CN117982623A - Medicine for preventing and/or treating rheumatoid arthritis - Google Patents
Medicine for preventing and/or treating rheumatoid arthritis Download PDFInfo
- Publication number
- CN117982623A CN117982623A CN202410044198.7A CN202410044198A CN117982623A CN 117982623 A CN117982623 A CN 117982623A CN 202410044198 A CN202410044198 A CN 202410044198A CN 117982623 A CN117982623 A CN 117982623A
- Authority
- CN
- China
- Prior art keywords
- annexin
- treatment
- pharmaceutical composition
- rheumatoid arthritis
- joint
- 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.)
- Pending
Links
- 206010039073 rheumatoid arthritis Diseases 0.000 title claims abstract description 62
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 title description 10
- 239000000203 mixture Substances 0.000 claims abstract description 79
- 238000011282 treatment Methods 0.000 claims abstract description 53
- 238000009472 formulation Methods 0.000 claims abstract description 39
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 32
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 102000000412 Annexin Human genes 0.000 claims abstract description 17
- 108050008874 Annexin Proteins 0.000 claims abstract description 17
- 230000006378 damage Effects 0.000 claims abstract description 14
- 230000002265 prevention Effects 0.000 claims abstract description 10
- 208000002193 Pain Diseases 0.000 claims abstract description 9
- 230000036407 pain Effects 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 208000037976 chronic inflammation Diseases 0.000 claims abstract description 5
- 230000008407 joint function Effects 0.000 claims abstract description 5
- 210000005067 joint tissue Anatomy 0.000 claims abstract description 5
- 230000001737 promoting effect Effects 0.000 claims abstract description 5
- 230000008929 regeneration Effects 0.000 claims abstract description 5
- 238000011069 regeneration method Methods 0.000 claims abstract description 5
- 230000008439 repair process Effects 0.000 claims abstract description 5
- 230000006020 chronic inflammation Effects 0.000 claims abstract description 4
- 102000004121 Annexin A5 Human genes 0.000 claims description 23
- 108090000672 Annexin A5 Proteins 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 230000002757 inflammatory effect Effects 0.000 claims description 15
- 102000004889 Interleukin-6 Human genes 0.000 claims description 12
- 108090001005 Interleukin-6 Proteins 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 12
- 229940100601 interleukin-6 Drugs 0.000 claims description 12
- 230000028709 inflammatory response Effects 0.000 claims description 11
- 102000003810 Interleukin-18 Human genes 0.000 claims description 10
- 108090000171 Interleukin-18 Proteins 0.000 claims description 10
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 claims description 6
- 102000003777 Interleukin-1 beta Human genes 0.000 claims description 6
- 108090000193 Interleukin-1 beta Proteins 0.000 claims description 6
- 210000001188 articular cartilage Anatomy 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 5
- 230000000241 respiratory effect Effects 0.000 claims description 5
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 claims description 4
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 claims description 4
- 239000003862 glucocorticoid Substances 0.000 claims description 4
- 229940037128 systemic glucocorticoids Drugs 0.000 claims description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 3
- 229960000074 biopharmaceutical Drugs 0.000 claims description 3
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 3
- 239000003018 immunosuppressive agent Substances 0.000 claims description 3
- 239000007927 intramuscular injection Substances 0.000 claims description 3
- 238000010255 intramuscular injection Methods 0.000 claims description 3
- 238000010253 intravenous injection Methods 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000000845 cartilage Anatomy 0.000 abstract description 7
- 241000699670 Mus sp. Species 0.000 description 37
- 206010003246 arthritis Diseases 0.000 description 24
- 238000002474 experimental method Methods 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 17
- 208000009386 Experimental Arthritis Diseases 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 230000001965 increasing effect Effects 0.000 description 15
- 208000024891 symptom Diseases 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 11
- 230000007423 decrease Effects 0.000 description 10
- -1 il18 Proteins 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- 208000000114 Pain Threshold Diseases 0.000 description 9
- 210000004969 inflammatory cell Anatomy 0.000 description 9
- 238000010603 microCT Methods 0.000 description 9
- 230000037040 pain threshold Effects 0.000 description 9
- 230000008961 swelling Effects 0.000 description 9
- 101100396994 Drosophila melanogaster Inos gene Proteins 0.000 description 8
- 101150033527 TNF gene Proteins 0.000 description 8
- 210000001503 joint Anatomy 0.000 description 8
- 230000006872 improvement Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 210000003414 extremity Anatomy 0.000 description 6
- 238000002649 immunization Methods 0.000 description 6
- 230000003053 immunization Effects 0.000 description 6
- 230000008595 infiltration Effects 0.000 description 6
- 238000001764 infiltration Methods 0.000 description 6
- 239000007928 intraperitoneal injection Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 208000006820 Arthralgia Diseases 0.000 description 5
- 206010015150 Erythema Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 230000002917 arthritic effect Effects 0.000 description 5
- 231100000321 erythema Toxicity 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 208000018937 joint inflammation Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000011269 treatment regimen Methods 0.000 description 5
- 102000000503 Collagen Type II Human genes 0.000 description 4
- 108010041390 Collagen Type II Proteins 0.000 description 4
- 241000287828 Gallus gallus Species 0.000 description 4
- 101000883515 Homo sapiens Chitinase-3-like protein 1 Proteins 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 210000000544 articulatio talocruralis Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 102000054350 human CHI3L1 Human genes 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002417 nutraceutical Substances 0.000 description 4
- 235000021436 nutraceutical agent Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 210000005222 synovial tissue Anatomy 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RZSYLLSAWYUBPE-UHFFFAOYSA-L Fast green FCF Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC(O)=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 RZSYLLSAWYUBPE-UHFFFAOYSA-L 0.000 description 3
