DE69814618T2 - Behandlung von infarkten durch inhibierung von nf-kappab - Google Patents
Behandlung von infarkten durch inhibierung von nf-kappab Download PDFInfo
- Publication number
- DE69814618T2 DE69814618T2 DE69814618T DE69814618T DE69814618T2 DE 69814618 T2 DE69814618 T2 DE 69814618T2 DE 69814618 T DE69814618 T DE 69814618T DE 69814618 T DE69814618 T DE 69814618T DE 69814618 T2 DE69814618 T2 DE 69814618T2
- Authority
- DE
- Germany
- Prior art keywords
- use according
- inhibitor
- inhibitors
- activation
- proteasome
- 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.)
- Expired - Lifetime
Links
- 230000002401 inhibitory effect Effects 0.000 title 1
- 239000003112 inhibitor Substances 0.000 claims abstract description 72
- 208000028867 ischemia Diseases 0.000 claims abstract description 38
- 230000034190 positive regulation of NF-kappaB transcription factor activity Effects 0.000 claims abstract description 38
- 229940079156 Proteasome inhibitor Drugs 0.000 claims abstract description 33
- 239000003207 proteasome inhibitor Substances 0.000 claims abstract description 33
- 102000044159 Ubiquitin Human genes 0.000 claims abstract description 20
- 108090000848 Ubiquitin Proteins 0.000 claims abstract description 20
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 230000037361 pathway Effects 0.000 claims abstract description 9
- 206010061216 Infarction Diseases 0.000 claims description 44
- 230000007574 infarction Effects 0.000 claims description 44
- 241000124008 Mammalia Species 0.000 claims description 25
- 102000018745 NF-KappaB Inhibitor alpha Human genes 0.000 claims description 23
- 108010052419 NF-KappaB Inhibitor alpha Proteins 0.000 claims description 23
- 230000000302 ischemic effect Effects 0.000 claims description 19
- 206010063837 Reperfusion injury Diseases 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 17
- 230000026731 phosphorylation Effects 0.000 claims description 17
- 238000006366 phosphorylation reaction Methods 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 15
- 230000006378 damage Effects 0.000 claims description 14
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 11
- DAQAKHDKYAWHCG-RWTHQLGUSA-N lactacystin Chemical group CC(=O)N[C@H](C(O)=O)CSC(=O)[C@]1([C@@H](O)C(C)C)NC(=O)[C@H](C)[C@@H]1O DAQAKHDKYAWHCG-RWTHQLGUSA-N 0.000 claims description 11
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 claims description 10
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 claims description 10
- 229960000187 tissue plasminogen activator Drugs 0.000 claims description 10
- 230000002490 cerebral effect Effects 0.000 claims description 9
- 208000010125 myocardial infarction Diseases 0.000 claims description 8
- 108090000695 Cytokines Proteins 0.000 claims description 7
- -1 peptidyl aldehyde Chemical class 0.000 claims description 7
- 102000004127 Cytokines Human genes 0.000 claims description 6
- 239000003146 anticoagulant agent Substances 0.000 claims description 6
- 230000001413 cellular effect Effects 0.000 claims description 6
- 230000002537 thrombolytic effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000002792 vascular Effects 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 229940127219 anticoagulant drug Drugs 0.000 claims description 3
- 229920000447 polyanionic polymer Polymers 0.000 claims description 3
- 230000000770 proinflammatory effect Effects 0.000 claims description 3
- 150000003431 steroids Chemical class 0.000 claims description 3
- 229960000103 thrombolytic agent Drugs 0.000 claims description 3
- 206010030113 Oedema Diseases 0.000 claims description 2
- 238000010606 normalization Methods 0.000 claims description 2
- 210000000748 cardiovascular system Anatomy 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 230000001706 oxygenating effect Effects 0.000 claims 1
- 125000001151 peptidyl group Chemical group 0.000 claims 1
