
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 | |
EA030589B1 (ru) | Применение ландиолола гидрохлорида в длительном лечении тахиаритмии | |
WO2012020377A1 (en) | Use of dronedarone for the preparation of a medicament for rhythm- and rate-controlling in patients with atrial fibrillation | |
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 | |
EP2387996A1 (en) | Use of dronedarone for the preparation of a medicament for the prevention of cardiovascular events in patients with permanent atrial fibrillation | |
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 | |
WO2022147318A1 (en) | Methods of treatment | |
TW201208676A (en) | Use of dronedarone for the preparation of a medicament for the prevention of cardiovascular hospitalization or of mortality in patients with lone atrial fibrillation | |
Forrest | The treatment of hypertension in older patients: a double-blind, between-patient study in previously treated patients comparing a diuretic, a beta-receptor antagonist, and their fixed combination | |
Tkacova et al. | B026: Acute and chronic reduction of blood pressure by CPAP in patients with refractory hypertension and obstructive sleep apnea | |
WO2012013750A1 (en) | Use of dronedarone for the preparation of a medicament for the hospitalization burden in patient with atrial fibrillation |