CN102119023A - 阿帕地松单位剂量 - Google Patents
阿帕地松单位剂量 Download PDFInfo
- Publication number
- CN102119023A CN102119023A CN2009801313956A CN200980131395A CN102119023A CN 102119023 A CN102119023 A CN 102119023A CN 2009801313956 A CN2009801313956 A CN 2009801313956A CN 200980131395 A CN200980131395 A CN 200980131395A CN 102119023 A CN102119023 A CN 102119023A
- Authority
- CN
- China
- Prior art keywords
- unit dose
- handkerchief
- ground
- saline
- measures
- 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.)
- Granted
Links
- 229950001316 apadenoson Drugs 0.000 title abstract description 3
- FLEVIENZILQUKB-XTWQNQIISA-N chembl1950649 Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC(C#CC[C@@H]3CC[C@H](CC3)C(=O)OC)=NC(N)=C2N=C1 FLEVIENZILQUKB-XTWQNQIISA-N 0.000 title abstract description 3
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 230000010412 perfusion Effects 0.000 claims abstract description 7
- 230000002107 myocardial effect Effects 0.000 claims abstract description 5
- 241000878003 Dendrolycopodium obscurum Species 0.000 claims description 25
- 239000003937 drug carrier Substances 0.000 claims description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 239000000872 buffer Substances 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 16
- 239000001509 sodium citrate Substances 0.000 claims description 11
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 11
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 9
- 229920000858 Cyclodextrin Polymers 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 8
- 238000005516 engineering process Methods 0.000 claims description 5
- 208000031481 Pathologic Constriction Diseases 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 210000004351 coronary vessel Anatomy 0.000 claims description 3
- 230000002496 gastric effect Effects 0.000 claims description 2
- 208000037804 stenosis Diseases 0.000 claims description 2
- 230000036262 stenosis Effects 0.000 claims description 2
- 238000003384 imaging method Methods 0.000 abstract description 7
- 239000002831 pharmacologic agent Substances 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 8
- 230000017531 blood circulation Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229960005305 adenosine Drugs 0.000 description 4
- 210000004165 myocardium Anatomy 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 208000009982 Ventricular Dysfunction Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- -1 hydroxyethyl- Chemical group 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000012217 radiopharmaceutical Substances 0.000 description 2
- 230000006815 ventricular dysfunction Effects 0.000 description 2
- 241000282817 Bovidae Species 0.000 description 1
- 241000282421 Canidae Species 0.000 description 1
