WO1996012496A1 - Use of n-[(1s,trans)-2-hydroxycyclopentyl]-adenosine for reducing myocardial injury - Google Patents
Use of n-[(1s,trans)-2-hydroxycyclopentyl]-adenosine for reducing myocardial injury Download PDFInfo
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- WO1996012496A1 WO1996012496A1 PCT/EP1995/004089 EP9504089W WO9612496A1 WO 1996012496 A1 WO1996012496 A1 WO 1996012496A1 EP 9504089 W EP9504089 W EP 9504089W WO 9612496 A1 WO9612496 A1 WO 9612496A1
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- formula
- compound
- acceptable salt
- solvate
- physiologically acceptable
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- GYWXTRVEUURNEW-TVDBPQCTSA-N (2R,3R,4S,5R)-2-[6-[[(1S,2S)-2-hydroxycyclopentyl]amino]-9-purinyl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(N[C@@H]3[C@H](CCC3)O)=C2N=C1 GYWXTRVEUURNEW-TVDBPQCTSA-N 0.000 title description 8
- 208000037891 myocardial injury Diseases 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000012453 solvate Substances 0.000 claims abstract description 32
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 26
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 31
- 239000003527 fibrinolytic agent Substances 0.000 claims description 20
- 229960000103 thrombolytic agent Drugs 0.000 claims description 20
- 210000004351 coronary vessel Anatomy 0.000 claims description 19
- 241001465754 Metazoa Species 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 230000002537 thrombolytic effect Effects 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 239000003146 anticoagulant agent Substances 0.000 claims description 10
- 230000010410 reperfusion Effects 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- 230000017531 blood circulation Effects 0.000 claims description 9
- 238000007675 cardiac surgery Methods 0.000 claims description 9
- 206010002388 Angina unstable Diseases 0.000 claims description 8
- 208000007814 Unstable Angina Diseases 0.000 claims description 8
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 8
- 210000004165 myocardium Anatomy 0.000 claims description 8
- 206010000891 acute myocardial infarction Diseases 0.000 claims description 7
- 238000007887 coronary angioplasty Methods 0.000 claims description 7
- 230000002939 deleterious effect Effects 0.000 claims description 7
- 108010058207 Anistreplase Proteins 0.000 claims description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 5
- 108010023197 Streptokinase Proteins 0.000 claims description 5
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 claims description 5
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 claims description 5
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims description 5
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims description 5
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 5
- 108010073863 saruplase Proteins 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 229960005202 streptokinase Drugs 0.000 claims description 5
- 229960000187 tissue plasminogen activator Drugs 0.000 claims description 5
- 229960005356 urokinase Drugs 0.000 claims description 5
- 108010088842 Fibrinolysin Proteins 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229940012957 plasmin Drugs 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- -1 plasm in Proteins 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 206010061216 Infarction Diseases 0.000 description 9
- 230000007574 infarction Effects 0.000 description 9
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- 230000006698 induction Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
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- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 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 2
- 229960005305 adenosine Drugs 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 230000003531 anti-dysrhythmic effect Effects 0.000 description 2
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- 230000000747 cardiac effect Effects 0.000 description 2
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- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
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- 239000008215 water for injection Substances 0.000 description 2
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- TXUZTJPPOVABRH-JYHQXFQUSA-N CCC1OC([n]2c(N)c(C(NC)=N)nc2)[IH][C@@H]1C Chemical compound CCC1OC([n]2c(N)c(C(NC)=N)nc2)[IH][C@@H]1C TXUZTJPPOVABRH-JYHQXFQUSA-N 0.000 description 1
- PSPPXRNUZVTTON-RNFRBKRXSA-N C[C@H](CC1)O[C@H]1[n]1c2ncnc(N)c2nc1 Chemical compound C[C@H](CC1)O[C@H]1[n]1c2ncnc(N)c2nc1 PSPPXRNUZVTTON-RNFRBKRXSA-N 0.000 description 1
- 0 Cc1c2nc[n]([C@@]3OI(CO)CC3)c2nc(*)n1 Chemical compound Cc1c2nc[n]([C@@]3OI(CO)CC3)c2nc(*)n1 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000007201 Myocardial reperfusion injury Diseases 0.000 description 1