- 101150012417 IL1B gene Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000000378 dietary effect Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 210000002683 foot Anatomy 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 231100000915 pathological change Toxicity 0.000 description 3
- 230000036285 pathological change Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- OARRHUQTFTUEOS-UHFFFAOYSA-N safranin Chemical compound [Cl-].C=12C=C(N)C(C)=CC2=NC2=CC(C)=C(N)C=C2[N+]=1C1=CC=CC=C1 OARRHUQTFTUEOS-UHFFFAOYSA-N 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 210000001258 synovial membrane Anatomy 0.000 description 3
- 229940126585 therapeutic drug Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 206010051728 Bone erosion Diseases 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 206010023232 Joint swelling Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229940008126 aerosol Drugs 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 210000003423 ankle Anatomy 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000003435 antirheumatic agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000000452 mid-foot Anatomy 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 230000008092 positive effect Effects 0.000 description 2
- 229940098458 powder spray Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229940098465 tincture Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000001364 upper extremity Anatomy 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 238000011763 DBA/1J (JAX™ mouse strain) Methods 0.000 description 1
- 101100447432 Danio rerio gapdh-2 gene Proteins 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 101150112014 Gapdh gene Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000015580 Increased body weight Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 206010023203 Joint destruction Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 206010033372 Pain and discomfort Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000002506 anticoagulant protein Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000008611 intercellular interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 238000012257 pre-denaturation Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000031337 regulation of inflammatory response Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000002437 synoviocyte Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 210000003371 toe Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000037221 weight management Effects 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a medicament for the prevention and/or treatment of rheumatoid arthritis, in particular, the present invention provides the use of annexin for the preparation of a composition or formulation for the treatment of rheumatoid arthritis, including but not limited to: improving chronic inflammation of joint, inhibiting damage to joint bone and/or cartilage tissue, promoting repair and regeneration of damaged joint tissue, improving joint function and reducing pain.
Description
Technical Field
The invention relates to the field of medicines, in particular to a medicine for preventing and/or treating rheumatoid arthritis.
Background
Rheumatoid arthritis (Rheumatoid Arthritis, RA) is an immunologically mediated chronic inflammatory disease that affects mainly joints, causing pain, swelling, stiffness and dysfunction. It is a systemic disease that may affect multiple organ systems. The pathogenesis of RA involves complex interactions of genetic, environmental factors and autoimmune reactions. Currently, treatment of RA is focused mainly on alleviating symptoms, slowing disease progression and improving quality of life. Currently, the treatment of RA is largely dependent on drug therapies, including non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, biological agents, and the like. However, these treatments are often accompanied by varying degrees of side effects and limited efficacy, especially in long-term therapies, and therefore, the search for new treatments is an urgent need in this field.
In recent years, research on new therapeutic targets for rheumatoid arthritis has been continued. Annexin A5 (Annexin A5 or AnxA5, A5) has attracted attention in the scientific community as an anti-inflammatory and anticoagulant protein. Preliminary studies have shown that A5 plays a role in regulating immune responses, maintaining normal cell function, and inhibiting apoptosis. In the context of RA, the anti-inflammatory effect of A5 may have significance in reducing the inflammatory response of the joint and preventing joint destruction.
The experimental study of the invention discusses the application of A5 in the treatment of rheumatoid arthritis, and the treatment effect of A5 on RA animal models is studied, including the alleviation of arthritis symptoms and the improvement of bone conditions. The results of this study indicate that A5 not only reduces the inflammatory response of the joint, but also improves bone structure, indicating its great potential as a potential therapeutic drug for RA. This finding may have a significant impact on the treatment of RA, providing new treatment options for RA patients.
Disclosure of Invention
The invention aims to provide a novel rheumatoid arthritis treatment method, namely, a medicine for treating rheumatoid arthritis is prepared by utilizing the anti-inflammatory and bone-protecting properties of annexin A5. The invention provides a new application of annexin A5 in preparing a rheumatoid arthritis therapeutic drug based on an experimental result of relieving arthritis symptoms and improving bone conditions in an animal model.
The annexin A5 provided by the invention is used for preparing medicines for preventing and/or treating rheumatoid arthritis, and can be used singly or in combination with other antirheumatic medicines to enhance the treatment effect. The new treatment is expected to provide a safer, more effective treatment option for RA patients, especially for those patients who are not sensitive or intolerant to conventional treatments.
In a first aspect of the invention there is provided the use of annexin for the preparation of a composition or formulation for the prevention and/or treatment of Rheumatoid Arthritis (RA).
In a first aspect of the invention there is provided the use of annexin for the preparation of a pharmaceutical composition or a pharmaceutical formulation, the group of pharmaceutical compositions or pharmaceutical formulations being for the prevention and/or treatment of Rheumatoid Arthritis (RA).
Among other symptomatic features of rheumatoid arthritis include, but are not limited to, chronic inflammation and pain of the joint.
In another preferred embodiment, the annexin comprises annexin A5.
In another preferred embodiment, the composition or formulation is used for preventing and/or treating chronic inflammation of rheumatoid arthritis.