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 abstract description 7
- 108010057466 NF-kappa B Proteins 0.000 description 18
- 208000006011 Stroke Diseases 0.000 description 18
- 210000001519 tissue Anatomy 0.000 description 17
- 230000010410 reperfusion Effects 0.000 description 14
- 235000010338 boric acid Nutrition 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 210000003657 middle cerebral artery Anatomy 0.000 description 12
- 230000009467 reduction Effects 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 11
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 11
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 11
- 241000700159 Rattus Species 0.000 description 11
- 230000004913 activation Effects 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 230000000926 neurological effect Effects 0.000 description 11
- 230000019491 signal transduction Effects 0.000 description 11
- 102000003945 NF-kappa B Human genes 0.000 description 10
- 210000000440 neutrophil Anatomy 0.000 description 10
- 206010053648 Vascular occlusion Diseases 0.000 description 9
- 239000004327 boric acid Substances 0.000 description 9
- 208000021331 vascular occlusion disease Diseases 0.000 description 9
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000007971 neurological deficit Effects 0.000 description 8
- 208000007536 Thrombosis Diseases 0.000 description 7
- 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 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 208000032843 Hemorrhage Diseases 0.000 description 5
- DAQAKHDKYAWHCG-UHFFFAOYSA-N Lactacystin Natural products CC(=O)NC(C(O)=O)CSC(=O)C1(C(O)C(C)C)NC(=O)C(C)C1O DAQAKHDKYAWHCG-UHFFFAOYSA-N 0.000 description 5
- 208000034158 bleeding Diseases 0.000 description 5
- 230000000740 bleeding effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 206010043647 Thrombotic Stroke Diseases 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000034512 ubiquitination Effects 0.000 description 4
- 238000010798 ubiquitination Methods 0.000 description 4
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 3
- 239000004677 Nylon Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 108010023197 Streptokinase Proteins 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 125000005619 boric acid group Chemical class 0.000 description 3
- 230000005779 cell damage Effects 0.000 description 3
- 238000004040 coloring Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000010191 image analysis Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000003447 ipsilateral effect Effects 0.000 description 3
- 210000004165 myocardium Anatomy 0.000 description 3
- 229920001778 nylon Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000013222 sprague-dawley male rat Methods 0.000 description 3
- 229960005202 streptokinase Drugs 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- 208000010444 Acidosis Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 108010024212 E-Selectin Proteins 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 206010058558 Hypoperfusion Diseases 0.000 description 2
- 239000004395 L-leucine Substances 0.000 description 2
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 2
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 2
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 2
- 230000007950 acidosis Effects 0.000 description 2
- 208000026545 acidosis disease Diseases 0.000 description 2
- 230000003501 anti-edematous effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000006931 brain damage Effects 0.000 description 2
- 231100000874 brain damage Toxicity 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 208000037887 cell injury Diseases 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 231100000318 excitotoxic Toxicity 0.000 description 2