- ORCVUFSKYJNEQI-KKJSVHSVSA-N OC[C@H]([C@H](C1)O)O[C@H]1[n]1c2ncnc(N[C@@H](CCC3)[C@H]3O)c2nc1 Chemical compound OC[C@H]([C@H](C1)O)O[C@H]1[n]1c2ncnc(N[C@@H](CCC3)[C@H]3O)c2nc1 ORCVUFSKYJNEQI-KKJSVHSVSA-N 0.000 description 1
- YEZOBWILXCIADB-OTICRUEKSA-N OC[C@H]([C@H]([C@H]1O)O)O[C@H]1N1C=NC2[IH](N[C@@H](CCC3)[C@H]3O)=NC=NC12 Chemical compound OC[C@H]([C@H]([C@H]1O)O)O[C@H]1N1C=NC2[IH](N[C@@H](CCC3)[C@H]3O)=NC=NC12 YEZOBWILXCIADB-OTICRUEKSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000003257 anti-anginal effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 230000003243 anti-lipolytic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- 229950003616 azaperone Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000001101 cardioplegic effect Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 229910052801 chlorine Chemical group 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical class OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 208000024535 susceptibility to myocardial infarction Diseases 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compound of formula (1a), or physiologically acceptable salts or solvates thereof, in the reduction of myocardial infarction arising from severe myocardial ischaemia.
Description
USE OF N-l(lS,lRANS)-2-HYDROXYCYCLOPENTYLl-ADENOSINE FOR REDUCING MYOCAR DIAL INJURY The present invention relates to a new medical use of certain compounds and pharmaceutical compositions containing the same and more particularly relates to a new use of compounds which act as agonists at adenosine-1 (A1) receptors, and pharmaceutical compositions containing such compounds. International patent application publication number WO 92/20346 discloses a method of reducing myocardial reperfusion injury which comprises administration of adenosine, an adenosine-1 receptor agonist or an adenosine-2 receptor agonist, together with the antiarrhythmic agent lidocaine. International patent application publication number WO 92105177 discloses compounds which have adenosine agonist activity and which are said to be useful as anti-hypertensive and anti-ischaemic agents. European patent application publication number 0322 242 generally discloses compounds of formula (I): EMI1.1 Where X represents a hydrogen or chlorine atom, or a methyl group; and R represents a cycloalkyl or cycloalkenyl ring containing 5 to 8 carbon atoms, which ring is substituted by a hydroxy group, and is optionally substituted by a C19alkyl group; and salts and solvates thereof. Furthermore, EP0322242 specifically discloses N-[(1 S,trans)-2- hydroxycyclopentyl]adenosine, which has the structure: EMI2.1 EP0322242 describes the subject compounds as being useful as anti-lipolytic agents. Furthermore, it is stated that "the compounds of the invention may independently affect cardiac function by reducing heart rate and conduction. The compounds may thus be used in the therapy of a number of cardiovascular disorders, for example cardiac arrythmias, particularly following myocardial infarction, and angina." The teaching of EP0322242 therefore, is that the above compounds of formula (I) thus possess the potential to exert anti-anginal and antidysrhythmic activities, similar to those exerted by ss-adrenoceptor blocking agents and calcium channel blocking agents. The priority document for EP0322242, namely G88729994, also describes compounds of formula (I) as being useful in reducing heart rate and conduction, and furthermore, "that the compounds may thus be used in the therapy of a number of cardiovascular disorders, for example ischaemic heart disease." Go8729994 is teaching that the compounds of formula (I) therefore have potential to exert antidysrhythmic activities as discussed above, which dysrhythmic activities may be associated with, or result from, ischaemic heart disease. The type of ischaemic heart disease which may, for example, represent one possible cause of cardiac dysrhythmia, is "mild" ischaemic heart disease. The term 'mild' ischaemic heart disease as used herein denotes ischaemic heart disease not resulting in irreversible myocardial damage (i.e. infarction). We have now unexpectedly found that a compound of formula (la) as described above is useful in the reduction of deleterious effects to the myocardium, such as reduction of myocardial infarction, arising from severe myocardial ischaemia. The term "severe myocardial ischaemia" as used herein denotes an ischaemic condition arising from abrupt interruption of coronary artery blood flow followed by reperfusion on restoration of such coronary artery blood flow. Such severe myocardial ischaemia can accompany, for example, coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), acute myocardial infarction, unstable angina and cardiac surgery including, in particular, cardiac transplantation. In a first aspect, the invention provides the use of a compound of formula (la), or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the reduction of myocardial infarction arising from severe myocardial ischaemia as described above. There is further provided use of a compound of formula (lea), or a physiologically acceptable salt or solvate thereof, in the manufacture of a medicament for the reduction of deleterious effects to the myocardium, particularly impairment of cardiac function, associated with any of coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), acute myocardial infarction, unstable angina and cardiac surgery. Furthermore, a compound of formula (la) may be beneficial as an adjunct to cardioplegic treatment administered during cardiac surgery. In a second or alternative aspect, the present invention provides a method of reducing myocardial infarction arising from severe myocardial ischaemia in a human or animal subject as described above, which method comprises administering to said subject an effective amount of a compound of formula (la), or a physiologically acceptable salt or solvate thereof. There is further provided by the present invention, a method of reducing deleterious effects to the myocardium associated with any of coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), acute myocardial infarction, unstable angina and cardiac surgery, in a human or animal subject, which method comprises administering to said subject an effective amount of a compound of formula (la), or a physiologically acceptable salt or solvate thereof. Physiologically acceptable salts of a compound of formula (la) are disclosed in EP0322242 and include acid addition salts derived from inorganic or organic acids, such as sulphates, phosphates, benzoates, camphor sulphonates, ptoluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, citrates, maleates, sal icyl ates, fumarates, succinates, lactates, glutarates, glutaconates, acetates and tricarballylates. Solvates include hydrates. A compound of formula (la) is effective in the reduction of myocardial infarction arising from severe myocardial ischaemia, if administered prior to the onset of abrupt interruption of coronary blood flow experienced during severe myocardial ischaemia. Furthermore, a particularly unexpected finding is that a compound of formula (la) is effective in the reduction of myocardial infarction arising from severe myocardial ischaemia, if administered after the onset of abrupt interruption in coronary blood flow but prior to the onset of reperfusion. A compound of formula (la) is therefore useful as an adjunct to thrombolysis. In a further or alternative aspect of the present invention there is provided a product containing a compound of formula (la), or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, as a combined preparation for simultaneous, separate or sequential use, during a thrombolytic procedure. Suitable thrombolytic agents include, for example, APSAC, aspirin, plasmin, prourokinase, streptokinase, tissue plasminogen activator and urokinase. Where a compound of formula (la) is administered simultaneously with a thrombolytic agent, the active agents may be combined in a single pharmaceutical composition. Such compositions are novel and form a further aspect of the present invention. The invention thus provides a pharmaceutical composition comprising a compound of formula (la) or a physiologically acceptable salt or solvate thereof and a thrombolytic agent together with a pharmaceutically acceptable excipient. The present invention further provides use of a compound of formula (lea), or a physiologically acceptable salt or solvate thereof, in the manufacture of a medicament comprising a compound of formula (lea) or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, for use during a thrombolytic procedure. There is provided use of a thrombolytic agent substantially as described above, in the manufacture of medicament comprising a compound of formula (1a) or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, for use during a thrombolytic procedure. Furthermore, use of a compound of formula (lea) or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, in the manufacture of a medicament for use during a thrombolytic procedure. The invention provides a method of treatment of a human or animal subject which method comprises administering to said subject effective amounts of a compound of formula (1 a), or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, simultaneously, separately, or sequentially during a thrombolytic procedure. Compositions according to the invention are conveniently formulated for parenteral administration. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Preferably the compositions will be presented as solutions for intravenous administration, such as injectable unit dosage forms or the like. There is further provided by the present invention a pharmaceutical composition comprising a compound of formula (lea), or a physiologically acceptable salt or solvate thereof adapted for injectable administration for the reduction of myocardial infarction arising from severe myocardial ischaemia, together with one or more pharmaceutically acceptable carriers or excipients therefor. Furthermore a pharmaceutical composition comprising a compound of formula (lea), or a physiologically acceptable salt or solvate thereof as described above, for reducing deleterious effects to the myocardium associated with coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, acute myocardial infarction, unstable angina and cardiac surgery. Suitably, a compound of formula (la) is present in a composition according to the present invention at a concentration in the range of 1 to 500slg/ml, particularly 10 to 300g/ml, more particularly 50 to 1501lg/ml, and preferably at about 100Crg/ml. A particularly apt composition according to the present invention comprises, or consists essentially of: (a) 50 to 150zg/ml, preferably about 1001lg/ml, of a compound of formula (la), or a physiologically acceptable salt or solvate thereof; (b) 8.5 to 9.5mgiml, preferably about 9.00mgiml, of a sodium salt, preferably sodium chloride; (c) water being present as the balance of the composition, typically to formulate the composition in 1.0ml injectable form. Suitable doses of a compound of formula (la) or a physiologically acceptable salt or solvate thereof, for use in the methods of the invention will vary with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or veterinarian. In general, however, a suitable dose will be in the range of from about 0.0002 to about 0.1 mg/kg body weight of the recipient, such as from about 0.0003 mg/kg to about 0.05 mg/kg, preferably from about 0.0004 mg/kg to about 0.01 mg/kg. Methods for the preparation of a compound of formula (la) are described in EP0322242. As hereinbefore described, it is a particularly unexpected aspect of the present invention that, not only does administration of a compound of formula (la) prior to abrupt interruption of coronary artery blood flow provide protection against myocardial infarction, but protection is also afforded if the compound of formula (la) is administered after interruption in coronary artery blood flow but before reperfusion. This means that the methods of the present invention are applicable not only where severe myocardial ischaemia is planned or expected, for example in cardiac surgery, but also in cases of unexpected severe myocardial ischaemia, for example in heart attack, unstable angina and during thrombolysis. The invention is further illustrated by the following non-limiting examples. ExamPle 1 Cardioorotective Action of N4( IS. trans)-2-hvdroxvcvcloPentvlladenosine Surgical Preparation Rabbits New Zealand White rabbits (male, weight range 2.4-3.2kg, Charles River Ltd) were anaesthetised with Na pentobarbitone. The trachea was cannulated and the animal was respired with room air, the right jugular vein was cannulated to allow subsequent administration of anaesthetic and drug substances. The right femoral artery was cannulated for measurement of blood pressure, heart rate was electronically derived from the pressure signal. Subcutaneous needles were positioned on the limbs and lead Il of the electrocardiograph (ECG) was recorded. The heart was exposed by a left lateral thoracotomy in the 5th rib space, the pericardium was cut and a braided polyester suture was passed around a branch of the left coronary artery. A plastic sheath was passed over the suture and the artery was occluded by pulling the suture through the sheath and clamping it against the myocardial surface, subsequent release of the clamp allowed repeated occlusion and reperfusion of the vessel. As it was not always possible to visualise the coronary artery, successful occlusion was confirmed by an elevation in the ST segment of the ECG, an index of myocardial ischaemia. Data were recorded and analysed using a Modular Instruments Inc data acquisition system. Animals were heparinised and allowed 15 minutes recovery after surgery was completed prior to the start of the experiment. Pigs Large White pigs (either sex, weight range 25 - 35 kgs, Ashwell Farms Ltd) were sedated with azaperone and anaesthetised with Na pentobarbitone. The trachea was cannulated and the animal respired with room air. The left femoral vein was cannulated to allow constant infusion of anaesthetic. The right femoral vein was cannulated for drug administration, the right femoral artery was cannulated for measurement of blood pressure, heart rate was electronically derived from the pressure signal. The right carotid artery was cannulated and the cannula was advanced into the left ventricle to allow measurement of left ventricular pressure. Sub-cutaneous needles were positioned on the limbs and lead II of the ECG was recorded. The heart was exposed by a midline stemotomy, the pericardium