In another preferred embodiment, the composition or formulation is used for the prevention and/or treatment of rheumatoid arthritis pain.
In another preferred embodiment, the composition or formulation is used for preventing and/or treating inflammatory cell infiltration caused by rheumatoid arthritis, joint swelling, destruction of articular cartilage, bone tissue, and/or reduced range of motion of the joint and joint pain.
In another preferred embodiment, the composition or formulation is used to reduce the inflammatory response of the joint, in particular to reduce infiltration of inflammatory cells and reduce swelling of the joint
In another preferred embodiment, the composition or formulation is used to inhibit the destruction of articular cartilage and bone tissue, and is embodied by slowing the progression of cartilage and bone erosion.
In another preferred embodiment, the composition or formulation is used to improve joint function, including increasing range of motion of the joint and reducing joint pain.
In another preferred embodiment, the prevention and/or treatment of rheumatoid arthritis further comprises reducing the need for anti-inflammatory agents to be administered to the patient, e.g., reducing the anti-inflammatory agent dosage.
In another preferred embodiment, the prevention and/or treatment of rheumatoid arthritis further comprises improving the quality of life of the patient.
In another preferred embodiment, the composition or formulation is capable of modulating the level of an inflammatory factor, e.g., reducing the expression of an inflammatory factor, including but not limited to specific cytokines and chemokines, such as factors like IL6 (interleukin-6), IL1b (interleukin-1 beta), tnfa (tumor necrosis factor-alpha), IL18 (interleukin-18) and Inos (inducible nitric oxide synthase).
In another preferred embodiment, the composition or formulation is capable of promoting repair and regeneration of damaged joint tissue, enhancing therapeutic efficacy.
In another preferred embodiment, the "reducing the arthritic response" is a significant decrease in the arthritis score of mice treated with annexin A5 as compared to the arthritis score of the model group. Preferably, the average decrease ratio P1 of the arthritis score of the annexin A5 low dose group is greater than or equal to 0.7, more preferably greater than or equal to 0.6, relative to P0 of the model group; in the annexin A5 high dose group, the average reduction ratio P2 of the arthritis score relative to P0 in the model group is P2/P0 not less than 0.5, more preferably not less than 0.4, still more preferably not less than 0.3.
In another preferred embodiment, the terms "modulating inflammatory factor level" and "reducing inflammatory factor expression" refer to a significant decrease in the levels of factors such as IL6, IL1b, IL18, tnfa, and Inos in the synovial tissue of mice treated with annexin A5, as compared to the model group. Preferably, the average reduction ratio Q1 of IL6 levels in annexin A5 low dose groups is Q1/Q0.gtoreq.0.7, more preferably.gtoreq.0.6, relative to Q0 in the model group; in the annexin A5 high dose group, the average reduction ratio Q2 of IL6 levels is Q2/Q0.gtoreq.0.gtoreq.0, more preferably.gtoreq.0.5, still more preferably.gtoreq.0.4, relative to Q0 of the model group. The trend was similar for factors such as Il1b, il18, tnfa and Inos to decrease.
In another preferred embodiment, the term "inhibiting destruction of articular cartilage and bone tissue" means that the reduction in bone volume fraction (BV/TV) is significantly reduced, the reduction in bone trabecular number (Tb.N) is smaller, and the increase in bone trabecular separation (Tb.Sp) is smaller in Micro-CT analysis of mice treated with annexin A5 as compared to the model group. The improvement in BV/TV, tb.N and Tb.Sp was more pronounced in the annexin A5 high dose group, and more preferably reached near normal control.
In another preferred embodiment, the composition or formulation further comprises other agents for preventing and/or treating rheumatoid arthritis.
In another preferred embodiment, the other agent for preventing and/or treating rheumatoid arthritis is selected from the group consisting of: glucocorticoids, non-steroidal anti-inflammatory drugs, immunosuppressants, and biologicals.
In another preferred example, the composition or the preparation is in the form of oral preparation, external preparation or injection preparation.
In another preferred embodiment, the composition or formulation is in the form of a solid, liquid or semi-solid formulation.
In another preferred example, the formulation of the composition or the preparation is powder, granule, capsule, injection, tincture, oral liquid, tablet, lozenge, powder spray, aerosol or spray.
In another preferred embodiment, the composition or formulation is in the form of a respiratory administration formulation.
In another preferred example, the injection is intravenous injection, intramuscular injection, subcutaneous preparation, or respiratory administration preparation.
In another preferred embodiment, the respiratory tract administration formulation is an intra-airway nebulizer.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
Fig. 1: the weight change during the experiment for each group of mice in example 1 is shown, including data for the control group, model group, A5 low dose group, and A5 high dose group.
Fig. 2: the general observations of the individual groups of mouse joints in the experiment in example 1 are shown.
Fig. 3: results of the evaluation of joint inflammation index of each group of mice in example 1 are shown.
Fig. 4: the joint tenderness threshold for each group of mice in example 1 is shown.
Fig. 5: results of micro-CT analysis of metacarpal joints of each group of mice in example 1 are shown.
Fig. 6: results of the bone volume fraction (BV/TV), bone small Liang Shu (Tb.N), and trabecular separation (Tb.Sp) analysis of each group of mice in example 1 are shown.
Fig. 7: the results observed after hematoxylin-eosin staining of the joint sections of each group of mice in example 1 are shown.
Fig. 8: the results observed after safranin fast green staining of the joint sections of each group of mice in example 1 are shown.