- 201000000057 Coronary Stenosis Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282323 Felidae Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- QJGQUHMNIGDVPM-BJUDXGSMSA-N Nitrogen-13 Chemical compound [13N] QJGQUHMNIGDVPM-BJUDXGSMSA-N 0.000 description 1
- IGLNJRXAVVLDKE-OIOBTWANSA-N Rubidium-82 Chemical compound [82Rb] IGLNJRXAVVLDKE-OIOBTWANSA-N 0.000 description 1
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 1
- 229940068274 adenosine injection Drugs 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- QVGXLLKOCUKJST-BJUDXGSMSA-N oxygen-15 atom Chemical compound [15O] QVGXLLKOCUKJST-BJUDXGSMSA-N 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940056501 technetium 99m Drugs 0.000 description 1
- BKVIYDNLLOSFOA-OIOBTWANSA-N thallium-201 Chemical compound [201Tl] BKVIYDNLLOSFOA-OIOBTWANSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 238000001291 vacuum drying Methods 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
-
- 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
- A61K9/08—Solutions
-
- 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)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
- Rheumatology (AREA)
- Pathology (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Saccharide Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
本发明提供药理学应激剂阿帕地松的一种单位剂量,以及其作为用于心肌灌注成像的药理剂的应用。
Description
相关申请的交叉引用
本申请要求2008年7月3日提交的美国临时申请No.61/078,169以及2009年2月27日提交的美国临时申请No.61/155,937的优先权,这两个申请的全部内容具体引入本文。
技术领域
本发明涉及药理应激剂阿帕地松(Apadenoson)的一种单位剂量,以及其作为用于心肌灌注成像的药理剂(pharmacologic agent)的用途。
背景技术
阿帕地松(如下所示)在US 6,322,771中最早被描述为药理学应激剂,
其可用于临床灌注成像技术(例如,用于诊断和评价冠状动脉疾病的程度)。该药剂曾进入临床I期和临床II期实验。2005年,Hendel博士等向美国心脏病协会报告了127例患者SPECT Tc99m sestamibi示踪剂成像研究的初步结果,使用1μg/kg或2μg/kg静脉推注阿帕地松对阿帕地松与腺苷进行了比较。该报告称阿帕地松安全且具有良好的耐受性,值得进行III期临床评估。2006年,Kern博士等向美国心脏病协会报告了阿帕地松的II期临床研究结果,其中一个目标就是确定III期临床实验的适当剂量。研究了0.5、1.0、2.0和2.5μg/kg的静脉推注剂量。对患者来说,当剂量从0.5增加到2μg/kg时,冠脉血流平均峰速出现相应增加(见图1)。根据这些数据,认为阿帕地松应该基于体重而非单位剂量进行给药。
以体重为基础进行药剂的胃肠外施用有其固有的局限性以及操作者出错的机会。这种类型的给药需要按照患者体重计算施用药量,从较大剂量中施用所计算的量,并丢弃任何剩余的药剂。因此,期望提供单位剂量的药剂,并且这也是有益的。
发明概述
本发明提供一种新的适于胃肠外施用的阿帕地松单位剂量。
本发明还提供利用阿帕地松单位剂量作为药理应激剂的一种新的诊断心肌功能障碍的方法。
鉴于发现给予1μg/kg或2μg/kg剂量的阿帕地松时没有观察到剂量效应曲线,已经实现了本发明的这些和其它方面。
附图说明
图1显示来自II期临床研究一个患者的平均峰流线速度(average peak flow wire velocity)。UC Irvine的独立研究者Morton Kern博士主持了有100名患者的该项II期临床研究,其中通过冠脉内注射施用腺苷,并用流线(flow wire)来监测冠脉血流速度。左侧,三次腺苷注射增加血流速度,这与已经充分表征的腺苷药理学作用一致。右侧,增加阿帕地松推注剂量,在所示安全剂量内获得与腺苷相当的峰流。
图2显示图1所述研究中33个患者的平均峰流线速度。
发明详述
前述报道增加冠脉血流速度(coronary blood flow velocity,CBFV)对应于阿帕地松剂量从0.5增至2μg/kg是基于在有限数量患者中CBFV的增加(见图1)。然而,现已发现,如果考虑到全部患者样本(如图2所示),那么≥1μg/kg的剂量、尤其是1~2.5μg/kg之间的剂量观察不到剂量效应。根据这一点,申请人已经令人惊奇地发现,阿帕地松实际上能够通过单位剂量来施用,而不是根据图1报告结果而预测的基于重量给药。
因此,在一个实施方案中,本发明提供了一种新的阿帕地松单位剂量,其包含:(a)阿帕地松和(b)药学可接受的载体,其中所述单位剂量适于胃肠外施用。
在另一个实施方案中,所述单位剂量适于静脉施用。
在另一个实施方案中,存在于该单位剂量中的阿帕地松的量选自76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174和175μg。阿帕地松重量的附加实例包括(a)100、110、120、130、140和150μg;(b)100μg;和(c)150μg。