was cut and the left anterior descending coronary artery was dissected free of connective tissue and underlying myocardium. A suture was placed around the artery and the vessels were occluded by tying the suture on to a plastic sheath, reperfusion was achieved by removal of the sheath restoring blood flow. Animals were heparinised (250 ulkg) and allowed 15 minutes recovery after surgery was completed prior to the start of the experiment. Data were recorded and analysed using a Modular Instruments Inc data acquisition system. Induction of Infarction Rabbits Infarcts were induced by occluding the coronary artery for 30 minutes and allowing subsequent reperfusion for a period not less than 2 hours. N-[(IS, trans)-2 Hydroxycyclopentyl]adenosine (compound of formula (la)) was administered as a bolus over 1 minute either 10 or 60 minutes prior to the induction of severe myocardial ischaemia or 10 minutes prior to, or upon, reperfusion (the results are shown in Figures 1 and 2 respectively). Alternatively, N-[(i S,trans)-2hydroxycyclopentyl]adenosine was administered as a 30 minute infusion ending 10 minutes prior to the induction of severe myocardial ischaemia (the results are shown in Figure 3). Pins Infarcts were induced by occluding the coronary artery for 50 minutes and allowing subsequent reperfusion for a period not less than 3 hours. N-[(1S,trans)-2- hydroxycyclopentyl]adenosine was administered as a bolus over 1 minute, 10 minutes prior to the induction of severe myocardial ischaemia (the results are shown in Figure 4). Measurement of Infarct Size Infarct size was expressed as a percentage of the area that was at risk of infarction. Hearts were removed after the period of reperfusion and flushed with heparinised saline and area at risk was defined by occluding the coronary artery and injecting fluorescent microspheres. Hearts were then cut into slices and stained with triphenyltetrazolium chloride to disclose the area of necrosis; the viable tissue is stained red while necrotic tissue remain unstained. After staining, the slices are illuminated with UV light and the areas which were perfused with fluorescent microspheres glow, any dark areas are considered to have been at risk of infarction. The areas of necrosis and risk are then measured by computer planimetry and the results expressed as percentage of area at risk of infarction which has subsequently become necrotic. Example 2 A pharmaceutical formulation containing N-[(1S,trans)-2- hydroxycyclopentyl]adenosine was prepared as follows. Quantities per mL: N-[(1 S,trans)-2-hydroxycyclopentyl]adenosine 1 00g Sodium Chloride 9.00mg Water for injection to 1.0my N-((1 S,trans)-2-hydroxycyclopentyl]adenosine and sodium chloride were dissolved in turn in the major portion of water for injection and mixed thoroughly. The solution was filtered through a sterilised 0.2 micron filter then filled aseptically under air into clean ampoules. The ampoules were then sealed and the sealed ampoules autoclaved at 1210C for 15 minutes.
Claims
r : w 1. A pharmaceutical composition comprising a compound of formula (it), or
a physiologically acceptable salt or solvate thereof,
EMI11.1
adapted for injectable administration for the reduction of myocardial
infarction arising from severe myocardial ischaemia, together with one or
more pharmaceutically acceptable carriers or excipients therefor.
2. A pharmaceutical composition comprising a compound of formula (lea), or
a physiologically acceptable salt or solvate thereof,
EMI11.2
for reducing deleterious effects to the myocardium associated with any of
coronary artery bypass grafting, percutaneous transluminal coronary
angioplasty, acute myocardial infarction, unstable angina and cardiac
surgery.
3. A composition according to claim 1 or 2, wherein said compound of
formula (1 a), or a physiologically acceptable salt or solvate thereof, is
present at a concentration in the range of 50 to 150rg/ml.
4. A composition according to Claim 3, wherein said compound of formula
(la) is present at a concentration of about 100Crg/ml.
5. A pharmaceutical composition comprising:
(a) 50 to 150 > g/mí of a compound of formula (la) or a physiologically
acceptable salt or solvate thereof;
EMI12.1
(b) 8.5 to 9.5 mgtml of sodium chloride; and
(c) water being present as the balance of the composition.
6. Use of a compound of formula (1 a), or a physiologically acceptable salt
or solvate thereof,
EMI13.1
in the manufacture of medicament for the reduction of myocardial
infarction arising from severe myocardial ischaemia.
7. Use of a compound of formula (lea), or a physiologically acceptable salt
or solvate thereof,
EMI13.2
in the manufacture of a medicament for reducing deleterious effects to
the myocardium associated with any of coronary artery bypass grafting,
percutaneous transluminal coronary angioplasty, acute myocardial
infarction, unstable angina and cardiac surgery.
8. Use according to claim 6 or 7, wherein said compound of formula (1 a), or
a physiologically acceptable salt or solvate thereof, is included in said
medicament at a concentration in the range of 50 to 1 50giml.
9. A method of reducing myocardial infarction arising from severe
myocardial ischaemia in a human or animal subject, which method
comprises administering an effective amount of a compound of formula
(lea), or a physiologically acceptable salt or solvate thereof,
EMI14.1
to a said human or animal subject.
10. A method of reducing deleterious effects to the myocardium associated
with any of coronary artery bypass grafting, percutaneous transluminal
coronary angioplasty, acute myocardial infarction, unstable angina and
cardiac surgery, in a human or animal subject, which method comprises
administering an effective amount of a compound of formula (lea), or a
physiologically acceptable salt or solvate thereof,
EMI15.1
to a said human or animal patient.
11. A method according to of claim 9 or 10, wherein an effective amount of
said compound of formula (lea), or a physiologically acceptable salt or
solvate thereof, is in the range of 0.0004 to 0.Olmglkg body weight of
said subject.
12. A method according to any of claims 9 to 11, wherein said compound of
formula (lea), or physiologically acceptable salt or solvate thereof, is
administered prior to the onset of abrupt interruption of coronary artery
blood flow experienced during severe myocardial ischaemia.
13. A method according to any of claims 9 to 11, wherein said compound of
formula (1 a), or physiologically acceptable salt or solvate thereof, is
administered after the onset of abrupt interruption of coronary artery
blood flow but prior to the onset of reperfusion.
14. A product containing a compound of formula (lea), or a physiologically
acceptable salt or solvate thereof
EMI16.1
and a thrombolytic agent, as a combined preparation for simultaneous,
separate or sequential use, during a thrombolytic procedure.
15. A pharmaceutical composition comprising a compound of formula (lea), or
a physiologically acceptable salt or solvate thereof,
EMI16.2
and a thrombolytic agent, together with a pharmaceutically acceptable
excipient.
16. Use of a compound of formula (lea), or a physiologically acceptable salt
thereof,
EMI17.1
in the manufacture of a medicament comprising a compound of formula
(1 a), and a thrombolytic agent, for use during a thrombolytic procedure.
17. Use of a thrombolytic agent in the manufacture of medicament
comprising:
(a) a compound of formula (1 a), and
EMI17.2
(b) a thrombolytic agent, for use during a thrombolytic procedure.
18. Use of a compound of formula (lea),
EMI18.1
and a thrombolytic agent, in the manufacture of a medicament for use
during a thrombolytic procedure.
19. A method of treatment of a human or animal subject which method
comprises administering effective amounts of a compound of formula (1a),
EMI18.2
and a thrombolytic agent, simultaneously, separately, or sequentially
during a thrombolytic procedure.
20. A product as defined in claim 14, wherein said thrombolytic agent is
selected from the group consisting of APSAC, aspirin, plasmin,
prourokinase, streptokinase, tissue plasminogen activator and urokinase.
21. A composition according to claim 15, wherein said thrombolytic agent is
selected from the group consisting of APSAC, aspirin, plasmin,
prourokinase, streptokinase, tissue plasminogen activator and urokinase.
22. Use according to any of claims 16 to 18, wherein said thrombolytic agent
is selected from the group consisting of APSAC, aspirin, plasm in,
prourokinase, streptokinase, tissue plasminogen activator and urokinase.
23. A method according to claim 19, wherein said thrombolytic agent is
selected from the group consisting of APSAC, aspirin, plasmin,
prourokinase, streptokinase, tissue plasminogen activator and urokinase.
24. A pharmaceutical composition substantially as herein before described.
25. Use in the manufacture of a medicament substantially as herein before
described.
26. A method of treatment of a human or animal subject substantially as
herein before described.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU38434/95A AU3843495A (en) | 1994-10-20 | 1995-10-18 | Use of n-{(1s,trans)-2-hydroxycyclopentyl}-adenosine for reducing myocardial injury |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9421133A GB9421133D0 (en) | 1994-10-20 | 1994-10-20 | Medicaments |
| GB9421133.1 | 1994-10-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996012496A1 true WO1996012496A1 (en) | 1996-05-02 |
Family
ID=10763123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1995/004089 WO1996012496A1 (en) | 1994-10-20 | 1995-10-18 | Use of n-[(1s,trans)-2-hydroxycyclopentyl]-adenosine for reducing myocardial injury |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3843495A (en) |
| GB (1) | GB9421133D0 (en) |
| WO (1) | WO1996012496A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999017784A1 (en) * | 1997-10-07 | 1999-04-15 | Regents Of The University Of California Corporation | Treating occlusive peripheral vascular disease and coronary disease with combinations of heparin and an adenoside a2 agonist, or with adenosine |
| US5972903A (en) * | 1997-10-07 | 1999-10-26 | Regents Of The University Of California Corporation | Method for promoting angiogenesis using heparin and adenosine |
| US6476351B1 (en) * | 1996-01-05 | 2002-11-05 | Lazare Kaplan International, Inc. | Laser marking system |
| US7414036B2 (en) | 2002-01-25 | 2008-08-19 | Muscagen Limited | Compounds useful as A3 adenosine receptor agonists |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0322242A2 (en) * | 1987-12-23 | 1989-06-28 | Glaxo Group Limited | Adenosine derivatives |
| WO1992020346A1 (en) * | 1991-05-22 | 1992-11-26 | Vanderbilt University | Method and composition to reduce myocardial reperfusion injury |
| WO1993023418A1 (en) * | 1992-05-14 | 1993-11-25 | Novo Nordisk A/S | Purine derivatives |
-
1994
- 1994-10-20 GB GB9421133A patent/GB9421133D0/en active Pending
-
1995
- 1995-10-18 WO PCT/EP1995/004089 patent/WO1996012496A1/en active Application Filing
- 1995-10-18 AU AU38434/95A patent/AU3843495A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0322242A2 (en) * | 1987-12-23 | 1989-06-28 | Glaxo Group Limited | Adenosine derivatives |
| WO1992020346A1 (en) * | 1991-05-22 | 1992-11-26 | Vanderbilt University | Method and composition to reduce myocardial reperfusion injury |
| WO1993023418A1 (en) * | 1992-05-14 | 1993-11-25 | Novo Nordisk A/S | Purine derivatives |
Non-Patent Citations (5)
| Title |
|---|
| A. TSUCHIDA: "Pretreatment with the adenosine A1 selective agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), causes a sustained limitation of infarct size in rabbits.", CARDIOVASC. RES., vol. 27, no. 4, 1993, pages 652 - 656 * |
| E.D. NORTON: "The effects of intravenous infusions of selective adenosine A1-receptor and A2-receptor agonists on myocardial reperfusion injury.", AM HEART J, vol. 123, no. 2, 1992, pages 332 - 338 * |
| J.D. THORNTON: "Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction.", CIRCULATION, vol. 85, no. 2, 1992, pages 659 - 665 * |
| M. KARMAZYN: "Adenosine A1 receptor activation attenuates cardiac injury produced by hydrogen peroxide.", CIRC. RES., vol. 71, no. 5, 1992, pages 1107 - 1110 * |
| M.F. GURDEN: "Functional characterization of three adenosine receptor types.", BR. J. PHARMACOL., vol. 109, no. 3, 1992, pages 693 - 698 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6476351B1 (en) * | 1996-01-05 | 2002-11-05 | Lazare Kaplan International, Inc. | Laser marking system |
| WO1999017784A1 (en) * | 1997-10-07 | 1999-04-15 | Regents Of The University Of California Corporation | Treating occlusive peripheral vascular disease and coronary disease with combinations of heparin and an adenoside a2 agonist, or with adenosine |
| US5972903A (en) * | 1997-10-07 | 1999-10-26 | Regents Of The University Of California Corporation | Method for promoting angiogenesis using heparin and adenosine |
| US6440947B1 (en) | 1997-10-07 | 2002-08-27 | The Regents Of The University Of California | Method for treating occlusive peripheral vascular disease and coronary disease |
| US7414036B2 (en) | 2002-01-25 | 2008-08-19 | Muscagen Limited | Compounds useful as A3 adenosine receptor agonists |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9421133D0 (en) | 1994-12-07 |
| AU3843495A (en) | 1996-05-15 |
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