WO1999043308A2 - Treating pulmonary hypertension through tenascin suppression and elastase inhibition - Google Patents
Treating pulmonary hypertension through tenascin suppression and elastase inhibition Download PDFInfo
- Publication number
- WO1999043308A2 WO1999043308A2 PCT/IB1999/000413 IB9900413W WO9943308A2 WO 1999043308 A2 WO1999043308 A2 WO 1999043308A2 IB 9900413 W IB9900413 W IB 9900413W WO 9943308 A2 WO9943308 A2 WO 9943308A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pulmonary hypertension
- elastase
- tenascin
- inhibitor
- treating pulmonary
- Prior art date
Links
- 208000002815 pulmonary hypertension Diseases 0.000 title claims abstract description 31
- 102000016387 Pancreatic elastase Human genes 0.000 title claims abstract description 19
- 108010067372 Pancreatic elastase Proteins 0.000 title claims abstract description 19
- 102000007000 Tenascin Human genes 0.000 title claims abstract description 19
- 108010008125 Tenascin Proteins 0.000 title claims abstract description 19
- 230000005764 inhibitory process Effects 0.000 title abstract description 3
- 230000001629 suppression Effects 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000003602 elastase inhibitor Substances 0.000 claims abstract description 15
- 229940122858 Elastase inhibitor Drugs 0.000 claims abstract description 7
- 102000002149 Elafin Human genes 0.000 claims abstract description 4
- 108010015972 Elafin Proteins 0.000 claims abstract description 4
- 229930064664 L-arginine Natural products 0.000 claims abstract description 4
- 235000014852 L-arginine Nutrition 0.000 claims abstract description 4
- MDCUNMLZLNGCQA-HWOAGHQOSA-N elafin Chemical group N([C@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H]1C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H]2CSSC[C@H]3C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](CSSC[C@H]4C(=O)N5CCC[C@H]5C(=O)NCC(=O)N[C@H](C(N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H]5N(CCC5)C(=O)[C@H]5N(CCC5)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)[C@H](C)NC2=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N4)C(=O)N[C@@H](CSSC1)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N3)=O)[C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)C(C)C)C(C)C)C(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)N MDCUNMLZLNGCQA-HWOAGHQOSA-N 0.000 claims abstract description 4
- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 claims abstract description 3
- 239000003112 inhibitor Substances 0.000 claims description 19
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 claims description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 201000008312 primary pulmonary hypertension Diseases 0.000 claims description 3
- 208000037812 secondary pulmonary hypertension Diseases 0.000 claims description 3
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 abstract description 5
- 230000009467 reduction Effects 0.000 abstract description 4
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 20
- 238000009472 formulation Methods 0.000 description 17
- 150000001875 compounds Chemical class 0.000 description 14
- 101000737561 Rattus norvegicus Complement factor D Proteins 0.000 description 13
- 241000700159 Rattus Species 0.000 description 10
- 210000001147 pulmonary artery Anatomy 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- QVCMHGGNRFRMAD-XFGHUUIASA-N monocrotaline Chemical compound C1OC(=O)[C@](C)(O)[C@@](O)(C)[C@@H](C)C(=O)O[C@@H]2CCN3[C@@H]2C1=CC3 QVCMHGGNRFRMAD-XFGHUUIASA-N 0.000 description 6
- 230000004872 arterial blood pressure Effects 0.000 description 5
- QPNKYNYIKKVVQB-UHFFFAOYSA-N crotaleschenine Natural products O1C(=O)C(C)C(C)C(C)(O)C(=O)OCC2=CCN3C2C1CC3 QPNKYNYIKKVVQB-UHFFFAOYSA-N 0.000 description 5
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 5
- 229960001123 epoprostenol Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- QVCMHGGNRFRMAD-UHFFFAOYSA-N monocrotaline Natural products C1OC(=O)C(C)(O)C(O)(C)C(C)C(=O)OC2CCN3C2C1=CC3 QVCMHGGNRFRMAD-UHFFFAOYSA-N 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 239000000512 collagen gel Substances 0.000 description 4
- 230000003511 endothelial effect Effects 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000000750 progressive effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 3
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 241000220479 Acacia Species 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000016942 Elastin Human genes 0.000 description 2
- 108010014258 Elastin Proteins 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 101710127721 Membrane protein Proteins 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 208000011191 Pulmonary vascular disease Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229920002549 elastin Polymers 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000000004 hemodynamic effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 230000008692 neointimal formation Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- 231100000216 vascular lesion Toxicity 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000007592 Apolipoproteins Human genes 0.000 description 1
- 108010071619 Apolipoproteins Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108090000059 Complement factor D Proteins 0.000 description 1
- 102000003706 Complement factor D Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- -1 cachets Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 230000009133 cooperative interaction Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008497 endothelial barrier function Effects 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000001739 rebound effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
Definitions
- a variety of therapies have been introduced to try to prevent progression of the pulmonary vascular lesions associated with pulmonary hypertension.
- vasodilators such as calcium channel blockers, prostacyclin, and, potentially, nitric oxide therapy, and using anticoagulants to prevent thromboses.
- Recent reports have shown that even in the absences of beneficial acute hemodynamic response, long term prostacyclin has proven effective in a subset of patients for improving symptoms and cardiac output, particularly with exercise. In rare cases, hemodynamic studies show a reduction from systemic to virtually normal levels of pulmonary artery pressure. No patient has, however, been successfully weaned from this therapy and severe rebound effects have been demonstrated upon attempt at withdrawal of prostacyclin.
- the oral and inhaled prostacyclin analogs may provide as or more effective therapies than intravenous prostacyclin and will certainly be more convenient.
- lung transplant appears the only option, and this carries high mortality and morbidity rates in terms of immunosuppressive therapy.
- a strategy aimed both at preventing and inducing structural regression of the vascular disease associated with pulmonary hypertension is needed.
- the present invention is based upon the discovery that pulmonary hypertension can be treated based upon the suppression of tenascin.
- Tenascin can be suppressed directly, such as by antisense therapy, or indirectly, by inhibiting serine elastases such as endogenous vascular elastase, a novel enzyme which has been found to increase tenascin levels, or by inhibiting matrix metalloproteinases which may be activated serine elastases.
- the present invention relates to a method and composition for treating pulmonary hypertension comprising administering to a subject in need thereof, preferably a human being, an inhibitor of elastase, preferably endogenous vascular elastase.
- the inhibitor is a serine elastase inhibitor, such as elafin.
- Another preferred inhibitor is L-arginine.
- pulmonary hypertension is understood to refer to both primary and secondary pulmonary hypertension.
- kits for accomplishing such treatment comprising (i) an effective amount of an inhibitor of elastase, preferably endogenous vascular elastase, (ii) one or more pharmaceutically acceptable carriers and/or additives, and (iii) instructions for use in treating pulmonary hypertension.
- instructions for use shall mean any FDA- mandated labelling, instructions, or package inserts that relate to the administration of endogenous vascular elastase inhibitors for the purpose of treating pulmonary hypertension.
- instructions for use may include, but are not limited to, indications for pulmonary hypertension, identification of specific symptoms of pulmonary hypertension that can be ameliorated by the claimed treatment, and recommended dosage amounts for subjects suffering from pulmonary hypertension.
- the amount of endogenous vascular elastase inhibitor, which is required in a medication or diagnostic aid according to the invention to achieve the desired effect will depend on a number of factors, in particular the specific application, the nature of the particular compound used, the mode of administration, and the condition of the patient.
- a daily dose per patient for the treatment of pulmonary hypertension is in the range 25 ⁇ g to 250 mg; typically from 0.5 ⁇ g to 2.5 mg, preferably from 7 ⁇ g to 285 ⁇ g, per day per kilogram body weight.
- an intravenous dose in the range 0.5 ⁇ g to 1.5 mg per kilogram body weight per day may conveniently be administered as an infusion of from 0.5 ng to 1.0 ⁇ g per kilogram body weight per minute.
- Infusion fluids suitable for this purpose contain, for example, from 10 ng to 10 ⁇ g per milliliter.
- Ampoules for injection contain, for example, from 0.1 ⁇ g to 1.0 mg and orally administrable unit dose formulations, such as tablets or capsules, contain, for example, from 0.1 to 100 mg, typically from 1 to 50 mg.
- a single unit dose formulation may be administered.
- the endogenous vascular elastase inhibitors are typically admixed with, inter alia, an acceptable carrier.
- the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
- the carrier may be a solid or a liquid, or both, and is preferably formulated with the inhibitor as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the active inhibitor.
- One or more inhibitors may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy for admixing the components.
- pharmacologically active substances may be present in the formulations of the present invention which are known to be useful for treating pulmonary hypertension.
- the inhibitors of the invention may be present in combination with prostacyclin.
- compositions of the invention include those suitable for oral, inhalation (in solid and liquid forms), rectal, topical, buccal (e.g. sub-lingual), parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular form of inhibitor which is being used.
- Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of inhibitor; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water or water-in-oil emulsion.
- Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients).
- the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
- a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
- Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound(s), in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the active compound(s) in an inert base such as gelatin and glycerin or sucrose and acacia.
- Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of endogenous vascular elastase inhibitors, which preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood. Injectable formulations according to the invention generally contain from 0.1 to 5 % w/v of active compound and are administered at a rate of 0.1 ml/min/kg.
- Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound(s) with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
- Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
- the active compound is generally present at a concentration of from 0.1 to 15% w/w, for example, from 0.5 to 2% w/w.
- Formulations for transdermal administration may be delivered by iontophoresis (see, for example, Pharmaceutical Research 3(6), 318, (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound(s).
- Suitable formulations comprise citrate or bis/tris buffer (pH 6) or ethanol/ water and contain from 0.1 to 0.2 M active ingredient(s).
- the invention is further illustrated by the following, non-limiting examples.
- Increased elastase activity has been demonstrated to play a pivotal role in the pathobiology of pulmonary hypertension in rats with monocrotaline-induced pulmonary vascular disease, as well as in experimental coronary artery neointimal formation where there appears to be a cooperative interaction with cytokines, especially inter leukin IB, in inducing the vascular disease.
- increased expression of the matrix glycoprotein tenascin is evident in obstructive pulmonary arteries with extensive neointimal formation as assessed in lung biopsy and in monocrotaline induced pulmonary vascular disease.
- EVE endogenous vascular elastase
- one or more serum factors which appear to include apolipoprotein Al can stimulate elastase activity by an integrin- mediated event which results in phosphorylation of focal adhesion kinase (FAK) and extracellular related kinase (ERK1/2) which transactivates AML-1 , a putative elastase transcription factor.
- FGF focal adhesion kinase
- ERK1/2 extracellular related kinase transcription factor
- the matrix glycoprotein tenascin which can be induced by FGF-2 directly or through the elastase-driven upregulation of matrix metalloproteinases.
- the tenascin serves to alter the smooth muscle cell cytoskeleton and, by clustering the avB3 integrin receptors, also clusters the receptors for growth factors, such as epidermal growth factor (EGF) which rapidly phosphorylate upon addition of the ligand, culminating in a nuclear signal.
- EGF epidermal growth factor
- Hypertrophied pulmonary arteries when placed in floating collagen gels, show regression of the medial thickening to normal values when they are treated with elastase or matrix metalloproteinase inhibitors or tenascin antisense agents. There is a progressive reduction in medial width when the hypertrophied pulmonary arteries are placed in released collagen gels and a progressive increase when placed in restrained collagen gels. This regression appears to be associated with reduced tenascin expression and apoptosis.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method for treating pulmonary hypertension is described comprising administering an elastase inhibitor to a patient. Inhibition of elastase suppresses tenascin, which leads to a reduction of the smooth muscle cell proliferation associated with pulmonary hypertension. More specifically, the tenascin suppressant is L-arginine and the elastase inhibitor is elafin.
Description
TREATING PULMONARY HYPERTENSION THROUGH TENASCIN SUPPRESSION AND ELASTASE INHIBITION
BACKGROUND OF THE INVENTION
A variety of therapies have been introduced to try to prevent progression of the pulmonary vascular lesions associated with pulmonary hypertension. Lowering pulmonary artery pressure with vasodilators, such as calcium channel blockers, prostacyclin, and, potentially, nitric oxide therapy, and using anticoagulants to prevent thromboses, are current strategies in use. Recent reports have shown that even in the absences of beneficial acute hemodynamic response, long term prostacyclin has proven effective in a subset of patients for improving symptoms and cardiac output, particularly with exercise. In rare cases, hemodynamic studies show a reduction from systemic to virtually normal levels of pulmonary artery pressure. No patient has, however, been successfully weaned from this therapy and severe rebound effects have been demonstrated upon attempt at withdrawal of prostacyclin. The oral and inhaled prostacyclin analogs may provide as or more effective therapies than intravenous prostacyclin and will certainly be more convenient. In cases where regression has not been achieved, lung transplant appears the only option, and this carries high mortality and morbidity rates in terms of immunosuppressive therapy. Thus, a strategy aimed both at preventing and inducing structural regression of the vascular disease associated with pulmonary hypertension is needed.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery that pulmonary hypertension can be treated based upon the suppression of tenascin. Tenascin can be suppressed directly, such as by antisense therapy, or indirectly, by inhibiting serine elastases such as endogenous vascular elastase, a novel enzyme
which has been found to increase tenascin levels, or by inhibiting matrix metalloproteinases which may be activated serine elastases.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS In one embodiment, the present invention relates to a method and composition for treating pulmonary hypertension comprising administering to a subject in need thereof, preferably a human being, an inhibitor of elastase, preferably endogenous vascular elastase. Preferably, the inhibitor is a serine elastase inhibitor, such as elafin. Another preferred inhibitor is L-arginine. The term pulmonary hypertension is understood to refer to both primary and secondary pulmonary hypertension.
The present invention also relates to kits for accomplishing such treatment comprising (i) an effective amount of an inhibitor of elastase, preferably endogenous vascular elastase, (ii) one or more pharmaceutically acceptable carriers and/or additives, and (iii) instructions for use in treating pulmonary hypertension.
As used herein, the phrase "instructions for use" shall mean any FDA- mandated labelling, instructions, or package inserts that relate to the administration of endogenous vascular elastase inhibitors for the purpose of treating pulmonary hypertension. For example, instructions for use may include, but are not limited to, indications for pulmonary hypertension, identification of specific symptoms of pulmonary hypertension that can be ameliorated by the claimed treatment, and recommended dosage amounts for subjects suffering from pulmonary hypertension. The amount of endogenous vascular elastase inhibitor, which is required in a medication or diagnostic aid according to the invention to achieve the desired effect will depend on a number of factors, in particular the specific application, the nature of the particular compound used, the mode of administration, and the condition of the patient. In general, a daily dose per patient for the treatment of pulmonary hypertension is in the range 25 μg to 250
mg; typically from 0.5 μg to 2.5 mg, preferably from 7 μg to 285 μg, per day per kilogram body weight. For example, an intravenous dose in the range 0.5 μg to 1.5 mg per kilogram body weight per day may conveniently be administered as an infusion of from 0.5 ng to 1.0 μg per kilogram body weight per minute. Infusion fluids suitable for this purpose contain, for example, from 10 ng to 10 μg per milliliter. Ampoules for injection contain, for example, from 0.1 μg to 1.0 mg and orally administrable unit dose formulations, such as tablets or capsules, contain, for example, from 0.1 to 100 mg, typically from 1 to 50 mg. For diagnostic purposes, a single unit dose formulation may be administered. In the manufacture of a pharmaceutical composition or kit according to the invention, hereinafter referred to as a "formulation", the endogenous vascular elastase inhibitors are typically admixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the inhibitor as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the active inhibitor. One or more inhibitors may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy for admixing the components.
In addition to an inhibitor of endogenous vascular elastase, other pharmacologically active substances may be present in the formulations of the present invention which are known to be useful for treating pulmonary hypertension. For example, the inhibitors of the invention may be present in combination with prostacyclin.
The formulations of the invention include those suitable for oral, inhalation (in solid and liquid forms), rectal, topical, buccal (e.g. sub-lingual), parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case
will depend on the nature and severity of the condition being treated and on the nature of the particular form of inhibitor which is being used.
Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of inhibitor; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water or water-in-oil emulsion. Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients).
In general, the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound(s), in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the active compound(s) in an inert base such as gelatin and glycerin or sucrose and acacia.
Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of endogenous vascular elastase inhibitors, which preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of
subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood. Injectable formulations according to the invention generally contain from 0.1 to 5 % w/v of active compound and are administered at a rate of 0.1 ml/min/kg.
Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound(s) with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w, for example, from 0.5 to 2% w/w. Formulations for transdermal administration may be delivered by iontophoresis (see, for example, Pharmaceutical Research 3(6), 318, (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound(s). Suitable formulations comprise citrate or bis/tris buffer (pH 6) or ethanol/ water and contain from 0.1 to 0.2 M active ingredient(s). The invention is further illustrated by the following, non-limiting examples.
Increased elastase activity has been demonstrated to play a pivotal role in the pathobiology of pulmonary hypertension in rats with monocrotaline-induced pulmonary vascular disease, as well as in experimental coronary artery neointimal formation where there appears to be a cooperative interaction with cytokines, especially inter leukin IB, in inducing the vascular disease. In addition, increased expression of the matrix glycoprotein tenascin is evident in obstructive pulmonary arteries with extensive neointimal formation as assessed in lung biopsy and in monocrotaline induced pulmonary vascular disease.
An early increase in elastase activity has been shown with the development of the vascular lesions in monocrotaline (Mc)-treated rats and a later increase with progressive disease. A cause and effect relationship is demonstrated in studies in which elastase inhibitors have been used prior to the Mc-induced endothelial injury to prevent the structural changes and associated pulmonary hypertension or, when they have been administered later in the course of the disease to retard its progression.
Subsequent studies related the endogenous vascular elastase (EVE) in the pulmonary arteries of rats with pulmonary hypertension from other etiologies, e.g. , hypoxia. Here, an early increase in elastase activity is followed by the development of pulmonary hypertension (PH) but a later increase in elastase does not occur. This model differs from the Mc-induced PH in that it is not progressive and, in fact, will regress upon removal of the rats from the hypoxic environment. Subsequent studies showed that EVE is produced by the smooth muscle cells of the vessel wall and that it appears to be structurally related to the serine proteinase, adipsin.
This mechanism of elastase induction is further supported by in vitro studies. Common to all clinical and experimental PH producing stimuli or etiologies is evidence of endothelial perturbation and injury. It is believed that the structural and functional endothelial alterations result in loss of the endothelial barrier function and that, as a result, serum or endothelial factors 'leak' into the subendothelium and stimulate elastase activity in smooth muscle cells. Studies have, in fact, shown that one or more serum factors which appear to include apolipoprotein Al can stimulate elastase activity by an integrin- mediated event which results in phosphorylation of focal adhesion kinase (FAK) and extracellular related kinase (ERK1/2) which transactivates AML-1 , a putative elastase transcription factor. It has also been shown that the endogenous vascular elastase (EVE) releases potent growth factors, such as fibroblast growth factor (FGF)-2, from an inactive form bound to proteoglycans
in the extracellular matrix to a biologically active form which promotes smooth muscle cell proliferation.
This effect is enhanced through the concomitant expression of the matrix glycoprotein tenascin which can be induced by FGF-2 directly or through the elastase-driven upregulation of matrix metalloproteinases. The tenascin serves to alter the smooth muscle cell cytoskeleton and, by clustering the avB3 integrin receptors, also clusters the receptors for growth factors, such as epidermal growth factor (EGF) which rapidly phosphorylate upon addition of the ligand, culminating in a nuclear signal. Cell culture studies have shown that tenascin promotes FGF-2 dependent and is a prerequisite for EGF-dependent SMC proliferation. It has also been shown that the degradation products of elastin, elastin peptides, cooperatively interact with cytokines such as interleukin 1 B in inducing SMC fibronectin production, the latter being a promoter of SMC migration. It has also been shown that, when SMC are stress-unloaded by floating them in collagen gels, matrix metalloproteinases are downregulated, as is tenascin, and the cells undergo apoptosis or programmed cell death. Tenascin is critical to this process, since its supplementation in the gels will rescue cells. Hypertrophied pulmonary arteries, when placed in floating collagen gels, show regression of the medial thickening to normal values when they are treated with elastase or matrix metalloproteinase inhibitors or tenascin antisense agents. There is a progressive reduction in medial width when the hypertrophied pulmonary arteries are placed in released collagen gels and a progressive increase when placed in restrained collagen gels. This regression appears to be associated with reduced tenascin expression and apoptosis.
In vivo induction of pulmonary hypertension with serine elastase inhibitors in experimental rats.
Pulmonary artery pressure was monitored in groups of rats (n=6) at 21 and 28 days after injection with monocrotaline. Rats were given either the
orally bioavailible serine elastase inhibitor Ik or related compound M249314 (both from Zeneca) twice daily by gavage between 21 and 28 days. Control groups of rats were given vehicle between 21 and 28 days instead of inhibitor. As shown in Figure 1 (in vivo administration of serine elastase inhibitors reverse progressive increases in pulmonary artery pressure following monocrotaline injection into the rat), orally bioavailible highly selective serine elastase inhibitors produce a significant reduction in the levels of pulmonary artery pressure when comparing values in the control and untreated rats. This clearly shows that the orally bioavailible inhibitors given for 7 days are highly effective in inducing regression of pulmonary hypertension.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the invention.
Claims
1. A method for treating pulmonary hypertension comprising administering to a subject in need thereof an effective amount of an inhibitor of elastase.
2. The method as claimed in claim 1 wherein the subject is a human being.
3. The method as claimed in claim 1 wherein the inhibitor is a serine elastase inhibitor.
4. The method as claimed in claim 1 wherein the inhibitor is elafin.
5. The method as claimed in claim 1 wherein the inhibitor is L-arginine.
6. The method as claimed in claim 1 wherein the subject suffers from primary pulmonary hypertension.
7. The method as claimed in claim 1 wherein the subject suffers from secondary pulmonary hypertension.
8. A method for treating pulmonary hypertension comprising administering to a subject in need thereof an effective amount of an agent to suppress tenascin.
9. The method as claimed in claim 8 wherein the subject is a human being.
10. The method as claimed in claim 8 wherein the agent to suppress tenascin is a serine elastase inhibitor.
11. The method as claimed in claim 10 wherein the inhibitor is elafin.
12. The method as claimed in claim 8 wherein the agent to suppress tenascin is L-arginine.
13. The method as claimed in claim 8 wherein the subject suffers from primary pulmonary hypertension.
14. The method as claimed in claim 8 wherein the subject suffers from secondary pulmonary hypertension.
15. A kit for treating pulmonary hypertension comprising (i) an effective amount of an inhibitor of elastase, (ii) one or more pharmaceutically acceptable carriers and/or additives, and (iii) instructions for use in treating pulmonary hypertension.
16. A kit for treating pulmonary hypertension comprising (i) an effective amount of an agent to suppress tenascin, (ii) one or more pharmaceutically acceptable carriers and/or additives, and (iii) instructions for use in treating pulmonary hypertension.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7618998P | 1998-02-27 | 1998-02-27 | |
| US60/076,189 | 1998-02-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1999043308A2 true WO1999043308A2 (en) | 1999-09-02 |
| WO1999043308A3 WO1999043308A3 (en) | 1999-10-28 |
Family
ID=22130483
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB1999/000413 WO1999043308A2 (en) | 1998-02-27 | 1999-02-26 | Treating pulmonary hypertension through tenascin suppression and elastase inhibition |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1999043308A2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004073623A2 (en) | 2003-02-14 | 2004-09-02 | Children's Hospital & Research Center At Oakland | Treatment of conditions associated with decreased nitric oxide bioavailability, including elevated arginase conditions |
| US6849605B1 (en) | 1999-03-05 | 2005-02-01 | The Trustees Of University Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of viral infections |
| FR2930036A1 (en) * | 2008-04-11 | 2009-10-16 | Assist Publ Hopitaux De Paris | METHOD FOR DIAGNOSING PULMONARY ARTERIAL HYPERTENSION |
| US7648840B2 (en) | 2004-12-01 | 2010-01-19 | Children's Hospital & Research Center At Oakland | Diagnosis of conditions associated with decreased arginine bioavailability |
| US7704958B1 (en) | 1999-03-05 | 2010-04-27 | Bio Holding, Inc. | Methods and compositions for inhibiting apoptosis using serine protease inhibitors |
| WO2016030323A1 (en) * | 2014-08-26 | 2016-03-03 | Proteo Biotech Ag | Use of elafin for disorders associated with elastase independent increase in troponin |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995009636A1 (en) * | 1993-10-04 | 1995-04-13 | The Trustees Of Columbia University In The City Ofnew York | Method of inducing vasorelaxation to treat pulmonary hypertension |
| WO1998008500A1 (en) * | 1996-08-26 | 1998-03-05 | Board Of Regents, The University Of Texas System | Hypertonic arginine compositions and methods |
| WO1999017800A1 (en) * | 1997-10-03 | 1999-04-15 | Amgen Inc. | Secretory leukocyte protease inhibitor dry powder pharmaceutical compositions |
| US5895788A (en) * | 1996-01-31 | 1999-04-20 | The Board Of Trustees Of The University Of Arkansas | Use of L-arginine and salts thereof in drinking water for the prevention and/or treatment of pulmonary hypertension syndrome in avians |
-
1999
- 1999-02-26 WO PCT/IB1999/000413 patent/WO1999043308A2/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995009636A1 (en) * | 1993-10-04 | 1995-04-13 | The Trustees Of Columbia University In The City Ofnew York | Method of inducing vasorelaxation to treat pulmonary hypertension |
| US5895788A (en) * | 1996-01-31 | 1999-04-20 | The Board Of Trustees Of The University Of Arkansas | Use of L-arginine and salts thereof in drinking water for the prevention and/or treatment of pulmonary hypertension syndrome in avians |
| WO1998008500A1 (en) * | 1996-08-26 | 1998-03-05 | Board Of Regents, The University Of Texas System | Hypertonic arginine compositions and methods |
| WO1999017800A1 (en) * | 1997-10-03 | 1999-04-15 | Amgen Inc. | Secretory leukocyte protease inhibitor dry powder pharmaceutical compositions |
Non-Patent Citations (8)
| Title |
|---|
| ADNOT, S. ET AL: "Loss of endothelium-dependent relaxation during chronic hypoxic pulmonary hypertension: Recovery on return to room air or after treatment with L-arginine" BIOL. NITRIC OXIDE, PROC. INT. MEET., 2ND (1992), MEETING DATE 1991, VOLUME 1, 32-4. EDITOR(S): MONCADA, SALVADOR. PUBLISHER: PORTLAND PRESS, LONDON, UK. , XP002113476 * |
| BOEGER, R. H. (1) ET AL: "Differential systemic and pulmonary hemodynamic effects of L-arginine in patients with coronary artery disease or primary pulmonary hypertension." INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, (1996) VOL. 34, NO. 8, PP. 323-328. , XP002113471 * |
| GOSSAGE J R ET AL: "THE NEUTROPHIL ELASTASE INHIBITOR SC-39026 ALTERS THE DEVELOPMENT OF SUSTAINED PULMONARY HYPERTENSION SECONDARY TO CONTINUOUS AIR EMBOLIZATION (CAE)." 1991 INTERNATIONAL CONFERENCE OF THE AMERICAN LUNG ASSOCIATION AND THE AMERICAN THORACIC SOCIETY, ANAHEIM, CALIFORNIA, USA, MAY 12-15, 1991. AM REV RESPIR DIS. (1991) 143 (4 PART 2), A187. , XP002113475 * |
| MCCAFFREY, MARTIN J. ET AL: "Effect of L-arginine infusion of infants with persistent pulmonary hypertension of the newborn." PEDIATRIC RESEARCH, (1994) VOL. 37, NO. 4 PART 2, PP. 341A. MEETING INFO.: 105TH ANNUAL MEETING OF THE AMERICAN PEDIATRIC SOCIETY AND THE 64TH ANNUAL MEETING OF THE SOCIETY FOR PEDIATRIC RESEARCH SAN DIEGO, CALIFORNIA, USA MAY 7-11, 1995 , XP002113470 * |
| MEHTA S. ET AL: "Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension." CIRCULATION, (1995) 92/6 (1539-1545). , XP002113477 * |
| RABINOVITCH, MARLENE: "Elastase and elastase inhibitors and pulmonary and coronary artery disease" INT. CONGR. SER. (1998), 1155(ATHEROSCLEROSIS XI), 317-326 , XP002113474 * |
| RABINOVITCH, MARLENE: "Elastase and the pathobiology of unexplained pulmonary hypertension" CHEST (1998), 114(3, SUPPL., BRENOT MEMORIAL SYMPOSIUM ON THE PATHOGENESIS OF PRIMARY PULMONARY HYPERTENSION, 1997), 213S-224S , XP002113473 * |
| WEBSTER, J. ET AL: "Elastase-specific inhibitor elafin and endogenous vascular elastase (EVE) in vascular development." FASEB JOURNAL, (1997) VOL. 11, NO. 3, PP. A224. MEETING INFO.: ANNUAL MEETING OF THE PROFESSIONAL RESEARCH SCIENTISTS ON EXPERIMENTAL BIOLOGY 97 NEW ORLEANS, LOUISIANA, USA APRIL 6-9, 1997 , XP002113472 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7704958B1 (en) | 1999-03-05 | 2010-04-27 | Bio Holding, Inc. | Methods and compositions for inhibiting apoptosis using serine protease inhibitors |
| US6849605B1 (en) | 1999-03-05 | 2005-02-01 | The Trustees Of University Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of viral infections |
| US8071551B2 (en) | 1999-03-05 | 2011-12-06 | BioHolding, Inc. | Methods and compositions for treating diabetes |
| EP1596854A4 (en) * | 2003-02-14 | 2007-06-06 | Childrens Hosp & Res Ct Oak | TREATMENT OF PATHOLOGICAL CONDITIONS ASSOCIATED WITH REDUCED BIOAVAILABILITY OF NITRIC OXIDE, INCLUDING PATHOLOGICAL CONDITIONS CAUSED BY HIGH ACTIVITY OF ARGINASE |
| US7651846B2 (en) | 2003-02-14 | 2010-01-26 | Children's Hospital & Research Center At Oakland | Treatment and diagnosis of conditions associated with elevated arginase activity |
| WO2004073623A2 (en) | 2003-02-14 | 2004-09-02 | Children's Hospital & Research Center At Oakland | Treatment of conditions associated with decreased nitric oxide bioavailability, including elevated arginase conditions |
| EP1596854A2 (en) * | 2003-02-14 | 2005-11-23 | Children's Hospital & Research Center at Oakland | Treatment of conditions associated with decreased nitric oxide bioavailability, including elevated arginase conditions |
| EP2397128A1 (en) * | 2003-02-14 | 2011-12-21 | Children's Hospital & Research Center at Oakland | Use of L-arginine optionally combined with magnesium for the treatment of sickle cell disease and/or pulmonary hypertension |
| US7648840B2 (en) | 2004-12-01 | 2010-01-19 | Children's Hospital & Research Center At Oakland | Diagnosis of conditions associated with decreased arginine bioavailability |
| US8309320B2 (en) | 2004-12-01 | 2012-11-13 | Children's Hospital & Research Center At Oakland | Diagnosis of conditions associated with decreased arginine bioavailability |
| FR2930036A1 (en) * | 2008-04-11 | 2009-10-16 | Assist Publ Hopitaux De Paris | METHOD FOR DIAGNOSING PULMONARY ARTERIAL HYPERTENSION |
| WO2009136112A1 (en) * | 2008-04-11 | 2009-11-12 | Assistance Publique - Hôpitaux De Paris | Method for diagnosing pulmonary artery hypertension |
| US8609356B2 (en) | 2008-04-11 | 2013-12-17 | Assistance Publique-Hopitaux De Paris | Method for diagnosing pulmonary artery hypertension |
| WO2016030323A1 (en) * | 2014-08-26 | 2016-03-03 | Proteo Biotech Ag | Use of elafin for disorders associated with elastase independent increase in troponin |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999043308A3 (en) | 1999-10-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100638684B1 (en) | 9-deoxy-2 ', 9-alpha-methano-3-oxa-4,5,6-trinor-3,7- (1', 3'-interphenylene) for the treatment of peripheral vascular disease Use of -13,14-dihydro-prostaglandin F1 | |
| EP0644760B1 (en) | Use of imidazole for the treatment of diseases characterized by neovascularization | |
| EP1937286B1 (en) | Compositions comprising dimethyl sulfoxide (dmso) | |
| US9782429B2 (en) | Formulation having mobilizing activity | |
| JP4568383B2 (en) | Method for promoting angiogenesis | |
| EP0697862B1 (en) | Pharmaceutical compositions and methods using isobutyramide for treating betaglobin disorders | |
| JP2003535034A (en) | Dipeptidyl peptidase IV inhibitors and methods for producing and using dipeptidyl peptidase IV inhibitors | |
| CA2223403A1 (en) | Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) n-¬(aminoiminomethyl)phenylalkyl|-azaheterocyclylamide compounds | |
| CA2139851A1 (en) | Method of treating hyperproliferative vascular disease | |
| EP1369119B1 (en) | Il-12 expression controlling agents | |
| EP0774255B1 (en) | Use of ursolic acid for the manufacture of a medicament for suppressing metastasis | |
| EP0605589A1 (en) | Pharmaceutical compositions comprising natriuretic peptides or neutral endopeptidase inhibitors for treating or preventing myointimal proliferation | |
| CA2274686A1 (en) | Sulfonic acid or sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds | |
| US4916117A (en) | Treatment of inflammation using alpha 1-antichymotrypsin | |
| EP1086099A4 (en) | Sulfonic acid or sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds | |
| Baxter | Can lithium carbonate prolong the antidepressant effect of sleep deprivation? | |
| WO1999043308A2 (en) | Treating pulmonary hypertension through tenascin suppression and elastase inhibition | |
| EP1116487A2 (en) | Reduction of postoperative complications of cardiopulmonary bypass (CPB) surgery | |
| Taenaka et al. | Survival from DIC following amniotic fluid embolism: Successful treatment with a serine proteinase inhibitor; FOY® | |
| US5962025A (en) | Method for treatment of systemic sclerosis and related fibrotic diseases | |
| US20120100229A1 (en) | Treatment and Prevention of White Matter Injury with KATP Channel Activators | |
| JP3901520B2 (en) | Treatment and prevention of mucosal tissue damage | |
| US20080132568A1 (en) | Compounds with anti-androgenic activity and the use thereof | |
| McDermott Jr et al. | Bleeding esophageal varices: A study of the cause of the associated “hepatic coma” | |
| EP0232697B1 (en) | Pharmaceutical compositions containing acth fragments for the therapy of shock conditions and of respiratory and cardiocirculatory insufficiencies |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): JP |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| AK | Designated states |
Kind code of ref document: A3 Designated state(s): JP |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 122 | Ep: pct application non-entry in european phase |