CA2241981C - Method of inhibiting photoaging of skin - Google Patents
Method of inhibiting photoaging of skin Download PDFInfo
- Publication number
- CA2241981C CA2241981C CA002241981A CA2241981A CA2241981C CA 2241981 C CA2241981 C CA 2241981C CA 002241981 A CA002241981 A CA 002241981A CA 2241981 A CA2241981 A CA 2241981A CA 2241981 C CA2241981 C CA 2241981C
- Authority
- CA
- Canada
- Prior art keywords
- inhibitor
- skin
- uvb
- activity
- mmp
- 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
- 206010051246 Photodermatosis Diseases 0.000 title claims abstract description 33
- 230000008845 photoaging Effects 0.000 title claims abstract description 33
- 230000002401 inhibitory effect Effects 0.000 title claims description 10
- 238000000034 method Methods 0.000 title description 5
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims abstract description 39
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims abstract description 38
- 239000003112 inhibitor Substances 0.000 claims abstract description 35
- 230000000694 effects Effects 0.000 claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 claims abstract description 22
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 15
- 102000020233 phosphotransferase Human genes 0.000 claims abstract description 15
- 230000004913 activation Effects 0.000 claims abstract description 12
- 102000030782 GTP binding Human genes 0.000 claims abstract description 9
- 108091000058 GTP-Binding Proteins 0.000 claims abstract description 9
- 230000001939 inductive effect Effects 0.000 claims abstract description 6
- 239000003862 glucocorticoid Substances 0.000 claims description 7
- 108010030545 N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide Proteins 0.000 claims description 4
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 4
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 claims description 4
- 229950001858 batimastat Drugs 0.000 claims description 4
- NITYDPDXAAFEIT-DYVFJYSZSA-N ilomastat Chemical compound C1=CC=C2C(C[C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)CC(=O)NO)=CNC2=C1 NITYDPDXAAFEIT-DYVFJYSZSA-N 0.000 claims description 4
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 claims description 4
- 229950008959 marimastat Drugs 0.000 claims description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 3
- 235000005282 vitamin D3 Nutrition 0.000 claims description 3
- 239000011647 vitamin D3 Substances 0.000 claims description 3
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 claims description 3
- 229940021056 vitamin d3 Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- ZKRFOXLVOKTUTA-KQYNXXCUSA-N 9-(5-phosphoribofuranosyl)-6-mercaptopurine Chemical group O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=S)=C2N=C1 ZKRFOXLVOKTUTA-KQYNXXCUSA-N 0.000 claims 2
- 229940122091 Geranylgeranyltransferase inhibitor Drugs 0.000 claims 2
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 claims 2
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 claims 2
- 229940123468 Transferase inhibitor Drugs 0.000 claims 2
- 102000023732 binding proteins Human genes 0.000 claims 2
- 108091008324 binding proteins Proteins 0.000 claims 2
- 150000004492 retinoid derivatives Chemical class 0.000 claims 2
- 239000003558 transferase inhibitor Substances 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 230000006698 induction Effects 0.000 description 22
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 18
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 18
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 16
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 9
- 229940124761 MMP inhibitor Drugs 0.000 description 7
- 102100030416 Stromelysin-1 Human genes 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 6
- 206010015150 Erythema Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 101710108790 Stromelysin-1 Proteins 0.000 description 6
- 231100000321 erythema Toxicity 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 5
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- 102000008186 Collagen Human genes 0.000 description 5
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 230000000475 sunscreen effect Effects 0.000 description 5
- 239000000516 sunscreening agent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 230000004568 DNA-binding Effects 0.000 description 4
- 108010067306 Fibronectins Proteins 0.000 description 4
- 102000016359 Fibronectins Human genes 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 108091007196 stromelysin Proteins 0.000 description 4
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 102000016942 Elastin Human genes 0.000 description 3
- 108010014258 Elastin Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 3
- 102100028848 Stromelysin-2 Human genes 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- -1 clays Chemical compound 0.000 description 3
- 229920002549 elastin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 102000016914 ras Proteins Human genes 0.000 description 3
- 239000003642 reactive oxygen metabolite Substances 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 101710132601 Capsid protein Proteins 0.000 description 2
- 102000011068 Cdc42 Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 108010085895 Laminin Proteins 0.000 description 2
- 102100030417 Matrilysin Human genes 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000012641 Pigmentation disease Diseases 0.000 description 2
- 101710108792 Stromelysin-2 Proteins 0.000 description 2
- 102100028847 Stromelysin-3 Human genes 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 108010051348 cdc42 GTP-Binding Protein Proteins 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 235000020945 retinal Nutrition 0.000 description 2
- 239000011604 retinal Substances 0.000 description 2
- 229960003471 retinol Drugs 0.000 description 2
- 235000020944 retinol Nutrition 0.000 description 2
- 239000011607 retinol Substances 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 2
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 1
- NSMXQKNUPPXBRG-SECBINFHSA-N (R)-lisofylline Chemical compound O=C1N(CCCC[C@H](O)C)C(=O)N(C)C2=C1N(C)C=N2 NSMXQKNUPPXBRG-SECBINFHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- MEZZCSHVIGVWFI-UHFFFAOYSA-N 2,2'-Dihydroxy-4-methoxybenzophenone Chemical compound OC1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1O MEZZCSHVIGVWFI-UHFFFAOYSA-N 0.000 description 1
- TYYHDKOVFSVWON-UHFFFAOYSA-N 2-butyl-2-methoxy-1,3-diphenylpropane-1,3-dione Chemical compound C=1C=CC=CC=1C(=O)C(OC)(CCCC)C(=O)C1=CC=CC=C1 TYYHDKOVFSVWON-UHFFFAOYSA-N 0.000 description 1
- ZGIGZINMAOQWLX-NCZFFCEISA-N 3,7,11-Trimethyl-2,6,10-dodecatrienyl acetate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\COC(C)=O ZGIGZINMAOQWLX-NCZFFCEISA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 102000004266 Collagen Type IV Human genes 0.000 description 1
- 108010042086 Collagen Type IV Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 239000003298 DNA probe Substances 0.000 description 1
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- ZGIGZINMAOQWLX-UHFFFAOYSA-N Farnesyl acetate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOC(C)=O ZGIGZINMAOQWLX-UHFFFAOYSA-N 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 102000003817 Fos-related antigen 1 Human genes 0.000 description 1
- 108090000123 Fos-related antigen 1 Proteins 0.000 description 1
- 101150096607 Fosl2 gene Proteins 0.000 description 1
- 102000013382 Gelatinases Human genes 0.000 description 1
- 108010026132 Gelatinases Proteins 0.000 description 1
- 101000684275 Homo sapiens ADP-ribosylation factor 3 Proteins 0.000 description 1
- 101000990912 Homo sapiens Matrilysin Proteins 0.000 description 1
- 101001130437 Homo sapiens Ras-related protein Rap-2b Proteins 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 108040006417 JUN kinase kinase activity proteins Proteins 0.000 description 1
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 1
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 1
- 108090000855 Matrilysin Proteins 0.000 description 1
- 108010076497 Matrix Metalloproteinase 10 Proteins 0.000 description 1
- 108010076502 Matrix Metalloproteinase 11 Proteins 0.000 description 1
- 108010016160 Matrix Metalloproteinase 3 Proteins 0.000 description 1
- 101150101095 Mmp12 gene Proteins 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 102100031421 Ras-related protein Rap-2b Human genes 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- NCYCYZXNIZJOKI-OVSJKPMPSA-N Retinaldehyde Chemical compound O=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 1
- 108050005271 Stromelysin-3 Proteins 0.000 description 1
- 101150109894 TGFA gene Proteins 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 229960005193 avobenzone Drugs 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical compound NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 238000002038 chemiluminescence detection Methods 0.000 description 1
- 229960004703 clobetasol propionate Drugs 0.000 description 1
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960004960 dioxybenzone Drugs 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000002337 electrophoretic mobility shift assay Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000006353 environmental stress Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 229940007703 farnesyl acetate Drugs 0.000 description 1
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000007804 gelatin zymography Methods 0.000 description 1
- 125000002350 geranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 206010024217 lentigo Diseases 0.000 description 1
- 101150077696 lip-1 gene Proteins 0.000 description 1
- YAFQFNOUYXZVPZ-UHFFFAOYSA-N liproxstatin-1 Chemical compound ClC1=CC=CC(CNC=2C3(CCNCC3)NC3=CC=CC=C3N=2)=C1 YAFQFNOUYXZVPZ-UHFFFAOYSA-N 0.000 description 1
- 229950011606 lisofylline Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- DXGLGDHPHMLXJC-UHFFFAOYSA-N oxybenzone Chemical compound OC1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1 DXGLGDHPHMLXJC-UHFFFAOYSA-N 0.000 description 1
- 229960001173 oxybenzone Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 230000000886 photobiology Effects 0.000 description 1
- 230000008832 photodamage Effects 0.000 description 1
- 230000003711 photoprotective effect Effects 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 201000007271 pre-malignant neoplasm Diseases 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
- A61K31/403—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 carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/58—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing atoms other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur or phosphorus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
- A61K2800/782—Enzyme inhibitors; Enzyme antagonists
Abstract
Photoaging of undamaged skin due to UVB irradiation exposure is inhibited by administering an agent that inhibits at least one of (1) the activity of UVB irradiation inducible MMPs in the skin, (2) one or both of the transcription factors AP-1 and NF-.lambda.B or (3) at least one of the GTP binding proteins or kinases involved in the activation and/or production of jun or fos proteins that comprise AP-1; and topically administering said inhibitor to the skin prior to such exposure.
Description
METHOD OF INHIBITING PHOTOAGING OF SKIN
TECHNICAL FIELD
This invention is in the field of photoprotection.
More particularly it relates to a method for inhibiting photoaging of undamaged skin using inhibitors of matrix metalloproteinase (MMP) production and/or activity.
BACKGROUND
Photoaging is a term used to describe the changes in appearance and function of skin as a result of repeated exposure to sunlight. The ultraviolet (UV) component of sunlight, particularly middle UV (called UVB, 290-320nm wavelength) is the principal causative agent of photoaging. The extent of UVB exposure required to cause photoaging is not currently known. Repeated exposure to UVB at levels that cause erythema and tanning are, however, commonly associated with photoaging. Clinically, photoaging is characterized by coarseness, wrinkling, mottled pigmentation, sallowness, laxity, telangiectasia, lentigines, purpura and easy bruising, atrophy, fibrotic depigmented areas, and ultimately premalignant and malignant neoplasms. Photoaging commonly occurs in skin that is habitually exposed to sunlight such as the face, ears, bald areas of the scalp, neck, and hands.
Procedures for preventing photoaging of unaged skin and treating already photoaged skin are available.
Sunscreens are commonly used to prevent photoaging of skin areas that are habitually exposed to sunlight. Sunscreens are topical preparations that absorb, reflect, or scatter UV. Some are based on opaque particulate materials such as zinc oxide, titanium oxide, clays, and ferric chloride.
Because such preparations are visible and occlusive, many people consider these opaque formulations cosmetically unacceptable. Other sunscreens contain chemicals such a g-aminobenzoic acid (PABA), oxybenzone, dioxybenzone, WO 97125969 PC'g'/US97/00791 ethylhexyl-methoxy cinnamide and butylmethoxydibenzoylmethane that are nonopaque and colorless because they do not absorb light of visible wavelengths. While these nonopaque sunscreens may be more acceptable cosmetically they are still relatively short-lived and susceptible to being removed by washing or perspiration. Additionally all sunscreens reduce vitamin D production.
Rieger, M.M. Cosmetics and Toiletries {1993) 108:43-56 reviews the role of reactive oxygen species (ROS) in UV-induced aging of skin. This article reports that topical application of known antioxidants to the skin can reduce the presence of ROS in the skin and thus reduce photodamage.
Retinoids have been used to retard the effects of photoaging in sun-damaged skin. U.S. Pat. No. 4,877,805 describes the treatment of photoaged skin as intervention therapy to decelerate the photoaging process. The patent indicates that there is little point in beginning such 2o treatment until the effects of aging begin to appear. In this regard the present applicants know of no art that suggests the use of retinoids to prevent photoaging of undamaged skin.
MMPs are a family of enzymes that play a major role in physiological and pathological destruction of connective tissue. Over 10 members of the family have been identified. They are referred to numerically (MMP-1, MMP-2, etc.) as well as by common name. They appear to share several structural and functional properties but differ in their tissue substrate specificities. They include interstitial collagenase (MMP-1) and PMN-collagenase (MMP-8) that degrade collagen types I, II, III, VII, VIII, IX, and gelatin: the 72kDa (MMP-2) and 92kDa (MMP-9) type IV collagenases/gelatinases that degrade collagen types IV, V, VII, X, XT, gelatin, elastin, and fibronectin; stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) that degrade fibronectin, PG core protein, collagen types IV, _ V, IX, and X, laminin and elastin: PUMP-1 (MMP-7) that degrades collagen type IV, gelatin, laminin, fibronectin and PG core protein: and metalloelastase (MMP-12) that degrades elastin and fibronectin.
The expression of MMP genes is induced by the transcription factors AP-1 and NF-xB. Angel, P. et al., Cell (1987) 49:729-739 and Sato, H. and Seiki, M., Oncogene (1993) 8:395-405. AP-1 and NF-xB activities are mediated by cytokines (e-a., interlukins IL-1, IL-6, and TNFa), growth factors (TGFa, bFGF), and environmental stress such as oxidants, heat, and ultraviolet irradiation. AP-1 induction and production of jun proteins (C-jun, jun-B, and jun-D) and foe proteins (C-foe, foe-B, fra-1, and fra-2) that make up AP-1 are mediated by a host of molecules (e. g. RAC, CDC42, MEKR, JNKK, JNK, RAS, RAF, MEK, and ERR). It is known that AP-1 and NF=xB are activated in mammalian cells exposed to W
light. Devary, Y., et at. Science (1993) 261:1442-1445.
Wlaschek, M. et al., Photochemistry and Photobiology (1994) 59(5):550-556, also report that WA irradiation of fibroblasts resulted in an IL-1 and IL-6-mediated induction of MMP-1 and that such induction might contribute to the loss of collagen in photoaging.
Inhibitors of MMPs or the transcription factors that affect their expression are also known. Hill, P.A. et al., Biochem J (1995) 308: 167-175 describes two MMP
inhibitors, CT1166 and 8031-7467. Gowravaram, M.R. et al., J Med Chem (1995) 38:2570-2581 describes the development of a series of hydroxamates that inhibit MMPs and mentions thiols, phosphonates, phosphinates, phosphoramidates and N-carboxy alkyls as known MMP
inhibitors. This paper indicates that MMP inhibitors include a moiety that chelates zinc and a peptidic fragment that binds a subset of the specificity pockets of MMPs. Hodgson, J., Biotechnology (1995) 13:554-557 reviews the clinical status of several MMP inhibitors, including Galardin, Batimastat, and Marimastat. Other MMP inhibitors include butanediamide (Conway, J.G. et al., J. Exp Med (1995) 182:449-457), TIMPs (Mauch C., et al., Arch Dermatol Res (1994) 287:107-114), and retinoids (Fanjul, A. et al., Nature (1994) 372:107-111; Nicholson, R.C. et al., EMBO Journal (1990) 9(13) 4443-4454; and Bailly, C. et al., J Investig Derm (1990) 94 (1) :47-51) .
DISCLOSURE OF THE INVENTION
The present invention is based on applicants discovery that WB exposure rapidly upgrades AP-1 and NF-kB in the exposed skin and leads to MMP induction. The elevated levels of MMPs that result from WB exposure act to degrade connective tissue proteins in skin. Such damage, if imperfectly repaired, results in solar scars which accumulate through repeated WB exposure and also cause photoaging.
Accordingly, applicants prevent photoaging of undamaged human skin due to exposure of the skin to WB by administering an inhibitor of a WB-inducible MMP to the human prior to said exposure in an amount sufficient to inhibit induction and/or activities of WB-inducible MMPs.
Surprisingly, this occurs at WB doses below those that cause erythema as well as at those which cause erythema.
The invention provides use of at least one inhibitor of (a) the activity of WB irradiation inducible matrix metalloproteinases (MMPs) in human skin, (b) one or both 4a of the transcription factors AP-1 and NF-KB and (c) at least one of the GTP binding proteins or kinases involved in activation or production of jun or fos proteins that comprise AP-1; in topically administrable form in an amount sufficient to inhibit production or activity of WB-inducible MMPs, one or both of AP-1 and NF-~B, or at least one of the GTP binding proteins or kinases involved in the activation or production of jun or fos proteins for inhibiting photoaging of unphotodamaged skin of a human due to exposure of the skin of the human to ultraviolet B irradiation (WB).
The invention also provides a commercial package comprising at least one inhibitor of (a) the activity of WB
irradiation inducible matrix metalloproteinases (MMPs) in human skin, (b) one or both of the transcription factors AP-1 and NF-KB and (c) at least one of the GTP binding proteins or kinases involved in activation or production of jun or fos proteins that comprise AP-1; in topically administrable form in an amount sufficient to inhibit production or activity of WB-inducible MMPs, one or both of AP-1 and NF-KB, or at least one of the GTP binding proteins or kinases involved in the activation or production of jun or fos proteins together with instructions for use for inhibiting photoaging of unphotodamaged skin of a human due to exposure of the skin of the human to ultraviolet B irradiation (WB).
Another aspect of this invention is the use of an inhibitor of UVB-inducible MMP induction or activity in the 4b manufacture of a medicament for preventing photoaging of undamaged skin due to repeated WB exposure.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
Fig. 1 is a flow chart showing the pathways by which WB induces MMP production.
Figs. 2a-d, 3a-b, 4a-d, and 5a-a are graphs of test results described in the Examples, infra.
MODES FOR CARRYING OUT THE INVENTION
The present invention is used to inhibit (i.e. reduce 5 or prevent) photoaging of undamaged human skin, that is, skin that does not show the effects of photoaging.
Treatment according to this invention should thus be practiced on skin such as that of the head, neck, hands, and arms that in typical, everyday living are habitually exposed to sunlight before such skin exhibits the telltale signs of photoaging. Because repeated exposure to doses of UVB below that which causes erythema can lead to photoaging, the invention should be practiced on skin subject to such low dose exposure. In this regard UVB
doses in the range of 30-50 mJ/cm2 skin cause erythema in most fair-skinned people. Accordingly the invention will prevent photoaging of skin subjected to doses below this range (typically above about 3 mJ/cmZ which is equivalent to a few minutes of sunlight exposure).
Photoaging is prevented or inhibited according to th~
invention by inhibiting WH-induced degradation of the dermal extracellular matrix by l~Ps. This is accomplished by administering a MMP inhibitor to the skin that is to be exposed to sunlight. In this regard the term "lip Z5 inhibitor" intends those agents that directly or indirectly inhibit (i.e., reduce significantly or eliminate) the expression of UVB-inducible I~iPa in such skin or inhibit the enzymatic activity of such IMPS.
"Indirect inhibition" is intended to mean interaction with either or-both of the transcription factors AP-1 and NF- KB
f and/or one or more of the molecules involved in the three kinase cascades that result in jun and fos protein induction in the skin in a manner that reduces or eliminates the expression of UVB-inducible MMPs.
TECHNICAL FIELD
This invention is in the field of photoprotection.
More particularly it relates to a method for inhibiting photoaging of undamaged skin using inhibitors of matrix metalloproteinase (MMP) production and/or activity.
BACKGROUND
Photoaging is a term used to describe the changes in appearance and function of skin as a result of repeated exposure to sunlight. The ultraviolet (UV) component of sunlight, particularly middle UV (called UVB, 290-320nm wavelength) is the principal causative agent of photoaging. The extent of UVB exposure required to cause photoaging is not currently known. Repeated exposure to UVB at levels that cause erythema and tanning are, however, commonly associated with photoaging. Clinically, photoaging is characterized by coarseness, wrinkling, mottled pigmentation, sallowness, laxity, telangiectasia, lentigines, purpura and easy bruising, atrophy, fibrotic depigmented areas, and ultimately premalignant and malignant neoplasms. Photoaging commonly occurs in skin that is habitually exposed to sunlight such as the face, ears, bald areas of the scalp, neck, and hands.
Procedures for preventing photoaging of unaged skin and treating already photoaged skin are available.
Sunscreens are commonly used to prevent photoaging of skin areas that are habitually exposed to sunlight. Sunscreens are topical preparations that absorb, reflect, or scatter UV. Some are based on opaque particulate materials such as zinc oxide, titanium oxide, clays, and ferric chloride.
Because such preparations are visible and occlusive, many people consider these opaque formulations cosmetically unacceptable. Other sunscreens contain chemicals such a g-aminobenzoic acid (PABA), oxybenzone, dioxybenzone, WO 97125969 PC'g'/US97/00791 ethylhexyl-methoxy cinnamide and butylmethoxydibenzoylmethane that are nonopaque and colorless because they do not absorb light of visible wavelengths. While these nonopaque sunscreens may be more acceptable cosmetically they are still relatively short-lived and susceptible to being removed by washing or perspiration. Additionally all sunscreens reduce vitamin D production.
Rieger, M.M. Cosmetics and Toiletries {1993) 108:43-56 reviews the role of reactive oxygen species (ROS) in UV-induced aging of skin. This article reports that topical application of known antioxidants to the skin can reduce the presence of ROS in the skin and thus reduce photodamage.
Retinoids have been used to retard the effects of photoaging in sun-damaged skin. U.S. Pat. No. 4,877,805 describes the treatment of photoaged skin as intervention therapy to decelerate the photoaging process. The patent indicates that there is little point in beginning such 2o treatment until the effects of aging begin to appear. In this regard the present applicants know of no art that suggests the use of retinoids to prevent photoaging of undamaged skin.
MMPs are a family of enzymes that play a major role in physiological and pathological destruction of connective tissue. Over 10 members of the family have been identified. They are referred to numerically (MMP-1, MMP-2, etc.) as well as by common name. They appear to share several structural and functional properties but differ in their tissue substrate specificities. They include interstitial collagenase (MMP-1) and PMN-collagenase (MMP-8) that degrade collagen types I, II, III, VII, VIII, IX, and gelatin: the 72kDa (MMP-2) and 92kDa (MMP-9) type IV collagenases/gelatinases that degrade collagen types IV, V, VII, X, XT, gelatin, elastin, and fibronectin; stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) that degrade fibronectin, PG core protein, collagen types IV, _ V, IX, and X, laminin and elastin: PUMP-1 (MMP-7) that degrades collagen type IV, gelatin, laminin, fibronectin and PG core protein: and metalloelastase (MMP-12) that degrades elastin and fibronectin.
The expression of MMP genes is induced by the transcription factors AP-1 and NF-xB. Angel, P. et al., Cell (1987) 49:729-739 and Sato, H. and Seiki, M., Oncogene (1993) 8:395-405. AP-1 and NF-xB activities are mediated by cytokines (e-a., interlukins IL-1, IL-6, and TNFa), growth factors (TGFa, bFGF), and environmental stress such as oxidants, heat, and ultraviolet irradiation. AP-1 induction and production of jun proteins (C-jun, jun-B, and jun-D) and foe proteins (C-foe, foe-B, fra-1, and fra-2) that make up AP-1 are mediated by a host of molecules (e. g. RAC, CDC42, MEKR, JNKK, JNK, RAS, RAF, MEK, and ERR). It is known that AP-1 and NF=xB are activated in mammalian cells exposed to W
light. Devary, Y., et at. Science (1993) 261:1442-1445.
Wlaschek, M. et al., Photochemistry and Photobiology (1994) 59(5):550-556, also report that WA irradiation of fibroblasts resulted in an IL-1 and IL-6-mediated induction of MMP-1 and that such induction might contribute to the loss of collagen in photoaging.
Inhibitors of MMPs or the transcription factors that affect their expression are also known. Hill, P.A. et al., Biochem J (1995) 308: 167-175 describes two MMP
inhibitors, CT1166 and 8031-7467. Gowravaram, M.R. et al., J Med Chem (1995) 38:2570-2581 describes the development of a series of hydroxamates that inhibit MMPs and mentions thiols, phosphonates, phosphinates, phosphoramidates and N-carboxy alkyls as known MMP
inhibitors. This paper indicates that MMP inhibitors include a moiety that chelates zinc and a peptidic fragment that binds a subset of the specificity pockets of MMPs. Hodgson, J., Biotechnology (1995) 13:554-557 reviews the clinical status of several MMP inhibitors, including Galardin, Batimastat, and Marimastat. Other MMP inhibitors include butanediamide (Conway, J.G. et al., J. Exp Med (1995) 182:449-457), TIMPs (Mauch C., et al., Arch Dermatol Res (1994) 287:107-114), and retinoids (Fanjul, A. et al., Nature (1994) 372:107-111; Nicholson, R.C. et al., EMBO Journal (1990) 9(13) 4443-4454; and Bailly, C. et al., J Investig Derm (1990) 94 (1) :47-51) .
DISCLOSURE OF THE INVENTION
The present invention is based on applicants discovery that WB exposure rapidly upgrades AP-1 and NF-kB in the exposed skin and leads to MMP induction. The elevated levels of MMPs that result from WB exposure act to degrade connective tissue proteins in skin. Such damage, if imperfectly repaired, results in solar scars which accumulate through repeated WB exposure and also cause photoaging.
Accordingly, applicants prevent photoaging of undamaged human skin due to exposure of the skin to WB by administering an inhibitor of a WB-inducible MMP to the human prior to said exposure in an amount sufficient to inhibit induction and/or activities of WB-inducible MMPs.
Surprisingly, this occurs at WB doses below those that cause erythema as well as at those which cause erythema.
The invention provides use of at least one inhibitor of (a) the activity of WB irradiation inducible matrix metalloproteinases (MMPs) in human skin, (b) one or both 4a of the transcription factors AP-1 and NF-KB and (c) at least one of the GTP binding proteins or kinases involved in activation or production of jun or fos proteins that comprise AP-1; in topically administrable form in an amount sufficient to inhibit production or activity of WB-inducible MMPs, one or both of AP-1 and NF-~B, or at least one of the GTP binding proteins or kinases involved in the activation or production of jun or fos proteins for inhibiting photoaging of unphotodamaged skin of a human due to exposure of the skin of the human to ultraviolet B irradiation (WB).
The invention also provides a commercial package comprising at least one inhibitor of (a) the activity of WB
irradiation inducible matrix metalloproteinases (MMPs) in human skin, (b) one or both of the transcription factors AP-1 and NF-KB and (c) at least one of the GTP binding proteins or kinases involved in activation or production of jun or fos proteins that comprise AP-1; in topically administrable form in an amount sufficient to inhibit production or activity of WB-inducible MMPs, one or both of AP-1 and NF-KB, or at least one of the GTP binding proteins or kinases involved in the activation or production of jun or fos proteins together with instructions for use for inhibiting photoaging of unphotodamaged skin of a human due to exposure of the skin of the human to ultraviolet B irradiation (WB).
Another aspect of this invention is the use of an inhibitor of UVB-inducible MMP induction or activity in the 4b manufacture of a medicament for preventing photoaging of undamaged skin due to repeated WB exposure.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
Fig. 1 is a flow chart showing the pathways by which WB induces MMP production.
Figs. 2a-d, 3a-b, 4a-d, and 5a-a are graphs of test results described in the Examples, infra.
MODES FOR CARRYING OUT THE INVENTION
The present invention is used to inhibit (i.e. reduce 5 or prevent) photoaging of undamaged human skin, that is, skin that does not show the effects of photoaging.
Treatment according to this invention should thus be practiced on skin such as that of the head, neck, hands, and arms that in typical, everyday living are habitually exposed to sunlight before such skin exhibits the telltale signs of photoaging. Because repeated exposure to doses of UVB below that which causes erythema can lead to photoaging, the invention should be practiced on skin subject to such low dose exposure. In this regard UVB
doses in the range of 30-50 mJ/cm2 skin cause erythema in most fair-skinned people. Accordingly the invention will prevent photoaging of skin subjected to doses below this range (typically above about 3 mJ/cmZ which is equivalent to a few minutes of sunlight exposure).
Photoaging is prevented or inhibited according to th~
invention by inhibiting WH-induced degradation of the dermal extracellular matrix by l~Ps. This is accomplished by administering a MMP inhibitor to the skin that is to be exposed to sunlight. In this regard the term "lip Z5 inhibitor" intends those agents that directly or indirectly inhibit (i.e., reduce significantly or eliminate) the expression of UVB-inducible I~iPa in such skin or inhibit the enzymatic activity of such IMPS.
"Indirect inhibition" is intended to mean interaction with either or-both of the transcription factors AP-1 and NF- KB
f and/or one or more of the molecules involved in the three kinase cascades that result in jun and fos protein induction in the skin in a manner that reduces or eliminates the expression of UVB-inducible MMPs.
Fig. I schematically represents the pathways of WH-inducible MMP expression. As shown in Fig. 1, WH
exposure generates reactive oxygen intermediates (ROI) which stimulate AP-1 and NF-KB activity, which in turn induces cytokines and growth factors. The interaction of those cytokines and factors with their receptors trigger the small GTP binding proteins RAC/CDC42 and RAS. Those proteins activate the three kinase cascades that are essential to production of the jun and fos proteins which make-up AP-1. AP-1 induces expression of certain MMPS.
The agents that prevent photoaging can act on the MMPS, the transcription factors AP-1 and NF-KB, and/or one or more of the molecules involved in the three kinase cascades shown in Fig. 1. Aspirin and E5510 (described by Fujimori, T., et at., Jpn J Pharmacol (1991) 55(1):81-91) inhibit NF-KB activation. Farnesyl transferasa inhibitors such as B-581 (described by Garcia A.M., et al., J Hiol Chem (1993) 268(25):18415-18), HZA-5B (described by Dalton M.B. et al., Cancer Res (1995) 55(15):3295-3304), farnesyl acetate, and (a-hydroxyfarnesyl) phosphoric acid act on RAS and inhibit activation of the ERK cascade: whereas geranyl geranyltransferaso inhibitors and lisofylline inhibit activation of the JNK cascade. Compounds such as SB202190 (described by Lee, J.C., et al., Nature (1994) 372:739-746) and PD98059 (described by Dudley, D.T., et al., PNAS (USA) (1995) 92:7686-7689) inhibit specific kinases in the cascades. Retinoids such as those disclosed in U.S. Pat. No. 4,877,805 and the dissociating retinoids that are specific for AP-1 antagonism such as those described by Fanjul, et al. (Nature (I994) 372:104-110), gluc~cbrticoids, and Vitamin D3 target AP-1. Other retinoids, besides retinol, include natural and synthetic analogs of vitamin A (retinol), vitamin A aldehyde (retinal), vitamin A acid (retinoic acid, including aIl-tr ns and 13-cis retinoic acid), and other as described in EP 379367 A2. Finally, MMPs may be inhibited by BB2284 (described by Gearing, A.J.H. et al., Nature (1994) 370:555-557), GI129471 (described by McGeehan G.M., et al., Nature (1994) 370:558-561), TIMPS, Galardin, r Batimastat, and Marimastat, and hydroxamates, and other . 5 known inhibitors.
One or more of these MMP inhibitors are preferably administered topically to the skin that is to be exposed to sunlight. For such administration they will normally be formulated as creams, gels, ointments, sprays or lotions. Conventional pharmacologically and cosmetically acceptable vehicles may be used to formulate the inhibitor(s). Examples of such vehicles are described in U.S. Pat. No. 4,877,805 and EPA Pub. No. 0586106 A1. As indicated, one or more inhibitors may be present in a given formulation. For instance, a combination of inhibitors that act on two or more different molecules involved in effecting MMP degradation of the skin may be used. The formulations may also contain additives such as, emollients, skin permeation enhancers, pigments, and perfumes. In addition, the formulation may contain ingredients such as absorbent particles (e. g. polymer beads) that provide sustained release of the inhibitors to the skin. The weight concentration of inhibitors) in the formulation will usually be 0.01 to 10~, more usually 0.1~ to 1~. Normally about 50 mg of formulation will be applied per cm2 of skin.
The inhibitors are preferably applied to the undamaged skin prior to exposure to sunlight. The application regimen (i.e. daily, weekly, etc.) will primarily depend upon the longevity (e. g., metabolism, half-life in the skin) of the inhibitors) and the molecular targets of their action. It may also be effected by bathing, perspiration, and the extent of sunlight exposure. Usually they will be applied daily.
WO 9'7/25969 PCT/US97/00791 The invention is further illustrated by the following examples. These examples are not intended to limit the invention in any manner.
EXAMPLES
~~,.termination of Molecular Basis of UVB-Induced Photoaqinc_r I~~.cth UVB Dose Induction of MMPs The time course of changes in MMP-1, MMP-3, MMP-9, and MMP-2 mRNA, protein, and enzymatic activity levels following UVB exposure were determined as follows.
Subjects were adult Caucasians {approximately equal numbers of males and females) with light to mild pigmentation. The UVB dose required to cause barely perceptible skin reddening (minimal erythema dose, or "MED") for each subject was determined 24 hours post irradiation. pne (1) MED for all subjects ranged from 30-50 mJ/cm2. The subjects' buttocks were irradiated with 2 MED UVB with an Ultralite Panelite lamp containing four F36T12 ERE-VHO UVB tubes. Irradiation intensity was monitored with an IL443 Phototherapy Radiometer and a SED240/UVB/W photodetector. UVB output, measured 48 cm from the source, was 0.5 mW/cmz. For each subject skin was removed by keratome from four sites (one non-irradiated, three irradiated) at 8, 16, 24, 48 and 72 hours following irradiation. Tissue was snap frozen and total RNA
- isolated and analyzed by Northern blot as described by Fisher, G.J. et al., J Invest Dermatol (1991) 96:699-707.
Band intensities were quantified by PhosphorImager.
Values for MMP transcripts were normalized to those for control gene 36B4. The results of these tests are shown in Figs. 2a {MMP-1), 2b {MMP-3), 2c (MMP-9), and 2d (MMP--2). Results are means ~ SEM (n=6 for 8, 16, 48, and 72 hours and n=17 for no UVB control and 24 hours) and are presented as fold increase of normalized values relative to non-irradiated skin. The bands displayed in the Figures are composites from several individuals.
exposure generates reactive oxygen intermediates (ROI) which stimulate AP-1 and NF-KB activity, which in turn induces cytokines and growth factors. The interaction of those cytokines and factors with their receptors trigger the small GTP binding proteins RAC/CDC42 and RAS. Those proteins activate the three kinase cascades that are essential to production of the jun and fos proteins which make-up AP-1. AP-1 induces expression of certain MMPS.
The agents that prevent photoaging can act on the MMPS, the transcription factors AP-1 and NF-KB, and/or one or more of the molecules involved in the three kinase cascades shown in Fig. 1. Aspirin and E5510 (described by Fujimori, T., et at., Jpn J Pharmacol (1991) 55(1):81-91) inhibit NF-KB activation. Farnesyl transferasa inhibitors such as B-581 (described by Garcia A.M., et al., J Hiol Chem (1993) 268(25):18415-18), HZA-5B (described by Dalton M.B. et al., Cancer Res (1995) 55(15):3295-3304), farnesyl acetate, and (a-hydroxyfarnesyl) phosphoric acid act on RAS and inhibit activation of the ERK cascade: whereas geranyl geranyltransferaso inhibitors and lisofylline inhibit activation of the JNK cascade. Compounds such as SB202190 (described by Lee, J.C., et al., Nature (1994) 372:739-746) and PD98059 (described by Dudley, D.T., et al., PNAS (USA) (1995) 92:7686-7689) inhibit specific kinases in the cascades. Retinoids such as those disclosed in U.S. Pat. No. 4,877,805 and the dissociating retinoids that are specific for AP-1 antagonism such as those described by Fanjul, et al. (Nature (I994) 372:104-110), gluc~cbrticoids, and Vitamin D3 target AP-1. Other retinoids, besides retinol, include natural and synthetic analogs of vitamin A (retinol), vitamin A aldehyde (retinal), vitamin A acid (retinoic acid, including aIl-tr ns and 13-cis retinoic acid), and other as described in EP 379367 A2. Finally, MMPs may be inhibited by BB2284 (described by Gearing, A.J.H. et al., Nature (1994) 370:555-557), GI129471 (described by McGeehan G.M., et al., Nature (1994) 370:558-561), TIMPS, Galardin, r Batimastat, and Marimastat, and hydroxamates, and other . 5 known inhibitors.
One or more of these MMP inhibitors are preferably administered topically to the skin that is to be exposed to sunlight. For such administration they will normally be formulated as creams, gels, ointments, sprays or lotions. Conventional pharmacologically and cosmetically acceptable vehicles may be used to formulate the inhibitor(s). Examples of such vehicles are described in U.S. Pat. No. 4,877,805 and EPA Pub. No. 0586106 A1. As indicated, one or more inhibitors may be present in a given formulation. For instance, a combination of inhibitors that act on two or more different molecules involved in effecting MMP degradation of the skin may be used. The formulations may also contain additives such as, emollients, skin permeation enhancers, pigments, and perfumes. In addition, the formulation may contain ingredients such as absorbent particles (e. g. polymer beads) that provide sustained release of the inhibitors to the skin. The weight concentration of inhibitors) in the formulation will usually be 0.01 to 10~, more usually 0.1~ to 1~. Normally about 50 mg of formulation will be applied per cm2 of skin.
The inhibitors are preferably applied to the undamaged skin prior to exposure to sunlight. The application regimen (i.e. daily, weekly, etc.) will primarily depend upon the longevity (e. g., metabolism, half-life in the skin) of the inhibitors) and the molecular targets of their action. It may also be effected by bathing, perspiration, and the extent of sunlight exposure. Usually they will be applied daily.
WO 9'7/25969 PCT/US97/00791 The invention is further illustrated by the following examples. These examples are not intended to limit the invention in any manner.
EXAMPLES
~~,.termination of Molecular Basis of UVB-Induced Photoaqinc_r I~~.cth UVB Dose Induction of MMPs The time course of changes in MMP-1, MMP-3, MMP-9, and MMP-2 mRNA, protein, and enzymatic activity levels following UVB exposure were determined as follows.
Subjects were adult Caucasians {approximately equal numbers of males and females) with light to mild pigmentation. The UVB dose required to cause barely perceptible skin reddening (minimal erythema dose, or "MED") for each subject was determined 24 hours post irradiation. pne (1) MED for all subjects ranged from 30-50 mJ/cm2. The subjects' buttocks were irradiated with 2 MED UVB with an Ultralite Panelite lamp containing four F36T12 ERE-VHO UVB tubes. Irradiation intensity was monitored with an IL443 Phototherapy Radiometer and a SED240/UVB/W photodetector. UVB output, measured 48 cm from the source, was 0.5 mW/cmz. For each subject skin was removed by keratome from four sites (one non-irradiated, three irradiated) at 8, 16, 24, 48 and 72 hours following irradiation. Tissue was snap frozen and total RNA
- isolated and analyzed by Northern blot as described by Fisher, G.J. et al., J Invest Dermatol (1991) 96:699-707.
Band intensities were quantified by PhosphorImager.
Values for MMP transcripts were normalized to those for control gene 36B4. The results of these tests are shown in Figs. 2a {MMP-1), 2b {MMP-3), 2c (MMP-9), and 2d (MMP--2). Results are means ~ SEM (n=6 for 8, 16, 48, and 72 hours and n=17 for no UVB control and 24 hours) and are presented as fold increase of normalized values relative to non-irradiated skin. The bands displayed in the Figures are composites from several individuals.
As shown in Figs. 2a-d, induction of MMP-1, MMP-3, and MMP-9 mRNAs was maximal (6-60 fold) within 16 to 24 hours and returned to near baseline within 48 to 72 hours.
MMP-2 mRNA was detectable, but only elevated 1.6-fold 24 hours post irradiation. Time courses for induction of MMP-1 and MMP-9 proteins and activities by 2 MED WB
paralleled those observed for their mRNAs. Neither MMP-2 protein nor activity was induced.
Northern analysis of WB-treated skin with a MMP-3 IO (stromelysin I)-specific probe yielded results identical to those obtained with a full-length MMP-3 probe (Fig.
2b), while hybridization with a MMP-10 (stromelysin II)-specific probe yielded no signal. This indicates that among the stromelysins, WB induces predominantly stromelysin I.
Low Dose WH :~,nduction of MMPs Subjects were exposed to WH doses ranging from 0.01 to 2 MED as described above. Full thickness skin samples (6mm cylinders) were obtained 24 hours after irradiation from treated and untreated sites. The samples were homogenized in 20mM Tris HC1 (pH 7.6), SmM CaClz, and centrifuged at 30o0xg for 10 minutes. Supernatants were used to measure MMP-1 and MMP-9 proteins by Western blot (100 ~g/lane), using chemiluminescence detection and activity by hydrolysis of 3H librillar collagen (100 ~g/assay) according to Hu, C.L. et al., Anal Biochea (1978) 88:638-643 and gelatin zymography (20 ~g/assay) , according to Hibbs, M.S. et al., J Biol Chem (1985) 260:2493-2500, respectively. The MMP-1 and MMP-9 antibodies used are described by werb, Z. et al., J Cell t Biol (1989) 109:877-889 and Murphy, G. et al., Biochem J
(1989) 258:463-472, respectively. The results of these tests are shown in Figures 3a and 3b.
In Fig. 3a, MMP-1 protein values are shown by the open bars whereas MMP-1 activity values are shown by the cross-hatched bars. The Fig. 3a inset shows representative Western blots from two subjects. The larger 54 KDa band is intact MMP-1 and the smaller 45 KDa band is the proteolytically processed activated farm of 5 MMP- 1, In~Fig. 3b MMP-9 protein values are shown by the open bars where MMP-9 activity values are shown by the cross-hatched bars. The Fig. 3b inset shows a representative Western blot (left panel) and a representative zymogram 10 (right panel). Multiple bands on the zymogram are proteolytically processed active forms of MMP-9.
Hand intensities were quantified by laser densitometry. Results are given as means ~ SEM of n=10.
As shown in Figs. 3a and 3b, induction of MMP-1 and MMP-9 proteins and activities was dose dependent, and !or both MMPs changes in protein and activity mirrored each other. MMP-1 was induced by all doses or WH tested, while MMP-9 was induced by doses _> 0.1 MED. Induction was maximal at one (1) MED and approximately halt maximal at 0.1 MED. 0.1 MED WB is equivalent to two to three minutes solar irradiation on a summer day, which causes no perceptible skin reddening.
Low Dose WH Induction of AP-1 and NF- H
Subjects were irradiated and tissue samples taken as described above. Nuclear extracts were prepared from the samples as described by Fisher, G.J. et al., J Hiol Chem (1994) 269:20629-20635. Biopsies (approx. 200 mg wet weighty containing -l0a cells yielded 500 ~g nuclear extract protein, on average. Electrophoretic mobility shift assays (e ~sg nuclear extract protein) were performed using 32P-labeled DNA probes containing AP-1 and NF-rcB
consensus and mutated DNA-binding sequences as described by Fisher, G.J. et al.,.~usra. Antibodies for supershifts were obtained from Santa Cruz Biotechnology. Jun and toe antibodies had broad reactivity to all jun and foe family i >
MMP-2 mRNA was detectable, but only elevated 1.6-fold 24 hours post irradiation. Time courses for induction of MMP-1 and MMP-9 proteins and activities by 2 MED WB
paralleled those observed for their mRNAs. Neither MMP-2 protein nor activity was induced.
Northern analysis of WB-treated skin with a MMP-3 IO (stromelysin I)-specific probe yielded results identical to those obtained with a full-length MMP-3 probe (Fig.
2b), while hybridization with a MMP-10 (stromelysin II)-specific probe yielded no signal. This indicates that among the stromelysins, WB induces predominantly stromelysin I.
Low Dose WH :~,nduction of MMPs Subjects were exposed to WH doses ranging from 0.01 to 2 MED as described above. Full thickness skin samples (6mm cylinders) were obtained 24 hours after irradiation from treated and untreated sites. The samples were homogenized in 20mM Tris HC1 (pH 7.6), SmM CaClz, and centrifuged at 30o0xg for 10 minutes. Supernatants were used to measure MMP-1 and MMP-9 proteins by Western blot (100 ~g/lane), using chemiluminescence detection and activity by hydrolysis of 3H librillar collagen (100 ~g/assay) according to Hu, C.L. et al., Anal Biochea (1978) 88:638-643 and gelatin zymography (20 ~g/assay) , according to Hibbs, M.S. et al., J Biol Chem (1985) 260:2493-2500, respectively. The MMP-1 and MMP-9 antibodies used are described by werb, Z. et al., J Cell t Biol (1989) 109:877-889 and Murphy, G. et al., Biochem J
(1989) 258:463-472, respectively. The results of these tests are shown in Figures 3a and 3b.
In Fig. 3a, MMP-1 protein values are shown by the open bars whereas MMP-1 activity values are shown by the cross-hatched bars. The Fig. 3a inset shows representative Western blots from two subjects. The larger 54 KDa band is intact MMP-1 and the smaller 45 KDa band is the proteolytically processed activated farm of 5 MMP- 1, In~Fig. 3b MMP-9 protein values are shown by the open bars where MMP-9 activity values are shown by the cross-hatched bars. The Fig. 3b inset shows a representative Western blot (left panel) and a representative zymogram 10 (right panel). Multiple bands on the zymogram are proteolytically processed active forms of MMP-9.
Hand intensities were quantified by laser densitometry. Results are given as means ~ SEM of n=10.
As shown in Figs. 3a and 3b, induction of MMP-1 and MMP-9 proteins and activities was dose dependent, and !or both MMPs changes in protein and activity mirrored each other. MMP-1 was induced by all doses or WH tested, while MMP-9 was induced by doses _> 0.1 MED. Induction was maximal at one (1) MED and approximately halt maximal at 0.1 MED. 0.1 MED WB is equivalent to two to three minutes solar irradiation on a summer day, which causes no perceptible skin reddening.
Low Dose WH Induction of AP-1 and NF- H
Subjects were irradiated and tissue samples taken as described above. Nuclear extracts were prepared from the samples as described by Fisher, G.J. et al., J Hiol Chem (1994) 269:20629-20635. Biopsies (approx. 200 mg wet weighty containing -l0a cells yielded 500 ~g nuclear extract protein, on average. Electrophoretic mobility shift assays (e ~sg nuclear extract protein) were performed using 32P-labeled DNA probes containing AP-1 and NF-rcB
consensus and mutated DNA-binding sequences as described by Fisher, G.J. et al.,.~usra. Antibodies for supershifts were obtained from Santa Cruz Biotechnology. Jun and toe antibodies had broad reactivity to all jun and foe family i >
members, respectively. NF-xB antibody was specific for p65/Rel A. The results of these assays are shown in Figs. 4a, 4b, 4c and 4d (NS designates non-specific examples). The insets for these Figs. show representative AP-1 and NF-xB retarded complexes. +Compet designates addition of 100-fold excess unlabelled probe; Mut designates mutated 32P probe.
Fig. 4a depicts AP-1 and NF-xB binding in non-irradiated and irradiated (four hours after 2 MED WB) skin. As shown in Fig. 4a binding of both transcription factors to their DNA response elements was specific as demonstrated by loss o! retarded complexes with mutated labeled probes. Antibody supershifts demonstrated that the specific AP-1 and NF-xB retarded complexes obser~~red with extract from WB-irradiated skin contained jun and fos proteins,, and Rel A protein, respectively.
Figs. 4b and 4c show the time courses of induction of AP-1 and NF-xB DNA binding, respectively, by 2 MED WH.
The results reported are means t SEM, n~9. As shown, induction of both factors occurred within 15 minutes.
Fig. 4d shows the dose dependence of induction of AP-1 (represented by open bars) and NF~xB (represented by cross-hatched bars). DNA binding was measured 30 minutes after irradiation. As shown halt maximal induction of both factors occurred at approximately 0.1 MED and maximal induction occurred at one (1) MED. Tha WB dose dependencies for induction o! these rectors closely matched those reported above for induction o= lip-1 and I~IP-9, consistent with the participation of these transcription factors in the We-induced increases in these two- NIPS .
Inhibition of WH Induction of AP-1 h~tP-1 and IMP-9 0.1% all-traps retinoic acid (t-RA). and its vehicle (70% ethanol and 30% propylene glycol) or 0.05% o! the glucocorticoid (GC) clobetasol propionate and its vehicle (2% propylene glycol plus 2% sorbitan sesquioleate fn white petrolatum) were applied (300 mg formulation/6 cmz skin) to subjects for 48 hours as described by Fisher, G.J. et al., J Invest Dermatol (1991) 96:699-707. Treated skin sites were then irradiated with 2 MED WB. Skin was obtained as described above 30 minutes after exposure to AP-1 measurements or 24 hours after exposure for MMP
measurements. AP-1 measurements and MMP-1 and MMP-9 measurements were made as described abov~. To determine whether t-RA altered WB-induced skin reddening, subjects were treated with 0.1% t-RA and its vehicle for 24 hours.
Treated areas were irradiated with 10-80 mJ/cm2 WH and skin reddening determined 24 hours after by a Minolta chromameter. The results of these tests are shown in Figs. 5a, 5b, 5c, 5d and 5e.
Figs. 5 a reports the AP-1 measurements. As shown pretreatment of skin with t-RA reduced WB-induced AP-1 DNA binding by approximately 70;.
Figs. 5b and 5c report the MMP-1 and MMP-9 measurements. As shown, t-RA pretreatment reduced WH-induced MMP-1 and MMP-9 mRNAs, proteins and activities 50%-80$.
Fig. 5d reports tests on the effect of t-RA
pretreatment on skin reddening. As shown, although t-RA
absorption overlaps th~ UVH range (t-RA Amax ~ 351 nm), t-RA did not reduce WB-induced skin reddening. This indicates that the observed reductions in AP-land MMP
induction were specific rather than due to absorption or WB by t-RA.
Fig. 5e reports the effects o! pretreatment of the skin with G~ As shown GC pretreatment reduced MMP- 1 and MMP-9 activities to extents similar to those observed from t-RA pretreatments.
Fig. 4a depicts AP-1 and NF-xB binding in non-irradiated and irradiated (four hours after 2 MED WB) skin. As shown in Fig. 4a binding of both transcription factors to their DNA response elements was specific as demonstrated by loss o! retarded complexes with mutated labeled probes. Antibody supershifts demonstrated that the specific AP-1 and NF-xB retarded complexes obser~~red with extract from WB-irradiated skin contained jun and fos proteins,, and Rel A protein, respectively.
Figs. 4b and 4c show the time courses of induction of AP-1 and NF-xB DNA binding, respectively, by 2 MED WH.
The results reported are means t SEM, n~9. As shown, induction of both factors occurred within 15 minutes.
Fig. 4d shows the dose dependence of induction of AP-1 (represented by open bars) and NF~xB (represented by cross-hatched bars). DNA binding was measured 30 minutes after irradiation. As shown halt maximal induction of both factors occurred at approximately 0.1 MED and maximal induction occurred at one (1) MED. Tha WB dose dependencies for induction o! these rectors closely matched those reported above for induction o= lip-1 and I~IP-9, consistent with the participation of these transcription factors in the We-induced increases in these two- NIPS .
Inhibition of WH Induction of AP-1 h~tP-1 and IMP-9 0.1% all-traps retinoic acid (t-RA). and its vehicle (70% ethanol and 30% propylene glycol) or 0.05% o! the glucocorticoid (GC) clobetasol propionate and its vehicle (2% propylene glycol plus 2% sorbitan sesquioleate fn white petrolatum) were applied (300 mg formulation/6 cmz skin) to subjects for 48 hours as described by Fisher, G.J. et al., J Invest Dermatol (1991) 96:699-707. Treated skin sites were then irradiated with 2 MED WB. Skin was obtained as described above 30 minutes after exposure to AP-1 measurements or 24 hours after exposure for MMP
measurements. AP-1 measurements and MMP-1 and MMP-9 measurements were made as described abov~. To determine whether t-RA altered WB-induced skin reddening, subjects were treated with 0.1% t-RA and its vehicle for 24 hours.
Treated areas were irradiated with 10-80 mJ/cm2 WH and skin reddening determined 24 hours after by a Minolta chromameter. The results of these tests are shown in Figs. 5a, 5b, 5c, 5d and 5e.
Figs. 5 a reports the AP-1 measurements. As shown pretreatment of skin with t-RA reduced WB-induced AP-1 DNA binding by approximately 70;.
Figs. 5b and 5c report the MMP-1 and MMP-9 measurements. As shown, t-RA pretreatment reduced WH-induced MMP-1 and MMP-9 mRNAs, proteins and activities 50%-80$.
Fig. 5d reports tests on the effect of t-RA
pretreatment on skin reddening. As shown, although t-RA
absorption overlaps th~ UVH range (t-RA Amax ~ 351 nm), t-RA did not reduce WB-induced skin reddening. This indicates that the observed reductions in AP-land MMP
induction were specific rather than due to absorption or WB by t-RA.
Fig. 5e reports the effects o! pretreatment of the skin with G~ As shown GC pretreatment reduced MMP- 1 and MMP-9 activities to extents similar to those observed from t-RA pretreatments.
Claims (21)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Use of at least one inhibitor of (a) the activity of UVB irradiation inducible matrix metalloproteinases (MMPs) in human skin, (b) one or both of the transcription factors AP-1 and NF-~B and (c) at least one of the GTP binding proteins or kinases involved in activation or production of jun or fos proteins that comprise AP-1; in topically administrable form in an amount sufficient to inhibit production or activity of UVB-inducible MMPs, one or both of AP-1 and NF-~B, or at least one of the GTP binding proteins or kinases involved in the activation or production of jun or fos proteins for inhibiting photoaging of unphotodamaged skin of a human due to exposure of the skin of the human to ultraviolet B irradiation (UVB).
2. The use of claim 1 in inhibiting photoaging induced by exposure to a dose of UVB below the minimum dose required to cause reddening of said skin.
3. The use of claim 2 wherein said UVB dose is above about 5 mJ/cm2.
4. The use of claim 1 wherein the inhibitor inhibits the activity of at least one of AP-1 and NF-~B.
5. The use of claim 1 wherein the inhibitor inhibits the activity of UVB-inducible MMPs.
6. The use of claim 1 wherein the inhibitor inhibits a GPT binding protein or kinase essential to the production of jun or fos proteins.
7. The use of claim 4 wherein the inhibitor inhibits AP-1 and is a retinoid, a glucocorticoid, or Vitamin D3.
8. The use of claim 4 wherein the inhibitor inhibits NF-~B and is a glucocorticoid, aspirin or E5510.
9. The use of claim 5 wherein the inhibitor is a TIMP, Galardin, Batimastat, Marimastat, or a hydroxamate.
10. The use of claim 6 wherein the inhibitor is a famesyl transferase inhibitor, a geranyl geranyltransferase inhibitor, SB202190, or PD98059.
11. The use of an inhibitor of an ultraviolet B
irradiation inducible matrix metalloproteinase in the manufacture of a medicament for preventing photoaging of undamaged human skin.
irradiation inducible matrix metalloproteinase in the manufacture of a medicament for preventing photoaging of undamaged human skin.
12. A commercial package comprising at least one inhibitor of (a) the activity of UVB irradiation inducible matrix metalloproteinases (MMPs) in human skin, (b) one or both of the transcription factors AP-1 and NF-~B and (c) at least one of the GTP binding proteins or kinases involved in activation or production of jun or fos proteins that comprise AP-1; in topically administrable form in an amount sufficient to inhibit production or activity of UVB-inducible MMPs, one or both of AP-1 and NF-~B, or at least one of the GTP binding proteins or kinases involved in the activation or production of jun or fos proteins together with instructions for use for inhibiting photoaging of unphotodamaged skin of a human due to exposure of the skin of the human to ultraviolet B irradiation (UVB).
13. A commercial package according to claim 12 wherein said instructions are for inhibiting photoaging induced by exposure to a dose of UVB below the minimum dose required to cause reddening of said skin.
14. A commercial package according to claim 13 wherein said UVB dose is above about 5 mJ/cm2.
15. A commercial package according to claim 12 wherein the inhibitor inhibits the activity of at least one of AP-1 and NF-~B.
16. A commercial package according to claim 12 wherein the inhibitor inhibits the activity of UVB-inducible MMPs.
17. A commercial package according to claim 12 wherein the inhibitor inhibits a GPT binding protein or kinase essential to the production of jun or fos proteins.
18. A commercial package according to claim 15 wherein the inhibitor inhibits AP-1 and is a retinoid, a glucocorticoid, or Vitamin D3.
19. A commercial package according to claim 15 wherein the inhibitor inhibits NF-~B and is a glucocorticoid, aspirin or E5510.
20. A commercial package according to claim 16 wherein the inhibitor is a TIMP, Galardin, Batimastat, Marimastat, or a hydroxamate.
21. A commercial package according to claim 17 wherein the inhibitor is a famesyl transferase inhibitor, a geranyl geranyltransferase inhibitor, SB202190, or PD98059.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/588,771 US5837224A (en) | 1996-01-19 | 1996-01-19 | Method of inhibiting photoaging of skin |
US08/588,771 | 1996-01-19 | ||
PCT/US1997/000791 WO1997025969A1 (en) | 1996-01-19 | 1997-01-17 | Method of inhibiting photoaging of skin |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2241981A1 CA2241981A1 (en) | 1997-07-24 |
CA2241981C true CA2241981C (en) | 2002-03-19 |
Family
ID=24355242
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002241981A Expired - Lifetime CA2241981C (en) | 1996-01-19 | 1997-01-17 | Method of inhibiting photoaging of skin |
Country Status (21)
Country | Link |
---|---|
US (1) | US5837224A (en) |
EP (1) | EP0883398A4 (en) |
JP (1) | JP3705820B2 (en) |
CN (1) | CN1086937C (en) |
AR (1) | AR005650A1 (en) |
BR (1) | BR9707018A (en) |
CA (1) | CA2241981C (en) |
CO (1) | CO4770951A1 (en) |
CZ (1) | CZ291530B6 (en) |
EE (1) | EE9800216A (en) |
HK (1) | HK1018885A1 (en) |
HU (1) | HUP9900655A3 (en) |
LT (1) | LT4515B (en) |
MY (1) | MY119711A (en) |
NO (1) | NO983019L (en) |
NZ (1) | NZ330860A (en) |
PL (1) | PL327827A1 (en) |
SI (1) | SI9720015A (en) |
SK (1) | SK95998A3 (en) |
TR (1) | TR199801376T2 (en) |
WO (1) | WO1997025969A1 (en) |
Families Citing this family (83)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6528483B2 (en) | 1995-06-07 | 2003-03-04 | André Beaulieu | Method of producing concentrated non-buffered solutions of fibronectin |
SK73898A3 (en) * | 1995-12-08 | 1999-01-11 | Agouron Pharma | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation |
US6500948B1 (en) | 1995-12-08 | 2002-12-31 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof |
US5837224A (en) * | 1996-01-19 | 1998-11-17 | The Regents Of The University Of Michigan | Method of inhibiting photoaging of skin |
US6174915B1 (en) | 1997-03-25 | 2001-01-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
US6008243A (en) * | 1996-10-24 | 1999-12-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
CA2281944C (en) * | 1997-02-25 | 2007-05-15 | The Regents Of The University Of Michigan | Methods and compositions for preventing and treating chronological aging in human skin |
US5985900A (en) * | 1997-04-01 | 1999-11-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
US20050058709A1 (en) * | 1997-06-04 | 2005-03-17 | Fisher Gary J. | Methods for inhibiting photoaging of human skin using orally-administered agent |
TWI234467B (en) * | 1997-06-04 | 2005-06-21 | Univ Michigan | Composition for inhibiting photoaging of skin |
JP3973748B2 (en) * | 1998-01-14 | 2007-09-12 | 花王株式会社 | Hair growth inhibitor |
US6683069B1 (en) * | 1998-04-02 | 2004-01-27 | Regents Of The University Of Michigan | Methods and compositions for reducing UV-induced inhibition of collagen synthesis in human skin |
FR2777183B1 (en) * | 1998-04-10 | 2001-03-02 | Oreal | USE OF AT LEAST ONE HYDROXYSTILBENE IN A COMPOSITION FOR PROMOTING DEQUAMATION OF THE SKIN AND COMPOSITION COMPRISING SAME |
FR2777186B1 (en) * | 1998-04-10 | 2001-03-09 | Oreal | USE OF AT LEAST ONE HYDROXYSTILBENE IN A FIRMING COMPOSITION |
US20060212025A1 (en) | 1998-11-30 | 2006-09-21 | Light Bioscience, Llc | Method and apparatus for acne treatment |
US9192780B2 (en) | 1998-11-30 | 2015-11-24 | L'oreal | Low intensity light therapy for treatment of retinal, macular, and visual pathway disorders |
US6283956B1 (en) * | 1998-11-30 | 2001-09-04 | David H. McDaniels | Reduction, elimination, or stimulation of hair growth |
US6887260B1 (en) | 1998-11-30 | 2005-05-03 | Light Bioscience, Llc | Method and apparatus for acne treatment |
US6071955A (en) * | 1999-02-25 | 2000-06-06 | The Regents Of The University Of California | FXR, PPARA and LXRA activators to treat acne/acneiform conditions |
WO2000051562A1 (en) * | 1999-03-03 | 2000-09-08 | Shiseido Company, Ltd. | Matrix metalloprotease inhibitor and utilization thereof |
AU4064100A (en) * | 1999-04-01 | 2000-10-23 | Board Of Trustees Of The University Of Arkansas, The | P38mapk inhibitor and uses thereof |
US20040235950A1 (en) * | 1999-05-20 | 2004-11-25 | Voorhees John J. | Compositions and methods for use against acne-induced inflammation and dermal matrix-degrading enzymes |
US7268148B2 (en) * | 1999-05-20 | 2007-09-11 | Regents Of The University Of Michigan | Compositions and methods for use against acne-induced inflammation and dermal matrix-degrading enzymes |
WO2001005430A1 (en) * | 1999-07-20 | 2001-01-25 | Merck & Co., Inc. | Sustained release drug dispersion delivery device |
US6982284B1 (en) | 1999-09-10 | 2006-01-03 | Applied Genetics Incorporated Dermatics | Compositions and methods for modification of skin lipid content |
DE19955349A1 (en) * | 1999-11-17 | 2001-08-02 | Switch Biotech Ag | Use of novel polypeptide or its variant or nucleic acid encoding the polypeptide for diagnosing and/or preventing and/or treating skin disorders and/or treatment in wound healing or for identifying active substances |
JP4074043B2 (en) | 2000-03-27 | 2008-04-09 | 株式会社資生堂 | Skin basement membrane formation promoter, artificial skin formation promoter, and method for producing artificial skin |
DE10020447A1 (en) * | 2000-03-31 | 2001-10-11 | Henkel Kgaa | Use of protease inhibitors in cosmetics and pharmacy |
CA2414406A1 (en) * | 2000-06-26 | 2002-01-03 | The Regents Of The University Of Michigan | Use of egf-r protein tyrosine kinase inhibitors for preventing photoaging in human skin |
US20040185127A1 (en) * | 2001-06-29 | 2004-09-23 | Lerner David S. | Cosmetic composition and method |
WO2002019982A2 (en) * | 2000-06-29 | 2002-03-14 | Quick Med Technologies, Inc. | Cosmetic composition and method for reducing or preventing wrinkling |
WO2002003940A2 (en) | 2000-07-06 | 2002-01-17 | The Regents Of The University Of Michigan | Uva (>360-400) and uvb (300-325) specific sunscreens |
FR2811563B1 (en) * | 2000-07-13 | 2003-06-20 | Oreal | COMPOSITION, ESPECIALLY COSMETIC, COMPRISING DHEA AND / OR A PRECURSOR OR DERIVATIVE, AND AT LEAST ONE COMPOUND INCREASING THE SYNTHESIS OF GLYCOSAMINOGLYCANS |
FR2811561B1 (en) * | 2000-07-13 | 2003-03-21 | Oreal | COMPOSITION, ESPECIALLY COSMETIC, CONTAINING DHEA AND / OR A CHEMICAL OR BIOLOGICAL PRECURSOR OR DERIVATIVE THEREOF, AND A METALLOPROTEINASE INHIBITOR |
US20020119107A1 (en) * | 2000-12-18 | 2002-08-29 | James Varani | Method for protecting and restoring skin using selective MMP inhibitors |
DE10102784A1 (en) * | 2001-01-22 | 2002-08-01 | Henkel Kgaa | Cosmetic or pharmaceutical preparations for the treatment of epithelial cover tissue |
JP2002277455A (en) * | 2001-03-15 | 2002-09-25 | Shiseido Co Ltd | Composition and method for detecting skin aging gene |
NZ535101A (en) | 2002-03-08 | 2007-07-27 | Eisai Co Ltd | Macrocyclic compounds useful as pharmaceuticals |
US7354956B2 (en) * | 2002-04-12 | 2008-04-08 | L'oreal | Composition containing a sapogenin and use thereof |
US20050202001A1 (en) * | 2002-04-24 | 2005-09-15 | Han-Mo Koo | Enhancement of human epidermal melanogenesis |
CN101601702B (en) * | 2002-06-25 | 2012-04-18 | 株式会社资生堂 | Anti-aging agent |
US20050049248A1 (en) * | 2002-07-29 | 2005-03-03 | Lockwood Samuel Fournier | Carotenoid ether analogs or derivatives for controlling C-reactive protein levels |
US7320997B2 (en) * | 2002-07-29 | 2008-01-22 | Cardax Pharmaceuticals, Inc. | Pharmaceutical compositions including carotenoid ester analogs or derivatives for the inhibition and amelioration of disease |
US20050059659A1 (en) * | 2002-07-29 | 2005-03-17 | Lockwood Samuel Fournier | Carotenoid analogs or derivatives for controlling C-reactive protein levels |
US20050004235A1 (en) * | 2002-07-29 | 2005-01-06 | Lockwood Samuel Fournier | Carotenoid analogs or derivatives for the inhibition and amelioration of liver disease |
US20050148517A1 (en) * | 2002-07-29 | 2005-07-07 | Lockwood Samuel F. | Carotenoid ether analogs or derivatives for controlling connexin 43 expression |
US7521584B2 (en) * | 2002-07-29 | 2009-04-21 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of disease |
US20050059635A1 (en) * | 2002-07-29 | 2005-03-17 | Lockwood Samuel Fournier | Carotenoid ester analogs or derivatives for controlling C-reactive protein levels |
US7763649B2 (en) * | 2002-07-29 | 2010-07-27 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for controlling connexin 43 expression |
US20050143475A1 (en) * | 2002-07-29 | 2005-06-30 | Lockwood Samuel F. | Carotenoid analogs or derivatives for the inhibition and amelioration of ischemic reperfusion injury |
US20050009788A1 (en) * | 2002-07-29 | 2005-01-13 | Lockwood Samuel Fournier | Carotenoid ester analogs or derivatives for controlling connexin 43 expression |
US7345091B2 (en) * | 2002-07-29 | 2008-03-18 | Cardax Pharmaceuticals, Inc. | Carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
US20050026874A1 (en) * | 2002-07-29 | 2005-02-03 | Lockwood Samuel Fournier | Carotenoid ether analogs or derivatives for the inhibition and amelioration of liver disease |
US7375133B2 (en) * | 2002-07-29 | 2008-05-20 | Cardax Pharmaceuticals, Inc. | Pharmaceutical compositions including carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
US7723327B2 (en) * | 2002-07-29 | 2010-05-25 | Cardax Pharmaceuticals, Inc. | Carotenoid ester analogs or derivatives for the inhibition and amelioration of liver disease |
KR20050069975A (en) * | 2002-07-29 | 2005-07-05 | 하와이 바이오테크, 인코포레이티드 | Structural carotenoid analogs for the inhibition and amelioration of disease |
KR20060041161A (en) | 2003-04-10 | 2006-05-11 | 라이트 바이오사이언스, 엘엘씨 | Photomodulation methods and devices for regulating cell proliferation and gene expression |
KR101160343B1 (en) * | 2003-07-31 | 2012-06-26 | 젠틀웨이브즈 엘엘씨. | System and method for the photodynamic treatment of burns, wounds, and related skin disorders |
US20050058611A1 (en) * | 2003-08-22 | 2005-03-17 | L'oreal | Preventing and/or combating collagen fiber degradation induced under conditions of natural exposure to sunlight |
FR2858932B1 (en) * | 2003-08-22 | 2009-10-30 | Oreal | COMPOSITION FOR CONTROLLING THE DEGRADATION OF INDUCED COLLAGEN FIBERS IN NATURAL SOLAR EXPOSURE CONDITIONS |
US20050261367A1 (en) * | 2004-03-29 | 2005-11-24 | Howard Murad | Methods for treating dermatological and other health-related conditions in a patient |
CA2564066A1 (en) * | 2004-04-14 | 2005-11-03 | Hawaii Biotech, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of inflammation |
US20060058269A1 (en) * | 2004-04-14 | 2006-03-16 | Lockwood Samuel F | Carotenoid analogs or derivatives for the inhibition and amelioration of inflammation |
US8338648B2 (en) * | 2004-06-12 | 2012-12-25 | Signum Biosciences, Inc. | Topical compositions and methods for epithelial-related conditions |
US20060265030A1 (en) * | 2004-11-12 | 2006-11-23 | Light Bioscience, Llc | System and method for photodynamic cell therapy |
WO2006071456A2 (en) * | 2004-12-02 | 2006-07-06 | The University Of North Carolina At Chapel Hill | Inhibition of hsp27 phosphorylation for treatment of blistering disorders |
WO2007064871A2 (en) * | 2005-12-02 | 2007-06-07 | Howard Murad | Diagnostic and treatment regimen for achieving body water homeostasis |
US7642402B2 (en) * | 2005-12-20 | 2010-01-05 | Kao Corporation | Human photoaged skin model |
US8771647B2 (en) * | 2005-12-20 | 2014-07-08 | Kao Corporation | Human photoaged skin model |
WO2007134219A2 (en) * | 2006-05-11 | 2007-11-22 | Living Proof, Inc. | In situ polymerization for skin treatment |
KR100879558B1 (en) * | 2007-07-31 | 2009-01-22 | 라이브켐 주식회사 | Compositions for skin protection and improvement of skin diseases containing the dibenzo-p-dioxine derivatives |
US20110177014A1 (en) * | 2008-04-01 | 2011-07-21 | Biopharmacopae Design International Inc. | Extracts from plants of the tsuga genus and uses thereof in the treatment of inflammation, irritation and/or infection |
EP2276455A2 (en) * | 2008-04-22 | 2011-01-26 | Centre National de la Recherche Scientifique | Use of k1f13a and ap-1 inhibitors for inhibiting melanogenesis |
TWI495465B (en) | 2009-09-30 | 2015-08-11 | Shiseido Co Ltd | A heparinase activity inhibitor and a wrinkle improving agent and a pharmaceutical composition containing the same |
BR112012007090A2 (en) | 2009-09-30 | 2018-06-05 | Shiseido Company, Ltd. | heparanase activity inhibitor |
US8435541B2 (en) | 2010-09-02 | 2013-05-07 | Bath & Body Works Brand Management, Inc. | Topical compositions for inhibiting matrix metalloproteases and providing antioxidative activities |
US10267796B2 (en) * | 2010-10-25 | 2019-04-23 | The Procter & Gamble Company | Screening methods of modulating adrenergic receptor gene expressions implicated in melanogenesis |
ES2896354T3 (en) | 2012-12-21 | 2022-02-24 | Astellas Inst For Regenerative Medicine | Methods for the production of platelets from pluripotent stem cells |
JP2015221768A (en) * | 2014-05-23 | 2015-12-10 | 日本メナード化粧品株式会社 | External or internal preparation for skin |
JP2016216435A (en) * | 2015-05-18 | 2016-12-22 | 共栄化学工業株式会社 | Evaluation method |
JP6157659B1 (en) * | 2016-02-10 | 2017-07-05 | イノレックス インベストメント コーポレイション | Synergistic compositions, formulations and related methods for reducing UV-induced lipid peroxidation |
US9943566B2 (en) | 2016-03-16 | 2018-04-17 | Geoffrey Brooks Consultants, Llc | NF-κB inhibitor composition for skin health |
CN112263529A (en) * | 2020-10-27 | 2021-01-26 | 圣菲之美(湖北)生物科技有限公司 | Anti-aging composition and preparation method and application thereof |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4877805A (en) * | 1985-07-26 | 1989-10-31 | Kligman Albert M | Methods for treatment of sundamaged human skin with retinoids |
US4603146A (en) * | 1984-05-16 | 1986-07-29 | Kligman Albert M | Methods for retarding the effects of aging of the skin |
US5019569A (en) * | 1986-11-03 | 1991-05-28 | Ortho Pharmaceutical Corporation | Reversal of glucocorticoid-induced skin atrophy |
DE3853427T2 (en) * | 1987-04-06 | 1995-12-14 | Daltex Medical Sciences Inc | TREATING AGED SKIN WITH ORAL 13-CIS RETINIC ACID. |
US4994491A (en) * | 1988-12-14 | 1991-02-19 | Molecular Design International | Dermal uses of trans-retinoids for the treatment of cancer |
MY106263A (en) * | 1989-01-19 | 1995-04-29 | Ortho Pharma Corp | Method for the treatment or prevention of intrinsically aged skin with retinoids |
US5002760A (en) * | 1989-10-02 | 1991-03-26 | Katzev Phillip K | Retinol skin care composition |
US5051449A (en) * | 1991-02-27 | 1991-09-24 | Kligman Albert M | Treatment of cellulite with retinoids |
EP0614353A1 (en) * | 1991-11-25 | 1994-09-14 | Richardson-Vicks, Inc. | Compositions for regulating skin wrinkles and/or skin atrophy |
GR1002207B (en) * | 1992-08-06 | 1996-03-27 | Johnson & Johnson Consumer | Skin care compositions containing imidazoles. |
WO1996023490A1 (en) * | 1995-02-03 | 1996-08-08 | Cosmederm Technologies | Formulations and methods for reducing skin irritation |
NZ313369A (en) * | 1995-06-08 | 2000-01-28 | Johnson & Johnson Consumer | Sunscreen compositions containing inorganic sunscreen agent and anionic surfactant |
US5837224A (en) * | 1996-01-19 | 1998-11-17 | The Regents Of The University Of Michigan | Method of inhibiting photoaging of skin |
-
1996
- 1996-01-19 US US08/588,771 patent/US5837224A/en not_active Expired - Lifetime
-
1997
- 1997-01-17 CA CA002241981A patent/CA2241981C/en not_active Expired - Lifetime
- 1997-01-17 CO CO97001933A patent/CO4770951A1/en unknown
- 1997-01-17 JP JP52622497A patent/JP3705820B2/en not_active Expired - Fee Related
- 1997-01-17 PL PL97327827A patent/PL327827A1/en unknown
- 1997-01-17 TR TR1998/01376T patent/TR199801376T2/en unknown
- 1997-01-17 SK SK959-98A patent/SK95998A3/en unknown
- 1997-01-17 SI SI9720015A patent/SI9720015A/en unknown
- 1997-01-17 NZ NZ330860A patent/NZ330860A/en not_active IP Right Cessation
- 1997-01-17 WO PCT/US1997/000791 patent/WO1997025969A1/en active IP Right Grant
- 1997-01-17 MY MYPI97000167A patent/MY119711A/en unknown
- 1997-01-17 EE EE9800216A patent/EE9800216A/en unknown
- 1997-01-17 HU HU9900655A patent/HUP9900655A3/en unknown
- 1997-01-17 CZ CZ19982258A patent/CZ291530B6/en not_active IP Right Cessation
- 1997-01-17 CN CN97191735A patent/CN1086937C/en not_active Expired - Fee Related
- 1997-01-17 AR ARP970100191A patent/AR005650A1/en unknown
- 1997-01-17 BR BR9707018A patent/BR9707018A/en not_active IP Right Cessation
- 1997-01-17 EP EP97903847A patent/EP0883398A4/en not_active Withdrawn
-
1998
- 1998-06-29 NO NO983019A patent/NO983019L/en not_active Application Discontinuation
- 1998-07-09 LT LT98-091A patent/LT4515B/en not_active IP Right Cessation
-
1999
- 1999-09-14 HK HK99103976A patent/HK1018885A1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
SI9720015A (en) | 1999-10-31 |
CZ291530B6 (en) | 2003-03-12 |
AR005650A1 (en) | 1999-07-14 |
US5837224A (en) | 1998-11-17 |
AU1831797A (en) | 1997-08-11 |
AU701132B2 (en) | 1999-01-21 |
EP0883398A4 (en) | 1999-05-12 |
CN1086937C (en) | 2002-07-03 |
NZ330860A (en) | 1999-11-29 |
CN1211178A (en) | 1999-03-17 |
EP0883398A1 (en) | 1998-12-16 |
PL327827A1 (en) | 1999-01-04 |
JP2000503660A (en) | 2000-03-28 |
HUP9900655A1 (en) | 1999-07-28 |
CA2241981A1 (en) | 1997-07-24 |
CO4770951A1 (en) | 1999-04-30 |
HUP9900655A3 (en) | 2000-09-28 |
MY119711A (en) | 2005-07-29 |
CZ225898A3 (en) | 1998-10-14 |
LT4515B (en) | 1999-06-25 |
BR9707018A (en) | 1999-07-20 |
LT98091A (en) | 1999-02-25 |
WO1997025969A1 (en) | 1997-07-24 |
JP3705820B2 (en) | 2005-10-12 |
HK1018885A1 (en) | 2000-01-07 |
NO983019D0 (en) | 1998-06-29 |
SK95998A3 (en) | 1999-01-11 |
EE9800216A (en) | 1999-04-15 |
TR199801376T2 (en) | 1998-10-21 |
NO983019L (en) | 1998-08-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2241981C (en) | Method of inhibiting photoaging of skin | |
AU737376B2 (en) | Methods and compositions for preventing and treating chronological aging in human skin | |
CA2601462C (en) | Compositions and methods for inhibiting photoaging of skin | |
AU701132C (en) | Method of inhibiting photoaging of skin | |
KR100352687B1 (en) | Cosmetics to prevent photoaging | |
JP2002510621A (en) | Methods and compositions for reducing ultraviolet-induced inhibition of collagen synthesis in human skin | |
MXPA99007883A (en) | Methods and compositions for preventing and treating chronological aging in human skin | |
Cunliffe | Vitamin a in Dermatology | |
AU2002301116B2 (en) | Compositions and Methods for Inhibiting Photoaging of Skin | |
Riccardi | Reversal of photoaging of the skin by topical d-alpha tocopherol, ascorbic acid, and L-selenomethionine: A comparative analysis performed by light and transmission electron microscopy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKEX | Expiry |
Effective date: 20170117 |