Fig. 9: the results of analysis of inflammatory factor mRNA levels of joint synovial tissue of mice of each group of mice in example 1, including IL6 (interleukin-6), IL1b (interleukin-1. Beta.), tnfa (tumor necrosis factor-. Alpha.), IL18 (interleukin-18), inos (inducible nitric oxide synthase) levels in the joint synovial tissue of the mice are shown.
Correlation definition
Unless specifically indicated, the following terms used in the specification and claims have the following meanings:
As used herein, the term "comprising" includes both open and semi-closed definitions as well as closed and open definitions. In other words, the term includes "consisting of … …" and "consisting essentially of … …".
Annexin A5 (Annexin A5 or AnxA5, A5)
Annexin A5 is a protein on the cell membrane and belongs to the annexin family. Such proteins are typically expressed on the cell surface of a variety of cell types and are involved in intercellular interactions and signaling processes. A5 plays a role in a variety of biological processes including cell adhesion, migration, proliferation and apoptosis. It is particularly important in the regulation of the immune system, as it affects the activity of immune cells, including the regulation of inflammatory responses.
Exogenous A5, i.e. A5 additionally introduced in the experiment or therapy, plays its role mainly by the effect on inflammatory cells. In autoimmune diseases such as RA, inflammatory cells such as neutrophils and macrophages play a key role in the development of the disease and manifestation of symptoms. Inflammatory factors and enzymes released by these cells cause tissue damage and pain.
Exogenous A5 has the ability to modulate immune responses, which can inhibit the activation of inflammatory cells and/or reduce the inflammatory mediators they release. In this way, A5 helps to reduce inflammation and joint pain, reduce joint damage, and potentially improve overall symptoms in RA patients. In clinical applications, this anti-inflammatory effect of exogenous A5 is a key advantage as a potential therapeutic drug. By modulating the activity of A5, the inflammatory response is reduced, protecting joint tissue from further damage, and thus as a new strategy for treating rheumatoid arthritis.
The annexin useful in the present invention is not particularly limited and may be an annexin derived from any organism, preferably from a mammal (e.g., primate), more preferably from a human. Furthermore, it is understood that "annexin" includes wild-type or mutant (including truncated) annexins, as long as the mutant annexin retains or retains the detoxification activity of the wild-type annexin.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Detailed Description
In one embodiment, the A5 is used to treat rheumatoid arthritis by reducing the inflammatory response of the joint.
In another embodiment, the composition or formulation is used to reduce the inflammatory response at the joint site, specifically by reducing infiltration of inflammatory cells and reducing joint swelling
In another embodiment, the composition or formulation is used to inhibit the destruction of articular cartilage and bone tissue, and is specifically characterized by slowing the progression of cartilage and bone erosion.
In another embodiment, the composition or formulation is used to improve joint function, including increasing range of motion of the joint and reducing joint pain.
In another embodiment, the rheumatoid arthritis treatment further comprises reducing the need for anti-inflammatory drugs in the patient.
In another embodiment, the rheumatoid arthritis treatment further comprises improving the quality of life of the patient.
In another embodiment, the composition or formulation is capable of promoting repair and regeneration of damaged joint tissue, enhancing therapeutic efficacy.
In another embodiment, the composition or formulation further comprises other agents for preventing and/or treating rheumatoid arthritis.
In another embodiment, the additional agent for preventing and/or treating rheumatoid arthritis is selected from the group consisting of: glucocorticoids, non-steroidal anti-inflammatory drugs, immunosuppressants, and biologicals.
In another embodiment, the composition or formulation for treating rheumatoid arthritis comprises a pharmaceutical composition or formulation, a food composition or formulation, a nutraceutical composition or formulation, or a dietary supplement.
In another embodiment, the composition or formulation is in the form of an oral formulation, an external formulation or an injectable formulation.
In another embodiment, the composition or formulation is in the form of a solid, liquid or semi-solid formulation.
In another embodiment, the composition or formulation is in the form of a powder, granule, capsule, injection, tincture, oral liquid, tablet, buccal tablet, powder spray, aerosol or spray.
In another embodiment, the composition or formulation is in the form of a respiratory administration formulation.
In another embodiment, the injection is an intravenous injection, an intramuscular injection, a subcutaneous preparation, or a respiratory administration preparation.
In another embodiment, the respiratory tract administration formulation is an intra-airway nebulizer.
In another embodiment, the subject is a human or non-human mammal (e.g., a rodent).
In another embodiment, the therapeutic objectives of rheumatoid arthritis include reducing joint inflammation, inhibiting bone and cartilage destruction, improving joint function, reducing pain, and improving quality of life.
The compositions of the present invention include (but are not limited to): pharmaceutical compositions, food compositions, health care compositions, dietary supplements, and the like.
Representatively, the cell-free fat extract of the present invention may be formulated into pharmaceutical compositions such as dosage forms of tablets, capsules, powders, microgranules, solutions, lozenges, jellies, cream formulations, spirits, suspensions, tinctures, cataplasms, liniments, lotions, and aerosols. The pharmaceutical compositions can be prepared by generally known preparation techniques, and suitable pharmaceutical additives can be added to the medicament.
The compositions of the present invention may also include a pharmaceutically, food, nutraceutical or dietary acceptable carrier. "pharmaceutically, food, nutraceutical or dietary acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically, food, nutraceutical or dietary acceptable carrier parts are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifiers (e.g. wetting agents (e.g. sodium lauryl sulphate), colorants, flavourings, stabilizers, antioxidants, preservatives, pyrogen-free water etc.
The mode of administration of the compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular), topical, with oral and injectable administration being preferred modes of administration.
The formulation of the composition or the preparation provided by the invention is oral preparation, external preparation or injection preparation. Typically, solid dosage forms for oral administration or administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents.
Liquid dosage forms for oral administration or administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The main advantages of the invention include:
The invention provides a novel method for treating RA, which has potential higher curative effect and lower side effect. Can be used as independent treatment or combined with the existing treatment method to provide a more flexible treatment scheme and a more diversified treatment option for RA patients.
A5 shows remarkable effect of improving arthritis symptoms in animal experiments, and shows that the compound has potential to be an effective RA treatment drug.
A5 as a naturally occurring anti-inflammatory protein may be used with lower side effects, has better safety than traditional antirheumatic drugs, and may reduce side effects of long-term use of the drugs.
Embodiments of the present invention relate to a detailed description of the dosage, mode of administration, course of treatment, and potential combination with other drugs of annexin A5, as will be further described in the detailed description section.
Examples:
Annexin A5: annexin-V (sc-4252), available from Santa Cruz Biotechnology.
Example 1:
1. Experimental details
1.1 Establishment of a mouse collagen-induced arthritis (CIA) model:
Primary immunization on day 0 (D0): primary immunization of mice was performed using chicken type II collagen and complete freund's adjuvant.
Boosting on day 21 (D21): chicken type II collagen and incomplete freund's adjuvant were used for booster immunization.
The specific scheme is as follows: 32 8 week old DBA/1J mice (Jiangsu Ji, animal procedures approved by the Shanghai university of transportation animal ethics Committee) were housed under Specific Pathogen Free (SPF) conditions, and after one week of adaptive feeding 24 received primary immunization with complete Freund's adjuvant (5 mg/ml, chondrex) and emulsified chicken type II collagen (2 mg/ml, chondrex). After 21 days, booster injections were given as incomplete Freund's adjuvant (5 mg/ml, chondrex) and emulsified chicken type II collagen (2 mg/ml, chondrex). The dosage weight ratio of the molding reagent is 5mg/kg.
On day 24 after primary immunization (D24), CIA mouse construction was completed, 24 CIA mice were randomly divided into 3 groups of 8.
The modeling conditions of the present invention are shown in table 1 below:
TABLE 1
Group number | Group of | Primary immunization dose | Intensified injection dosage |
1 | Control group | - | - |
2 | Model group | 100μl | 100μl |
3 | A5 Low dose group | 100μl | 100μl |
4 | A5 high dose group | 100μl | 100μl |
1.2 Grouping and administration:
Random grouping (D21): mice were randomly divided into control, model, A5 low dose, and A5 high dose groups.
Intraperitoneal injection treatment: from D24, the intraperitoneal injection treatment was performed every 3 days, continuing until D59.
Dosing regimen: the dosing schedule for three groups (8 per group) of CIA mice is shown in table 2 below:
TABLE 2
Group number | Group of | Number of animals | Administration of drugs | Administration mode |
1 | Control group | 8 | 100 Μl of physiological saline | Intraperitoneal injection |
2 | Model group | 8 | 100 Μl of physiological saline | Intraperitoneal injection |
3 | A5 Low dose group | 8 | 50μg AnxA5 | Intraperitoneal injection |
4 | A5 high dose group | 8 | 150μg AnxA5 | Intraperitoneal injection |
1.3 Measurement collection of data
1.3.1 Weighing and pain threshold test:
Time point: d0, D7, D14, D21, D28, D35, D42, D49, D56, D63.
Pain threshold test method: and (5) hot plate experiment. Animals were placed on a hotplate and timing was started, and the time at which the animals responded (e.g., licked their feet) was recorded or the experiment was terminated until 30 seconds. After all experimental animals were tested, the average latency or termination time was calculated per group and statistically evaluated.
1.3.2 Arthritis scoring
Time point: d21, D24, D28, D31, D35, D38, D42, D45, D49, D52, D56, D59, D63.
Scoring criteria:
0 point: there was no evidence of erythema and swelling.
1, The method comprises the following steps: erythema and mild swelling are localized to the midfoot or ankle joint.
2, The method comprises the following steps: erythema and mild swelling spread from the ankle joint to the midfoot.
3, The method comprises the following steps: erythema and mild swelling spread from ankle joint to joint.
4, The following steps: erythema and severe swelling include ankle, foot and toe.
Scoring is performed: scoring was performed by experienced researchers without knowledge of treatment groups.
1.3.3 Analysis of micro-CT and inflammatory factor mRNA levels: at the end of the experiment, to assess the pathological changes of arthritis.
1.4 End of experiment and pathological tissue analysis:
micro-CT analysis: on day 63 post-group dosing (D63), after injection sampling was completed, mice were sacrificed, forelimbs and hindlimbs were removed, and immediately fixed in 4% paraformaldehyde for 48 hours. The microstructure of each limb was analyzed using SIEMENS Inveon PET/CT computed tomography (SIEMENS, germany) with the following parameters: voltage, 80kV; current, 500 μa; exposure time, 1800 milliseconds; total rotation, 220 °. The bone volume percent (BV/TV), trabecular thickness (tb.th), small Liang Shu (tb.n) and trabecular spacing (tb.sp) of the ROI were calculated using SIEMENS Inveon Research Workplace software.
Histological evaluation: the mice were decalcified with 10% edta for 4 weeks after limb fixation. After embedding the wax blocks, the articular sagittal sections were sectioned to 5 μm. Sections were stained with hematoxylin-eosin and safranin fast green to observe structure.
Inflammatory factor level: to determine the mouse arthromeningitis factor mRNA levels, including IL6 (interleukin-6), IL1b (interleukin-1. Beta.), tnfa (tumor necrosis factor-alpha.), IL18 (interleukin-18), inos (inducible nitric oxide synthase), experiments were performed after euthanasia of the mice. Immediately after mice were sacrificed, the limb joint synovial membranes were taken, rinsed 2 times in PBS, and immersed in RNALADDER to prevent RNA degradation. mRNA is extracted from the tissue using total RNA extraction reagent (EZBioscience, USA). 1 μg of total mRNA was reverse transcribed into cDNA using reverse transcription reagent (EZBioscience, USA). Subsequently, qRT-PCR was performed using SYBR Green qRT-PCR (ROX 2plus; EZBioscience, USA). The cycle parameters were 95℃for 5 minutes (pre-denaturation); 95 ℃,10 seconds (denaturation); 60℃for 30 seconds (extension) for 40 cycles. Finally, the relative expression level was calculated using the 2 -ΔΔCt method and expressed as a fold change in relative Gapdh.
2. Statistical analysis
Analysis of variance (ANOVA) methods were used to compare significant differences between control, model, A5 low dose and A5 high dose.
P <0.033: data differences between experimental groups were shown to be statistically significant, but at a lower level.
P <0.002: data differences between experimental groups were shown to be statistically more significant, indicating more significant differences.
P <0.001: the data differences between the experimental groups are shown to have very high statistical significance, the differences are very significant and the results are very reliable.
3. Results
3.1 Weight changes
The weight change may reflect the health status of the mice and the impact of medication. In fig. 1, the normal control group mice weight gradually increased from the average 21.64 g at the beginning of the experiment to the average 26.4 g at the end of the experiment throughout the experiment period (day 0 to day 63), showing a normal growth curve. In contrast, the weight gain of CIA model group mice was inhibited, and the average value was reduced from 21.18 g to 21.0 g, and this inhibition of weight gain was possibly associated with pain and discomfort caused by arthritis, which symptoms may lead to loss of appetite and thus affect weight gain.
The mice in the A5-treated group had an increased body weight compared to the model group, showing a positive effect of A5 treatment. The weight of the mice in the A5 low dose group increased from 21.62 g to 21.8 g on average, while the weight of the mice in the A5 high dose group increased from 21.89 g to 22.8 g on average. The increase in body weight was more pronounced throughout the experiment, especially in the high dose group, indicating that high dose A5 treatment may be more effective in alleviating CIA-induced symptoms, improving the health of the mice.
The results indicate that A5 has improved CIA-induced systemic effects, including weight management and possible appetite recovery, providing data support for A5 as a potential anti-inflammatory treatment regimen.
3.2 Pain threshold
An increase in pain threshold indicates a reduction in pain sensation, which is an important indicator for evaluating the effect of anti-inflammatory drugs. In fig. 4, the pain threshold of the control mice at the start of the experiment was 15.57 on average, while the pain threshold of the CIA model mice was reduced to 10.45 on day 7 of the experiment, significantly lower than 14.7 of the control group, indicating a successful establishment of the model and its resulting pain state. The pain threshold is significantly raised by A5 treatment, particularly in the high dose group; for example, by day 28, the pain threshold reached 10.2 for the high dose group, and by day 63 of the experiment, this value was further raised to 13.2, approaching the level of the control group at the start of the experiment. Elevation of the pain threshold of the A5 treatment group indicates the effectiveness of this treatment regimen in reducing joint inflammatory pain. Moreover, this result not only demonstrates the ability of A5 to alleviate the symptoms of arthritis, but also suggests that it may have a direct impact on the pain mechanism caused by arthritis.
For arthritic symptoms in mice, micro-CT analysis and histological evaluation focused on the proximal toe (finger) joints and ankle joints of the mice forelimbs and hindlimbs, which often show significant pathological changes in RA.
3.3 Arthritis scoring
A decrease in the arthritis score indicates a decrease in inflammatory response and an increase in therapeutic efficacy. From day 21 of the experiment, the arthritis score of the control mice remained at 0, indicating no inflammatory symptoms. In fig. 2 and 3, the end limb of the CIA model group became red and swollen compared to the normal control group, and the score was gradually increased from the proximal toe (finger) joint toward the ankle (wrist) joint during the experiment, reaching an average of 10.6 minutes by day 63, reflecting the typical clinical manifestations of Rheumatoid Arthritis (RA). A5 treated groups (particularly high dose groups) showed significant improvement in arthritic symptoms, including reduction in limb swelling and reduction in arthritis scores, in the middle of the experiment (day 42) compared to the model group. For example, on day 42, the high dose group had an average score of 5.25 points, with a significant improvement in arthritic symptoms compared to 8 points at the same time point in the model group. This improvement persists over time, with the high dose group score reaching an average of 6.2 points to the end of the experiment, while the model group is 10.6 points, showing a more durable and pronounced effect of the high dose A5 treatment. The alleviation of swelling of the limb and the reduction of the arthritis score in the A5-treated group indicate the potential efficacy of this treatment regimen in reducing arthritic conditions.
3.4Micro-CT analysis
Micro-CT analysis provides detailed information about bone conditions, which is critical for assessing the efficacy of arthritis treatment. In fig. 5, micro-CT analysis showed severe bone destruction, especially in the proximal toe (finger) joints, in the CIA model group, compared to the normal control group, which was manifested by a significant decrease in bone volume fraction (BV/TV), a decrease in bone size Liang Shu (Trabecular number, tb.n), and an increase in trabecular separation (Trabecular separation, tb.sp). For example, micro-CT analysis of the anterior paw of the mice in the experiment showed that the bone volume fraction (BV/TV) was reduced from 54.13% to 38.90% in the control group, the reduction was 28.15%, which visually reflects the severity of bone mass and bone structural damage in the RA symptoms. In addition, model group bone loss Liang Shu (tb.n) was also reduced from 226.81 to 213.76 in the control group by 5.76%, while trabecular separation (tb.sp) increased from 135.89 to 170.40 by 25.40%. These changes reflect typical bone loss and bone structural disruption in RA. In contrast, the A5 treated mice exhibited significant bone improvement. In mice receiving A5 treatment, micro-CT analysis revealed significant upregulation of BV/TV and tb.n, and downregulation of tb.sp, BV/TV was reduced to 48.05% in the A5 low dose treatment group, 24.00% in comparison to the model group, while BV/TV was almost leveled to the control group in the high dose group, showing significant efficacy of high dose A5 in restoring bone mass. Similarly, the Tb.Th of the low dose group was reduced to 206.86 by 8.79% and the Tb.Th of the high dose group was 229.86, even increased over the control group, representing the potential of A5 for maintaining or even enhancing bone structure. In the expression of tb.sp, the A5 low dose group was reduced to 130.07, 23.15% lower, while the tb.sp of the high dose group was reduced to 107.02, 21.20% lower, indicating that the high dose A5 treatment was particularly effective in reducing trabecular bone separation. The results show that the treatment scheme not only can relieve joint inflammation symptoms caused by RA, but also can effectively inhibit further damage and loss of bone, and promote maintenance and recovery of bone structure. The improvement in bone conditions in the A5 treatment group indicated the potential efficacy of this treatment regimen in preventing bone destruction and improving bone density.
3.5 Histological evaluation
By using hematoxylin-eosin and safranin fast green staining techniques (shown in fig. 7 and 8, respectively), a significant change in articular cartilage internal structure was observed in mice of the model group compared to the normal control group, including increased proliferation of synovium and infiltration of inflammatory cells. These changes reflect typical pathological features of RA, such as joint inflammation, cartilage destruction and synovial cell activation. In the A5-treated group, we observed a gradual decrease in the pathological changes of the joints of mice with increasing A5 dose. Specifically, the application of A5 not only reduces the proliferation of synovium, but also reduces the infiltration of inflammatory cells, which indicates that A5 has a remarkable inhibiting effect on the joint inflammation of RA. More importantly, in the A5 high dose treatment group, the joint histology was restored to a level close to that of the normal control group, indicating that high doses of A5 were able to reduce inflammation as well as promote repair and regeneration of damaged cartilage. Histological evaluation results indicate a positive effect of the treatment regimen in reducing inflammatory cell infiltration and promoting restoration of cartilage structure.
3.6 Inflammatory factor levels
In the normal control group, the average level of IL6 was 0.6161, whereas in the CIA model group, this level was increased to 1.053, increased by 70.94%, which clearly reflects the inflammatory response caused by arthritis. The mean level of IL6 was reduced to 0.7066 in the low dose A5 treated group, 32.86% less than in the model group, and further reduced to 0.6485 in the high dose group, 38.46% less than in the model group, demonstrating the utility of A5 in reducing inflammation. The average Il1b level of the control group was 3.14. The level in the CIA model group increased sharply to 23.3, an increase of 642.04%, which is a significant inflammatory response caused by CIA. After A5 low dose treatment, the mean Il1b level was reduced to 11.15, by 52.15%, more to 9.499 in the high dose group, by 59.27%, further emphasizing the potential of A5 for inhibiting inflammation. The control group had an average level of Tnfa of 1.183, while the model group had risen to 1.778, an increase of 50.29%. The lower dose group had a slight decrease in the level of Tnfa to 1.174 and the higher dose group to 1.04, which was 41.52% less than the model group, demonstrating the inhibition of Tnfa by A5. The average level of control IL18 was 1.974. The rise in CIA model group was 5.596, increasing 183.49%. In the A5 treated group, the level of the low dose group was 3.379, which was 39.59% less than the model group, while the high dose group was further 2.941% less than the model group, which was 47.44% less than the model group, showing the effect of A5 in modulating IL18 levels. The average level of control Inos was 1.028, whereas in the model group this level increased to 2.456, an increase of 138.91%. The Inos level was reduced to 1.504 in the low dose group, which was reduced by 38.78% compared to the model group, and to 1.474 in the high dose group, which was reduced by 39.90% after A5 treatment, indicating the potential efficacy of A5 in inhibiting Inos expression.
The results indicate that A5 treatment is effective in reducing the level of inflammatory factors in synovial tissue of joints caused by CIA model, reducing inflammatory response, and showing more remarkable effects at high doses. This supports the potential use of A5 as an anti-inflammatory drug, potentially for the treatment of rheumatoid arthritis.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
1. Use of annexin in the manufacture of a pharmaceutical composition for the prevention and/or treatment of rheumatoid arthritis, characterized in that said annexin comprises annexin A5.
2. Use of annexin for the preparation of a pharmaceutical composition for the prevention and/or treatment of chronic inflammation in the treatment of rheumatoid arthritis, characterized in that said annexin comprises annexin A5.
3. Use of annexin for the preparation of a pharmaceutical composition for the prevention and/or treatment of pain in rheumatoid arthritis, characterized in that said annexin comprises annexin A5.
4. Use according to any one of claims 1-3, wherein the pharmaceutical composition is for reducing an inflammatory response of a joint;
preferably, the pharmaceutical composition is for modulating inflammatory factor levels;
preferably, the pharmaceutical composition is for reducing inflammatory factor expression;
Preferably, the inflammatory factor comprises interleukin-6, interleukin-1 beta, tumor necrosis factor-alpha, interleukin-18, inducible nitric oxide synthase.
5. The use according to any one of claims 1-4, wherein the pharmaceutical composition is for inhibiting destruction of articular cartilage and/or bone tissue.
6. The use according to any one of claims 1-5, wherein the pharmaceutical composition is for improving joint function.
7. The use according to any one of claims 1-6, wherein the pharmaceutical composition is for promoting repair and regeneration of damaged joint tissue.
8. The use according to any one of claims 1-7, wherein the pharmaceutical composition further comprises other medicaments for the prevention and/or treatment of rheumatoid arthritis;
Preferably, the other agent for preventing and/or treating rheumatoid arthritis is selected from the group consisting of: glucocorticoids, non-steroidal anti-inflammatory drugs, immunosuppressants, and biologicals.
9. The use according to any one of claims 1 to 8, wherein the composition or formulation is for use in the treatment of a human or non-human mammal.
10. The use according to any one of claims 1 to 9, wherein the pharmaceutical composition is an injectable preparation, a subcutaneous preparation, or a respiratory administration preparation,
Preferably, the formulation is an injection,
More preferably, the injection is intravenous injection or intramuscular injection.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410044198.7A CN117982623A (en) | 2024-01-11 | 2024-01-11 | Medicine for preventing and/or treating rheumatoid arthritis |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410044198.7A CN117982623A (en) | 2024-01-11 | 2024-01-11 | Medicine for preventing and/or treating rheumatoid arthritis |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117982623A true CN117982623A (en) | 2024-05-07 |
Family
ID=90888020
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410044198.7A Pending CN117982623A (en) | 2024-01-11 | 2024-01-11 | Medicine for preventing and/or treating rheumatoid arthritis |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117982623A (en) |
-
2024
- 2024-01-11 CN CN202410044198.7A patent/CN117982623A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9795580B2 (en) | Ketone supplements for treatment of angelman syndrome | |
JPH10114681A (en) | Anti-fibrosis agent | |
US11298403B2 (en) | Therapeutic agent for inflammatory bowel disease | |
Guo et al. | Fumigaclavine C ameliorates dextran sulfate sodium-induced murine experimental colitis via NLRP3 inflammasome inhibition | |
EP1891961B1 (en) | Use of 5'-methylthioadenosine (mta) in the prevention and/or treatment of autoimmune diseases and/or transplant rejection | |
WO2020175817A1 (en) | Composition for preventing, ameliorating, or treating fibrosis | |
KR102271821B1 (en) | Composition Comprising Orlistat and Akkermansia muciniphila EB-AMDK19 | |
CN111939179B (en) | Application of cobra venom or cobra venom extract in preparation of medicine for reducing uric acid and/or resisting gouty arthritis | |
CN117982623A (en) | Medicine for preventing and/or treating rheumatoid arthritis | |
CN114569585A (en) | Application of patchouli alcohol in preparation of medicine for treating rheumatoid arthritis | |
CN114699410A (en) | Application of cepharanthine in preparing medicine for treating rheumatoid arthritis | |
JP2009298702A (en) | Oral administration composition | |
CN112569222A (en) | Application of trifluroicaritin in preparation of medicine for improving pain, swelling and motor function | |
CN114209684A (en) | Application of itaconic acid in preparation of medicine for preventing and/or treating overweight or obesity or health-care product for preventing overweight or obesity | |
WO2021070121A1 (en) | Gastrointestinal health composition | |
KR100793236B1 (en) | A pharmaceutical composition for treating colitis | |
EP3639835A1 (en) | Use ofcimicifugae foetidae | |
CN105395584B (en) | The application of Pien Tze Huang and its preparation in the drug of preparation treatment multiple sclerosis | |
KR101824329B1 (en) | Composition comprising the fraction of Moutan Cortex Radicis extract for preventing or treating liver disases | |
KR102454513B1 (en) | Composition for preventing and treating arthritis comprising of Artemisia argyi thereof | |
CN112121050B (en) | Application of ATF4 inhibitor in preparation of drug for preventing or treating ankylosing spondylitis | |
WO2022100399A1 (en) | Therapeutic application of cell-free fat extract to arthritis | |
JP7343902B2 (en) | Compounds for use in the prevention and/or treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis | |
CN117838774A (en) | Formula medicine for preventing and treating neutrophil activity related diseases | |
CN113730395A (en) | Application of chrysin in medicine for treating alcoholic liver injury |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination |