CN113940934A - Application of sinomenine in medicine for treating autoimmune thyroid disease - Google Patents
Application of sinomenine in medicine for treating autoimmune thyroid disease Download PDFInfo
- Publication number
- CN113940934A CN113940934A CN202111407516.4A CN202111407516A CN113940934A CN 113940934 A CN113940934 A CN 113940934A CN 202111407516 A CN202111407516 A CN 202111407516A CN 113940934 A CN113940934 A CN 113940934A
- Authority
- CN
- China
- Prior art keywords
- sinomenine
- medicament
- thyroid
- autoimmune thyroid
- treating
- 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
- INYYVPJSBIVGPH-UHFFFAOYSA-N 14-episinomenine Natural products C1CN(C)C2CC3=CC=C(OC)C(O)=C3C31C2C=C(OC)C(=O)C3 INYYVPJSBIVGPH-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 208000010928 autoimmune thyroid disease Diseases 0.000 title claims abstract description 72
- 239000003814 drug Substances 0.000 title claims abstract description 66
- INYYVPJSBIVGPH-QHRIQVFBSA-N Sinomenine Chemical compound C([C@@H]1N(CC2)C)C3=CC=C(OC)C(O)=C3[C@@]32[C@@H]1C=C(OC)C(=O)C3 INYYVPJSBIVGPH-QHRIQVFBSA-N 0.000 title claims abstract description 45
- RARWEROUOQPTCJ-RBUKOAKNSA-N cepharamine Natural products C1CC2=CC=C(OC)C(O)=C2[C@@]2(CCN3C)[C@]13C=C(OC)C(=O)C2 RARWEROUOQPTCJ-RBUKOAKNSA-N 0.000 title claims abstract description 45
- 229930002966 sinomenine Natural products 0.000 title claims abstract description 45
- REKJPVUFKQYMHW-UHFFFAOYSA-N 2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid Chemical compound CC1=NC(C(F)(F)F)=C(C(O)=O)S1 REKJPVUFKQYMHW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 230000001363 autoimmune Effects 0.000 claims abstract description 18
- 239000003200 antithyroid agent Substances 0.000 claims abstract description 15
- 229940043671 antithyroid preparations Drugs 0.000 claims abstract description 15
- 208000024799 Thyroid disease Diseases 0.000 claims abstract description 10
- 238000011282 treatment Methods 0.000 claims description 38
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 26
- 208000023328 Basedow disease Diseases 0.000 claims description 23
- 102000011923 Thyrotropin Human genes 0.000 claims description 18
- 108010061174 Thyrotropin Proteins 0.000 claims description 18
- 201000006594 toxic diffuse goiter Diseases 0.000 claims description 16
- PMRYVIKBURPHAH-UHFFFAOYSA-N methimazole Chemical compound CN1C=CNC1=S PMRYVIKBURPHAH-UHFFFAOYSA-N 0.000 claims description 12
- 229960002178 thiamazole Drugs 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 5
- 108090000253 Thyrotropin Receptors Proteins 0.000 claims description 4
- 102000003911 Thyrotropin Receptors Human genes 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 67
- 210000001685 thyroid gland Anatomy 0.000 description 29
- 229940079593 drug Drugs 0.000 description 18
- 230000000694 effects Effects 0.000 description 16
- 102000004127 Cytokines Human genes 0.000 description 15
- 108090000695 Cytokines Proteins 0.000 description 15
- 208000015023 Graves' disease Diseases 0.000 description 15
- 230000002757 inflammatory effect Effects 0.000 description 14
- 230000008506 pathogenesis Effects 0.000 description 11
- 210000001744 T-lymphocyte Anatomy 0.000 description 10
- 230000003110 anti-inflammatory effect Effects 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 239000009395 Zhengqing Fengtongning Substances 0.000 description 9
- 210000003719 b-lymphocyte Anatomy 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 208000003807 Graves Disease Diseases 0.000 description 8
- 208000001204 Hashimoto Disease Diseases 0.000 description 8
- 230000007423 decrease Effects 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
- 210000003289 regulatory T cell Anatomy 0.000 description 8
- 230000000391 smoking effect Effects 0.000 description 8
- 230000006016 thyroid dysfunction Effects 0.000 description 8
- 208000023275 Autoimmune disease Diseases 0.000 description 7
- 210000000447 Th1 cell Anatomy 0.000 description 7
- 102100036922 Tumor necrosis factor ligand superfamily member 13B Human genes 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000006378 damage Effects 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 206010020850 Hyperthyroidism Diseases 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- 210000000068 Th17 cell Anatomy 0.000 description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 6
- 101710181056 Tumor necrosis factor ligand superfamily member 13B Proteins 0.000 description 6
- 230000005856 abnormality Effects 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 230000007613 environmental effect Effects 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 210000004698 lymphocyte Anatomy 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 5
- 102100037850 Interferon gamma Human genes 0.000 description 5
- 108010074328 Interferon-gamma Proteins 0.000 description 5
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 5
- 230000002159 abnormal effect Effects 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 210000002950 fibroblast Anatomy 0.000 description 5
- 230000001506 immunosuppresive effect Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 208000025747 Rheumatic disease Diseases 0.000 description 4
- 210000004241 Th2 cell Anatomy 0.000 description 4
- 239000002662 enteric coated tablet Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000003325 follicular Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 208000003532 hypothyroidism Diseases 0.000 description 4
- 230000002989 hypothyroidism Effects 0.000 description 4
- 230000006058 immune tolerance Effects 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000001717 pathogenic effect Effects 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 230000000552 rheumatic effect Effects 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 3
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 241001111421 Pannus Species 0.000 description 3
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 3
- 230000000947 anti-immunosuppressive effect Effects 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 208000026278 immune system disease Diseases 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 102000054765 polymorphisms of proteins Human genes 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229940091258 selenium supplement Drugs 0.000 description 3
- 210000001258 synovial membrane Anatomy 0.000 description 3
- 235000015398 thunder god vine Nutrition 0.000 description 3
- 208000021510 thyroid gland disease Diseases 0.000 description 3
- 239000005495 thyroid hormone Substances 0.000 description 3
- 229940036555 thyroid hormone Drugs 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 2
- 101150013553 CD40 gene Proteins 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 2
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 102000013691 Interleukin-17 Human genes 0.000 description 2
- 108050003558 Interleukin-17 Proteins 0.000 description 2
- 102100030703 Interleukin-22 Human genes 0.000 description 2
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 2
- 208000023178 Musculoskeletal disease Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 2
- 241000830536 Tripterygium wilfordii Species 0.000 description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- 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 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000030741 antigen processing and presentation Effects 0.000 description 2
- 235000006533 astragalus Nutrition 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 229960002986 dinoprostone Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000009266 disease activity Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000019975 dosage compensation by inactivation of X chromosome Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000009533 lab test Methods 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 208000017445 musculoskeletal system disease Diseases 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000000242 pagocytic effect Effects 0.000 description 2
- 231100000255 pathogenic effect Toxicity 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 230000000405 serological effect Effects 0.000 description 2
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 2
- 239000007939 sustained release tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- GMRQFYUYWCNGIN-UHFFFAOYSA-N 1,25-Dihydroxy-vitamin D3' Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CC(O)C1=C GMRQFYUYWCNGIN-UHFFFAOYSA-N 0.000 description 1
- GMRQFYUYWCNGIN-ZVUFCXRFSA-N 1,25-dihydroxy vitamin D3 Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-ZVUFCXRFSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241001061264 Astragalus Species 0.000 description 1
- 241000045403 Astragalus propinquus Species 0.000 description 1
- 108010028006 B-Cell Activating Factor Proteins 0.000 description 1
- 208000012639 Balance disease Diseases 0.000 description 1
- 206010051728 Bone erosion Diseases 0.000 description 1
- 241000202726 Bupleurum Species 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 206010010264 Condition aggravated Diseases 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- 208000003164 Diplopia Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 108090000852 Forkhead Transcription Factors Proteins 0.000 description 1
- 102000004315 Forkhead Transcription Factors Human genes 0.000 description 1
- 102100027581 Forkhead box protein P3 Human genes 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 206010018498 Goitre Diseases 0.000 description 1
- 208000003084 Graves Ophthalmopathy Diseases 0.000 description 1
- 101000861452 Homo sapiens Forkhead box protein P3 Proteins 0.000 description 1
- 101100246021 Homo sapiens PTPN22 gene Proteins 0.000 description 1
- 101001135589 Homo sapiens Tyrosine-protein phosphatase non-receptor type 22 Proteins 0.000 description 1
- 241000702617 Human parvovirus B19 Species 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010082786 Interleukin-1alpha Proteins 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 206010023230 Joint stiffness Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 102000043129 MHC class I family Human genes 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 description 1
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 1
- 101150021299 PTPN22 gene Proteins 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 102000009843 Thyroglobulin Human genes 0.000 description 1
- 108010034949 Thyroglobulin Proteins 0.000 description 1
- 208000009453 Thyroid Nodule Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 102100033138 Tyrosine-protein phosphatase non-receptor type 22 Human genes 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 210000001766 X chromosome Anatomy 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- KQJSQWZMSAGSHN-JJWQIEBTSA-N celastrol Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)[C@](C)(C(O)=O)CC[C@]1(C)CC[C@]2(C)C4=CC=C1C3=CC(=O)C(O)=C1C KQJSQWZMSAGSHN-JJWQIEBTSA-N 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 210000001608 connective tissue cell Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 208000001936 exophthalmos Diseases 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000000185 follicular epithelial cell Anatomy 0.000 description 1
- 201000003872 goiter Diseases 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 230000008938 immune dysregulation Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000005550 inflammation mediator Substances 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000004073 interleukin-2 production Effects 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- 108010074109 interleukin-22 Proteins 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 201000008494 nodular goiter Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000004796 pathophysiological change Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 102200057606 rs231775 Human genes 0.000 description 1
- 102220013088 rs3729547 Human genes 0.000 description 1
- 102220109911 rs756630815 Human genes 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- -1 such as AR Proteins 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 210000002437 synoviocyte Anatomy 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 210000004233 talus Anatomy 0.000 description 1
- 229960002175 thyroglobulin Drugs 0.000 description 1
- 238000009601 thyroid function test Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 230000007371 visceral function Effects 0.000 description 1
- 229940126673 western medicines Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses application of sinomenine in a medicament for treating autoimmune thyroid diseases. The invention discloses application of sinomenine or pharmaceutically acceptable salts thereof in preparing a medicament for treating autoimmune thyroid diseases. The use of sinomenine or its pharmaceutically acceptable salt in combination with antithyroid agent in the preparation of a medicament for treating autoimmune thyroid disorders. The experimental result of the invention fully supports the new application of sinomenine hydrochloride in treating refractory autoimmune thyroid diseases.
Description
The present application claims priority to chinese patent application 202011340479.5 entitled "use of sinomenine in a medicament for the treatment of autoimmune thyroid disorders" filed on 25/11/2020, which is incorporated herein by reference in its entirety.
Technical Field
The application relates to the field of medicines, in particular to application of sinomenine hydrochloride in medicines for treating autoimmune thyroid diseases.
Background
Rheumatoid Arthritis (RA) is a well-known chronic inflammatory joint disease, and its pathological features are autoimmune, pannus formation, cartilage and bone destruction, even involving heart, lung and other systemic system damage, and its prevalence rate is about 0.5-1.0% of the global population. Autoimmune thyroid disease (AITD), one of the most common organ-specific Autoimmune diseases due to the attack of the immune system on the thyroid gland, is classified as "T cell-mediated organ-specific Autoimmune disease" with a global prevalence of about 5%. Clinically, Hashimoto Thyroiditis (HT) and Graves' disease (GD) are mainly involved, showing hyperthyroidism and hypothyroidism, respectively. AITD is characterized by the presence of circulating antibodies against various thyroid autoantigens and by the presence of diffuse lymphocytic infiltrates within the thyroid tissue.
Sinomenine is a Chinese medicine for dispelling pathogenic wind and removing dampness and treating arthralgia, and can inhibit inflammatory cytokine and promote apoptosis to play an anti-inflammatory role; can inhibit specific T cell in vitro activation proliferation and dendritic cell bioactivity to inhibit autoimmune reaction. However, no research report is available on the therapeutic effect of sinomenine on rheumatoid arthritis.
Disclosure of Invention
The embodiment of the application aims to provide a technical problem of application of sinomenine in a medicine for treating autoimmune thyroid diseases.
In order to achieve the purpose, the technical scheme adopted by the application is as follows:
in one aspect, the invention provides an application of sinomenine or a pharmaceutically acceptable salt thereof in a medicament for treating autoimmune thyroid diseases.
Preferably, the sinomenine or the pharmaceutically acceptable salt thereof is applied to a drug for treating Hashimoto's thyroiditis, a drug for treating toxic diffuse goiter (Graves disease) or a drug for treating toxic diffuse goiter combined with Hashimoto's thyroiditis.
Preferably, the sinomenine pharmaceutically acceptable salt is sinomenine hydrochloride.
Preferably, the dosage form of the sinomenine hydrochloride is a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
On the other hand, the invention provides the application of the sinomenine or the medicinal salt thereof in combination with an antithyroid drug in the preparation of drugs for treating autoimmune thyroid diseases;
preferably, the antithyroid drug is methimazole.
The application of the invention is that the medicine for treating autoimmune thyroid diseases is a medicine for treating Hashimoto's thyroiditis, a medicine for treating toxic diffuse goiter (Graves disease) or a medicine for treating toxic diffuse goiter combined with Hashimoto's thyroiditis (Graves disease combined with Hashimoto's thyroiditis).
According to the application, the sinomenine medicinal salt is sinomenine hydrochloride.
The application of the sinomenine hydrochloride is characterized in that the sinomenine hydrochloride is in a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
The use according to the present invention, wherein the drug is a drug that improves the level of thyroid stimulating hormone receptor antibody (Trab) in autoimmune thyroid diseases.
The use of the invention, wherein the medicament is a medicament for improving the Thyroid Stimulating Hormone (TSH) level of autoimmune thyroid diseases.
In still another aspect, the present invention provides a pharmaceutical composition for treating autoimmune thyroid diseases, wherein the pharmaceutical composition comprises sinomenine or a pharmaceutically acceptable salt thereof, an antithyroid drug and a pharmaceutically acceptable adjuvant or additive;
preferably, the antithyroid drug is methimazole; and/or
The medicinal salt of sinomenine is sinomenine hydrochloride.
The pharmaceutical composition of the invention, wherein the autoimmune thyroid disease is hashimoto's thyroiditis, toxic diffuse goiter or toxic diffuse goiter combined with hashimoto's thyroiditis.
The application of the sinomenine in the medicine for treating the autoimmune thyroid diseases provided by the embodiment of the application has commonality between Rheumatoid Arthritis (RA) and the autoimmune thyroid diseases (AITD) in a plurality of aspects such as pathogenesis, clinical manifestation and the like.
Sinomenine has obvious curative effect on RA patients, and obviously inhibits inflammatory cytokines to play anti-inflammatory and immunosuppressive roles, so that sinomenine can be preliminarily considered to improve AITD symptoms.
The invention provides a new pharmaceutical application of sinomenine hydrochloride in autoimmune thyroid diseases. Through a series of clinical researches, the inventor finds that the combination treatment of the sinomenine hydrochloride and the methimazole can improve Trab level and TSH level of a patient, and compared with a control group, the difference is statistically significant. Obviously, sinomenine hydrochloride has advantages in improving Trab and TSH, and is helpful for patients to quickly reach the standard of anti-hyperthyroidism drug disuse. The sinomenine hydrochloride and methimazole combined treatment group has no obvious adverse reaction. The experimental result of the invention fully supports the new application of sinomenine hydrochloride in treating refractory autoimmune thyroid diseases.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
It should be noted that the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present application, "a plurality" means two or more unless specifically limited otherwise.
The invention provides an application of sinomenine or a medicinal salt thereof in a medicament for treating autoimmune thyroid diseases.
Preferably, the sinomenine or the pharmaceutically acceptable salt thereof is applied to a drug for treating Hashimoto's thyroiditis, a drug for treating toxic diffuse goiter (Graves disease) or a drug for treating toxic diffuse goiter combined with Hashimoto's thyroiditis.
Preferably, the sinomenine pharmaceutically acceptable salt is sinomenine hydrochloride.
Preferably, the dosage form of the sinomenine hydrochloride is a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
On the other hand, the invention provides the application of the sinomenine or the medicinal salt thereof in combination with an antithyroid drug in the preparation of drugs for treating autoimmune thyroid diseases;
preferably, the antithyroid drug is methimazole.
The application of the invention is that the medicine for treating autoimmune thyroid diseases is a medicine for treating Hashimoto's thyroiditis, a medicine for treating toxic diffuse goiter (Graves disease) or a medicine for treating toxic diffuse goiter combined with Hashimoto's thyroiditis (Graves disease combined with Hashimoto's thyroiditis).
According to the application, the sinomenine medicinal salt is sinomenine hydrochloride.
The application of the sinomenine hydrochloride is characterized in that the sinomenine hydrochloride is in a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
The use according to the present invention, wherein the drug is a drug that improves the level of thyroid stimulating hormone receptor antibody (Trab) in autoimmune thyroid diseases.
The use of the invention, wherein the medicament is a medicament for improving the Thyroid Stimulating Hormone (TSH) level of autoimmune thyroid diseases.
In still another aspect, the present invention provides a pharmaceutical composition for treating autoimmune thyroid diseases, wherein the pharmaceutical composition comprises sinomenine or a pharmaceutically acceptable salt thereof, an antithyroid drug and a pharmaceutically acceptable adjuvant or additive;
preferably, the antithyroid drug is methimazole; and/or
The medicinal salt of sinomenine is sinomenine hydrochloride.
The pharmaceutical composition of the invention, wherein the autoimmune thyroid disease is hashimoto's thyroiditis, toxic diffuse goiter or toxic diffuse goiter combined with hashimoto's thyroiditis.
Sinomenine is a Chinese medicine for dispelling pathogenic wind and removing dampness and treating arthralgia, and can inhibit inflammatory cytokine and promote apoptosis to play an anti-inflammatory role; can inhibit specific T cell in vitro activation proliferation and dendritic cell bioactivity to inhibit autoimmune reaction. RA and AITD patients have similar clinical characteristic expression, and immune function disorder, inflammatory factor induction and the like are used as common pathogenesis, so if a medicament has pharmacological efficacy of remarkably inhibiting inflammatory effect or regulating autoimmune reaction, the medicament can be used as a potential medicament for treating RA or AITD. Early-stage research proves that the sinomenine hydrochloride has obvious curative effect on RA, but no report that sinomenine can effectively improve AITD symptoms exists at present. Based on this, we preliminarily believe that sinomenine hydrochloride capable of effectively treating RA has the same therapeutic effect on AITD, and follow-up experiments will further study and verify the hypothesis.
1 clinical presentation and diagnostic Studies
1.1 thyroid function and antibody detection
RA and AITD patients show thyroid dysfunction and TPOAb and TGAb antibody indexes are positive, and the diagnosis result is obtained by detecting the autoantibody level in serum in clinic. AITD causes cellular damage and thyroid dysfunction through humoral and cellular immune-mediated immune mechanisms, and various enzymes and antibodies against thyroid-specific components are present in thyroid tissue. For example, autoantibody concentrations in patients with Graves' disease cannot be correlated with thyroid hormone levels, and fluctuations in antibody titers can lead to hyperthyroidism or hypothyroidism. Qinhua et al carried out thyroid function test to 100 women RA patients and 57 normal women respectively, and the result shows that complicated thyroid dysfunction 37 in the RA patient, 4 in the control group, and observe that group TPOAb, TGAb positive rate are higher than the control group, and two sets of differences all have statistical significance, indicate that RA patient complicated thyroid dysfunction degree and RA patient's state of an illness activity have the relevance. Saqre IM et al, by studying 60 RA patients and 60 normal controls, showed that 38.3% of RA patients had thyroid dysfunction, with significant differences compared to 6.7% of the normal controls, and confirmed that the levels of serum TPOAb and TGAb were significantly higher in RA patients than in controls, suggesting that most RA patients had thyroid abnormalities. Therefore, the method has practical significance for screening the thyroid hormone dysfunction of RA patients, especially young female patients and patients with high disease activity and detecting the markers TPOAb and TGAb antibodies of AITD.
1.2 thyroid abnormality in RA patients and rheumatic manifestation in AITD patients
Studies have shown that RA patients have a 3-fold higher incidence of thyroid dysfunction than the general population. Shiroky JB and other similar studies found 18/27 hypothyroidism, 6/27 confirmed HT, 1/27 confirmed Graves disease, and 2 multiple nodular goiter and familial thyroid disease in the RA cohort in case-controlled studies, suggesting that most patients with RA will have thyroid disease or thyroid hyperchromia has occurred clinically.
Early reports indicated that patients with thyroid dysfunction developed a worsening of musculoskeletal disease with clinical symptoms including scapulohumeral periarthritis, joint stiffness, shoulder girdle pain and weakness that were clinically different from myopathies associated with thyroid dysfunction and similar to RA symptoms. Careful examination of rheumatic manifestations in a population of thyroidically normal Chronic Lymphocytic Thyroiditis (CLT) patients by Tagoe CE et al has shown that a broad autoimmune process may exist in a subset of CLT patients with normal thyroid function, with significant rheumatic manifestations, more common in hypothyroidism patients. Rheumatic manifestations in AITD patients may involve a variety of organs and tissues, mainly affecting joints, muscles and skin. Delamere J P et al have shown that abnormalities or changes in thyroid status may accelerate or exacerbate musculoskeletal disease, symptoms that have been shown to be similar to polymyalgia rheumatica, supporting a correlation between RA and AITD.
2 study of pathogenesis
The pathogenesis of RA and AITD is not clear, and epidemiological data suggest that epigenetic, immune balance disorders, endocrine, environmental factors may all play a role.
2.1 common genetic relationships exist
Thomas D J et al observed that AITD occurred more frequently in the first and second parents of RA than expected, and had some familial aggregation suggesting that both may have a common susceptibility gene. By serological examination of 504 members of the 58 RA families for thyroid autoantibodies, simman a J et al compared the serological data and found that 6% of the people had thyroid disease and five times as many women as men. Thyroglobulin antibodies were present in 5% of men and 11% of women, and thyroid microsomal antibodies were present in 5% of men and 15% of women. These ratios are much larger than published ratios by the general population. Differences still exist after analysis individually by age group. The results confirmed that there was a common genetic linkage between RA and AITD.
TABLE 1 susceptibility genes for RA and AITD
Wenjin, Sanders P A and the like found that the occurrence of AITD can be caused by a plurality of genes such as HLA gene complex, CD40, CTLA 4, PTPN22 and the like, and immunological abnormality of the genes is also a physiological mechanism influencing RA. In the review by Ivica L et al it was written that HLA-DRb1-Arg74 (human leukocyte antigen DR containing arginine at position. beta.74) carries the greatest risk among the consensus susceptibility genes involved in the pathogenesis of AITD. The TSH receptor genes CD40 and CD25 have been shown to be closely related to Graves' disease, where the reduction of T regulatory cell function by certain CD25 polymorphisms may contribute to autoimmune development. CTLA-4 is a member of the immunoglobulin superfamily, a costimulatory molecule expressed by activated T cells. Three single nucleotide polymorphisms in the CTLA-4 gene, C318T, A49G and C60T, have been shown to be associated with type 1 diabetes, RA, SLE, celiac disease, multiple sclerosis and AITD. The PTPN22 gene encodes a protein lymphotyrosine phosphatase that is a negative regulator of T cell receptor signaling, and partial polymorphisms thereof have been found to be associated with AITD, RA, and other autoimmune diseases.
2.2 being influenced by common environmental factors
The environmental factors can enhance the autoimmune ability of genetically susceptible individuals and break the tolerance of genetically resistant individuals, thereby increasing the risk of autoimmune diseases. Many environmental risk factors, such as smoking, hormones, diet, drugs, toxins, infections, stress are important in determining whether a person will develop an autoimmune disease.
Strong epidemiological evidence supports smoking as one of the dangerous environmental factors for RA development. Multiple studies have shown that smoking causes an increased risk of RA, and that there is a dose-dependent effect between the years of smoking and the development of RA, which can induce an inflammatory response as well as Th1 and Th17 cell-mediated immune responses in patients with RA. In addition to playing an important role in RA, smoking also increases the risk of AITD, and in particular may cause non-specific immunity, increase the susceptibility to Graves' disease and exacerbate its clinical manifestations. Smoking induces polyclonal activation of B cells and T cells, thereby inducing IL-2 production. Smoking or passive smoking increases serum IgE levels and increases the risk of developing allergic symptoms, possibly by destroying cells to increase antigen presentation. Viral infection is also one of the important environmental factors in pathogenesis, especially human parvovirus B19(HPVB19) and Hepatitis C Virus (HCV). Infection with HPVB19 or HCV viruses causes various immune diseases including RA, systemic lupus erythematosus, AITD, and the like.
2.3 helper T cell subset imbalance
Helper T cells can be divided into various cell subtypes: th1, Th2, Th17 and Treg cells, and Th1/Th2 and Th17/Treg cell subset imbalance are important factors causing the development of RA and AITD diseases. The balance shift of Th1/Th2 cytokines can cause a series of pathophysiological changes and immune dysfunction of the body. Most studies have shown that Th1 and Th2 cells are a bridge between GD and HT interconversion, and when Th1 cell-mediated immunity plays a major role, cytotoxic T cells and macrophages are activated, thyroid follicular epithelial cells are destroyed, and then the thyroid gland undergoes various degrees of damage and functional changes, and when Th2 cells begin to dominate, B cells and plasma cells become active and produce large amounts of thyroid autoantibodies resulting in immune tolerance. Th17 lymphocyte is a kind of lymphocyte characterized by producing IL-17A, IL-17F, IL-21 and IL-22, can strengthen autoimmune reaction, and can stimulate blood vessel related cells (epithelial cells) or connective tissue cells (fibroblasts and macrophages) in the occurrence and development of AITD diseases, and the cells can cause tissue damage under autoimmune inflammation conditions. Treg cells are primarily responsible for maintaining immune tolerance and immunosuppression. Forkhead box protein 3(forkhead box P3, Foxp3) is a marker molecule of Treg cells, and is involved in the differentiation, maintenance and functional processes of Treg cells. In AITD disease, dysfunction of the Foxp3 gene can cause immune dysregulation, resulting in a breakdown of immune tolerance. In the initial stage of arthritis diseases, the Th1 subgroup has obvious advantages compared with Th2, a large amount of cytokines such as TNF-alpha, IFN-gamma, IL-2 and the like secreted by Th1 cells exist in synovial membrane and peripheral blood of RA, the proliferation of RA synovial cells and cartilage destruction can be promoted, and pannus formation can be promoted by inducing endothelial cell activation and chemokine amplification to cause disease aggravation; pain and fever symptoms can be induced by promoting prostaglandin E2 synthesis and hyperalgesia. The increased Th17/Treg ratio in RA patients stimulates the body to produce more proinflammatory cytokines, chemokines and other inflammatory mediators including nitric oxide, prostaglandins and matrix metalloproteinases to exacerbate the inflammatory response, and promotes pannus formation by activating endothelial cells and stimulating fibroblasts to secrete vascular endothelial growth factor.
2.4B lymphocyte, tumor necrosis factor family B cell activating factor (BAFF) abnormalities
B lymphocytes are involved in autoimmune processes, while BAFF plays an important role in proliferation and activation of B cells, and the over-expression of BAFF may accelerate the disease progression of autoimmune diseases. B cells are activated in patients with Graves and produce trabs which, by binding to the receptor, chronically stimulate the receptor, as a result of which the production and secretion of the thyroid hormones T4 and T3 increase, leading to hyperthyroidism. During HT, B cells produce both Tg and TPO thyroid autoantibodies, and antibody-dependent cell-mediated cytotoxicity is an important factor in causing apoptosis of thyroid follicular cells. In the early stage of RA, BAFF can inhibit phagocytic function of cells, potentiate inflammatory factors, induce production of inflammatory mediators, and under the influence of BAFF, T cells differentiate into Th1 and Th17 cells, and B cells are activated and produce autoantibodies. Thus, overexpression of B lymphocytes and BAFF catalyzes RA with AITD disease.
2.5 involvement of cytokines in Induction
Research shows that six cytokines such as interleukin, interferon, tumor necrosis factor and the like are all involved in the common pathogenesis of RA and AITD. In RA, IL-2 and IL-6 are key inflammatory cytokines, which can promote infiltration of lymphocytes to thyroid tissue and induce osteoclast differentiation to cause articular surface damage. In RA synovium and peripheral blood of patients with large amount of cytokines such as TNF-alpha, IFN-gamma, etc., in RA synovium, the fibroblast subpopulation highly expressing IL-6 and IFN-gamma inducible protein 30 is excessive, and in addition, IFN-gamma produced by CD8+ T cells is enriched. IFN- γ plays an important role in innate and adaptive immune responses, contributing to the development and progression of RA as it activates antigen presenting cells, CD4+ T cells, monocytes/macrophages and induces Major Histocompatibility Complex (MHC) class II expression on cells, thereby increasing abnormal immune responses. In vitro experiments have demonstrated that IL-1, IFN-gamma and TNF-alpha stimulate thyroid follicular cells to produce cytokines which increase expression of thyroid follicular cell surface adhesion molecules, pro-inflammatory cell infiltration, and possibly nitric oxide and prostaglandin production, thereby increasing the inflammatory response of AITD. Thyroid tissue cytokines also play a role in T cell antigen presentation by increasing MHC class I and class II expression on the surface of thyroid follicular cells, leading to destruction of the thyroid by the cytotoxic action of T cells. In thyroid eye disease, the pathogenic effects of IL- β, TNF- α and IFN- γ exacerbate the inflammation and proliferation of fibroblasts, leading to the accumulation of glycosaminoglycans within the orbit. In Graves' disease, IL-1 β stimulates the production of hyaluronic acid in thyroid epithelial cells and fibroblasts, thereby promoting the development of goiter.
2.6X chromosome inactivation
There are studies that indicate that X chromosome inactivation bias (XCI) may be associated with better onset of RA and AITD in women and related immune pathogenesis. Women have a clear advantage over the background of susceptibility genes, as the X chromosome contains a number of sex-and immune-related genes, such as AR, IL2 receptor gamma chain, CD40 ligand and Foxp3, which are critical for determining hormone levels and immune tolerance. Ghazi C et al simultaneously examined the skewed XCI of 106 female patients with RA and 145 female patients with AITD, as controlled by 257 similarly aged healthy women. The results show that the prevalence of XCI profoundly skewed in female blood cells is significantly higher in RA and AITD patients (P <0.0001) compared to the control group, and it is believed that XCI may play a role in the etiology of autoimmune diseases, and in the female dominance of RA and AITD.
Clinical treatment
By consulting the Chinese and Western medicine clinical medicine discovery about treating RA and AITD diseases in recent ten years, only selenium supplement, vitamin D, glucocorticoid and methotrexate have the curative effect of treating RA and AITD in Western medicine, while single Chinese medicine or compound Chinese medicine has common curative effect on RA and AITD in traditional Chinese medicine, and common Chinese medicines include thunder god vine, bupleurum tenuifolium, astragalus mongholicus and the like.
Vitamin D plays an important role in the pathogenesis of RA and AITD in the treatment of disease in western medicine, and is associated with disease activity. The 1, 25-dihydroxyvitamin D3(1,25(OH)2D3) can directly act on a plurality of immune cells of a human body, and can selectively inhibit the proliferation and secretion of Th1 cells, thereby reducing the production of cytokines such as IL-2, INF-gamma and the like, and inhibiting over-active inflammatory reaction and adaptive immune activity. In experimental researches of Reishi Xiang and the like, RA model rats are found to have certain curative effect by applying selenium nanoparticles to treatment, selenium can participate in vivo antioxidant enzyme synthesis so as to regulate and control inflammatory reaction, and can play a role in immunoregulation by promoting the synthesis of immune globulin in immune cells, regulating the balance of Th1/Th2 cells and other mechanisms. Experimental research on the Wangbeilin shows that glucocorticoid has a treatment effect on RA patients. Such as prednisone, can effectively reduce capillary permeability to reduce inflammatory fluid exudation, inhibit expression of inducible nitric oxide synthase, regulate lymphocyte proliferation to induce apoptosis, and reduce production of IL-1 and TNF-alpha to exert immunosuppressive effect.
In the traditional Chinese medicine for treating RA, astragalus and radix bupleuri exert curative effects by reducing the level of inflammatory cytokines in serum and regulating signal pathways, and tripterygium wilfordii exerts curative effects from multiple pathogenesis. Tripterine can reduce the number of osteoclasts in arthritis; the ability to dose-dependently inhibit the expression of proinflammatory factors; can directly resist inflammatory mediators; can inhibit arthritis and the like by regulating the ratio of Th17/Treg cells. Tripterygium wilfordii is a Chinese herbal medicine anti-inflammatory immunomodulator, can reduce the level of thyroid gland autoantibodies, has a corrective effect on disorders of EAT mice in cellular immunity and humoral immunity, can inhibit hyperthyroidism autoimmune reaction, and can reduce, soften or eliminate the diffusely swollen thyroid gland or thyroid nodule.
At present, although no research supports that sinomenine hydrochloride can effectively treat AITD, the curative effect of treating RA is definite, and currently, the traditional Chinese medicine preparation, namely Zhengqingfengtongning, is clinically applied. Sinomenine treatment RA focuses on the anti-inflammatory analgesic effect of sinomenine, and sinomenine can play an anti-inflammatory role by reducing inflammatory cytokines such as TNF-alpha, IL-1 beta, IL-6, PGE2, 5-HT and the like in a sinomenine rat model experiment for reducing carrageenan inflammation, so that the phagocytic capacity of macrophages is enhanced, and bone erosion and joint structure damage are reduced; prostaglandin is one of main inflammation mediators, cyclooxygenase-2 (COX-2) induced by Lipopolysaccharide (LPS) can promote the synthesis of prostaglandin, and in vitro experiments prove that sinomenine has strong inhibition effect on the COX-2 and presents dose dependence, which indicates that the anti-inflammatory effect of sinomenine is partially derived from the sinomenine; in addition, sinomenine can also regulate and control inflammatory reaction by intervening NF-kB signal channel and negatively regulating the expression and activation of MMP-2 and MMP-9 in joint tissues. Besides the obvious anti-inflammatory effect, sinomenine also has unique advantages in the aspect of immunosuppression, can down-regulate the expression of intercellular adhesion molecule-1, regulate and control the ratio of T lymphocyte subtype Th1/Th2, improve the apoptosis level of lymphocytes, inhibit the differentiation of Th17 cells with pathogenic effect in RA patients, improve the proportion of Treg cells with immunosuppressive effect, and reduce B lymphocytes to generate antibodies so as to play the immunosuppressive effect.
5 conclusion and prospect
RA and AITD have commonness in many aspects such as pathogenesis, clinical manifestation, most western medicines can improve the index to a certain extent and can not regulate the visceral function by exerting the anti-inflammatory and immunosuppressive effects, if the medicines for treating RA complicated with AITD are to be developed, the traditional Chinese medicine starts from the disease mechanism, achieves the treatment purpose by regulating the visceral and organism immunologic functions, and has more prospective, and the compound dialectical treatment is also the unique advantage of the traditional Chinese medicine.
Although no experiment supports the curative effect of sinomenine on AITD, the anti-inflammatory and immunosuppressive effects of sinomenine are undoubted, and on the basis of the effect, sinomenine can be preliminarily considered to improve AITD symptoms.
EXAMPLE 1 treatment of Graves disease with Sinomenine hydrochloride in combination with antithyroid drugs
The main component of the zhengqingfengtongning sustained release tablet is sinomenine hydrochloride, and unless specifically stated otherwise, the zhengqingfengtongning sustained release tablet is used in combination with antithyroid drug therapy in the application
1.1 study design
Treatment group (zhengqing fengtongning enteric-coated tablet combined with methimazole): the patient information of taking the Zhengqing Fengtongning enteric-coated tablets and the MMI for the first time is collected firstly, and the selected objects cannot be selected or selected in an omission way until the collection of the number of cases using the Zhengqing Fengtongning enteric-coated tablets is completed or is not less than 100 cases.
Control treatment group (methimazole treatment): in the above queue, the initial recording point of the first patient is the starting point, and the information of the patients who have first visit and do not take the zhengqing fengtong ning enteric-coated tablets and take the MMI in the whole course is collected until the number of eligible cases is not less than 100 cases, or all eligible cases are collected until the last patient in the last queue is taken. The selected object cannot be selected, and the selected object cannot be missed.
1.2 randomized design and Blind implementation
The study used a continuous registration to control the queue's selective bias and the researcher's bias, and all study data had to be sourced from the unit's electronic information system to avoid information bias.
1.3 evaluation index
(1) The evaluation index of the curative effect is as follows: thyroid function, TRab, TSab, clinical symptoms (exophthalmos, diplopia, ghosting, nodules, etc.), urinary routine, and thyroid ultrasound.
(2) A safety index; adverse events such as hematuria, liver and kidney function, etc
1.4 results of the experiment
In this example, a total of 234 patients were enrolled, 144 in the treatment group and 90 in the control treatment group, with the results shown in table 2. The two cohorts did not differ statistically in gender, age, and whether they originated from professional departments.
TABLE 2 number of patients grouped in each center
1.41TSH Change
The results of comparing the TSH values at different time points with each other by considering the normal distribution of the TSH mean values are shown in Table 3, wherein at 3 rd month, the TSH values of the treatment group and the control treatment group have statistical significance (P < 0.05) for the difference between the groups, and the difference between the other time points has no statistical significance (P > 0.05).
The results of the intra-group comparisons of TSH decline at different time points are shown in Table 4, and at 6 months, the treatment groups showed statistical differences (P < 0.05), and at 12 months, they showed similar trends.
TABLE 3 comparison between TSH mean groups at different time points
TABLE 4 Intra-group comparison of TSH degradation values at different time points
1.42Trab Change
Considering the normal distribution characteristic of the Trab mean, the means of different time points are compared among groups, and as shown in table 5, the results show that the Trab drop values of different time points are compared among groups, the statistical difference (P < 0.05) exists in the comparison among groups at the 6 th month, and the statistical difference does not exist in other time points.
The results of the intra-group comparisons of Trab decline values at different time points are shown in table 6, showing that all time points, at 6 th, 9 th, 12 th and 15 th months, the intra-group comparisons of both groups showed statistical significance (P < 0.05), while at 3 months, the intra-group comparisons of both groups showed no statistical significance.
TABLE 5 comparison between different time-point Trab descending mean groups
TABLE 6 comparison of Trab descent values at different times
And (4) analyzing results:
the differences between the groups of TSH at month 3 were statistically significant in the treated group compared to the control treated group.
The differences between the TSH and Trab reduction values at month 6 in the treated group compared to the control group were statistically different. The same results were shown for the group comparison of TT3 (similar trends were shown at 12 months). The same was not shown in the contemporary control treatment group.
1.5 safety assay
The laboratory test abnormality data for the treatment and control patients are listed and detailed in table 7. In general, there were 83 cases with an abnormal value in the control treatment group and 57 cases with an abnormal value in the treatment group. Considering that the number of treatment groups in this study was 1.5 times the number of control treatment groups, the comparative differences between the two groups were statistically significant. Therefore, the safety of the laboratory examination after the combined application of zhengqing fengtongning is probably better than that of the control treatment group.
TABLE 7 laboratory survey anomaly data
And (4) conclusion:
in laboratory tests with Trab, the control treatment group was shown to increase initially with methimazole and then decrease. The decline of the treatment group is stable and continuous, the decline values of the two groups are statistically different at the 6 th month of medication, the decline trends of the 3 rd month and the 6 th month are consistent, and the 9 th month and the 12 th month still show the decline trend except the continuous decline trend. The differences between the groups of TSH at month 3 were statistically significant in the treated group compared to the control treated group.
The differences between the TSH and Trab reduction values at month 6 in the treated group compared to the control group were statistically different. The same results were shown for the group comparison of TT3 (similar trends were shown at 12 months). The same was not shown in the contemporary control treatment group. .
In general, there were 83 cases with an abnormal value in the control treatment group and 57 cases with an abnormal value in the treatment group. Considering that the number of treatment groups in this study was 1.5 times the number of control treatment groups, the comparative differences between the two groups were statistically significant. Therefore, the safety of the laboratory examination after the combined application of zhengqing fengtongning is probably better than that of the control treatment group.
In consideration of the consistent trend of various indexes, the applicant considers that sinomenine hydrochloride has advantages in the aspects of improving Trab and TSH, and is helpful for patients to quickly reach the standard of anti-hyperthyroidism drug withdrawal. The sinomenine hydrochloride and methimazole combined treatment group has no obvious adverse reaction. The experimental result of the invention fully supports the new application of sinomenine hydrochloride in treating refractory autoimmune thyroid diseases.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (9)
1. The use of sinomenine or its pharmaceutically acceptable salt in preparing medicine for treating autoimmune thyroid diseases is provided.
2. The use of sinomenine or its pharmaceutically acceptable salt in combination with antithyroid agent in the preparation of a medicament for treating autoimmune thyroid disorders;
preferably, the antithyroid drug is methimazole.
3. The use according to claim 1 or 2, wherein the medicament for the treatment of autoimmune thyroid disorders is a medicament for the treatment of hashimoto's thyroiditis, a medicament for the treatment of toxic diffuse goiter or a medicament for the treatment of toxic diffuse goiter combined with hashimoto's thyroiditis.
4. The use according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of sinomenine is sinomenine hydrochloride.
5. The use according to any one of claims 1 to 4, wherein the sinomenine hydrochloride is in a solid, semi-solid, liquid or gaseous formulation.
6. Use according to any one of claims 1 to 5, wherein the medicament is a medicament for ameliorating the thyroid stimulating hormone receptor antibody levels of autoimmune thyroid disorders.
7. The use according to any one of claims 1 to 5, wherein the medicament is a medicament for ameliorating the thyroid stimulating hormone level of autoimmune thyroid disorders.
8. The pharmaceutical composition for treating autoimmune thyroid diseases is characterized by comprising sinomenine or pharmaceutically acceptable salts thereof, antithyroid drugs and pharmaceutically acceptable auxiliary materials or additives;
preferably, the antithyroid drug is methimazole; and/or
The medicinal salt of sinomenine is sinomenine hydrochloride.
9. The pharmaceutical composition of claim 8, wherein the autoimmune thyroid disorder is hashimoto's thyroiditis, toxic diffuse goiter, or toxic diffuse goiter combined with hashimoto's thyroiditis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011340479.5A CN112569234A (en) | 2020-11-25 | 2020-11-25 | Application of sinomenine in medicine for treating autoimmune thyroid disease |
| CN2020113404795 | 2020-11-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113940934A true CN113940934A (en) | 2022-01-18 |
Family
ID=75123473
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011340479.5A Withdrawn CN112569234A (en) | 2020-11-25 | 2020-11-25 | Application of sinomenine in medicine for treating autoimmune thyroid disease |
| CN202111407516.4A Pending CN113940934A (en) | 2020-11-25 | 2021-11-24 | Application of sinomenine in medicine for treating autoimmune thyroid disease |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011340479.5A Withdrawn CN112569234A (en) | 2020-11-25 | 2020-11-25 | Application of sinomenine in medicine for treating autoimmune thyroid disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN112569234A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112569234A (en) * | 2020-11-25 | 2021-03-30 | 湖南正清制药集团股份有限公司 | Application of sinomenine in medicine for treating autoimmune thyroid disease |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111773221A (en) * | 2020-07-21 | 2020-10-16 | 李蕴麟 | Application of sinomenine and derivatives or pharmaceutically acceptable salts thereof in preparing medicine for treating breast diseases |
| CN112569234A (en) * | 2020-11-25 | 2021-03-30 | 湖南正清制药集团股份有限公司 | Application of sinomenine in medicine for treating autoimmune thyroid disease |
-
2020
- 2020-11-25 CN CN202011340479.5A patent/CN112569234A/en not_active Withdrawn
-
2021
- 2021-11-24 CN CN202111407516.4A patent/CN113940934A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111773221A (en) * | 2020-07-21 | 2020-10-16 | 李蕴麟 | Application of sinomenine and derivatives or pharmaceutically acceptable salts thereof in preparing medicine for treating breast diseases |
| CN112569234A (en) * | 2020-11-25 | 2021-03-30 | 湖南正清制药集团股份有限公司 | Application of sinomenine in medicine for treating autoimmune thyroid disease |
Non-Patent Citations (4)
| Title |
|---|
| A. ANTONELLI等: "Autoimmune thyroid disorders", 《AUTOIMMUNITY REVIEWS》 * |
| MINGGE LIANG等: " Methodological and reporting quality evaluation of meta-analyses on the Chinese herbal preparation Zheng Qing Feng Tong Ning for the treatment of rheumatoid arthritis", 《BMC COMPLEMENTARY MEDICINE AND THERAPIES》 * |
| WEIWEI LIU等: " Sinomenine Inhibits the Progression of Rheumatoid Arthritis by Regulating the Secretion of Inflammatory Cytokines and Monocyte/Macrophage Subsets", 《FRONTIERS IN IMMUNOLOGY》 * |
| 余克强: "青藤碱对类风湿关节炎树突状细胞趋化因子及受体的影响和机制", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112569234A (en) | 2021-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kim et al. | Metformin ameliorates experimental-obesity-associated autoimmune arthritis by inducing FGF21 expression and brown adipocyte differentiation | |
| Özenci et al. | Multiple Sclerosis: Levels of Interleukin‐10‐Secreting Blood Mononuclear Cells are Low in Untreated Patients but Augmented During Interferon‐β‐1b Treatment | |
| Shinto et al. | Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis | |
| Wang et al. | Extract from Eucommia ulmoides Oliv. ameliorates arthritis via regulation of inflammation, synoviocyte proliferation and osteoclastogenesis in vitro and in vivo | |
| Wei et al. | Inhibitory effect of a novel antirheumatic drug T-614 on the IL-6-induced RANKL/OPG, IL-17, and MMP-3 expression in synovial fibroblasts from rheumatoid arthritis patients | |
| Li et al. | Aconitine: a potential novel treatment for systemic lupus erythematosus | |
| Yli-Karjanmaa et al. | Topical administration of a soluble TNF inhibitor reduces infarct volume after focal cerebral ischemia in mice | |
| Ahmadi et al. | The effects of nanocurcumin on Treg cell responses and treatment of ankylosing spondylitis patients: A randomized, double‐blind, placebo‐controlled clinical trial | |
| Liu et al. | Dihydroartemisinin attenuates autoimmune thyroiditis by inhibiting the CXCR3/PI3K/AKT/NF-κB signaling pathway | |
| Wei et al. | T follicular helper cells in autoimmune diseases | |
| Yin et al. | Longdan Xiegan Decoction alleviates experimental autoimmune uveitis in rats by inhibiting Notch signaling pathway activation and Th17 cell differentiation | |
| Qian et al. | Effect of qianghuo erhuang decoction on T regulatory and T helper 17 cells in treatment of adjuvant-induced arthritis in rats | |
| Xiong et al. | Investigation of effects of farrerol on suppression of murine T lymphocyte activation in vitro and in vivo | |
| CN113940934A (en) | Application of sinomenine in medicine for treating autoimmune thyroid disease | |
| Marzano et al. | Leflunomide-induced subacute cutaneous lupus erythematosus with erythema multiforme-like lesions | |
| Wang et al. | Regulatory role of NKG2D+ NK cells in intestinal lamina propria by secreting double-edged Th1 cytokines in ulcerative colitis | |
| Jia et al. | Metformin reverses hashimoto’s thyroiditis by regulating key immune events | |
| Li et al. | Etanercept alleviates psoriasis by reducing the Th17/Treg ratio and promoting M2 polarization of macrophages | |
| Shnayder et al. | Cytokine imbalance as a biomarker of intervertebral disk degeneration | |
| Zhou et al. | Prednisone acetate modulates Th1/Th2 and Th17/Treg cell homeostasis in experimental autoimmune uveitis via orchestrating the Notch signaling pathway | |
| CN112843051A (en) | Application of ellagic acid and metabolic derivative urolithin compound thereof in preparation of immunoregulation medicine | |
| Boontaveeyuwat et al. | Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus (TEN-like ACLE) in SLE patients: a report of two cases | |
| Cheng et al. | Echinocystic acid ameliorates arthritis in SKG mice by suppressing Th17 cell differentiation and human rheumatoid arthritis fibroblast-like synoviocytes inflammation | |
| Zhou et al. | Mechanism of xiaoying daotan decoction in treating hashimoto’s thyroiditis based on the Notch/Treg/Th17 pathway | |
| Medina-Rodriguez et al. | Stress promotes the infiltration of peripheral immune cells to the brain |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220118 |