在另一个实施方案中,存在于所述单位剂量中的阿帕地松的量是在选自115、116、117、118、119、120、121、122、123、124至125μg的范围。阿帕地松重量的附加实例包括(a)115、120和125μg以及(b)120μg。
在另一个实施方案中,所述药学载体包含:环糊精。环糊精的实例包括α-CD或其衍生物(例如α-羟丙基-CD(HP-α-CD)),β-CD或其衍生物(例如β-羟丙基-CD(HP-β-CD),甲基化-β-环糊精,羟乙基-β-环糊精,以及磺丁基醚-β-CD),以及γ-CD或其衍生物(例如γ-羟丙基-CD(HP-γ-CD))。
CD(例如羟丙基-β-环糊精)浓度的实例包括选自以下的范围:(a)约0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1,2,3,4,5,6,7,8,9,和10%w/v;(b)约0.5,0.6.,0.7,0.8,0.9,1,2,3,至4%w/v;(c)约1%w/v;(d)约2%w/v终浓度。
在另一个实施方案中,所述药学载体包含:缓冲盐水。一种有用的缓冲剂是柠檬酸缓冲剂(例如柠檬酸钠)。柠檬酸可用于调节单位剂量的pH值。作为实例,所述药学载体包含:缓冲盐水,所述缓冲盐水包含:盐水,柠檬酸钠以及柠檬酸。可以想到,柠檬酸由于离子化作用而在最终单位剂量中可能不存在。
在另一个实施方案中,所述单位剂量的pH选自4.6,4.7,4.8,4.9,至5.0。单位剂量pH值的另一个实例为4.8。
在另一个实施方案中,所述单位剂量的体积选自1,1.5,2,2.5,3,3.5,4,4.5和5mL。体积的另一个实例选自2,3,4到5mL。
在另一个实施方案中,所述单位剂量包含:
(a)100μg阿帕地松;
(b)药学可接受的载体,其包含:
(bi)2%w/v HP-β-CD;
(bii)柠檬酸钠缓冲剂,其量将单位剂量的pH值缓冲至4.8;以及
(biii)盐水,其量形成1-5ml的单位剂量。
在另一个实施方案中,所述单位剂量包含:
(a)100μg阿帕地松;
(b)药学可接受的载体,其包含:
(bi)1%w/v HP-β-CD;
(bii)柠檬酸钠缓冲剂,其量将单位剂量的pH值缓冲至4.8;以及
(biii)盐水,其量形成1-5ml的单位剂量。
在另一个实施方案中,所述单位剂量包含:
(a)150μg阿帕地松;
(b)药学可接受的载体,其包含:
(bi)2%w/v HP-β-CD;
(bii)柠檬酸钠缓冲剂,其量将单位剂量的pH值缓冲至4.8;以及
(biii)盐水,其量形成1-5ml的单位剂量。
在另一个实施方案中,所述单位剂量包含:
(a)150μg阿帕地松;
(b)药学可接受的载体,其包含:
(bi)2%w/v HP-β-CD;
(bii)柠檬酸钠缓冲剂,其量将单位剂量的pH值缓冲至4.8;以及
(biii)盐水,其量形成1-5ml的单位剂量。
本发明的单位剂量可填充于任何有用的容器中,供贮存、运输以及使用。有用容器的一个实例是注射器本体。
在另一个实施方案中,本发明提供一种在哺乳动物中诊断心肌灌注异常的新方法,其包括:
(a)给该哺乳动物胃肠外施用单位剂量阿帕地松;以及
(b)对该哺乳动物实施检测冠脉狭窄存在状况、评估冠状动脉狭窄严重程度、或两者之组合的技术。
在另一个实施方案中,所述患者体重至少为40公斤。
在另一个实施方案中,所述给药方式为静脉施用。
在另一个实施方案中,所用技术为选自下述的成像技术:平面或单光子发射计算机断层成像(SPECT),γ相机闪烁显像,正电子发射断层成像(PET),核磁共振(NMR)成像,磁共振成像(MRI),灌注造影超声心动图,数字减影血管造影(DSA),以及超快X-射线计算机断层成像(CINE CT)。
在另一个实施方案中,本发明提供一种预填充注射器,其包含:注射器和阿帕地松的单位剂量,所述单位剂量包含:(a)阿帕地松和(b)药学可接受的载体,其中单位剂量适于胃肠外施用。注射器可以是任何已知用于胃肠外施用的注射器。例如,注射器可以包含:本体和可在本体内移动的活塞。所述本体可为圆柱形,其第一开放端用于接受活塞,第二端与第一端相对,所述第二端具有足以通过所述单位剂量的开口。所述注射器还可以包含:针(例如注射针)。所述针可被可拆卸地连接于或永久固定于本体。还可以有针保护器。
在另一个实施方案中,本发明提供一种用于医学治疗的新的阿帕地松单位剂量。
在另一个实施方案中,本发明提供阿帕地松单位剂量在制造用于诊断哺乳动物中心肌灌注异常之药物中的新用途。
本发明的阿帕地松单位剂量可作为药理学应激剂进行施用,也可以联合多种非侵入性诊断方法中任一项来测量心肌、冠脉和/或心室灌注的方面。可测量的方面包括人的冠状动脉狭窄,心肌功能障碍(例如心肌缺血、冠状动脉疾病、心室功能障碍以及通过无病变冠脉血管和/或狭窄冠脉血管的血流差异),心肌收缩功能障碍,局部心腔壁运动异常的存在状况,狭窄冠脉血管的功能显著性,冠状动脉疾病,缺血性心室功能障碍,冠状动脉血管舒张能力(储备能力)。放射性药物常用于诊断方法中。放射性药剂可以包含,例如,选自铊-201、锝-99m、氮-13、铷-82、碘-123以及氧-15的放射性核素。
无论是否描述为优选,本发明的任何实施方案或特征都可以与本发明的任何其它方面或特征相结合,也不论这些其它特征是否描述为优选。
释义
除非另外提到,本申请中提供的实施例是非穷举性的。这些实施例包括但不限于所记载的组别。
单位剂量是指单次施用给患者之药物的量。单位剂量通常不依赖于患者体重或者可以与特定体重范围相关(例如≥40kg)。
除非另外提到,在本申请包括权利要求中,当术语不用数量词限定时表示“至少一个”或者“一个或更多个”。
哺乳动物和患者涵盖了通常处于医疗护理中的恒温动物(例如,人和驯化的动物)。哺乳动物的实例包括(a)猫科、犬科、马科和牛科动物以及(b)人。
胃肠外施用包括静脉内、肌肉内和皮下途径。
剂量和配制
无菌注射溶液通常如下制备:将所需量的活性化合物以及根据需要将上述各种其它成分掺入合适溶剂中,随后进行无菌过滤(或其它一些除菌方式)。如果用无菌粉末制备无菌注射溶液,制备方法包括真空干燥和冷冻干燥技术,这些技术用于产生包括活性成分以及前述无菌过滤溶液中任何附加期望成分的粉末。
本说明书中引用的所有专利、专利申请、书籍和文献的内容通过引用全文并入本文。至于有任何不一致之处,则以本公开(包括其中任何释义)为准。
在上述教导基础上可对本发明进行许多改进和变化。因此可以理解,除非特别指出,在权利要求保护范围内可以实施本发明。
Claims (21)
1.一种阿帕地松单位剂量,其包含:(a)阿帕地松和(b)药学可接受的载体,其中该单位剂量适于胃肠外施用。
2.权利要求1的单位剂量,其中阿帕地松的量选自76~175μg。
3.权利要求2的单位剂量,其中阿帕地松的量选自100~150μg。
4.权利要求3的单位剂量,其中阿帕地松的量为100μg。
5.权利要求3的单位剂量,其中阿帕地松的量为150μg。
6.权利要求1的单位剂量,其中所述药学载体包含:环糊精(CD)。
7.权利要求6的单位剂量,其中所述环糊精为β-羟丙基-CD。
8.权利要求6的单位剂量,其中CD的浓度选自0.1~10%w/v的终浓度。
9.权利要求8的单位剂量,其中CD的浓度为1%w/v。
10.权利要求8的单位剂量,其中CD的浓度为2%w/v。
11.权利要求1的单位剂量,其中所述药学载体包含:缓冲盐水。
12.权利要求11的单位剂量,其中所述药学载体包含:缓冲盐水,所述缓冲盐水包含:盐水和柠檬酸钠。
13.权利要求1的单位剂量,其中所述单位剂量的pH选自4.6~5.0。
14.权利要求13的单位剂量,其中所述pH为4.8。
15.权利要求1的单位剂量,其中所述单位剂量的体积选自1~5mL。
16.权利要求1的单位剂量,其包含:
(a)100μg阿帕地松;
(b)药学可接受的载体,其包含:
(bi)2%w/v HP-β-CD;
(bii)其量将所述单位剂量缓冲至pH 4.8的柠檬酸钠缓冲剂;以及,
(biii)其量形成1~5mL单位剂量的盐水。
17.权利要求1的单位剂量,其包含:
(a)100μg阿帕地松;
(b)药学可接受的载体,其包含:
(bi)1%w/v HP-β-CD;
(bii)其量将所述单位剂量缓冲至pH 4.8柠檬酸钠缓冲剂;以及,
(biii)其量形成1~5mL单位剂量的盐水。
18.权利要求1的单位剂量,其包含:
(a)150μg阿帕地松;
(b)药学可接受的载体,其包含:
(bi)2%w/v HP-β-CD;
(bii)其量将所述单位剂量缓冲至pH 4.8的柠檬酸钠缓冲剂;以及,
(biii)其量形成1~5mL单位剂量的盐水。
19.权利要求1的单位剂量,其包含:
(a)150μg阿帕地松;
(b)药学可接受的载体,其包含:
(bi)2%w/v HP-β-CD;
(bii)其量将所述单位剂量缓冲至pH 4.8的柠檬酸钠缓冲剂;以及,
(biii)其量形成1~5mL单位剂量的盐水。
20.一种诊断哺乳动物中心肌灌流异常的方法,其包括:
(a)向该哺乳动物胃肠外施用阿帕地松单位剂量;和
(b)对该哺乳动物实施检测冠状动脉狭窄存在状况、评估冠状动脉狭窄严重程度或者其组合的技术。
21.权利要求20的方法,其中所述患者重至少40kg。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US7816908P | 2008-07-03 | 2008-07-03 | |
US61/078,169 | 2008-07-03 | ||
US15593709P | 2009-02-27 | 2009-02-27 | |
US61/155,937 | 2009-02-27 | ||
PCT/US2009/003939 WO2010002473A1 (en) | 2008-07-03 | 2009-07-02 | Unit dosage of apadenoson |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102119023A true CN102119023A (zh) | 2011-07-06 |
CN102119023B CN102119023B (zh) | 2014-04-09 |
Family
ID=41152021
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200980131395.6A Expired - Fee Related CN102119023B (zh) | 2008-07-03 | 2009-07-02 | 阿帕地松单位剂量 |
Country Status (24)
Country | Link |
---|---|
US (6) | US20100003193A1 (zh) |
EP (1) | EP2306971B1 (zh) |
JP (2) | JP2011526894A (zh) |
KR (2) | KR20110028531A (zh) |
CN (1) | CN102119023B (zh) |
AU (1) | AU2009266317B2 (zh) |
BR (1) | BRPI0913939A2 (zh) |
CA (1) | CA2729819C (zh) |
CY (1) | CY1116283T1 (zh) |
DK (1) | DK2306971T3 (zh) |
EA (1) | EA022348B1 (zh) |
ES (1) | ES2537069T3 (zh) |
HK (1) | HK1156250A1 (zh) |
HR (1) | HRP20150454T1 (zh) |
IL (2) | IL210428A (zh) |
MX (1) | MX2011000193A (zh) |
MY (1) | MY161655A (zh) |
NZ (1) | NZ590489A (zh) |
PL (1) | PL2306971T3 (zh) |
PT (1) | PT2306971E (zh) |
SI (1) | SI2306971T1 (zh) |
SM (1) | SMT201500123B (zh) |
WO (1) | WO2010002473A1 (zh) |
ZA (1) | ZA201100163B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MY161655A (en) | 2008-07-03 | 2017-04-28 | Univ Virginia Patent Foundation | Unit dosage of apadenoson |
ES2641855T3 (es) | 2012-02-03 | 2017-11-14 | Adenobio N.V. | Un método de uso de adenosina y dipiridamol para prueba de esfuerzo farmacológica con composiciones específicas, formas de dosificación unitarias y kits |
CN109020881B (zh) * | 2018-06-28 | 2020-04-28 | 新发药业有限公司 | 一种阿帕替尼的制备方法 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5091171B2 (en) | 1986-12-23 | 1997-07-15 | Tristrata Inc | Amphoteric compositions and polymeric forms of alpha hydroxyacids and their therapeutic use |
EP0443827B1 (en) * | 1990-02-21 | 1996-07-17 | Her Majesty The Queen In Right Of New Zealand | Rare earth substituted thallium-based superconductors |
IT1263831B (it) | 1993-01-29 | 1996-09-04 | Paolo Chiesi | Complessi di inclusione multicomponente ad elevata solubilita' costituiti da un farmaco di tipo basico, un acido ed una ciclodestrina |
US7214665B2 (en) | 2001-10-01 | 2007-05-08 | University Of Virginia Patent Foundation | 2-propynyl adenosine analogs having A2A agonist activity and compositions thereof |
US6232297B1 (en) * | 1999-02-01 | 2001-05-15 | University Of Virginia Patent Foundation | Methods and compositions for treating inflammatory response |
EP1150991B1 (en) * | 1999-02-01 | 2004-04-07 | University of Virginia Patent Foundation | Compositions for treating inflammatory response |
US7427606B2 (en) | 1999-02-01 | 2008-09-23 | University Of Virginia Patent Foundation | Method to reduce inflammatory response in transplanted tissue |
US6322771B1 (en) * | 1999-06-18 | 2001-11-27 | University Of Virginia Patent Foundation | Induction of pharmacological stress with adenosine receptor agonists |
US7255934B2 (en) * | 2000-10-23 | 2007-08-14 | National Institute Of Advanced Industrial Science And Technology | Composite structure body and method and apparatus for manufacturing thereof |
US6620645B2 (en) * | 2000-11-16 | 2003-09-16 | G.T. Equipment Technologies, Inc | Making and connecting bus bars on solar cells |
WO2003072597A1 (en) * | 2002-02-27 | 2003-09-04 | Ferring Bv | Intermediates and methods for making heptapeptide oxytocin analogues |
JP2006515829A (ja) * | 2002-04-10 | 2006-06-08 | ユニバーシティ オブ バージニア パテント ファウンデーション | 炎症性疾病の処置のための、a2aアデノシン受容体アゴニストの使用 |
US6662088B1 (en) * | 2002-06-28 | 2003-12-09 | General Electric Company | Methods and systems for inspecting aircraft fuselage frames |
JP2007536241A (ja) * | 2004-05-03 | 2007-12-13 | ユニバーシティ オブ バージニア パテント ファウンデーション | 糖尿病性腎症の処置のためのa2aアデノシンレセプターアゴニスト |
EP1778712B1 (en) * | 2004-08-02 | 2013-01-30 | University Of Virginia Patent Foundation | 2-propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity |
EP1729355B1 (en) | 2005-06-03 | 2008-11-19 | STMicroelectronics S.r.l. | Self-aligned process for manufacturing phase change memory cells |
US7767686B2 (en) | 2006-03-03 | 2010-08-03 | Covidien Ag | Method of using adenosine receptor blockers during tissue ablation |
DE102006022450A1 (de) | 2006-05-13 | 2007-11-15 | Lanxess Deutschland Gmbh | Wässrige Rußdispersionen für Ink-Jet |
US20090053168A1 (en) * | 2007-07-17 | 2009-02-26 | Richard Rickles | Treatments of b-cell proliferative disorders |
TW200905703A (en) * | 2007-07-27 | 2009-02-01 | Delta Electronics Inc | Magnetic device and manufacturing method thereof |
MY161655A (en) | 2008-07-03 | 2017-04-28 | Univ Virginia Patent Foundation | Unit dosage of apadenoson |
-
2009
- 2009-07-02 MY MYPI2010006339A patent/MY161655A/en unknown
- 2009-07-02 BR BRPI0913939A patent/BRPI0913939A2/pt not_active Application Discontinuation
- 2009-07-02 CN CN200980131395.6A patent/CN102119023B/zh not_active Expired - Fee Related
- 2009-07-02 MX MX2011000193A patent/MX2011000193A/es active IP Right Grant
- 2009-07-02 KR KR1020117002495A patent/KR20110028531A/ko active Application Filing
- 2009-07-02 JP JP2011516343A patent/JP2011526894A/ja not_active Withdrawn
- 2009-07-02 KR KR1020147003142A patent/KR20140021726A/ko not_active Application Discontinuation
- 2009-07-02 PL PL09773926T patent/PL2306971T3/pl unknown
- 2009-07-02 DK DK09773926.2T patent/DK2306971T3/en active
- 2009-07-02 NZ NZ590489A patent/NZ590489A/xx not_active IP Right Cessation
- 2009-07-02 CA CA2729819A patent/CA2729819C/en active Active
- 2009-07-02 ES ES09773926.2T patent/ES2537069T3/es active Active
- 2009-07-02 WO PCT/US2009/003939 patent/WO2010002473A1/en active Application Filing
- 2009-07-02 US US12/496,949 patent/US20100003193A1/en not_active Abandoned
- 2009-07-02 AU AU2009266317A patent/AU2009266317B2/en not_active Ceased
- 2009-07-02 SI SI200931189T patent/SI2306971T1/sl unknown
- 2009-07-02 PT PT97739262T patent/PT2306971E/pt unknown
- 2009-07-02 EP EP09773926.2A patent/EP2306971B1/en active Active
- 2009-07-02 EA EA201100132A patent/EA022348B1/ru not_active IP Right Cessation
-
2011
- 2011-01-02 IL IL210428A patent/IL210428A/en not_active IP Right Cessation
- 2011-01-06 ZA ZA2011/00163A patent/ZA201100163B/en unknown
- 2011-10-07 HK HK11110662.3A patent/HK1156250A1/zh not_active IP Right Cessation
-
2012
- 2012-07-09 US US13/544,364 patent/US20130017153A1/en not_active Abandoned
-
2013
- 2013-08-29 JP JP2013177622A patent/JP2013237702A/ja active Pending
- 2013-12-11 US US14/103,130 patent/US9415058B2/en active Active
-
2015
- 2015-04-27 HR HRP20150454TT patent/HRP20150454T1/hr unknown
- 2015-05-14 CY CY20151100432T patent/CY1116283T1/el unknown
- 2015-05-22 SM SM201500123T patent/SMT201500123B/xx unknown
-
2016
- 2016-05-10 IL IL245577A patent/IL245577B/en active IP Right Grant
- 2016-06-13 US US15/181,235 patent/US9662406B2/en active Active
-
2017
- 2017-05-19 US US15/600,303 patent/US20170252463A1/en not_active Abandoned
-
2018
- 2018-07-25 US US16/045,359 patent/US20190022253A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Glover et al. | Comparison between 201Tl and 99mTc sestamibi uptake during adenosine-induced vasodilation as a function of coronary stenosis severity | |
Criscione et al. | Development and application of a multimodal contrast agent for SPECT/CT hybrid imaging | |
JP2018076328A5 (zh) | ||
CA2594328A1 (en) | Method of detecting myocardial dysfunction in patients having a history of asthma or bronchospasm | |
US20190022253A1 (en) | Unit dosage of apadenoson | |
Cuocolo et al. | Resting technetium-99m methoxyisobutylisonitrile cardiac imaging in chronic coronary artery disease: comparison with rest-redistribution thallium-201 scintigraphy | |
Zhao et al. | Sulfonyl-Containing boronate caps for optimization of biological properties of 99mTc (III) Radiotracers [99mTcCl (CDO)(CDOH) 2B-R](CDOH2= Cyclohexanedione Dioxime) | |
Maffei et al. | Rationale, design and methods of CTCA-PRORECAD (Computed Tomography Coronary Angiography Prognostic Registry for Coronary Artery Disease): A multicentre and multivendor registry (452 views) | |
JP4863345B2 (ja) | 心筋用放射性画像診断剤又は放射性治療薬 | |
JP2914454B2 (ja) | 血管診断助剤 | |
Amorim et al. | Guideline for rest and stress myocardial perfusion scintigraphy | |
Kawano et al. | Phase I clinical study of NMB58, a novel positron emission tomography (PET)-myocardial perfusion imaging tracer, conducted to evaluate its safety and pharmacokinetics in Japanese healthy adult males | |
Sy et al. | Radiolabeling with Technetium 99m for the Diagnosis of Coronary Heart Disease in Senegal | |
Marini et al. | Current Practical Guidelines for the Most Common Nuclear Medicine Procedures | |
Waldeck et al. | Coincidence High-Resolution and High-Sensitivity PET Imaging of Cardiovascular Disease: A Powerful Tool for Disease Imaging. | |
UA108063C2 (xx) | Дозована лікарська форма ападенозону | |
MATRIX | EVALUATING THE CORRELATION BETWEEN TUMOR 2-DEOXY-2-[18F] FLUORO-D-GLUCOSE UPTAKE AND BLOOD FLOW IN AN EXPERIMENTAL LIVER TUMOR MODEL USING HYBRID POSITRON EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY | |
Ching et al. | Nuclear cardiology in Singapore: A review | |
Ueshima et al. | Paradoxical regional myocardial uptake between 201Thallium and 123I-BMIPP SPECT in patients with cardiomyopathy | |
Toia et al. | Imaging evaluation of cardiac stem cells transplantation | |
Watanabe et al. | Correlation between myocardial blood flow and fasting glucose metabolism in ischemic heart disease quantitative assessment by nitrogen-13 ammonia and fluorine-18 fluorodeoxyglucose positron emission tomography | |
WATANABE et al. | Clinical Studies | |
Wong et al. | 8.12: Systolic recovery following stress myocardial perfusion procedures-A comparison of the effects of stress in diabetic and nondiabetic individuals | |
Gunning et al. | Recent advances in myocardial perfusion scintigraphy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140409 |