CN113318231A - Application of 4-aminoquinoline compound - Google Patents
Application of 4-aminoquinoline compound Download PDFInfo
- Publication number
- CN113318231A CN113318231A CN202110204726.7A CN202110204726A CN113318231A CN 113318231 A CN113318231 A CN 113318231A CN 202110204726 A CN202110204726 A CN 202110204726A CN 113318231 A CN113318231 A CN 113318231A
- Authority
- CN
- China
- Prior art keywords
- acute
- pneumonia
- exudative
- inflammation
- levels
- 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
- FQYRLEXKXQRZDH-UHFFFAOYSA-N quinolin-4-ylamine Natural products C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 title claims abstract description 32
- -1 4-aminoquinoline compound Chemical class 0.000 title claims abstract description 26
- 206010061218 Inflammation Diseases 0.000 claims abstract description 91
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims abstract description 56
- 229960004171 hydroxychloroquine Drugs 0.000 claims abstract description 53
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 17
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims abstract description 11
- 229960003677 chloroquine Drugs 0.000 claims abstract description 11
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- 210000003722 extracellular fluid Anatomy 0.000 claims abstract description 7
- 210000004204 blood vessel Anatomy 0.000 claims abstract description 6
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims abstract description 3
- 230000001154 acute effect Effects 0.000 claims description 60
- 206010035664 Pneumonia Diseases 0.000 claims description 34
- 210000000416 exudates and transudate Anatomy 0.000 claims description 33
- 230000002159 abnormal effect Effects 0.000 claims description 25
- 210000002966 serum Anatomy 0.000 claims description 16
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 15
- 208000015181 infectious disease Diseases 0.000 claims description 15
- 230000002458 infectious effect Effects 0.000 claims description 15
- 210000004072 lung Anatomy 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 239000012530 fluid Substances 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 12
- 210000001519 tissue Anatomy 0.000 claims description 12
- 102100040247 Tumor necrosis factor Human genes 0.000 claims description 11
- 239000007928 intraperitoneal injection Substances 0.000 claims description 11
- 108090001005 Interleukin-6 Proteins 0.000 claims description 9
- 230000005484 gravity Effects 0.000 claims description 9
- 102000007644 Colony-Stimulating Factors Human genes 0.000 claims description 8
- 108010071942 Colony-Stimulating Factors Proteins 0.000 claims description 8
- 210000003734 kidney Anatomy 0.000 claims description 8
- 108010050904 Interferons Proteins 0.000 claims description 7
- 102000014150 Interferons Human genes 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 229940079322 interferon Drugs 0.000 claims description 7
- 210000004185 liver Anatomy 0.000 claims description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- ZAVJTSLIGAGALR-UHFFFAOYSA-N 2-(2,2,2-trifluoroacetyl)cyclooctan-1-one Chemical compound FC(F)(F)C(=O)C1CCCCCCC1=O ZAVJTSLIGAGALR-UHFFFAOYSA-N 0.000 claims description 5
- 206010030113 Oedema Diseases 0.000 claims description 5
- 229960002927 hydroxychloroquine sulfate Drugs 0.000 claims description 5
- 230000008595 infiltration Effects 0.000 claims description 5
- 238000001764 infiltration Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- 241001678559 COVID-19 virus Species 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 208000034486 Multi-organ failure Diseases 0.000 claims description 4
- 208000010718 Multiple Organ Failure Diseases 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 230000002538 fungal effect Effects 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 4
- 230000028327 secretion Effects 0.000 claims description 4
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 claims description 3
- 108010074328 Interferon-gamma Proteins 0.000 claims description 3
- 206010036790 Productive cough Diseases 0.000 claims description 3
- 239000003430 antimalarial agent Substances 0.000 claims description 3
- 230000001580 bacterial effect Effects 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 210000002216 heart Anatomy 0.000 claims description 3
- 244000052769 pathogen Species 0.000 claims description 3
- 230000009885 systemic effect Effects 0.000 claims description 3
- 230000003612 virological effect Effects 0.000 claims description 3
- AEUAEICGCMSYCQ-UHFFFAOYSA-N 4-n-(7-chloroquinolin-1-ium-4-yl)-1-n,1-n-diethylpentane-1,4-diamine;dihydrogen phosphate Chemical compound OP(O)(O)=O.ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 AEUAEICGCMSYCQ-UHFFFAOYSA-N 0.000 claims description 2
- 241000228212 Aspergillus Species 0.000 claims description 2
- 201000001178 Bacterial Pneumonia Diseases 0.000 claims description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 2
- 241000606161 Chlamydia Species 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 241001337994 Cryptococcus <scale insect> Species 0.000 claims description 2
- 241001115402 Ebolavirus Species 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 2
- 241000606768 Haemophilus influenzae Species 0.000 claims description 2
- 241000712431 Influenza A virus Species 0.000 claims description 2
- 241000713196 Influenza B virus Species 0.000 claims description 2
- 102000002227 Interferon Type I Human genes 0.000 claims description 2
- 108010014726 Interferon Type I Proteins 0.000 claims description 2
- 102000008070 Interferon-gamma Human genes 0.000 claims description 2
- 108010002350 Interleukin-2 Proteins 0.000 claims description 2
- 108090001007 Interleukin-8 Proteins 0.000 claims description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 2
- 241000589248 Legionella Species 0.000 claims description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 claims description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 claims description 2
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims description 2
- 241000235395 Mucor Species 0.000 claims description 2
- 241000204031 Mycoplasma Species 0.000 claims description 2
- 206010035737 Pneumonia viral Diseases 0.000 claims description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 2
- 241000606651 Rickettsiales Species 0.000 claims description 2
- 241000315672 SARS coronavirus Species 0.000 claims description 2
- 241000191967 Staphylococcus aureus Species 0.000 claims description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 2
- 241000907316 Zika virus Species 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 230000000078 anti-malarial effect Effects 0.000 claims description 2
- 229940088710 antibiotic agent Drugs 0.000 claims description 2
- 229940121375 antifungal agent Drugs 0.000 claims description 2
- 239000003429 antifungal agent Substances 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 239000003443 antiviral agent Substances 0.000 claims description 2
- 230000004900 autophagic degradation Effects 0.000 claims description 2
- 210000000621 bronchi Anatomy 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229960002328 chloroquine phosphate Drugs 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 230000004761 fibrosis Effects 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 229940047650 haemophilus influenzae Drugs 0.000 claims description 2
- 230000002008 hemorrhagic effect Effects 0.000 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims description 2
- 210000001503 joint Anatomy 0.000 claims description 2
- 210000000265 leukocyte Anatomy 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000003071 parasitic effect Effects 0.000 claims description 2
- 230000035699 permeability Effects 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 210000003491 skin Anatomy 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 208000024794 sputum Diseases 0.000 claims description 2
- 210000003802 sputum Anatomy 0.000 claims description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 210000001179 synovial fluid Anatomy 0.000 claims description 2
- 241000712461 unidentified influenza virus Species 0.000 claims description 2
- 208000009421 viral pneumonia Diseases 0.000 claims description 2
- 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 claims 2
- 102100031939 Erythropoietin Human genes 0.000 claims 2
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical group C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 claims 1
- 102100026720 Interferon beta Human genes 0.000 claims 1
- 102100037850 Interferon gamma Human genes 0.000 claims 1
- 108010047761 Interferon-alpha Proteins 0.000 claims 1
- 102000006992 Interferon-alpha Human genes 0.000 claims 1
- 108090000467 Interferon-beta Proteins 0.000 claims 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 claims 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 claims 1
- 229960001444 amodiaquine Drugs 0.000 claims 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 17
- 210000004027 cell Anatomy 0.000 abstract description 11
- 239000000203 mixture Substances 0.000 abstract description 5
- 230000008961 swelling Effects 0.000 abstract description 5
- 150000005011 4-aminoquinolines Chemical class 0.000 abstract description 3
- 241000699670 Mus sp. Species 0.000 description 42
- 230000004054 inflammatory process Effects 0.000 description 25
- 239000002158 endotoxin Substances 0.000 description 15
- 229920006008 lipopolysaccharide Polymers 0.000 description 15
- 238000010172 mouse model Methods 0.000 description 15
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 14
- 239000002953 phosphate buffered saline Substances 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 241000700605 Viruses Species 0.000 description 11
- 239000002253 acid Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 210000005259 peripheral blood Anatomy 0.000 description 8
- 239000011886 peripheral blood Substances 0.000 description 8
- 102000004889 Interleukin-6 Human genes 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 238000003305 oral gavage Methods 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 102000003390 tumor necrosis factor Human genes 0.000 description 5
- 210000000683 abdominal cavity Anatomy 0.000 description 4
- 230000005856 abnormality Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000003862 glucocorticoid Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 210000004969 inflammatory cell Anatomy 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000003951 Erythropoietin Human genes 0.000 description 3
- 108090000394 Erythropoietin Proteins 0.000 description 3
- 102000003777 Interleukin-1 beta Human genes 0.000 description 3
- 108090000193 Interleukin-1 beta Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 108020000999 Viral RNA Proteins 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- 229940105423 erythropoietin Drugs 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 210000004738 parenchymal cell Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 230000008718 systemic inflammatory response Effects 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 208000020053 Abnormal inflammatory response Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000006996 mental state Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 208000037890 multiple organ injury Diseases 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000036387 respiratory rate Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000028399 Critical Illness Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 208000005228 Pericardial Effusion Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940058934 aminoquinoline antimalarials Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000840 anti-viral 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
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001621 bismuth Chemical class 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 210000005086 glomerual capillary Anatomy 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000005337 ground glass Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 208000016254 weariness Diseases 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of a 4-aminoquinoline compound in preparing a medicament for inhibiting exudative inflammation. The invention provides an application of a 4-aminoquinoline compound or a pharmaceutically acceptable salt thereof in preparing a medicament or a medicinal composition for treating and/or preventing exudative inflammation; the pharmaceutical composition comprises: the 4-aminoquinoline compound or the pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable pharmaceutical auxiliary materials and/or one or more other active ingredients. The 4-aminoquinoline compounds provided by the invention, such as chloroquine and hydroxychloroquine, have good treatment effects on cell swelling and blood vessel and intercellular fluid exudation in an inflammatory state.
Description
Technical Field
The invention relates to an application of a 4-aminoquinoline compound or a pharmaceutically acceptable salt thereof in preparing a medicament or a medicinal composition for treating and/or preventing exudative inflammation.
Background
Extravasation, which refers to the process of fluid and cellular components within the blood vessels of inflamed local tissues, through the vessel wall into the interstitial tissues, body cavities, mucosal surfaces and body surfaces. In the case of inflammation in the body, exudation of fluids is usually accompanied, which is manifested in different stages of development of the disease, as well as in widely different pathological and clinical manifestations.
Acute exudative inflammation is common in acute infectious inflammation. Patients with acute bacterial, viral infections of the lungs, for example, are rapidly transformed from a plaque-like exudative infiltration of the lungs to severe or critical illness in the short term after attack by a large number of microorganisms and thus progress to respiratory failure and multiple organ failure, whereby it is believed that the disease is associated not only with microbial replication but also with exudation and attack by a large number of cytokines. At present, in clinical treatment, glucocorticoid is generally used to resist the reaction of body exudative inflammation, however, glucocorticoid cannot be regarded as an ideal treatment strategy, but the immunosuppression may affect the clearance rate of virus, so that the death rate of acute exudative inflammation and acute multiple organ failure caused by acute exudative inflammation is high, and the use of large dose of glucocorticoid has serious adverse reactions such as osteoporosis, and the clinical requirement cannot be well met.
Therefore, there is an urgent need in the art to develop a drug that can be effectively and safely used for acute exudative inflammation that spreads locally and rapidly throughout the body.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defect of side effect of a medicament for inhibiting acute exudative inflammation in the prior art, and provides an application of a 4-aminoquinoline compound or a pharmaceutically acceptable salt thereof in preparing a medicament or a pharmaceutical composition for treating and/or preventing exudative inflammation.
Hydroxychloroquine (HCQ) belongs to 4-aminoquinoline antimalarials, and in 1944, the hydroxychloroquine is artificially synthesized on the basis of chloroquine, and the difference between the hydroxychloroquine and the chloroquine is that one ethyl group in the chloroquine is replaced by hydroxyethyl group, so that the hydroxychloroquine is absorbed more quickly in the gastrointestinal tract of a human body and is distributed more widely in the human body. The toxicity is obviously reduced while the original drug effect of chloroquine is kept. Hydroxychloroquine was originally used for antimalarial therapy, beginning in 1955 for the treatment of Systemic Lupus Erythematosus (SLE) and in 1988 for the treatment of rheumatoid arthritis.
After a large amount of experimental researches and drug screening, the inventor discovers that the 4-aminoquinoline compounds, particularly chloroquine and hydroxychloroquine, have good treatment effects on cell swelling and blood vessel and intercellular fluid exudation in the acute inflammatory state. On the basis of this, the present invention has been completed.
The present invention solves the above-mentioned problems by the following technical means.
The invention provides an application of a 4-aminoquinoline compound or a pharmaceutically acceptable salt thereof in preparing a medicament or a medicinal composition for treating and/or preventing exudative inflammation; wherein, the pharmaceutical composition comprises: the 4-aminoquinoline compound or the pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable pharmaceutical auxiliary materials and/or one or more other active ingredients.
In one embodiment of the present invention, the 4-aminoquinoline compound may be a 4-aminoquinoline antimalarial drug conventional in the art. Such as piperaquine
Or a compound of formula I:
wherein R is1H, OH or halogen;
In a certain embodiment of the invention, the 4-aminoquinoline compound is amonoquinol
Chloroquine
Or hydroxychloroquine
Preferably chloroquine orHydroxychloroquine, more preferably hydroxychloroquine.
In one embodiment of the present invention, the pharmaceutically acceptable salt is hydrochloride, phosphate, sulfate, mesylate, citrate or fumarate; preferably a phosphate or sulphate.
In a certain scheme of the invention, the pharmaceutically acceptable salt of the 4-aminoquinoline compound can be chloroquine phosphate (diphosphate) or hydroxychloroquine sulfate; preferably hydroxychloroquine sulfate.
In one embodiment of the invention, the active ingredient is selected from the group consisting of antiviral agents, antibiotics, antifungal agents, antitumor agents, and autophagy inhibiting agents.
In one embodiment of the present invention, the pharmaceutical composition is in the form of an oral preparation or a parenteral preparation.
In one embodiment of the present invention, the dosage form of the pharmaceutical composition includes tablets, capsules, intravenous injection, intraperitoneal injection, inhalant, aerosol, lyophilized preparation, patch, gel, spray, or suppository.
In one embodiment of the present invention, the pharmaceutical composition is in unit dosage form.
In a certain embodiment of the invention, the pharmaceutical composition comprises 50mg to 2000mg of the 4-aminoquinoline compound or the pharmaceutically acceptable salt thereof, such as 100mg, 200mg, 300mg, 400mg, 1000mg, 1200mg, 1600mg, 1800mg of the 4-aminoquinoline compound or the pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the pharmaceutical composition comprises at least 50 wt% (e.g., 60 wt%, 70 wt%, 80 wt%, 90 wt%, 95 wt%, 98 wt%, 99 wt%) of the 4-aminoquinoline compound or the pharmaceutically acceptable salt thereof.
The inflammatory exudate of exudative inflammation has one or more of the following characteristics:
(1) abnormal specific gravity;
(2) abnormal IL-2 levels;
(3) abnormal IL-6 levels;
(4) abnormal IL-8 levels;
(5) abnormal IL-17 levels;
(6) an abnormal IP-10 level;
(7) abnormal Colony Stimulating Factor (CSF) levels; or
(8) Abnormal levels of Tumor Necrosis Factor (TNF).
In one embodiment of the invention, the exudative inflammation is further characterized by one or more of the following:
(9) abnormal serum Interferon (IFN) levels; or
(10) Abnormal levels of serum Erythropoietin (EPO).
In the present invention, the abnormality is an abnormal value having clinical significance obtained by a standard measurement method with reference to a normal population index or a self-measured normal value A0 of a subject in a normal period.
In one embodiment of the present invention, the abnormality is an abnormally increased or abnormally decreased level.
In one embodiment of the present invention, the abnormality is an abnormally high.
In one embodiment of the invention, the abnormality is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 150%, 180%, 200%, 300%, 500%, or 1000% above or below the normal value A0 for the measured value of the index of inflammatory exudate A1.
In one embodiment of the invention, the Colony Stimulating Factor (CSF) comprises G-CSF, M-CSF, GM-CSF, multi-CSF, or a combination thereof.
In one embodiment of the invention, the Tumor Necrosis Factor (TNF) comprises TNF- α, TNF- β, or a combination thereof, preferably TNF- α.
In one embodiment of the invention, the Interferon (IFN) comprises a type I interferon, a type II interferon, or a combination thereof, such as IFN- α, IFN- β, IFN- γ, or a combination thereof.
In one embodiment of the present invention, the inflammatory exudate comprises serous exudate, purulent exudate, catarrhal exudate, cellulosic exudate, hemorrhagic exudate or a combination thereof.
In one embodiment of the invention, the abnormal specific gravity comprises a specific gravity of > 1.018 inflammatory exudate.
In the present invention, the term "clinically significant" refers to a measurement value that can be used in conjunction with pathogen detection, imaging detection, and/or pathology detection to determine that a subject is suffering from exudative inflammation.
In one embodiment of the invention, the inflammatory exudate comprises an exudate derived from one or more of sputum, nasopharyngeal secretions, interstitial fluid of the lung, alveolar lavage fluid, interstitial fluid of the tissue, and synovial fluid.
In one embodiment of the invention, the exudative inflammation is characterized by one or more of the following:
(i) the permeability of tissue blood vessels is increased, so that leukocyte infiltration, edema and fibrosis are caused, the tissue fluid is filled, and the specific gravity of inflammatory exudate is higher than a normal value;
(ii) inflammatory exudate and/or serum IL-6 levels above normal;
(iii) inflammatory exudate and/or serum TNF-a levels above normal;
(iv) inflammatory exudate and/or serum IFN levels are below normal;
(v) inflammatory exudate and/or serum CSF levels above normal;
(vi) serum EPO levels were below normal.
In one embodiment of the present invention, the exudative inflammation comprises local exudative inflammation and/or systemic exudative inflammation.
In one embodiment of the present invention, the exudative inflammation comprises acute exudative inflammation and/or chronic exudative inflammation.
In one embodiment of the present invention, the exudative inflammation is acute exudative inflammation.
In a certain embodiment of the invention, the acute exudative inflammation is a disease with a time of onset of less than 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 20 days, 15 days, 7 days, or 3 days.
In one aspect of the invention, the time of onset refers to the occurrence of clinical symptoms and/or imaging symptoms, and/or laboratory examinations.
In one embodiment of the invention, the local exudative inflammation comprises exudative inflammation occurring in one or more of the lung, bronchi, kidney, heart, liver, skin and joints.
In one embodiment of the present invention, the local exudative inflammation is exudative pneumonia.
In one embodiment of the present invention, the local exudative inflammation is acute exudative pneumonia. In one embodiment of the present invention, the local exudative inflammation comprises infectious or non-infectious pneumonia.
In one aspect of the invention, the non-infectious pneumonia comprises cancerous pneumonia.
In one embodiment of the present invention, the acute exudative pneumonia comprises acute bacterial infectious pneumonia, acute viral infectious pneumonia, acute fungal pneumonia, acute parasitic infectious pneumonia, acute rickettsial infectious pneumonia, and acute mycoplasma/chlamydia infectious pneumonia.
In one embodiment of the present invention, the acute exudative pneumonia comprises community-acquired pneumonia or nosocomial infectious pneumonia.
In one embodiment of the invention, the acute bacterial pneumonia comprises acute exudative pneumonia caused by one or more pathogens selected from the group consisting of streptococcus pneumoniae, staphylococcus aureus, klebsiella pneumoniae, haemophilus influenzae, legionella and pseudomonas aeruginosa.
In one embodiment of the invention, the acute viral pneumonia comprises acute exudative pneumonia caused by one or more of influenza a virus, influenza b virus, avian influenza virus, SARS virus, MERS virus, zika virus, ebola virus and covi-19 virus.
In one embodiment of the present invention, the acute fungal pneumonia comprises acute exudative pneumonia caused by one or more of cryptococcus, aspergillus, mucor and candida.
In one embodiment of the invention, the exudative inflammation also includes the accompanying acute multiple organ failure.
The present invention also provides a method of treating exudative inflammation, particularly acute exudative inflammation, comprising the steps of: administering to a subject in need thereof an effective dose of a medicament or pharmaceutical composition comprising a 4-aminoquinoline compound or a pharmaceutically acceptable salt thereof as described above.
In one aspect of the present invention, the method further includes the steps of:
(I) determining one or more of the following: specific gravity of local exudate, interleukin in local focus or serum, interferon, colony stimulating factor, tumor necrosis factor;
(II) administering an effective dose of a drug or pharmaceutical composition comprising a 4-aminoquinoline compound or a pharmaceutically acceptable salt thereof as described above to the subject of (I) who is detected as having an abnormal index.
The present invention provides a method for treating exudative inflammation, in particular a product and method for treating acute exudative inflammation. Acute exudative inflammation refers to an inflammatory reaction that rapidly progresses to exudative fluid in a relatively short time, for example, acute exudative inflammation within 6 months, preferably within 3 months, or within 1 month. Generally, acute exudative inflammation within 15 days, preferably within 7 days, of the invention is more suitable for the active ingredient (e.g. hydroxychloroquine) and the pharmaceutical composition of the invention, with administration times varying from 1 to 30 days.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the 4-aminoquinoline compounds provided by the invention, such as chloroquine and hydroxychloroquine, have good treatment effects on improving cell swelling and exudation of blood vessels and intercellular fluid under an acute inflammatory state. Specifically, based on cells and animals, chloroquine, hydroxychloroquine and other drugs can obviously improve acute exudative inflammation of different parts, such as obviously reducing interstitial fluid, reducing local vascular permeability and reducing pulmonary mucus exudation, and obvious reduction of cytokines can be observed in an experimental group using the drugs, so that the drugs can be used for improving exudative inflammation, particularly acute exudative inflammation of the lung and the kidney, and have excellent effect on preventing or treating acute immune inflammatory response. In addition, the inventor also finds that when a large dose of hydroxychloroquine is used in a short period (converted to a dose far exceeding the recommended dose), no obvious drug-related toxic and side effects are found. The medicine has good inhibition effect on the novel coronavirus in vitro and in vivo under the condition of effectively reducing inflammatory exudation, and the minimum inhibition effective concentration reaches the mu M level.
Drawings
FIG. 1 shows the inhibition effect of HCQ treatment for 24h on viral RNA amplification, and when the concentration of the local hydroxychloroquine reaches 20. mu.M, the copy number of the virus has been reduced to 102。
FIG. 2 shows the virus inhibition rate of HCQ treatment for 24h, and it can be seen that the virus inhibition rate in vitro of hydroxychloroquine reaches more than 95% at lower concentration (more than 4. mu.M).
FIG. 3 shows the inhibitory effect of HCQ on cytokines in serum of mice with inflammation.
Detailed Description
To better understand the invention, certain terms are defined.
The term "treatment" as used herein refers to therapeutic treatment. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or leads to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or disorder.
The term "effective dose" as used herein refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The amount of a compound that constitutes an "effective dose" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as desired by one of skill in the art. The preferable effective dose of the invention is far higher than the instruction dose of the existing medicine, for example, the dose of the hydroxychloroquine for acute exudative inflammation is extremely high and can reach 1200 mg/day (calculated by hydroxychloroquine sulfate tablets (dispute)) in a human body, and can also be adjusted to 1000mg/d, 800mg/d, 500mg/d, 400mg/d, 200mg/d and the like according to the improvement degree of the exudative inflammation.
The term "patient" as used herein refers to any animal, preferably a mammal, most preferably a human, who is about to, or has received administration of the compound or composition according to the embodiments of the present invention. As used herein, the term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.
The term "pharmaceutical excipient" as used herein refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all substances contained in pharmaceutical formulations, except for the active ingredient. See the pharmacopoeia of the people's republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition).
The term "pharmaceutically acceptable" as used herein means that the acid or base, solvent, adjuvant, etc. used in preparing the salt is generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.
The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound prepared with a relatively non-toxic, pharmaceutically acceptable acid or base. When compounds contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, phosphorous acid, sulfuric acid, hydrogen sulfate, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When compounds contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).
Exudative inflammation "
As used herein, the term "exudative inflammation" refers to an inflammatory disease occurring locally or systemically, characterized primarily by fluid exudation. The exudative inflammation of the present invention may occur in one or more sites, and usually, it is preferably occurred in the lung, joints of gastrointestinal tract containing cavities, etc., and may also occur in the liver, kidney, spleen, heart, etc., parenchymal organs. One skilled in the art understands that diagnosis of exudative inflammation can be performed according to a variety of methods: for example, with clinical symptoms, exudative inflammation may manifest in the lungs as cough, expectoration, dyspnea; through laboratory examination, a large number of blood cells, inflammatory factors and the like can be found in secretions, wherein the appearance of learning parts, inflammatory cells (such as neutrophils, monocytes, eosinophils, macrophages and the like) and inflammatory factors has different expressions based on different diseases; through the imaging examination, symptoms such as lung macular shading, ground glass changes, pleural effusion, pericardial effusion, joint cavity effusion, parenchymal organ density reduction and the like can be found; by endoscopic or histological examination, swelling, congestion, exudation of fluid, and widening of the interstitium of the organ, such as lung foam-like fluid, pink secretion, etc., can be observed.
As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 treatment of LPS-induced acute Systemic Inflammatory Response (SIRS) in mice with hydroxychloroquine improves survival
A systemic inflammatory exudation mouse model is prepared by a method of intraperitoneal injection of Lipopolysaccharide (LPS), and the specific method comprises the following steps:
1. grouping mice: 8-12 weeks old female C57 mice (weight is about 22-25 g) are adaptively fed for one week, and then are randomly divided into 5 groups, namely a control group, a model group and a low-medium dose hydroxychloroquine group according to the weight of the mice, wherein each group comprises 10 mice.
2. Preparing a SIRS mouse model by intraperitoneal injection of lipopolysaccharide: after dissolving lipopolysaccharide powder in Phosphate Buffered Saline (PBS), the solution was intraperitoneally injected into mice at a ratio of 6 mg/kg (mg/kg) of body weight to obtain an inflammation mouse model, and a control group was intraperitoneally injected with PBS of the same volume as the control group. General conditions observed in animals include mental state, respiratory rate, defecation, death, etc. The successfully modeled mice are obviously reduced in respiratory rate, body temperature, mental weariness and activity and are in a coiled state.
3. Oral gavage administration: for the low dose group (10mg/kg), the medium dose group (50mg/kg) and the high dose group (100mg/kg) of the hydroxychloroquine-added inflammatory mice, the corresponding dose of hydroxychloroquine solution is administered by oral gavage, and the blank control group (normal mice) and the model group are administered with PBS of equal volume.
4. Then, the survival state of the mice was continuously observed for one week, and a survival curve was plotted.
The experimental results are as follows: in each administration group of hydroxychloroquine, the mental state of the mice is better than that of the model group, the survival rate of the mice is higher than that of the model group, and particularly, the survival rate of inflammatory mice with medium dose and high dose is obviously improved: the mice in the model group all died within 3 days, 1/10 in the low dose group survived for one week, 5/10 in the medium dose group survived for one week, 6/10 in the high dose group survived for one week, and the medium and high dose groups have significant differences compared with the model group, so that hydroxychloroquine significantly improves the prognosis of the model mice.
Example 2 treatment of multiple organ injury in mice with inflammation Using Hydroxychloroquine significantly prevented and reduced organ exudative inflammation
The method comprises the following steps of adopting an oral gavage administration mode to administer hydroxychloroquine with medium and high doses to inflammatory mice, carrying out sacrifice dissection on a model group and a treatment group which are normal, dead and end of an observation period, taking lung, kidney, spleen, liver and intestinal tissue organs of the mice, observing a specimen in general, and then carrying out HE staining pathological detection, wherein the specific steps are as follows:
1. grouping mice: female C57 mice (the weight is about 22-25 g) with the age of 8-12 weeks are adaptively fed in an SPF-level animal room for one week, and then are randomly divided into 5 groups according to the weight of the mice, namely a blank control (normal mice) group, an inflammation mouse model group, a hydroxychloroquine medium dose, a high dose preventive and inflammation mouse model group (hereinafter collectively referred to as a prevention group, 50mg/kg of medicine is applied one week earlier and then modeling is performed), an inflammation mouse hydroxychloroquine medium dose group (50mg/kg) and a high dose group (100mg/kg) (hereinafter collectively referred to as a dry pre-group), wherein the number of each group is 10.
2. Intraperitoneal injection of Lipopolysaccharide (LPS): LPS is injected into the abdominal cavity of a prevention group (after medicine application), a dry pre-treatment group and an inflammation mouse model group according to the proportion of 6 milligrams/kilogram (mg/kg) of body weight, and PBS with the same volume is injected into the abdominal cavity of a blank control group as a control.
3. Intragastric administration: for the prevention group and the intervention group, hydroxychloroquine is administered at the corresponding dose by oral gavage, and PBS with the same volume is administered to the blank control group and the inflammation mouse model group.
4. Continuously observing the survival state of the mouse, after 24 hours, euthanizing the mouse, collecting right lung leaves, right kidneys, spleens, middle liver leaves and intestinal tract jejunum segments, carrying out morphological observation on one part, respectively adding 4% paraformaldehyde tissue fixative with the volume being 10 times of that of the other part, standing and fixing for 24 hours at room temperature, dehydrating by using gradient alcohol, embedding into tissue blocks by using paraffin, cutting paraffin sections with the thickness of 0.5mm by using a paraffin slicer, carrying out the steps of dewaxing, hydrating, dyeing, washing off excessive variegated colors, sealing and the like, and finally observing the pathological change of the intestinal tract tissue under a microscope.
The experimental results are as follows: general specimen: compared with the blank group, the lung volume of the model group mouse is obviously increased, and a foam fluid is reserved on the section; the liver, kidney and spleen envelopes are slightly tense; microscopic examination: in the lung section, exudates appear in the alveolar cavity, the exudates are wide in edema and widened in pulmonary interstitium, are infiltrated by inflammatory cells and mainly take mononuclear cells; edema vacuoles can be seen in the liver, kidney and spleen, and glomerular capillary wall thickening, mesangial hyperplasia and mesangial area widening can be seen in microscopic examination.
The viscera of the drug for preventing hydroxychloroquine do not have obvious swelling, wherein the pulmonary interstitial microscopic examination does not have obvious broadening, a small amount of inflammatory cell infiltration exists, and the medium-dose and high-dose groups have certain effect on improving edema and have less inflammatory cell infiltration; no obvious exudation of fluid was observed in the other parenchymal organs, and the tissue structure was almost normal. Therefore, the hydroxychloroquine has a certain effect on treating and protecting the injury of multiple organs of an inflammatory mouse, and has a better multiple organ injury protection effect when being used prophylactically.
Example 3 amelioration of abnormal inflammatory response in inflammatory mice by Hydroxychloroquine
3.1 adopting the administration mode of gastric perfusion, hydroxychloroquine is administered to the inflammatory mice, peripheral blood is taken for detecting the level of conventional blood cells (including lymphocytes, neutrophils and the like), and the level of relevant inflammatory factors in the peripheral blood of the mice is determined by utilizing an Elisa method, and the specific steps are as follows:
1. grouping mice: 8-12 week-old female C57 mice (weight is about 22-25 g) are adaptively fed in an SPF animal room for one week, and then are randomly divided into 4 groups according to the weight of the mice, namely a blank control (normal mice) group, an inflammation mouse model group and an inflammation mouse hydroxychloroquine group (medium dose and high dose groups), wherein the number of each group is 10.
2. Intraperitoneal injection of Lipopolysaccharide (LPS): LPS is injected into the abdominal cavity of an inflammation mouse and hydroxychloroquine middle dose group, a high dose group and an inflammation mouse model group according to the proportion of 6 milligrams/kilogram (mg/kg) of body weight, and PBS with the same volume is injected into the abdominal cavity of a blank control group as a control.
3. Intragastric administration: for the medium-dose group and the high-dose group of the inflammatory mice and the hydroxychloroquine, the corresponding dose of hydroxychloroquine is given in an oral gavage mode, and the blank control group and the inflammatory mouse model group are given with PBS (phosphate buffer solution) with the same volume.
4. Continuously observing the survival state of the mouse, after 24 hours, collecting peripheral blood of the mouse by an eyeball taking-off method, immediately taking 10 microliters of whole blood and utilizing a full-automatic blood cell analyzer to detect the blood routine.
5. Collecting peripheral blood by using a heparin anticoagulation tube containing a small amount of liquid, fully and uniformly mixing the obtained whole blood with the anticoagulant, obtaining an upper plasma sample by centrifugal force of 3000rpm for 10 minutes, and detecting the level of the cell factor in the plasma by using an Elisa kit according to an operation instruction.
And (3) displaying a detection result: compared with a blank control group, the proportion of the lymphocytes of the mice with inflammation is obviously reduced, and the proportion of the neutral particles is obviously increased; the application of hydroxychloroquine effectively improves the level of lymphocytes and reduces the level of neutrophils, which shows that the inflammatory response caused by inflammation is relieved, the immune balance in acute inflammation is restored, and cytokine detection shows that IL-6, TNF-a, GM-CSF and the like are obviously reduced compared with a model group.
The experimental results show that hydroxychloroquine can reduce abnormal inflammatory reaction caused by inflammation.
3.2 adopting the administration mode of intraperitoneal injection, hydroxychloroquine is administered to the inflammatory mice, and the peripheral blood is taken to determine the level of relevant inflammatory factors in the peripheral blood of the mice by an Elisa method, and the specific steps are as follows:
1. grouping mice: after 8-week-old female C57 mice (the weight is about 20 g) are adaptively fed in an SPF-grade animal room for one week, the mice are randomly divided into 3 groups according to the weight of the mice, wherein the groups are a blank control (normal mice) group, an inflammation mouse model group and an inflammation mouse hydroxychloroquine group (50mg/kg), and the number of each group is 5.
2. And (3) intraperitoneal injection administration: for the hydroxychloroquine-added group of the inflammatory mice, 50mg/kg of hydroxychloroquine is administered by means of intraperitoneal injection, and equal volume of PBS is administered to the blank control group and the inflammatory mouse model group.
3. Intraperitoneal injection of Lipopolysaccharide (LPS): after the administration of hydroxychloroquine by intraperitoneal injection for 2 hours, LPS is intraperitoneally injected into an inflammation mouse and an inflammation mouse model group according to the proportion of 2 milligrams/kilogram (mg/kg) of body weight, and PBS with the same volume as that of a blank control group is intraperitoneally injected as a control.
4. The state of the mice was observed, and peripheral blood of the mice was collected by an eyeball-picking method 4 hours after LPS injection.
5. Collecting peripheral blood by using a heparin anticoagulation tube containing a small amount of liquid, fully and uniformly mixing the obtained whole blood with the anticoagulant, centrifuging at 3000rpm for 10 minutes to obtain an upper plasma sample, and detecting the level of the cell factor in the plasma by using an Elisa kit according to an operation instruction.
And (3) displaying a detection result: as shown in figure 3, compared with a blank control group, the cytokines IL-6, TNF-a and IL-1 beta in the model group are obviously increased, and the cytokines IL-6, TNF-a and IL-1 beta in the mouse subjected to hydroxychloroquine treatment are obviously reduced compared with the cytokines IL-6, TNF-a and IL-1 beta in the model group, and the result shows that hydroxychloroquine can reduce abnormal inflammatory response caused by inflammation. (Control: blank Control group, Model: inflammatory mouse Model, HCQ: inflammatory mouse hydroxychloroquine group; values of each group are expressed as mean. + -. standard error, (N ═ 5); statistics were performed by one-way ANOVA (one-way ANOVA); P < 0.0001; P < 0.001; P < 0.01; P < 0.05.)
| Cytokine | Control | Inflammation model group | Hydroxychloroquine (HCQ) |
| TNF-a(pg/mL) | 55.19±27.45 | 746.43±221.47 | 582.41±123.10 |
| IL-6(pg/mL) | 47.53±19.29 | 17894.46±703.00 | 14562.83±2305.89 |
| IL-1β(pg/mL) | 47.50±20.39 | 207.63±32.81 | 130.61±20.13 |
Example 4 Hydroxychloroquine in vitro prevention of Virus
Cells were grown to 80% plates and treated with hydroxychloroquine at various concentrations in the medium for 20 hours. The collected cells were washed with Phosphate Buffered Saline (PBS) and incubated for 1 hour with the isolated 2019-nCoV (from Wuhan virus institute in Chinese academy of sciences) virus. Then, the virus was removed, and after further culturing for 16 hours, the cells were collected, the viral RNA copy number was measured, and the virus inhibition rate was calculated. The results are shown in FIG. 1.
Example 5 inhibition of Virus amplification by Hydroxychloroquine in vitro
Cells were grown to 80% plates, collected, washed with Phosphate Buffered Saline (PBS), and incubated with 2019-nCoV virus for 1 hour. The virus was then removed and hydroxychloroquine was added at various concentrations after 3 hours of culture in medium. After further incubation for 24 hours, cells were harvested, viral RNA copy number was measured, and viral inhibition was calculated, and the results are shown in FIG. 2.
As can be seen in fig. 1 and 2, hydroxychloroquine, based on its antiviral activity, is expected to reduce the response to acute exudative inflammation while further inhibiting viral replication, and thus is superior to other immunosuppressive agents (e.g., glucocorticoids) in responding to acute exudative inflammation.
Claims (10)
1. The use of a 4-aminoquinoline compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament or pharmaceutical composition for the treatment and/or prevention of exudative inflammation; wherein, the pharmaceutical composition comprises: the 4-aminoquinoline compound or the pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable pharmaceutical auxiliary materials and/or one or more other active ingredients.
2. The use according to claim 1, wherein the 4-aminoquinoline is a 4-aminoquinoline antimalarial; for example
Or a compound of formula I:
wherein R is1H, OH or halogen;
and/or the pharmaceutically acceptable salt is hydrochloride, phosphate, sulfate, methanesulfonate, citrate or fumarate; preferably a phosphate or sulphate;
and/or, the active ingredient is selected from antiviral agents, antibiotics, antifungal agents, antitumor agents, and autophagy inhibiting agents;
and/or, the dosage form of the pharmaceutical composition is oral preparation or parenteral preparation; such as tablets, capsules, intravenous injections, intraperitoneal injections, inhalants, nebulizers, lyophilizates, patches, gels, sprays, or suppositories;
and/or, the pharmaceutical composition is a unit dose, for example, containing 50mg-2000mg of the 4-aminoquinoline compound or the pharmaceutically acceptable salt thereof;
and/or, the pharmaceutical composition at least contains 50 wt% of the 4-aminoquinoline compound or the pharmaceutically acceptable salt thereof.
3. The use according to claim 1 or 2, wherein the 4-aminoquinoline is amodiaquine, chloroquine or hydroxychloroquine; preferably chloroquine and/or hydroxychloroquine, more preferably hydroxychloroquine;
and/or the pharmaceutically acceptable salt of the 4-aminoquinoline compound is chloroquine phosphate or hydroxychloroquine sulfate; preferably hydroxychloroquine sulfate.
4. The use according to claim 1, wherein the inflammatory exudate from exudative inflammation is characterized by one or more of the following:
(1) abnormal specific gravity;
(2) abnormal IL-2 levels;
(3) abnormal IL-6 levels;
(4) abnormal IL-8 levels;
(5) abnormal IL-17 levels;
(6) an abnormal IP-10 level;
(7) abnormal CSF levels of colony stimulating factor; or
(8) Abnormal levels of tumor necrosis factor TNF;
preferably, the exudative inflammation is further characterized by one or more of the following:
(9) abnormal serum interferon IFN levels; or
(10) Abnormal levels of serum erythropoietin EPO.
5. The use according to claim 4, wherein the colony stimulating factor comprises G-CSF, M-CSF, GM-CSF, multi-CSF, or a combination thereof;
and/or, the tumor necrosis factor comprises TNF-alpha, TNF-beta or a combination thereof, preferably TNF-alpha;
and/or, the interferon includes type I interferon, type II interferon or their combination, such as IFN-alpha, IFN-beta, IFN-gamma or their combination;
and/or the inflammatory exudate comprises serous exudate, purulent exudate, catarrhal exudate, cellulosic exudate, hemorrhagic exudate or a combination thereof; alternatively, the inflammatory exudate comprises one or more of sputum, nasopharyngeal secretions, interstitial lung fluid, alveolar lavage fluid, interstitial fluid and synovial fluid;
and/or, said abnormal specific gravity comprises a specific gravity of inflammatory exudate > 1.018;
and/or, the exudative inflammation has one or more of the following characteristics:
(i) the permeability of tissue blood vessels is increased, so that leukocyte infiltration, edema and fibrosis are caused, the tissue fluid is filled, and the specific gravity of inflammatory exudate is higher than a normal value;
(ii) inflammatory exudate and/or serum IL-6 levels above normal;
(iii) inflammatory exudate and/or serum TNF-a levels above normal;
(iv) inflammatory exudate and/or serum IFN levels are below normal;
(v) inflammatory exudate and/or serum CSF levels above normal;
(vi) serum EPO levels were below normal.
6. The use of claim 4, wherein said exudative inflammation comprises topical exudative inflammation and/or systemic exudative inflammation; alternatively, the exudative inflammation comprises acute and/or chronic exudative inflammation, such as acute exudative inflammation; alternatively, the exudative inflammation also includes acute multiple organ failure that accompanies it.
7. The use of claim 6, wherein the local exudative inflammation comprises an exudative inflammation occurring in one or more of the lung, bronchi, kidney, heart, liver, skin and joints, or wherein the local exudative inflammation comprises infectious or non-infectious pneumonia;
and/or the acute exudative inflammation is a disease with a time of onset of less than 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 20 days, 15 days, 7 days, or 3 days.
8. The use according to claim 7, wherein the local exudative inflammation is exudative pneumonia, such as acute exudative pneumonia;
and/or, the non-infectious pneumonia comprises cancerous pneumonia.
9. The use of claim 8, wherein the acute exudative pneumonia comprises acute bacterial infectious pneumonia, acute viral infectious pneumonia, acute fungal pneumonia, acute parasitic infectious pneumonia, acute rickettsial infectious pneumonia, acute mycoplasma/chlamydia infectious pneumonia; alternatively, the acute exudative pneumonia comprises community-acquired pneumonia or nosocomial infectious pneumonia.
10. The use of claim 9, wherein said acute bacterial pneumonia comprises acute exudative pneumonia caused by one or more pathogens selected from the group consisting of streptococcus pneumoniae, staphylococcus aureus, klebsiella pneumoniae, haemophilus influenzae, legionella and pseudomonas aeruginosa;
and/or, the acute viral pneumonia comprises acute exudative pneumonia caused by one or more of influenza a virus, influenza b virus, avian influenza virus, SARS virus, MERS virus, zika virus, ebola virus and COVID-19 virus;
and/or the acute fungal pneumonia comprises acute exudative pneumonia caused by one or more of cryptococcus, aspergillus, mucor and candida.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010131276 | 2020-02-28 | ||
| CN2020101312769 | 2020-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113318231A true CN113318231A (en) | 2021-08-31 |
Family
ID=77414378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110204726.7A Pending CN113318231A (en) | 2020-02-28 | 2021-02-23 | Application of 4-aminoquinoline compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113318231A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113855674A (en) * | 2021-11-05 | 2021-12-31 | 中国科学院动物研究所 | Application of chloroquine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1558254A2 (en) * | 2002-05-17 | 2005-08-03 | Rajeev Raut | A process for preparing pharmaceutical compositions containing 4-aminoquinolines compounds for treatment of inflammatory disorders of the eye, compositions resulting therefrom |
| WO2014031769A2 (en) * | 2012-08-21 | 2014-02-27 | The Board Of Trustees Of The Leland Stanford Junior University | Treatment of diseases associated with inflammation |
| CN103687599A (en) * | 2011-09-29 | 2014-03-26 | 中国医学科学院基础医学研究所 | The use of chloroquine, chlorpromazine, derivatives thereof, or mixtures thereof in preparing medications for treating and/or preventing pulmonary infection and injury |
-
2021
- 2021-02-23 CN CN202110204726.7A patent/CN113318231A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1558254A2 (en) * | 2002-05-17 | 2005-08-03 | Rajeev Raut | A process for preparing pharmaceutical compositions containing 4-aminoquinolines compounds for treatment of inflammatory disorders of the eye, compositions resulting therefrom |
| CN103687599A (en) * | 2011-09-29 | 2014-03-26 | 中国医学科学院基础医学研究所 | The use of chloroquine, chlorpromazine, derivatives thereof, or mixtures thereof in preparing medications for treating and/or preventing pulmonary infection and injury |
| WO2014031769A2 (en) * | 2012-08-21 | 2014-02-27 | The Board Of Trustees Of The Leland Stanford Junior University | Treatment of diseases associated with inflammation |
Non-Patent Citations (3)
| Title |
|---|
| 刘丹;吕艳艳;刘焕;曹团平;王晓元;: "羟氯喹对老年类风湿关节炎患者血栓形成因子及炎症细胞因子的影响", 中华临床医师杂志(电子版), no. 24, pages 2469 - 2474 * |
| 张舸;杨群智;付爽;费雅楠;: "羟氯喹对类风湿关节炎患者关节滑液IL-1α和IL-6表达影响的研究", 医学研究杂志, no. 09, pages 100 - 102 * |
| 王丽华;曾文泓;: "羟氯喹联合甲氨蝶呤对类风湿关节炎大鼠外周血中IL-1、IL-6和TNF-α的影响", 中国医学创新, no. 26, pages 24 - 27 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113855674A (en) * | 2021-11-05 | 2021-12-31 | 中国科学院动物研究所 | Application of chloroquine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Nelson et al. | The effects of acute and chronic alcoholism on tumor necrosis factor and the inflammatory response | |
| WO2021191900A1 (en) | Methods for treating infectious diseases caused by coronavirus | |
| CN113318231A (en) | Application of 4-aminoquinoline compound | |
| KR20100075435A (en) | Osmolytes for treating allergic or viral respiratory diseases | |
| CN106466318A (en) | Application in preparation treatment medicine for treating diabetic nephropathy for the 1- heterocyclic substituted benzyl pyridine ketone compounds | |
| Laan et al. | The effect of aerosolized and intravenously administered clenbuterol and aerosolized fluticasone propionate on horses challenged with Aspergillus fumigatus antigen | |
| CN115590858A (en) | Application of cycloastragenol in preparation of anti-asthma medicine | |
| EP4142704A1 (en) | Compositions and methods for treating cytokine storms | |
| EP3928785A1 (en) | Medicine and food for preventing or treating covid-19, and application thereof | |
| TWI780460B (en) | A use of manufacturing a composition of lactobacillus paracasei gks6 for preventing and treating the renal function impairment | |
| CN112826820B (en) | NLRP3 inhibitor and application thereof | |
| CN115068492B (en) | Application of linarin in preparation of drugs for preventing or treating pulmonary fibrosis | |
| TW202408522A (en) | Use of a fused ring pyrimidine compound | |
| CN114917285B (en) | Application of polysaccharide compound in medicine for preventing and treating respiratory tract virus infection | |
| CN111096997B (en) | Application of ficus microcarpa extract in preventing or treating interstitial lung diseases | |
| CN114288284B (en) | Application of philippine in preparing medicine for preventing and treating acute pneumonia | |
| EP4104825A1 (en) | Pharmaceutical composition for inhibiting inflammatory response comprising hydroxyurea | |
| CN114129705B (en) | Application of polypeptide in medicine for preventing and treating pneumonia | |
| CN113730461A (en) | Application of Xuebijing injection in preparing medicine for inhibiting mRNA expression of IP-10 and RANTES | |
| CN113274389B (en) | Application of flufenidone in preparation of medicine for treating acute lung injury | |
| WO2022194166A1 (en) | Use of methotrexate analogue in treatment of inflammatory skin disease | |
| US20230404969A1 (en) | Compositions and method for effective management of peritonitis | |
| CN117137916A (en) | Application of hydrochloric acid demethyleneberberine in preparing medicament for preventing or treating psoriasis | |
| Pereira et al. | pNaKtide Ameliorates Systemic Inflammatory Response in Murine Model of Sepsis by Antagonism of Na, K-ATPase Signaling: FR-PO168 | |
| CN106924272B (en) | Application of methyl salicylate glucoside in preparation of medicines for preventing and/or treating systemic lupus erythematosus and complications thereof |
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 |