- 230000003492 excitotoxic effect Effects 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 229960003136 leucine Drugs 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000037420 neurological improvement Effects 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 229960005356 urokinase Drugs 0.000 description 2
- FWPWHHUJACGNMZ-NBBQQVJHSA-N (1s,2r,5r)-5-[(1s)-1-hydroxy-2-methylpropyl]-2-methyl-7-oxa-4-azabicyclo[3.2.0]heptane-3,6-dione Chemical compound N1C(=O)[C@H](C)[C@@H]2OC(=O)[C@@]21[C@@H](O)C(C)C FWPWHHUJACGNMZ-NBBQQVJHSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010051392 Diapedesis Diseases 0.000 description 1
- 229940127337 Glycine Antagonists Drugs 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 208000008574 Intracranial Hemorrhages Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- AUEJLPRZGVVDNU-UHFFFAOYSA-N N-L-tyrosyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-UHFFFAOYSA-N 0.000 description 1
- 208000006079 Near drowning Diseases 0.000 description 1
- 206010060860 Neurological symptom Diseases 0.000 description 1
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 description 1
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 1
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N Nitrogen oxide(NO) Natural products O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 108010035766 P-Selectin Proteins 0.000 description 1
- 102100023472 P-selectin Human genes 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 108010001859 Proto-Oncogene Proteins c-rel Proteins 0.000 description 1
- 102000000850 Proto-Oncogene Proteins c-rel Human genes 0.000 description 1
- 101150070524 Rel gene Proteins 0.000 description 1
- 208000003028 Stuttering Diseases 0.000 description 1
- 101710195626 Transcriptional activator protein Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 1
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000001964 calcium overload Effects 0.000 description 1
- 108010079785 calpain inhibitors Proteins 0.000 description 1
- 230000004670 cellular proteolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000003073 embolic effect Effects 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 108091006086 inhibitor proteins Proteins 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000004171 ischemic cascade Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000009251 neurologic dysfunction Effects 0.000 description 1
- 208000015015 neurological dysfunction Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 210000000063 presynaptic terminal Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000026938 proteasomal ubiquitin-dependent protein catabolic process Effects 0.000 description 1
- 230000004895 regional blood flow Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 108700021653 rel Genes Proteins 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000005167 vascular cell Anatomy 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Gastroenterology & Hepatology (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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Non-Silver Salt Photosensitive Materials And Non-Silver Salt Photography (AREA)
- Organic Insulating Materials (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Treatments For Attaching Organic Compounds To Fibrous Goods (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Investigation Of Foundation Soil And Reinforcement Of Foundation Soil By Compacting Or Drainage (AREA)
- Artificial Filaments (AREA)
- Transplanting Machines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80193697A | 1997-02-15 | 1997-02-15 | |
| US801936 | 1997-02-15 | ||
| US98833997A | 1997-12-03 | 1997-12-03 | |
| US988339 | 1997-12-03 | ||
| PCT/US1998/003077 WO1998035691A1 (en) | 1997-02-15 | 1998-02-17 | Treatment of infarcts through inhibition of nf-kappab |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69814618D1 DE69814618D1 (de) | 2003-06-18 |
| DE69814618T2 true DE69814618T2 (de) | 2004-03-25 |
Family
ID=27122399
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69814618T Expired - Lifetime DE69814618T2 (de) | 1997-02-15 | 1998-02-17 | Behandlung von infarkten durch inhibierung von nf-kappab |
Country Status (14)
| Country | Link |
|---|---|
| US (3) | US6271199B2 (https=) |
| EP (1) | EP0979096B1 (https=) |
| JP (1) | JP2001511814A (https=) |
| CN (1) | CN1159061C (https=) |
| AT (1) | ATE240113T1 (https=) |
| AU (1) | AU741802B2 (https=) |
| CA (1) | CA2281224A1 (https=) |
| DE (1) | DE69814618T2 (https=) |
| ES (1) | ES2196547T3 (https=) |
| IL (1) | IL131410A0 (https=) |
| NO (1) | NO321203B1 (https=) |
| NZ (1) | NZ337364A (https=) |
| PT (1) | PT979096E (https=) |
| WO (1) | WO1998035691A1 (https=) |
Families Citing this family (67)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6890909B1 (en) * | 1997-07-04 | 2005-05-10 | Fujisawa Pharmaceutical Co., Ltd. | Brain-protective agent |
| US6133308A (en) * | 1997-08-15 | 2000-10-17 | Millennium Pharmaceuticals, Inc. | Synthesis of clasto-lactacystin beta-lactone and analogs thereof |
| US20090042807A1 (en) * | 1998-05-20 | 2009-02-12 | Nisar Ahmed Khan | Oligopeptide treatment of ischemia reperfusion injury |
| US6844315B2 (en) | 1998-05-20 | 2005-01-18 | Erasmus Universiteit Rotterdam | Immunoregulator |
| US6921751B1 (en) | 1998-05-20 | 2005-07-26 | Erasmus Universiteit Rotterdam | Immunoregulator |
| US7175679B2 (en) | 2001-03-29 | 2007-02-13 | Biotempt B.V. | Oligopeptide treatment of NF-κB mediated inflammation |
| EP1138692A1 (en) | 2000-03-29 | 2001-10-04 | Erasmus Universiteit Rotterdam | Fragments of human chorionic gonadotropin (hcg) as immunoregulator |
| US8680059B2 (en) * | 1998-05-20 | 2014-03-25 | Biotempt B.V. | Oligopeptide acetate and formulations thereof |
| US20030220258A1 (en) * | 2001-12-21 | 2003-11-27 | Robbert Benner | Treatment of ischemic events |
| EP1223948A2 (en) * | 1999-09-13 | 2002-07-24 | CHARLOTTE-MECKLENBURG HOSPITAL doing business as Carolinas Medical Center | Method of inhibiting nf-kappa-b with heparin, for treating cardiovascular diseases and inflammations |
| US7358330B2 (en) | 2001-03-29 | 2008-04-15 | Biotempt B.V. | Immunoregulatory compositions |
| US7576174B2 (en) | 2000-03-29 | 2009-08-18 | Biotempt B.V. | Compositions capable of reducing elevated blood urea concentration |
| EP1300418A1 (en) | 2001-10-04 | 2003-04-09 | Erasmus Universiteit Rotterdam | Gene regulation by oligopeptides |
| USRE43279E1 (en) | 2000-03-29 | 2012-03-27 | Biotemp B.V. | Compositions capable of reducing elevated blood urea concentration |
| US6713459B1 (en) * | 2000-04-28 | 2004-03-30 | East Tennessee State University | Methods for the prophylactic and therapeutic treatment of cardiac tissue damage |
| JP4395549B2 (ja) * | 2000-11-16 | 2010-01-13 | ザ レジェンツ オブ ザ ユニヴァースティ オブ カリフォルニア | 薬物及び発酵生成物の発見のための海洋放線菌分類群 |
| ES2571219T3 (es) | 2001-01-25 | 2024-09-23 | The United States Of America Represented By The Sec Dep Of Health And Human Services | Formulación de compuestos de ácido borónico |
| BR0209883A (pt) | 2001-05-21 | 2004-06-08 | Alcon Inc | Uso de inibidores da proteasoma para o tratamento de distúrbios do olho seco |
| US7112588B2 (en) | 2001-05-21 | 2006-09-26 | Alcon, Inc. | Use of proteasome inhibitors to treat dry eye disorders |
| NZ532310A (en) * | 2001-10-05 | 2007-02-23 | Combinatorx Inc | Combinations comprising a tetra-substituted pyrimidopyrimidine and a corticosteroid for the treatment of immunoinflammatory disorders |
| CA2466928A1 (en) * | 2001-12-10 | 2003-07-03 | Yansheng Du | Treatment of neurodegenerative and cardiovascular disorders |
| US20080318871A1 (en) * | 2001-12-21 | 2008-12-25 | Khan Nisar A | Treatment of neurological disorders |
| US20080242837A1 (en) * | 2001-12-21 | 2008-10-02 | Khan Nisar A | Peptide compositions |
| US7560433B2 (en) | 2001-12-21 | 2009-07-14 | Biotempt B.V. | Treatment of multiple sclerosis (MS) |
| US7786084B2 (en) * | 2001-12-21 | 2010-08-31 | Biotempt B.V. | Treatment of burns |
| US7501391B2 (en) | 2001-12-21 | 2009-03-10 | Biotempt B.V. | Treatment of transplant survival |
| US7176232B2 (en) | 2002-06-24 | 2007-02-13 | The Regents Of The University Of California | Salinosporamides and methods for use thereof |
| US7517529B2 (en) * | 2003-04-08 | 2009-04-14 | Biotempt B.V. | Treatment of type I diabetes |
| US20050004164A1 (en) * | 2003-04-30 | 2005-01-06 | Caggiano Thomas J. | 2-Cyanopropanoic acid amide and ester derivatives and methods of their use |
| KR20060026052A (ko) * | 2003-06-20 | 2006-03-22 | 니리어스 파마슈티컬즈, 인코퍼레이션 | 암, 염증 및 감염성 질환의 치료를 위한 [3.2.0]헤테로사이클릭 화합물 및 그 유사체의 사용방법 |
| EP2441767B1 (en) * | 2003-06-20 | 2015-06-10 | The Regents of The University of California | Salinosporamides and methods for use thereof |
| WO2005023187A2 (en) | 2003-08-28 | 2005-03-17 | Kem David C | Inhibitor of cardiac tachyarrhythmias |
| US20090227505A1 (en) * | 2004-01-07 | 2009-09-10 | Biotempt B.V. | Methods and uses for protein breakdown products |
| SE0400399D0 (sv) * | 2004-02-20 | 2004-02-20 | Index Pharmaceuticals Ab | Methods and compositions for the treatment or prevention of secondary ischemic injury |
| US7579371B2 (en) | 2004-04-30 | 2009-08-25 | Nereus Pharmaceuticals, Inc. | Methods of using [3.2.0] heterocyclic compounds and analogs thereof |
| BRPI0509824A (pt) | 2004-04-30 | 2007-10-09 | Nereus Pharmaceuticals Inc | compostos heterocìclicos [3.2.0] e métodos de uso dos mesmos |
| US7425580B2 (en) * | 2004-05-19 | 2008-09-16 | Wyeth | (Diaryl-methyl)-malononitriles and their use as estrogen receptor ligands |
| US20060008454A1 (en) * | 2004-07-07 | 2006-01-12 | Dr. Helmut Brunar | Use of a compound for enhancing the expression of membrane proteins on the cell surface |
| WO2006002453A2 (en) * | 2004-07-07 | 2006-01-12 | Biodevelops Pharma Entwicklung Gmbh | Use of a deubiquitinating compound for enhancing the expression of membrane proteins on the cell surface |
| EP1785431B1 (en) * | 2004-08-30 | 2016-01-20 | Toray Industries, Inc. | Fractionation apparatus |
| WO2006062732A2 (en) * | 2004-11-19 | 2006-06-15 | Synta Pharmaceuticals Corp. | Compounds acting at the centrosome |
| SG157365A1 (en) * | 2004-12-03 | 2009-12-29 | Dana Farber Cancer Inst Inc | Compositions and methods for treating neoplastic diseases |
| JP4846799B2 (ja) * | 2005-07-05 | 2011-12-28 | バイオテンプト ベー．フェー． | 腫瘍の治療 |
| WO2007002972A2 (en) * | 2005-07-06 | 2007-01-11 | Biodevelops Pharma Entwicklung Gmbh | Use of a compound for enhancing the expression of membrane proteins on the cell surface |
| WO2007011757A1 (en) * | 2005-07-14 | 2007-01-25 | Myogen, Inc. | Use of inhibitors of the ubiquitin proteasome pathway for increasing contractility of the heart |
| US7691896B2 (en) * | 2005-08-10 | 2010-04-06 | President And Fellows Of Harvard College | Analogs of salinosporamide A |
| EP1864692A1 (en) * | 2006-06-07 | 2007-12-12 | Biotempt B.V. | Use of peptides for the control of radiation injury |
| ES2293834B1 (es) * | 2006-07-20 | 2009-02-16 | Consejo Superior Investig. Cientificas | Compuesto con actividad inhibidora de las interacciones ubc13-uev, composiciones farmaceuticas que lo comprenden y sus aplicaciones terapeuticas. |
| WO2008095195A2 (en) * | 2007-02-02 | 2008-08-07 | Nereus Pharmaceuticals, Inc. | Lyophilized formulations of salinosporamide a |
| DK2120991T3 (da) * | 2007-02-12 | 2014-04-28 | Biotempt Bv | Behandling af traumatisk blødning med korte oligopeptider |
| WO2008137780A2 (en) * | 2007-05-04 | 2008-11-13 | Nereus Pharmaceuticals, Inc. | Use of [3.2.0] heterocyclic compounds and analogs thereof for treating infectious diseases |
| US7442830B1 (en) | 2007-08-06 | 2008-10-28 | Millenium Pharmaceuticals, Inc. | Proteasome inhibitors |
| US8394816B2 (en) | 2007-12-07 | 2013-03-12 | Irene Ghobrial | Methods of using [3.2.0] heterocyclic compounds and analogs thereof in treating Waldenstrom's Macroglobulinemia |
| CN102089312A (zh) * | 2008-05-12 | 2011-06-08 | 尼瑞斯药品公司 | 作为蛋白酶体抑制剂的Salinosporamide衍生物 |
| EP2730579A1 (en) | 2008-06-17 | 2014-05-14 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
| AR075090A1 (es) | 2008-09-29 | 2011-03-09 | Millennium Pharm Inc | Derivados de acido 1-amino-2-ciclobutiletilboronico inhibidores de proteosoma,utiles como agentes anticancerigenos, y composiciones farmaceuticas que los comprenden. |
| EP2305285A1 (en) | 2009-09-29 | 2011-04-06 | Julius-Maximilians-Universität Würzburg | Means and methods for treating ischemic conditions |
| WO2011090159A1 (ja) | 2010-01-22 | 2011-07-28 | 独立行政法人科学技術振興機構 | 蛋白質の分解活性を測定するためのプローブ試薬 |
| MX2012011298A (es) | 2010-03-31 | 2012-11-06 | Millennium Pharm Inc | Derivados del acido 1-amino-2-ciclopropiletilboronico. |
| CN104411316B (zh) | 2012-05-09 | 2018-05-01 | 坎泰克斯制药股份有限公司 | 骨髓抑制的治疗 |
| CA2909519A1 (en) | 2013-04-16 | 2014-10-23 | Cipla Limited | Process for the preparation of bortezomib mannitol ester |
| CN111116622A (zh) | 2014-02-03 | 2020-05-08 | 俄亥俄州创新基金会 | 硼酸酯和其药物制剂 |
| MA39964A (fr) | 2014-05-20 | 2015-11-26 | Millennium Pharm Inc | Inhibiteurs du protéasome contenant du bore destinés à être utilisés après une thérapie contre le cancer primaire |
| US10052346B2 (en) | 2015-02-17 | 2018-08-21 | Cantex Pharmaceuticals, Inc. | Treatment of myelodysplastic syndromes with 2-O and,or 3-O desulfated heparinoids |
| EP3270891A1 (en) | 2015-03-17 | 2018-01-24 | Leon-Nanodrugs GmbH | Nanoparticles comprising a stabilized boronic acid compound |
| EP3700567A4 (en) * | 2017-10-26 | 2021-09-29 | The Regents of The University of California | INHIBITION OF OXIDATION-SPECIFIC EPITOPIA TO TREAT REPERFUSION ISCHEMIC DAMAGE |
| KR20250173600A (ko) | 2023-03-17 | 2025-12-10 | 옥시토프 파마 비.브이. | 항-포스포콜린 항체 및 그 사용 방법 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU661270B2 (en) | 1990-03-05 | 1995-07-20 | Cephalon, Inc. | Chymotrypsin-like proteases and their inhibitors |
| US5693617A (en) | 1994-03-15 | 1997-12-02 | Proscript, Inc. | Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein |
| US6660268B1 (en) | 1994-03-18 | 2003-12-09 | The President And Fellows Of Harvard College | Proteasome regulation of NF-KB activity |
| US6083903A (en) * | 1994-10-28 | 2000-07-04 | Leukosite, Inc. | Boronic ester and acid compounds, synthesis and uses |
| US6335358B1 (en) * | 1995-04-12 | 2002-01-01 | President And Fellows Of Harvard College | Lactacystin analogs |
| ES2285712T3 (es) | 1995-05-12 | 2007-11-16 | Anges Mg, Inc. | Medicamento para la terapia y profilaxis de varias enfermedades relacionadas con nf-kappa b. |
| US5942494A (en) | 1995-10-06 | 1999-08-24 | The Trustees Of Columbia University In The City Of New York | Stimulation of gene expression and synthesis of heat shock protein 72/73 (HSP 70) |
| DE69728880T2 (de) | 1996-03-19 | 2005-04-28 | Millennium Pharmaceuticals, Inc., Cambridge | KINASE FÜR DIE STELLEN-SPEZIFISCHE PHOSPHORYLIERUNG VON I-kappa-B-alpha |
| US6133308A (en) | 1997-08-15 | 2000-10-17 | Millennium Pharmaceuticals, Inc. | Synthesis of clasto-lactacystin beta-lactone and analogs thereof |
-
1998
- 1998-02-17 US US09/285,170 patent/US6271199B2/en not_active Expired - Lifetime
- 1998-02-17 EP EP98906511A patent/EP0979096B1/en not_active Expired - Lifetime
- 1998-02-17 NZ NZ337364A patent/NZ337364A/en unknown
- 1998-02-17 WO PCT/US1998/003077 patent/WO1998035691A1/en not_active Ceased
- 1998-02-17 CA CA002281224A patent/CA2281224A1/en not_active Abandoned
- 1998-02-17 JP JP53600398A patent/JP2001511814A/ja not_active Ceased
- 1998-02-17 CN CNB988033968A patent/CN1159061C/zh not_active Expired - Fee Related
- 1998-02-17 ES ES98906511T patent/ES2196547T3/es not_active Expired - Lifetime
- 1998-02-17 DE DE69814618T patent/DE69814618T2/de not_active Expired - Lifetime
- 1998-02-17 PT PT98906511T patent/PT979096E/pt unknown
- 1998-02-17 AT AT98906511T patent/ATE240113T1/de not_active IP Right Cessation
- 1998-02-17 AU AU61719/98A patent/AU741802B2/en not_active Ceased
- 1998-02-17 IL IL13141098A patent/IL131410A0/xx not_active IP Right Cessation
-
1999
- 1999-08-16 NO NO19993935A patent/NO321203B1/no unknown
-
2001
- 2001-07-30 US US09/919,116 patent/US20010053760A1/en not_active Abandoned
-
2002
- 2002-04-08 US US10/118,526 patent/US20030069189A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0979096A1 (en) | 2000-02-16 |
| CN1250376A (zh) | 2000-04-12 |
| EP0979096B1 (en) | 2003-05-14 |
| US20010053760A1 (en) | 2001-12-20 |
| ES2196547T3 (es) | 2003-12-16 |
| DE69814618D1 (de) | 2003-06-18 |
| NO993935D0 (no) | 1999-08-16 |
| CA2281224A1 (en) | 1998-08-20 |
| PT979096E (pt) | 2003-09-30 |
| CN1159061C (zh) | 2004-07-28 |
| AU6171998A (en) | 1998-09-08 |
| WO1998035691A1 (en) | 1998-08-20 |
| US6271199B2 (en) | 2001-08-07 |
| US20010002391A1 (en) | 2001-05-31 |
| NZ337364A (en) | 2001-06-29 |
| AU741802B2 (en) | 2001-12-13 |
| NO321203B1 (no) | 2006-04-03 |
| JP2001511814A (ja) | 2001-08-14 |
| ATE240113T1 (de) | 2003-05-15 |
| NO993935L (no) | 1999-10-04 |
| HK1025266A1 (en) | 2000-11-10 |
| US20030069189A1 (en) | 2003-04-10 |
| IL131410A0 (en) | 2001-01-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69814618T2 (de) | Behandlung von infarkten durch inhibierung von nf-kappab | |
| WO1998035691A9 (en) | Treatment of infarcts through inhibition of nf-kappab | |
| DE68916387T2 (de) | Verwendung von Nalmefen oder Naltrexon bei der Behandlung von Autoimmunerkrankungen. | |
| DE69636308T2 (de) | Tumornekrosefaktor alpha (tnf-alpha) hemmende arzneistoffe | |
| DE69028542T2 (de) | Felbamat zur Behandlung der Lennox-Gastaut syndrome | |
| Novak et al. | Effects of a single large intravenous dose of methylprednisolone sodium succinate | |
| US5310562A (en) | Composition and method for reparation and prevention of fibrotic lesions | |
| EP0458861B1 (en) | Composition for reparation and prevention of fibrotic lesions | |
| DE69711649T2 (de) | P1, p4-dithio-p2,p3-monochloromethylen 5',5'''-diadenosin-p1,p4-tetraphosphat verwendet als anti-thrombose mittel | |
| DE69506197T2 (de) | Verwendung eines Ascorbyl-tocopherylphosphats zur Herstellung eines Arzneimittels zur Behandlung der Pankreatitis | |
| Borel | Effect of some drugs on the chemotaxis of rabbit neutrophils in vitro | |
| Lauerma et al. | Topical FK506–clinical potential or laboratory curiosity? | |
| DE3390116C2 (de) | Verbesserte, Koffein enthaltende, analgetische und antiinflammatorische Mittel | |
| DE69413090T2 (de) | Verwendung von 5-Amino-Phthaloylhydrazid als antihypoxisches und defensives Mittel | |
| DE60026491T2 (de) | Melagatran zur behandlung von entzündungen | |
| Dow et al. | The effects of some anticonvulsant drugs on cobalt‐induced epilepsy | |
| DE2206570B2 (de) | Verwendung von ( + ) - Catechin | |
| EP1001756B1 (de) | Synergistisch wirkende zusammensetzungen zur selektiven bekämpfung von tumorgewebe | |
| Pumain | Electrophysiological abnormalities in chronic epileptogenic foci: an intracellular study | |
| DE69903964T2 (de) | Chemokin rezeptor antagonist und cyclosporin in kombinationstherapie | |
| Levi-Schaffer et al. | Nedocromil sodium ameliorates skin manifestations in a murine model of chronic graft-versus-host disease | |
| DE60006385T2 (de) | Pharmazeutische zusammensetzungen mit cholesterinsenkender wirkung, enthaltend 8-chloro-3(beta-diethyl-aminoethyl)-4-methyl-7-ethoxycarbonyl-methoxy cumarin und dessen salze | |
| DE3888144T2 (de) | Gehirn-Neuron schützendes Mittel, enthaltend eine Dihydropyridin-Verbindung. | |
| DE60103857T2 (de) | Verwendung von indoloquinoxalinen zur behandlung der multiplen sklerose | |
| Golden et al. | Penicillin spikes in rats: limitations of a simple model for the study of anticonvulsants |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition |