DE19920775A1 - Use of drugs to avoid nitrate tolerance - Google Patents
Use of drugs to avoid nitrate toleranceInfo
- Publication number
- DE19920775A1 DE19920775A1 DE19920775A DE19920775A DE19920775A1 DE 19920775 A1 DE19920775 A1 DE 19920775A1 DE 19920775 A DE19920775 A DE 19920775A DE 19920775 A DE19920775 A DE 19920775A DE 19920775 A1 DE19920775 A1 DE 19920775A1
- Authority
- DE
- Germany
- Prior art keywords
- nitrate
- xanthine oxidase
- inhibitor
- antagonists
- tolerance
- 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.)
- Withdrawn
Links
- 229910002651 NO3 Inorganic materials 0.000 title claims abstract description 32
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229940079593 drug Drugs 0.000 title description 4
- 239000003814 drug Substances 0.000 title description 4
- 230000001575 pathological effect Effects 0.000 claims abstract description 9
- 108010093894 Xanthine oxidase Proteins 0.000 claims description 14
- 102100033220 Xanthine oxidase Human genes 0.000 claims description 14
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 claims description 14
- 229960003459 allopurinol Drugs 0.000 claims description 14
- 239000005557 antagonist Substances 0.000 claims description 11
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 claims description 11
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 102000004190 Enzymes Human genes 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 6
- 150000003212 purines Chemical class 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 5
- HXNFUBHNUDHIGC-UHFFFAOYSA-N oxypurinol Chemical compound O=C1NC(=O)N=C2NNC=C21 HXNFUBHNUDHIGC-UHFFFAOYSA-N 0.000 claims description 5
- 239000003064 xanthine oxidase inhibitor Substances 0.000 claims description 5
- 229950002752 oxipurinol Drugs 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 claims description 3
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 claims description 2
- RHVYBZNTBGYKKV-UHFFFAOYSA-N [3-hydroxy-2,2-bis(hydroxymethyl)propyl] nitrate Chemical compound OCC(CO)(CO)CO[N+]([O-])=O RHVYBZNTBGYKKV-UHFFFAOYSA-N 0.000 claims 1
- 230000002526 effect on cardiovascular system Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000002123 temporal effect Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 description 8
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 6
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 6
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 5
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 4
- 206010002383 Angina Pectoris Diseases 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229960000201 isosorbide dinitrate Drugs 0.000 description 3
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 3
- 229960003827 isosorbide mononitrate Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 208000031225 myocardial ischemia Diseases 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- CMFNMSMUKZHDEY-UHFFFAOYSA-N peroxynitrous acid Chemical compound OON=O CMFNMSMUKZHDEY-UHFFFAOYSA-N 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- DVICWXUADSCSLL-DDEWRDOISA-N Alloxanthin/Tetradehydrozeaxanthin/(Cynthiaxanthin)/(Pectenoxanthin) Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1C#CC(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)C#CC1=C(C)C[C@@H](O)CC1(C)C DVICWXUADSCSLL-DDEWRDOISA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000819038 Chichester Species 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010020365 Homocystinuria Diseases 0.000 description 1
- 208000033892 Hyperhomocysteinemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002156 adsorbate Substances 0.000 description 1
- DVICWXUADSCSLL-GUPSQEAKSA-N all-trans-Alloxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C#CC1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C#CC2=C(C)CC(O)CC2(C)C DVICWXUADSCSLL-GUPSQEAKSA-N 0.000 description 1
- UFRRRMXNFIGHPC-CPZJCIGYSA-N alloxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C#CC1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC#CC2=C(C)CC(O)CC2(C)C UFRRRMXNFIGHPC-CPZJCIGYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000031852 maintenance of location in cell Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 description 1
- 229960002497 nicorandil Drugs 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- -1 nitric acid esters Chemical class 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- GSKDBLIBBOYOFU-UHFFFAOYSA-N oxadiazol-5-amine Chemical class NC1=CN=NO1 GSKDBLIBBOYOFU-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000009038 pharmacological inhibition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229960003402 propatylnitrate Drugs 0.000 description 1
- YZZCJYJBCUJISI-UHFFFAOYSA-N propatylnitrate Chemical compound [O-][N+](=O)OCC(CC)(CO[N+]([O-])=O)CO[N+]([O-])=O YZZCJYJBCUJISI-UHFFFAOYSA-N 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000007363 regulatory process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940124788 therapeutic inhibitor Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229960002485 trolnitrate Drugs 0.000 description 1
- HWKQNAWCHQMZHK-UHFFFAOYSA-N trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 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
- A61K31/33—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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
Die vorliegende Erfindung betrifft die Verwendung von Arzneistoffen zur Vermeidung von Nitrat- und/oder Nitratkreuztoleranz sowie von mit diesen einhergehenden pathologischen Phänomenen.The present invention relates to the use of drugs to avoid nitrate and / or nitrate cross tolerance and pathological phenomena associated with these.
Organische Salpetersäureester wie Glyceroltrinitrat (GTN) (Murrel, Lancet: 80, 113, 151 (1879)), Pentaerythrityltetranitrat (PETN) (Risemann et al., Circulation, Vol. XVII, 22 (1958), US-PS-2370437), Isosorbid-5-mononitrat (ISMN) (DE-OS-22 21 080, DE-OS-27 51 934, DE-OS-30 28 873, DE-PS-29 03 927, DE-OS-31 02 947, DE-OS-31 24 410, EP-A1-045076, EP-A1-057847, EP-A1-059664, EP-A1-064194, EP-A1-067964, EP-A1-143507, US-PS-3886186, US-PS-4065488, US-PS-4417065, US-PS-4431829), Isosorbiddinitrat (ISDN) (L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)), Propatylnitrat (Médard, Mem. Poudres 35: 113 (1953)), Trolnitrat (FR-PS-984523) oder Nicorandil (US-PS-4 200640) und ähnliche Verbindungen sind Vasodilatatoren, die zum Teil seit Jahrzehnten schwerpunktmäßig bei der Indikation Angina pectoris bzw. ischämischer Herzkrankheit (IHK) breitesten therapeutischen Einsatz finden (Nitrangin®, Pentalong®, Monolong®, u. a.). Die galenische Verarbeitung der organischen Nitrate zu pharmazeutischen Zubereitungen zur Behandlung von Angina pectoris bzw. der ischämischen Herzkrankheit sind allgemein bekannt. Sie erfolgt nach den dem pharmazeutischen Fachmann allgemein geläufigen Arbeitsweisen und -regeln, wobei sich die Auswahl der anzuwendenden Technologien und eingesetzten galenischen Hilfsstoffe in erster Linie nach dem zu verarbeitenden Wirkstoff richtet. Hierbei sind Fragen seiner chemisch-physikalischen Eigenschaften, insbesondere die den organischen Nitraten bekanntermaßen anhaftenden Sprengstoffeigenschaften, was der Beachtung besonderer Sicherheitsvorkehrungen und besonderer Verarbeitungstechnologien bedarf, der gewählten Applikationsform, der gewünschten Wirkungsdauer sowie der Vermeidung von Arzneistoff-Hilfsstoff- Inkompatibilitäten von besonderer Bedeutung. Für Arzneimittel mit der Indikation Angina pectoris bzw. ischämischer Herzkrankheit ist vor allem die perorale, parenterale, sublinguale oder transdermale Applikation in Form von Tabletten, Dragees, Kapseln, Lösungen, Sprays oder Pflastern beschrieben (DD-A5-293492, DE-AS-26 23 800, DE-OS-33 25 652, DE-OS-33 28 094, DE-PS-40 07 705, DE-OS-40 38 203, JP-Anmeldung 59/10513 (1982)). Neben den langjährig bekannten Anwendungen nitrosierend wirkender Substanzen ist deren Verwendung zur Behandlung und Prävention von Erkrankungen beschrieben, welche ihre Ursache in pathologisch erhöhten Konzentrationen schwefelhaltiger Aminosäuren in Körperflüssigkeiten haben. Diese Krankheitszustände, hervorgerufen durch angeborene oder erworbene Defekte im Metabolismus dieser Aminosäuren und die durch erhöhte Blut- und Urinkonzentrationen besagter Aminosäuren (Homocystinurie) charakterisiert sind, werden unter dem Begriff Homocysteinämie zusammengefaßt (WO-A1-92/18002). Die Verwendung bestimmter organischer Salpetersäureester als endothelprotektive Mittel (DE-A1-44 10 997) sowie als Mittel zur Behandlung von erektiler Dysfunktion (WO-A1-96/32118) wurden kürzlich beschrieben. Den bekannten organischen Nitraten (Salpetersäureestern) haftet eine Reihe therapeutischer Nachteile an. So ist z. B. die sogenannte Nitrattoleranz zu beobachten, d. h. die Abnahme der Nitratwirkung bei hoher Dosierung oder bei Applikation längerwirkender Nitrate. Ebenso sind Nebenwirkungen wie Kopfschmerzen, Schwindel, Übelkeit, Schwächegefühl, Hautrötung sowie die Gefahr eines stärkeren Blutdruckabfalls mit reflektorischer Tachykardie belegt (Mutschler, Arzneimittelwirkungen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1991). Der Metabolismus von GTN und weiterer organischer Nitrate wurde umfangreich untersucht (Taylor et al., Prog. Drug Metab., 10 (1987), 207). Dabei wurde unter anderem festgestellt, daß organische Nitrate eine ausgesprochene oxidative Wirkung auf thiolgruppentragende Verbindungen besitzen (Boschan et al., Chem. Rev. 55, 485 (1955); Taylor et al., Progress in drug metabolism, Vol. 10, 207 (1987); Feelisch et al., Methods in Nitric Oxide Research, John Wiley & Sons, Chichester, 1996)). Weiterhin ist es allgemein akzeptiert und wissenschaftlich umfangreich belegt, daß organische Nitrate über den NO-Mechanismus unvermeidlich gegenregulatorische Prozesse, z. B. die Bildung von Angiotensin II in der vaskulären Wand, auslösen, welche durch Aktivierung des endothelialen Enzyms NADH-Synthase große Mengen an Superoxidradikalen bilden, die selbst stark oxidativ wirken sowie augenblicklich mit dem aus organischen Nitraten freigesetzten NO reagieren. Nach gängiger Auffassung wird der Zustand der Nitrattoleranz determiniert durch einen massiven Anfall von Superoxid-Radikalen, die nach dem Reaktionsschema ON. + .O2 - → ONOO zur Bildung von Peroxynitrit und dadurch zur Inaktivierung von NO führen. Diese Auffassung wird bestärkt durch die Tatsache, daß der Nitrattoleranz in begrenzter Weise durch die Gabe von Antioxidantien wie Ascorbinsäure (Vitamin C) oder Vitamin E entgegengewirkt werden kann (Münzel et al., The physiology and pathophysiology of the nitric oxide/superoxide system, Vascular Endothelium (G. V. R. Born, C. J. Schwartz edt., p. 205-220, Schattauer Verlag, New York (1997); Harrison, J. Clin. Invest. 100(9) (1997), 2153; Miyamoto et al., Proc. Soc. Exp. Biol. Med. 211 (1996), 366). Trotz dieser Erkenntnisse gelang es bisher nicht, den therapeutischen Einsatz organischer Nitrate, obwohl ihre Wirkung auf der faktisch körpereigenen und somit pharmakologisch unbedenklichen Substanz NO beruht, mit Antioxidantien erfolgreich zu kombinieren. Miyamoto et al. (Proc. Soc. Exp. Biol. Med. 211 (1996), 366) fanden, daß die Xanthinoxidase-Inhibitoren AHPP, Allopurinol und Alloxanthin bei normaler NO-Reagibilität von Gefäßen zu einer speziesabhängigen minimalen Verstärkung (AHPP) oder nahezu keiner Verstärkung (Allopurinol) der NO-vermittelten Vasorelaxation führten, wobei es unter Allopurinol sogar zu einer gesteigerten Superoxidradikalbildung kam. Im Einklang mit der gängigen Meinung folgerten sie daher, daß die Xanthinoxidase vermittels der Superoxidbildung und des damit verbundenen NO-Verbrauchs ein regulatorisches Protein für die NO-Wirkung sei. Aus stöchiometrischer Sicht (Überangebot von NO bei Nitratgabe und im Zustand der Nitrattoleranz) ist diese Erklärung jedoch unplausibel, denn eine vollständige Inaktivierung des NO durch das seitens der Xanthinoxidase gebildete Superoxid, wie sie zur Erklärung der Nitrattoleranz postuliert wird, kann nicht stattfinden (Ellis et al., Europ. J. Pharmacol. 356 (1998), 41). Außerdem zerfällt Peroxynitrit selbst wieder in Superoxid- und NO-Radikale und dient somit eigenständig als NO-Quelle (Moro et al., Br. J Pharmacol. 116 (1995), 1999). Zusätzlich vermag die Xanthinoxidase ihrerseits unter hypoxischen Bedingungen NO aus organischen Nitraten freizusetzen (Millar et al., Biochem. Biophys. Res. Commun. 249 (1998), 767). Darüber hinaus hemmt NO selbst die Xanthinoxidase (Fukahori et al., Free Rad. Res. 21 (4) (1994), 203; Cote et al., Am. J. Physiol. 271 (1996), L869). Die galenische Verarbeitung von Xanthinoxidasehemmern wie Allopurinol oder Oxipurinol ist ebenso bekannt.Organic nitric acid esters such as glycerol trinitrate (GTN) (Murrel, Lancet: 80, 113, 151 (1879)), pentaerythrityl tetranitrate (PETN) (Risemann et al., Circulation, Vol. XVII, 22 (1958), US-PS-2370437), Isosorbide-5-mononitrate (ISMN) (DE-OS-22 21 080, DE-OS-27 51 934, DE-OS-30 28 873, DE-PS-29 03 927, DE-OS-31 02 947, DE -OS-31 24 410, EP-A1-045076, EP-A1-057847, EP-A1-059664, EP-A1-064194, EP-A1-067964, EP-A1-143507, US-PS-3886186, US -PS-4065488, US-PS-4417065, US-PS-4431829), isosorbide dinitrate (ISDN) (L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)), propatyl nitrate (Médard, Mem. Poudres 35: 113) (1953)), trolnitrate (FR-PS-984523) or Nicorandil (US-PS-4 200640) and similar compounds are vasodilators, some of which have for decades been the main therapeutic use for the indication of angina pectoris or ischemic heart disease (IHK) find (Nitrangin®, Pentalong®, Monolong®, etc.). The galenic processing of the organic nitrates into pharmaceutical preparations for the treatment of angina pectoris or ischemic heart disease are generally known. It is carried out in accordance with the working methods and rules which are generally familiar to the pharmaceutical expert, the choice of the technologies to be used and the galenic auxiliaries used being based primarily on the active substance to be processed. Questions of its chemical-physical properties, in particular the explosive properties known to be attached to the organic nitrates, which require attention to special safety precautions and special processing technologies, the chosen form of application, the desired duration of action and the avoidance of drug-auxiliary incompatibilities are of particular importance. For medicinal products with the indication angina pectoris or ischemic heart disease, peroral, parenteral, sublingual or transdermal application in the form of tablets, dragees, capsules, solutions, sprays or plasters is described above (DD-A5-293492, DE-AS-26 23 800, DE-OS-33 25 652, DE-OS-33 28 094, DE-PS-40 07 705, DE-OS-40 38 203, JP application 59/10513 (1982)). In addition to the long-known applications of nitrosating substances, their use for the treatment and prevention of diseases is described which are caused by pathologically increased concentrations of sulfur-containing amino acids in body fluids. These disease states, caused by congenital or acquired defects in the metabolism of these amino acids and which are characterized by increased blood and urine concentrations of said amino acids (homocystinuria), are summarized under the term homocysteinemia (WO-A1-92 / 18002). The use of certain organic nitric acid esters as endothelial protective agents (DE-A1-44 10 997) and as agents for the treatment of erectile dysfunction (WO-A1-96 / 32118) have recently been described. The known organic nitrates (nitric acid esters) have a number of therapeutic disadvantages. So z. B. to observe the so-called nitrate tolerance, ie the decrease in the nitrate effect at high doses or when long-acting nitrates are applied. Side effects such as headache, dizziness, nausea, weakness, reddening of the skin and the risk of a greater drop in blood pressure with reflex tachycardia are also documented (Mutschler, drug effects, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1991). The metabolism of GTN and other organic nitrates has been extensively investigated (Taylor et al., Prog. Drug Metab., 10 (1987), 207). Among other things, it was found that organic nitrates have a pronounced oxidative effect on compounds bearing thiol groups (Boschan et al., Chem. Rev. 55, 485 (1955); Taylor et al., Progress in drug metabolism, Vol. 10, 207 ( 1987); Feelisch et al., Methods in Nitric Oxide Research, John Wiley & Sons, Chichester, 1996)). Furthermore, it is generally accepted and scientifically well documented that organic nitrates inevitably counteract regulatory processes, e.g. B. trigger the formation of angiotensin II in the vascular wall, which form large amounts of superoxide radicals by activation of the endothelial enzyme NADH synthase, which themselves have a strong oxidative effect and instantly react with the NO released from organic nitrates. According to popular belief, the state of nitrate tolerance is determined by a massive attack of superoxide radicals, which according to the ON reaction scheme . + . O 2 - → ONOO lead to the formation of peroxynitrite and thereby inactivation of NO. This view is reinforced by the fact that nitrate tolerance can be counteracted to a limited extent by the administration of antioxidants such as ascorbic acid (vitamin C) or vitamin E (Münzel et al., The physiology and pathophysiology of the nitric oxide / superoxide system, Vascular Endothelium (GVR Born, CJ Schwartz edt., P. 205-220, Schattauer Verlag, New York (1997); Harrison, J. Clin. Invest. 100 (9) (1997), 2153; Miyamoto et al., Proc. Soc. Exp. Biol. Med. 211 (1996), 366. Despite these findings, it has not hitherto been possible to successfully combine the therapeutic use of organic nitrates with antioxidants, although their effect is based on the fact that the substance is actually the body's own and thus pharmacologically harmless NO Miyamoto et al. (Proc. Soc. Exp. Biol. Med. 211 (1996), 366) found that the xanthine oxidase inhibitors AHPP, allopurinol and alloxanthine with normal NO reactivity of vessels to a species-dependent minimal amplification (AHP P) or almost no increase (allopurinol) of the NO-mediated vasorelaxation, and there was even increased superoxide radical formation with allopurinol. In line with current opinion, they concluded that xanthine oxidase was a regulatory protein for the NO effect by means of superoxide formation and the associated NO consumption. From a stoichiometric point of view (excess supply of NO with nitrate administration and in the state of nitrate tolerance), this explanation is implausible, because a complete inactivation of the NO by the superoxide formed by the xanthine oxidase, as postulated to explain the nitrate tolerance, cannot take place (Ellis et al., Europ. J. Pharmacol. 356 (1998), 41). In addition, peroxynitrite itself breaks down again into superoxide and NO radicals and thus independently serves as a source of NO (Moro et al., Br. J Pharmacol. 116 (1995), 1999). In addition, the xanthine oxidase in turn is able to release NO from organic nitrates under hypoxic conditions (Millar et al., Biochem. Biophys. Res. Commun. 249 (1998), 767). In addition, NO itself inhibits xanthine oxidase (Fukahori et al., Free Rad. Res. 21 (4) (1994), 203; Cote et al., Am. J. Physiol. 271 (1996), L869). The galenical processing of xanthine oxidase inhibitors such as allopurinol or oxipurinol is also known.
Aufgabe der Erfindung ist es, durch die Verwendung geeigneter Arzneistoffe der Nitrat- und/oder Nitratkreuztoleranz sowie mit diesen einhergehenden pathologischen Phänomenen entgegenzuwirken.The object of the invention is to use nitrate and / or by using suitable medicinal substances Counteract nitrate tolerance and counteract these associated pathological phenomena.
Die Aufgabe der Erfindung wird gelöst durch die Verwendung von Antagonisten purinderivatmetabolisierender Enzyme zur Verhinderung oder Minderung von Nitrat- und/oder Nitratkreuztoleranz sowie von mit diesen einhergehenden pathologischen Phänomenen. Als Antagonist im Sinne der vorliegenden Erfindung werden dabei ein mit Purinderivaten konkurrierendes Substrat oder ein Inhibitor des Enzyms aufgefaßt. Die Begriffe kompetitiver oder nicht-kompetitiver Inhibitor sind gleichfalls zur Beschreibung des Begriffs Antagonist geeignet. Eine besondere und bevorzugte Ausführungsform der Erfindung ist die Verwendung von Antagonisten der Xanthinoxidase zur Verhinderung oder Minderung von Nitrat- und/oder Nitratkreuztoleranz sowie von mit diesen einhergehenden pathologischen Phänomenen, wobei der Antagonist die vorstehend beschriebene Bedeutung haben kann. Allopurinol oder Oxipurinol sind z. B. zwei typische bereits therapeutisch angewandte Inhibitoren der Xanthinoxidase.The object of the invention is achieved through the use of antagonists Purine derivative metabolizing enzymes for preventing or reducing nitrate and / or Nitrate cross tolerance and pathological phenomena associated with this. As an antagonist For the purposes of the present invention, they become a substrate competing with purine derivatives or an inhibitor of the enzyme. The terms competitive or non-competitive inhibitor are also suitable for describing the term antagonist. A special and preferred Embodiment of the invention is the use of antagonists of xanthine oxidase for Preventing or reducing nitrate and / or nitrate cross tolerance as well as with them accompanying pathological phenomena, the antagonist being the one described above Can have meaning. Allopurinol or oxipurinol are e.g. B. two typical already therapeutic inhibitors of xanthine oxidase used.
Überraschenderweise erwies es sich, daß die Nitrattoleranz durch das erfindungsgemäße Vorgehen, z. B. durch Hemmung der Xanthinoxidase mittels Allopurinol oder seines aktiven Metaboliten Oxipurinol (Alloxanthin) antagonisierbar und die Reagibilität der betrachteten Gefäße, die im Zustand der Nitrattoleranz Gefäße eben nicht mehr adäquat auf vorhandenes NO reagieren, gegenüber Stickstoffmonoxid wiederherstellbar war. Für den Fachmann unerwartet war die Tatsache, daß sich der Zustand erloschener (nicht vorhandener) NO-Wirkung aufheben und sich die Wirkung von exogen zugeführtem NO unter kontinuierlicher Nitratgabe wiederherstellen ließ. Erstmals konnte durch die erfindungsgemäße Verwendung erkannt werden, daß nicht die Superoxid-Radikalbildung ätiologisch für die Entwicklung der Nitrattoleranz verantwortlich ist, sondern vermutlich ein gesteigerter Purinkatabolismus, verursacht durch eine Aktivierung der Xanthinoxidase. Der daraus resultierende Mangel an Adenosintriphosphat (ATP) und Guanosintriphosphat (GTP) verhindert, daß NO seine physiologische Wirkung im Zellinnern entfalten kann: Sowohl für die Guanylatzyklase, als auch für die Ca++-ATPase herrscht Substratmangel, was direkt zu einer verminderten Bereitstellung des Second Messengers zyklisches GMP (cGMP), als auch zu einem verminderten Transport von zytosolischem Calcium in die zellulären Speicherorganellen führt. Ein weiteres unerwartetes Ergebnis war, daß es im Zustand der Nitrattoleranz zu einer Aktivierung der Xanthinoxidase kam. Die hier erfindungsgemäßen Ergebnisse, daß nämlich die pharmakologische Hemmung der Xanthinoxidase mit Allopurinol und Derivaten zu einer Verbesserung der Nitratwirkung führt, laufen damit der bisherigen Sichtweise konträr zuwider. Es konnte erstmals ein seit dem über hundertjährigen therapeutischen Einsatz organischer Nitrate bestehendes Anwendungsproblem gelöst werden, womit dieser Verbindungsklasse neue Perspektiven eröffnet werden, da sie nunmehr insbesondere hinsichtlich Dosierung, Anwendungshäufigkeit, Neben- und Wechselwirkung sowie der damit verbundenen besseren Wirksamkeit vielfältiger und variabler einsetzbar sind. Beispielsweise können sie nunmehr auch in normaler oder höherer Dosierung der Dauerbehandlung der Hypertonie zugeführt werden. In allen Fällen ist der Vorteil gegeben, nicht in größerem Umfang auf teurere und mit mehr Nebenwirkungen behaftete Begleit- oder Einzelmedikationen, wie beispielsweise mit Sydnoniminderivaten, Kalziumantagonisten, ACE-Hemmern oder ähnlichen, zurückgreifen zu müssen.Surprisingly, it turned out that the nitrate tolerance by the procedure according to the invention, for. B. by inhibition of xanthine oxidase by means of allopurinol or its active metabolite oxipurinol (alloxanthin) antagonizable and the reactivity of the considered vessels, which no longer react adequately to NO in the state of nitrate tolerance, could be restored to nitrogen monoxide. It was unexpected for the person skilled in the art that the state of the extinct (not present) NO effect can be eliminated and the effect of exogenously supplied NO can be restored with continuous nitrate administration. For the first time, it was possible to recognize from the use according to the invention that it is not the formation of superoxide radicals that is etiologically responsible for the development of the tolerance to nitrate, but probably an increased purine catabolism, caused by activation of the xanthine oxidase. The resulting lack of adenosine triphosphate (ATP) and guanosine triphosphate (GTP) prevents NO from developing its physiological effect inside the cell: Both for the guanylate cyclase and for the Ca ++ -ATPase there is a lack of substrate, which leads directly to a reduced availability of the Second Messengers cyclic GMP (cGMP), as well as reduced transport of cytosolic calcium into the cellular storage organelles. Another unexpected result was that activation of the xanthine oxidase occurred in the nitrate tolerance state. The results according to the invention here, namely that the pharmacological inhibition of xanthine oxidase with allopurinol and derivatives leads to an improvement in the nitrate effect, thus run counter to the previous view. It was possible for the first time to solve an application problem that had existed for over a hundred years since therapeutic use of organic nitrates, which opened up new perspectives for this class of compounds, since they can now be used in a variety of different ways in terms of dosage, frequency of use, side effects and interactions, as well as the associated improved effectiveness. For example, they can now be given to the permanent treatment of hypertension in normal or higher doses. In all cases, there is the advantage of not having to resort to more expensive accompanying or individual medications, such as sydnonimine derivatives, calcium channel blockers, ACE inhibitors or the like, to a greater extent.
Die nachfolgenden Beispiele sollen die Erfindung hinsichtlich ihres Wesens und ihrer Ausführung näher erläutern, ohne sie jedoch in ihrem Umfang zu beschränken.The following examples are intended to illustrate the invention in terms of its nature and implementation explain, but without restricting their scope.
2083 g eines 8%igen Glyceroltrinitratadsorbats an Polyvinylalkohol (PVA) (12% Vinylacetatgehalt) werden 30 min einer Temperatur von 60°C ausgesetzt, anschließend werden sie mit 1583 g PVA (12% Vinylacetatgehalt), 1250 g Allopurinol und 84 g Magnesiumstearat gemischt und zu Tabletten mit einer mittleren Masse von 400 mg verpreßt.2083 g of an 8% glycerol trinitrate adsorbate on polyvinyl alcohol (PVA) (12% vinyl acetate content) are exposed to a temperature of 60 ° C for 30 min, then they are treated with 1583 g PVA (12% Vinyl acetate content), 1250 g allopurinol and 84 g magnesium stearate mixed and into tablets with one average mass of 400 mg pressed.
Tabletten enthaltend 20 mg, 40 mg oder Retardtabletten enthaltend 40 mg oder 60 mg Isosorbidmononitrat sowie gleichzeitig 100 mg Allopurinol werden verblistert, mit Gebrauchsinformation versehen und räumlich in einer Verpackungseinheit zusammengefaßt.Tablets containing 20 mg, 40 mg or prolonged-release tablets containing 40 mg or 60 mg Isosorbide mononitrate and 100 mg allopurinol at the same time are blistered, with package leaflet provided and summarized spatially in a packaging unit.
Retardtabletten enthaltend 20 mg, 40 mg, 60 mg, 80 mg oder 120 mg Isosorbiddinitrat sowie gleichzeitig 100 mg Allopurinol werden verblistert, mit Gebrauchsinformation versehen und räumlich in einer Verpackungseinheit zusammengefaßt.Prolonged-release tablets containing 20 mg, 40 mg, 60 mg, 80 mg or 120 mg isosorbide dinitrate as well at the same time 100 mg allopurinol are blistered, provided with instructions for use and spatially in summarized in one packaging unit.
Tabletten enthaltend 20 mg Pentaerythrityltetranitrat und 100 mg Allopurinol werden verblistert, mit Gebrauchsinformation versehen und räumlich in einer Verpackungseinheit zusammengefaßt.Tablets containing 20 mg pentaerythrityl tetranitrate and 100 mg allopurinol are blistered with Instructions for use provided and spatially summarized in a packaging unit.
Tabletten enthaltend 50 mg Pentaerythrityltetranitrat und 300 mg Allopurinol werden verblistert, mit Gebrauchsinformation versehen und räumlich in einer Verpackungseinheit zusammengefaßt.Tablets containing 50 mg pentaerythrityl tetranitrate and 300 mg allopurinol are blistered with Instructions for use provided and spatially summarized in a packaging unit.
Tabletten enthaltend 80 mg Pentaerythrityltetranitrat und 100 mg Allopurinol werden verblistert, mit Gebrauchsinformation versehen und räumlich in einer Verpackungseinheit zusammengefaßt.Tablets containing 80 mg pentaerythrityl tetranitrate and 100 mg allopurinol are blistered with Instructions for use provided and spatially summarized in a packaging unit.
Tabletten enthaltend ein Koronartherapeutikum und Tabletten enthaltend einen Xanthinoxidasehemmer werden separat verblistert, mit Gebrauchsinformation versehen und räumlich getrennt in einer Verpackungseinheit zusammengefaßt.Tablets containing a coronary therapeutic and tablets containing a xanthine oxidase inhibitor are blistered separately, provided with instructions for use and spatially separated in one Packing unit summarized.
Claims (8)
- a) ein mit Purinderivaten konkurrierendes Substrat oder
- b) ein Inhibitor
- a) a substrate competing with purine derivatives or
- b) an inhibitor
- a) ein mit Purinderivaten konkurrierendes Substrat oder
- b) ein Inhibitor
- a) a substrate competing with purine derivatives or
- b) an inhibitor
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19920775A DE19920775A1 (en) | 1999-05-05 | 1999-05-05 | Use of drugs to avoid nitrate tolerance |
| EP00943550A EP1173214A2 (en) | 1999-05-05 | 2000-05-05 | Medicinal substance utilization for preventing nitrate tolerance |
| AU58020/00A AU5802000A (en) | 1999-05-05 | 2000-05-05 | Medicinal substance utilization for preventing nitrate tolerance |
| PL00352024A PL352024A1 (en) | 1999-05-05 | 2000-05-05 | Medicinal substance utilization for preventing nitrate tolerance |
| PCT/DE2000/001413 WO2000067731A2 (en) | 1999-05-05 | 2000-05-05 | Medicinal substance utilization for preventing nitrate tolerance |
| BG105955A BG105955A (en) | 1999-05-05 | 2001-09-26 | Medicinal substance utilization for preventing nitrate tolerance |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19920775A DE19920775A1 (en) | 1999-05-05 | 1999-05-05 | Use of drugs to avoid nitrate tolerance |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19920775A1 true DE19920775A1 (en) | 2000-11-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| DE19920775A Withdrawn DE19920775A1 (en) | 1999-05-05 | 1999-05-05 | Use of drugs to avoid nitrate tolerance |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1173214A2 (en) |
| AU (1) | AU5802000A (en) |
| BG (1) | BG105955A (en) |
| DE (1) | DE19920775A1 (en) |
| PL (1) | PL352024A1 (en) |
| WO (1) | WO2000067731A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002053144A1 (en) * | 2001-01-05 | 2002-07-11 | Parker John D | Regulation of organic nitrate tolerance |
| US20120135078A1 (en) * | 2009-05-29 | 2012-05-31 | University of Dindee | Angina treatment |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3839826A1 (en) * | 1988-11-25 | 1990-05-31 | Henning Berlin Gmbh | ALKALI AND EARTH ALKALINE SALTS OF OXIPURINOL IN AMORPHER OR CRYSTALLINE FORM AS A MEDICINE FOR TREATING HYPERURICAEMIA AND Gout |
-
1999
- 1999-05-05 DE DE19920775A patent/DE19920775A1/en not_active Withdrawn
-
2000
- 2000-05-05 EP EP00943550A patent/EP1173214A2/en not_active Withdrawn
- 2000-05-05 AU AU58020/00A patent/AU5802000A/en not_active Abandoned
- 2000-05-05 WO PCT/DE2000/001413 patent/WO2000067731A2/en not_active Ceased
- 2000-05-05 PL PL00352024A patent/PL352024A1/en not_active Application Discontinuation
-
2001
- 2001-09-26 BG BG105955A patent/BG105955A/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3839826A1 (en) * | 1988-11-25 | 1990-05-31 | Henning Berlin Gmbh | ALKALI AND EARTH ALKALINE SALTS OF OXIPURINOL IN AMORPHER OR CRYSTALLINE FORM AS A MEDICINE FOR TREATING HYPERURICAEMIA AND Gout |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002053144A1 (en) * | 2001-01-05 | 2002-07-11 | Parker John D | Regulation of organic nitrate tolerance |
| US6537992B2 (en) | 2001-01-05 | 2003-03-25 | John D. Parker | Regulation of organic nitrate tolerance |
| US20120135078A1 (en) * | 2009-05-29 | 2012-05-31 | University of Dindee | Angina treatment |
Also Published As
| Publication number | Publication date |
|---|---|
| PL352024A1 (en) | 2003-07-14 |
| EP1173214A2 (en) | 2002-01-23 |
| BG105955A (en) | 2002-06-28 |
| AU5802000A (en) | 2000-11-21 |
| WO2000067731A3 (en) | 2001-01-25 |
| WO2000067731A2 (en) | 2000-11-16 |
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