EP4188398A1 - Suppression of cytokine release and cytokine storm - Google Patents
Suppression of cytokine release and cytokine stormInfo
- Publication number
- EP4188398A1 EP4188398A1 EP21850964.4A EP21850964A EP4188398A1 EP 4188398 A1 EP4188398 A1 EP 4188398A1 EP 21850964 A EP21850964 A EP 21850964A EP 4188398 A1 EP4188398 A1 EP 4188398A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- curcumin
- cytokines
- disease
- cytokine
- subject
- 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
- 102000004127 Cytokines Human genes 0.000 title claims abstract description 164
- 108090000695 Cytokines Proteins 0.000 title claims abstract description 164
- 206010052015 cytokine release syndrome Diseases 0.000 title claims description 75
- 206010050685 Cytokine storm Diseases 0.000 title claims description 72
- 230000001629 suppression Effects 0.000 title description 16
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims abstract description 271
- 239000004148 curcumin Substances 0.000 claims abstract description 158
- 229940109262 curcumin Drugs 0.000 claims abstract description 158
- 235000012754 curcumin Nutrition 0.000 claims abstract description 145
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims abstract description 145
- 239000000203 mixture Substances 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 46
- 201000010099 disease Diseases 0.000 claims abstract description 43
- 238000011282 treatment Methods 0.000 claims abstract description 29
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 26
- 150000002632 lipids Chemical class 0.000 claims abstract description 23
- 208000024891 symptom Diseases 0.000 claims abstract description 18
- 206010067484 Adverse reaction Diseases 0.000 claims abstract description 11
- 230000006838 adverse reaction Effects 0.000 claims abstract description 11
- 230000001960 triggered effect Effects 0.000 claims abstract description 9
- 239000012736 aqueous medium Substances 0.000 claims abstract description 7
- 235000020241 curcumin extract Nutrition 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 154
- 230000009529 traumatic brain injury Effects 0.000 claims description 150
- -1 4-hydroxy-3-methoxyphenyl Chemical group 0.000 claims description 51
- 208000029028 brain injury Diseases 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 27
- 208000015181 infectious disease Diseases 0.000 claims description 22
- 229940079593 drug Drugs 0.000 claims description 21
- 239000002502 liposome Substances 0.000 claims description 20
- 241000700605 Viruses Species 0.000 claims description 18
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 16
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- 229960005160 dimyristoylphosphatidylglycerol Drugs 0.000 claims description 15
- BPHQZTVXXXJVHI-AJQTZOPKSA-N ditetradecanoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-AJQTZOPKSA-N 0.000 claims description 15
- 208000011580 syndromic disease Diseases 0.000 claims description 14
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 13
- 239000013543 active substance Substances 0.000 claims description 12
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 12
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 11
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 11
- 229930195729 fatty acid Natural products 0.000 claims description 11
- 239000000194 fatty acid Substances 0.000 claims description 11
- 150000004665 fatty acids Chemical class 0.000 claims description 11
- 208000024908 graft versus host disease Diseases 0.000 claims description 11
- WTIZXHYCCKUVHY-UHFFFAOYSA-N hept-1-ene-3,5-dione Chemical compound CCC(=O)CC(=O)C=C WTIZXHYCCKUVHY-UHFFFAOYSA-N 0.000 claims description 11
- 201000006417 multiple sclerosis Diseases 0.000 claims description 11
- 241000712461 unidentified influenza virus Species 0.000 claims description 11
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 claims description 10
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 claims description 10
- 208000000307 Crimean Hemorrhagic Fever Diseases 0.000 claims description 10
- 201000003075 Crimean-Congo hemorrhagic fever Diseases 0.000 claims description 10
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 10
- 206010033645 Pancreatitis Diseases 0.000 claims description 10
- 206010033647 Pancreatitis acute Diseases 0.000 claims description 10
- 201000003229 acute pancreatitis Diseases 0.000 claims description 10
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 claims description 10
- 238000001990 intravenous administration Methods 0.000 claims description 10
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N palmityl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 claims description 10
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 10
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 10
- 230000009467 reduction Effects 0.000 claims description 10
- 206010040070 Septic Shock Diseases 0.000 claims description 9
- 230000002490 cerebral effect Effects 0.000 claims description 9
- 230000036303 septic shock Effects 0.000 claims description 9
- 241000711573 Coronaviridae Species 0.000 claims description 8
- 235000012000 cholesterol Nutrition 0.000 claims description 8
- 239000000902 placebo Substances 0.000 claims description 8
- 229940068196 placebo Drugs 0.000 claims description 8
- LBTVHXHERHESKG-UHFFFAOYSA-N tetrahydrocurcumin Chemical compound C1=C(O)C(OC)=CC(CCC(=O)CC(=O)CCC=2C=C(OC)C(O)=CC=2)=C1 LBTVHXHERHESKG-UHFFFAOYSA-N 0.000 claims description 8
- 208000001490 Dengue Diseases 0.000 claims description 7
- 206010012310 Dengue fever Diseases 0.000 claims description 7
- 241000709661 Enterovirus Species 0.000 claims description 7
- 241000351643 Metapneumovirus Species 0.000 claims description 7
- 241000712464 Orthomyxoviridae Species 0.000 claims description 7
- 241000711504 Paramyxoviridae Species 0.000 claims description 7
- 208000002606 Paramyxoviridae Infections Diseases 0.000 claims description 7
- 241000725643 Respiratory syncytial virus Species 0.000 claims description 7
- 208000025729 dengue disease Diseases 0.000 claims description 7
- 210000002540 macrophage Anatomy 0.000 claims description 7
- 241000701161 unidentified adenovirus Species 0.000 claims description 7
- 230000003612 virological effect Effects 0.000 claims description 7
- UEPVWRDHSPMIAZ-IZTHOABVSA-N (1e,4z,6e)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)hepta-1,4,6-trien-3-one Chemical compound C1=C(O)C(OC)=CC(\C=C\C(\O)=C\C(=O)\C=C\C=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-IZTHOABVSA-N 0.000 claims description 6
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 6
- HJTVQHVGMGKONQ-LUZURFALSA-N Curcumin II Natural products C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=CC(O)=CC=2)=C1 HJTVQHVGMGKONQ-LUZURFALSA-N 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 206010023927 Lassa fever Diseases 0.000 claims description 6
- JYTVKRNTTALBBZ-UHFFFAOYSA-N bis demethoxycurcumin Natural products C1=CC(O)=CC=C1C=CC(=O)CC(=O)C=CC1=CC=CC(O)=C1 JYTVKRNTTALBBZ-UHFFFAOYSA-N 0.000 claims description 6
- PREBVFJICNPEKM-YDWXAUTNSA-N bisdemethoxycurcumin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)CC(=O)\C=C\C1=CC=C(O)C=C1 PREBVFJICNPEKM-YDWXAUTNSA-N 0.000 claims description 6
- NMRUIRRIQNAQEB-UHFFFAOYSA-N demethoxycurcumin Natural products OC(=CC(C=CC1=CC(=C(C=C1)O)OC)=O)C=CC1=CC=C(C=C1)O NMRUIRRIQNAQEB-UHFFFAOYSA-N 0.000 claims description 6
- YXAKCQIIROBKOP-UHFFFAOYSA-N di-p-hydroxycinnamoylmethane Natural products C=1C=C(O)C=CC=1C=CC(=O)C=C(O)C=CC1=CC=C(O)C=C1 YXAKCQIIROBKOP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012678 infectious agent Substances 0.000 claims description 6
- UEPVWRDHSPMIAZ-UHFFFAOYSA-N p-hydroxycinnamoyl feruloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(O)=CC(=O)C=CC=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-UHFFFAOYSA-N 0.000 claims description 6
- NAAJVHHFAXWBOK-UHFFFAOYSA-N (+)-ar-Turmerone Chemical compound CC(C)=CC(=O)CC(C)C1=CC=C(C)C=C1 NAAJVHHFAXWBOK-UHFFFAOYSA-N 0.000 claims description 5
- NAAJVHHFAXWBOK-ZDUSSCGKSA-N (+)-ar-Turmerone Natural products CC(C)=CC(=O)C[C@H](C)C1=CC=C(C)C=C1 NAAJVHHFAXWBOK-ZDUSSCGKSA-N 0.000 claims description 5
- VWEFYICUFMTXGX-FCXRPNKRSA-N (1e,6e)-1-(4-hydroxy-3-methoxyphenyl)-7-[4-hydroxy-3-(2-oxopropoxy)phenyl]hepta-1,6-diene-3,5-dione Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OCC(C)=O)C(O)=CC=2)=C1 VWEFYICUFMTXGX-FCXRPNKRSA-N 0.000 claims description 5
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 claims description 5
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 5
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 5
- FJLUATLTXUNBOT-UHFFFAOYSA-N 1-Hexadecylamine Chemical compound CCCCCCCCCCCCCCCCN FJLUATLTXUNBOT-UHFFFAOYSA-N 0.000 claims description 5
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 5
- 208000003829 American Hemorrhagic Fever Diseases 0.000 claims description 5
- 206010006895 Cachexia Diseases 0.000 claims description 5
- AFWKBSMFXWNGRE-ONEGZZNKSA-N Dehydrozingerone Chemical compound COC1=CC(\C=C\C(C)=O)=CC=C1O AFWKBSMFXWNGRE-ONEGZZNKSA-N 0.000 claims description 5
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 5
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 claims description 5
- 241000725177 Omsk hemorrhagic fever virus Species 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 208000000705 Rift Valley Fever Diseases 0.000 claims description 5
- 241000736032 Sabia <angiosperm> Species 0.000 claims description 5
- 208000003152 Yellow Fever Diseases 0.000 claims description 5
- CWRILEGKIAOYKP-SSDOTTSWSA-M [(2r)-3-acetyloxy-2-hydroxypropyl] 2-aminoethyl phosphate Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCCN CWRILEGKIAOYKP-SSDOTTSWSA-M 0.000 claims description 5
- VUBTYKDZOQNADH-UHFFFAOYSA-N acetyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)=O VUBTYKDZOQNADH-UHFFFAOYSA-N 0.000 claims description 5
- 229930183167 cerebroside Natural products 0.000 claims description 5
- 150000001784 cerebrosides Chemical class 0.000 claims description 5
- MXGYVBOZRLQICP-VUSYVUDMSA-N chembl494826 Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)\C=C(/O)\C=C\C1=CC=C(O)C(OC)=C1 MXGYVBOZRLQICP-VUSYVUDMSA-N 0.000 claims description 5
- 150000001840 cholesterol esters Chemical class 0.000 claims description 5
- 150000001982 diacylglycerols Chemical class 0.000 claims description 5
- NZZIMKJIVMHWJC-UHFFFAOYSA-N dibenzoylmethane Chemical compound C=1C=CC=CC=1C(=O)CC(=O)C1=CC=CC=C1 NZZIMKJIVMHWJC-UHFFFAOYSA-N 0.000 claims description 5
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 claims description 5
- 229940093541 dicetylphosphate Drugs 0.000 claims description 5
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 claims description 5
- MYIQANSQHADCLI-SAVPNDSOSA-L disodium;2-methoxy-4-[(1e,6e)-7-(3-methoxy-4-oxidophenyl)-3,5-dioxohepta-1,6-dienyl]phenolate Chemical compound [Na+].[Na+].C1=C([O-])C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C([O-])=CC=2)=C1 MYIQANSQHADCLI-SAVPNDSOSA-L 0.000 claims description 5
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 5
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 5
- 150000003904 phospholipids Chemical class 0.000 claims description 5
- 229920000058 polyacrylate Polymers 0.000 claims description 5
- 229920001281 polyalkylene Polymers 0.000 claims description 5
- WBHHMMIMDMUBKC-QJWNTBNXSA-M ricinoleate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC([O-])=O WBHHMMIMDMUBKC-QJWNTBNXSA-M 0.000 claims description 5
- 229940066675 ricinoleate Drugs 0.000 claims description 5
- VXUOFDJKYGDUJI-UHFFFAOYSA-N (2-hydroxy-3-tetradecanoyloxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C VXUOFDJKYGDUJI-UHFFFAOYSA-N 0.000 claims description 4
- 241000712892 Arenaviridae Species 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 241000711950 Filoviridae Species 0.000 claims description 4
- 241000710781 Flaviviridae Species 0.000 claims description 4
- 241000150350 Peribunyaviridae Species 0.000 claims description 4
- 241000711931 Rhabdoviridae Species 0.000 claims description 4
- 230000001580 bacterial effect Effects 0.000 claims description 4
- 230000012085 chronic inflammatory response Effects 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 4
- 230000002538 fungal effect Effects 0.000 claims description 4
- 230000002008 hemorrhagic effect Effects 0.000 claims description 4
- 208000006454 hepatitis Diseases 0.000 claims description 4
- 231100000283 hepatitis Toxicity 0.000 claims description 4
- 238000007918 intramuscular administration Methods 0.000 claims description 4
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 239000004952 Polyamide Substances 0.000 claims description 3
- 229920002732 Polyanhydride Polymers 0.000 claims description 3
- 229920000954 Polyglycolide Polymers 0.000 claims description 3
- 229920001710 Polyorthoester Polymers 0.000 claims description 3
- 230000000259 anti-tumor effect Effects 0.000 claims description 3
- 229920002988 biodegradable polymer Polymers 0.000 claims description 3
- 239000004621 biodegradable polymer Substances 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 3
- 150000003901 oxalic acid esters Chemical class 0.000 claims description 3
- 229920000218 poly(hydroxyvalerate) Polymers 0.000 claims description 3
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 3
- 229920002627 poly(phosphazenes) Polymers 0.000 claims description 3
- 229920002647 polyamide Polymers 0.000 claims description 3
- 229920001610 polycaprolactone Polymers 0.000 claims description 3
- 229920000515 polycarbonate Polymers 0.000 claims description 3
- 239000004417 polycarbonate Substances 0.000 claims description 3
- 229920006149 polyester-amide block copolymer Polymers 0.000 claims description 3
- 229920001855 polyketal Polymers 0.000 claims description 3
- 229920006324 polyoxymethylene Polymers 0.000 claims description 3
- 229920002635 polyurethane Polymers 0.000 claims description 3
- 239000004814 polyurethane Substances 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 150000003900 succinic acid esters Chemical class 0.000 claims description 3
- 229920001897 terpolymer Polymers 0.000 claims description 3
- 229920000331 Polyhydroxybutyrate Polymers 0.000 claims description 2
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 2
- 238000002659 cell therapy Methods 0.000 claims description 2
- 210000004443 dendritic cell Anatomy 0.000 claims description 2
- 239000007927 intramuscular injection Substances 0.000 claims description 2
- 239000007928 intraperitoneal injection Substances 0.000 claims description 2
- 229920001308 poly(aminoacid) Polymers 0.000 claims description 2
- 239000005015 poly(hydroxybutyrate) Substances 0.000 claims description 2
- 229920002463 poly(p-dioxanone) polymer Polymers 0.000 claims description 2
- 239000000622 polydioxanone Substances 0.000 claims description 2
- 229920000728 polyester Polymers 0.000 claims description 2
- 239000007929 subcutaneous injection Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 description 61
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 57
- 241000700159 Rattus Species 0.000 description 49
- 102100040247 Tumor necrosis factor Human genes 0.000 description 48
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 38
- 210000004027 cell Anatomy 0.000 description 36
- 230000000770 proinflammatory effect Effects 0.000 description 36
- 241000699670 Mus sp. Species 0.000 description 34
- 102000003814 Interleukin-10 Human genes 0.000 description 30
- 210000004556 brain Anatomy 0.000 description 30
- 108090000174 Interleukin-10 Proteins 0.000 description 29
- 239000003795 chemical substances by application Substances 0.000 description 27
- 230000003110 anti-inflammatory effect Effects 0.000 description 24
- 230000006378 damage Effects 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 23
- 208000014674 injury Diseases 0.000 description 22
- 102000000589 Interleukin-1 Human genes 0.000 description 21
- 108010002352 Interleukin-1 Proteins 0.000 description 21
- 230000002757 inflammatory effect Effects 0.000 description 20
- 206010040047 Sepsis Diseases 0.000 description 18
- 238000010171 animal model Methods 0.000 description 18
- 229960003387 progesterone Drugs 0.000 description 18
- 239000000186 progesterone Substances 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 17
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 16
- 238000004519 manufacturing process Methods 0.000 description 16
- 108010008165 Etanercept Proteins 0.000 description 15
- 102000004890 Interleukin-8 Human genes 0.000 description 15
- 108090001007 Interleukin-8 Proteins 0.000 description 15
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 15
- 229940106189 ceramide Drugs 0.000 description 15
- 229960000403 etanercept Drugs 0.000 description 15
- 108090001005 Interleukin-6 Proteins 0.000 description 14
- 102000004889 Interleukin-6 Human genes 0.000 description 14
- 102000018594 Tumour necrosis factor Human genes 0.000 description 14
- 108050007852 Tumour necrosis factor Proteins 0.000 description 14
- 208000027418 Wounds and injury Diseases 0.000 description 14
- 230000003247 decreasing effect Effects 0.000 description 14
- 229940100601 interleukin-6 Drugs 0.000 description 14
- 230000037361 pathway Effects 0.000 description 14
- 208000020431 spinal cord injury Diseases 0.000 description 14
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 13
- 102000000018 Chemokine CCL2 Human genes 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- 230000006872 improvement Effects 0.000 description 13
- 230000004054 inflammatory process Effects 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- 230000002035 prolonged effect Effects 0.000 description 13
- 238000011084 recovery Methods 0.000 description 13
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 206010061218 Inflammation Diseases 0.000 description 12
- 230000004913 activation Effects 0.000 description 12
- 230000007423 decrease Effects 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 230000000926 neurological effect Effects 0.000 description 12
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 12
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 11
- 230000001976 improved effect Effects 0.000 description 11
- 229960004023 minocycline Drugs 0.000 description 11
- ZIUSSTSXXLLKKK-KOBPDPAPSA-N (1e,4z,6e)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one Chemical compound C1=C(O)C(OC)=CC(\C=C\C(\O)=C\C(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 ZIUSSTSXXLLKKK-KOBPDPAPSA-N 0.000 description 10
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 10
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 10
- 239000003642 reactive oxygen metabolite Substances 0.000 description 10
- 230000004083 survival effect Effects 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 101001076407 Homo sapiens Interleukin-1 receptor antagonist protein Proteins 0.000 description 9
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 230000006698 induction Effects 0.000 description 9
- 229940076144 interleukin-10 Drugs 0.000 description 9
- 230000000324 neuroprotective effect Effects 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 8
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 8
- 108010036949 Cyclosporine Proteins 0.000 description 8
- 229940119178 Interleukin 1 receptor antagonist Drugs 0.000 description 8
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 8
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 8
- 230000001154 acute effect Effects 0.000 description 8
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 8
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 8
- 229960001265 ciclosporin Drugs 0.000 description 8
- 239000003407 interleukin 1 receptor blocking agent Substances 0.000 description 8
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 8
- 230000008506 pathogenesis Effects 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 206010054094 Tumour necrosis Diseases 0.000 description 7
- 230000009286 beneficial effect Effects 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000017531 blood circulation Effects 0.000 description 7
- 230000006931 brain damage Effects 0.000 description 7
- 231100000874 brain damage Toxicity 0.000 description 7
- 150000001783 ceramides Chemical class 0.000 description 7
- 210000000987 immune system Anatomy 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 7
- 229960003987 melatonin Drugs 0.000 description 7
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 7
- 238000010172 mouse model Methods 0.000 description 7
- 230000001537 neural effect Effects 0.000 description 7
- 230000001681 protective effect Effects 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 230000008733 trauma Effects 0.000 description 7
- 230000035899 viability Effects 0.000 description 7
- 230000009385 viral infection Effects 0.000 description 7
- 102000014914 Carrier Proteins Human genes 0.000 description 6
- 102000014150 Interferons Human genes 0.000 description 6
- 108010050904 Interferons Proteins 0.000 description 6
- 102000013519 Lipocalin-2 Human genes 0.000 description 6
- 108010051335 Lipocalin-2 Proteins 0.000 description 6
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 210000001130 astrocyte Anatomy 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 108091008324 binding proteins Proteins 0.000 description 6
- 230000002596 correlated effect Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 6
- 229940079322 interferon Drugs 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 210000000274 microglia Anatomy 0.000 description 6
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 6
- 238000004904 shortening Methods 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 230000008728 vascular permeability Effects 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 208000006011 Stroke Diseases 0.000 description 5
- 239000004098 Tetracycline Substances 0.000 description 5
- 230000001594 aberrant effect Effects 0.000 description 5
- 230000000735 allogeneic effect Effects 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 230000036765 blood level Effects 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 229930182912 cyclosporin Natural products 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 231100000517 death Toxicity 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 230000000302 ischemic effect Effects 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 201000004792 malaria Diseases 0.000 description 5
- 230000004112 neuroprotection Effects 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 239000000583 progesterone congener Substances 0.000 description 5
- 238000012552 review Methods 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 235000019364 tetracycline Nutrition 0.000 description 5
- 150000003522 tetracyclines Chemical class 0.000 description 5
- 229940040944 tetracyclines Drugs 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 4
- 102000019034 Chemokines Human genes 0.000 description 4
- 108010012236 Chemokines Proteins 0.000 description 4
- 102000003777 Interleukin-1 beta Human genes 0.000 description 4
- 108090000193 Interleukin-1 beta Proteins 0.000 description 4
- 102000015696 Interleukins Human genes 0.000 description 4
- 108010063738 Interleukins Proteins 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- 208000034486 Multi-organ failure Diseases 0.000 description 4
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 4
- 208000034038 Pathologic Neovascularization Diseases 0.000 description 4
- 206010037660 Pyrexia Diseases 0.000 description 4
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 4
- 208000036142 Viral infection Diseases 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 239000002260 anti-inflammatory agent Substances 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 208000025698 brain inflammatory disease Diseases 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 4
- 235000003373 curcuma longa Nutrition 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 206010014599 encephalitis Diseases 0.000 description 4
- 230000009931 harmful effect Effects 0.000 description 4
- 230000000971 hippocampal effect Effects 0.000 description 4
- 230000028709 inflammatory response Effects 0.000 description 4
- 206010022000 influenza Diseases 0.000 description 4
- 230000003907 kidney function Effects 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 230000006724 microglial activation Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 210000001616 monocyte Anatomy 0.000 description 4
- 230000004770 neurodegeneration Effects 0.000 description 4
- 230000003959 neuroinflammation Effects 0.000 description 4
- 230000007658 neurological function Effects 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 230000016273 neuron death Effects 0.000 description 4
- 230000009963 pathologic angiogenesis Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 229960000672 rosuvastatin Drugs 0.000 description 4
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 4
- 230000035939 shock Effects 0.000 description 4
- 229960002855 simvastatin Drugs 0.000 description 4
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 230000000451 tissue damage Effects 0.000 description 4
- 231100000827 tissue damage Toxicity 0.000 description 4
- 229960003989 tocilizumab Drugs 0.000 description 4
- 230000000472 traumatic effect Effects 0.000 description 4
- AURFZBICLPNKBZ-FZCSVUEKSA-N 3beta-hydroxy-5alpha-pregnan-20-one Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-FZCSVUEKSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010048962 Brain oedema Diseases 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- 244000163122 Curcuma domestica Species 0.000 description 3
- 229930105110 Cyclosporin A Natural products 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 241001115402 Ebolavirus Species 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 206010019196 Head injury Diseases 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 208000001953 Hypotension Diseases 0.000 description 3
- 102000019223 Interleukin-1 receptor Human genes 0.000 description 3
- 108050006617 Interleukin-1 receptor Proteins 0.000 description 3
- 102000004527 Interleukin-21 Receptors Human genes 0.000 description 3
- 108010017411 Interleukin-21 Receptors Proteins 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- 208000012902 Nervous system disease Diseases 0.000 description 3
- 108700012920 TNF Proteins 0.000 description 3
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 206010064097 avian influenza Diseases 0.000 description 3
- 210000004271 bone marrow stromal cell Anatomy 0.000 description 3
- 208000006752 brain edema Diseases 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- 230000016396 cytokine production Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 230000001066 destructive effect Effects 0.000 description 3
- 230000001627 detrimental effect Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 238000002565 electrocardiography Methods 0.000 description 3
- 231100000318 excitotoxic Toxicity 0.000 description 3
- 230000003492 excitotoxic effect Effects 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229930195712 glutamate Natural products 0.000 description 3
- 230000036543 hypotension Effects 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 230000015788 innate immune response Effects 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000002025 microglial effect Effects 0.000 description 3
- 230000007659 motor function Effects 0.000 description 3
- 210000001178 neural stem cell Anatomy 0.000 description 3
- 230000004766 neurogenesis Effects 0.000 description 3
- 230000003961 neuronal insult Effects 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 238000012261 overproduction Methods 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000004393 prognosis Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000011552 rat model Methods 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 150000003410 sphingosines Chemical class 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 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 description 2
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 102100035904 Caspase-1 Human genes 0.000 description 2
- 108090000426 Caspase-1 Proteins 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- 208000018652 Closed Head injury Diseases 0.000 description 2
- 235000003392 Curcuma domestica Nutrition 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 2
- 101001124991 Homo sapiens Nitric oxide synthase, inducible Proteins 0.000 description 2
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 208000002979 Influenza in Birds Diseases 0.000 description 2
- 101710104976 Interferon gamma-related Proteins 0.000 description 2
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 2
- 102000003815 Interleukin-11 Human genes 0.000 description 2
- 108090000177 Interleukin-11 Proteins 0.000 description 2
- 102000003810 Interleukin-18 Human genes 0.000 description 2
- 108090000171 Interleukin-18 Proteins 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- 102000000743 Interleukin-5 Human genes 0.000 description 2
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 2
- 208000032382 Ischaemic stroke Diseases 0.000 description 2
- 206010024238 Leptospirosis Diseases 0.000 description 2
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 2
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 2
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- 208000010718 Multiple Organ Failure Diseases 0.000 description 2
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 2
- 206010053159 Organ failure Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- AURFZBICLPNKBZ-UHFFFAOYSA-N Pregnanolone Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 AURFZBICLPNKBZ-UHFFFAOYSA-N 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- 241000219061 Rheum Species 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 102000011971 Sphingomyelin Phosphodiesterase Human genes 0.000 description 2
- 108010061312 Sphingomyelin Phosphodiesterase Proteins 0.000 description 2
- 102100030524 Suppressor of cytokine signaling 4 Human genes 0.000 description 2
- 101710137414 Suppressor of cytokine signaling 4 Proteins 0.000 description 2
- 101710137416 Suppressor of cytokine signaling 6 Proteins 0.000 description 2
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 2
- 208000001871 Tachycardia Diseases 0.000 description 2
- 102000002689 Toll-like receptor Human genes 0.000 description 2
- 108020000411 Toll-like receptor Proteins 0.000 description 2
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 241001115400 Zaire ebolavirus Species 0.000 description 2
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000011129 allogeneic cell therapy Methods 0.000 description 2
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 2
- 229960004238 anakinra Drugs 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229960005370 atorvastatin Drugs 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 230000001914 calming effect Effects 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 230000003683 cardiac damage Effects 0.000 description 2
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 2
- 229960003184 carprofen Drugs 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 210000000782 cerebellar granule cell Anatomy 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 210000001612 chondrocyte Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 230000003750 conditioning effect Effects 0.000 description 2
- 229960003624 creatine Drugs 0.000 description 2
- 239000006046 creatine Substances 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000008482 dysregulation Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000002518 glial effect Effects 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000004217 heart function Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000003960 inflammatory cascade Effects 0.000 description 2
- 230000006749 inflammatory damage Effects 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940100602 interleukin-5 Drugs 0.000 description 2
- 230000017306 interleukin-6 production Effects 0.000 description 2
- 238000000185 intracerebroventricular administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 230000005427 lymphocyte apoptotic process Effects 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000004973 motor coordination Effects 0.000 description 2
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 description 2
- 230000009223 neuronal apoptosis Effects 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000009527 percussion Methods 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000010837 poor prognosis Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- 238000011476 stem cell transplantation Methods 0.000 description 2
- 230000009469 supplementation Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 201000010740 swine influenza Diseases 0.000 description 2
- 210000002437 synoviocyte Anatomy 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 description 2
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 2
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 2
- 235000013976 turmeric Nutrition 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 description 1
- 101710158485 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010048998 Acute phase reaction Diseases 0.000 description 1
- 102000011690 Adiponectin Human genes 0.000 description 1
- 108010076365 Adiponectin Proteins 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 102000012002 Aquaporin 4 Human genes 0.000 description 1
- 108010036280 Aquaporin 4 Proteins 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 1
- 102100023995 Beta-nerve growth factor Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 208000007333 Brain Concussion Diseases 0.000 description 1
- 206010052346 Brain contusion Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 108010074051 C-Reactive Protein Proteins 0.000 description 1
- 102100032752 C-reactive protein Human genes 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 102100029855 Caspase-3 Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 102000009193 Caveolin Human genes 0.000 description 1
- 108050000084 Caveolin Proteins 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010051290 Central nervous system lesion Diseases 0.000 description 1
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 102000001327 Chemokine CCL5 Human genes 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- 241000709675 Coxsackievirus B3 Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 241000238710 Dermatophagoides Species 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000032163 Emerging Communicable disease Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 101150021185 FGF gene Proteins 0.000 description 1
- 206010053172 Fatal outcomes Diseases 0.000 description 1
- 102000053171 Glial Fibrillary Acidic Human genes 0.000 description 1
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 1
- 206010061431 Glial scar Diseases 0.000 description 1
- 206010018341 Gliosis Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 102100034221 Growth-regulated alpha protein Human genes 0.000 description 1
- 206010069767 H1N1 influenza Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000036066 Hemophagocytic Lymphohistiocytosis Diseases 0.000 description 1
- 208000032672 Histiocytosis haematophagic Diseases 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 description 1
- 101001010593 Homo sapiens Interleukin-21 receptor Proteins 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 101000720704 Homo sapiens Neuronal migration protein doublecortin Proteins 0.000 description 1
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000039996 IL-1 family Human genes 0.000 description 1
- 108091069196 IL-1 family Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 229940124042 Interleukin 10 antagonist Drugs 0.000 description 1
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 102000003812 Interleukin-15 Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 102100030704 Interleukin-21 Human genes 0.000 description 1
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 1
- 241001675748 Janaria Species 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 150000000963 Kdo2-lipid A derivatives Chemical class 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 208000035809 Lymphohistiocytosis Diseases 0.000 description 1
- 208000030289 Lymphoproliferative disease Diseases 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 241001115401 Marburgvirus Species 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 1
- 102000014962 Monocyte Chemoattractant Proteins Human genes 0.000 description 1
- 108010064136 Monocyte Chemoattractant Proteins Proteins 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 1
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- 102100025929 Neuronal migration protein doublecortin Human genes 0.000 description 1
- 206010071323 Neuropsychiatric syndrome Diseases 0.000 description 1
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 206010033627 Pancreatic injury Diseases 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- VABYUUZNAVQNPG-UHFFFAOYSA-N Piperlongumine Natural products COC1=C(OC)C(OC)=CC(C=CC(=O)N2C(C=CCC2)=O)=C1 VABYUUZNAVQNPG-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- 238000001604 Rao's score test Methods 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- 208000004346 Smoldering Multiple Myeloma Diseases 0.000 description 1
- 101150045565 Socs1 gene Proteins 0.000 description 1
- 101150043341 Socs3 gene Proteins 0.000 description 1
- 208000020339 Spinal injury Diseases 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 102000058018 Suppressor of Cytokine Signaling 1 Human genes 0.000 description 1
- 108700027336 Suppressor of Cytokine Signaling 1 Proteins 0.000 description 1
- 102000058015 Suppressor of Cytokine Signaling 3 Human genes 0.000 description 1
- 108700027337 Suppressor of Cytokine Signaling 3 Proteins 0.000 description 1
- 102000008036 Suppressor of Cytokine Signaling Proteins Human genes 0.000 description 1
- 108010075383 Suppressor of Cytokine Signaling Proteins Proteins 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 208000024340 acute graft versus host disease Diseases 0.000 description 1
- 208000029244 acute graft vs. host disease Diseases 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 210000001132 alveolar macrophage Anatomy 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000003092 anti-cytokine Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 208000037875 astrocytosis Diseases 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 208000029560 autism spectrum disease Diseases 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960003008 blinatumomab Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229950004398 broxuridine Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 210000002318 cardia Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 239000000064 cholinergic agonist Substances 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000012398 clinical drug development Methods 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 210000004922 colonic epithelial cell Anatomy 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 210000003618 cortical neuron Anatomy 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000001215 curcuma longa l. root Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 230000009266 disease activity Effects 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- ZGNITFSDLCMLGI-UHFFFAOYSA-N flubendiamide Chemical compound CC1=CC(C(F)(C(F)(F)F)C(F)(F)F)=CC=C1NC(=O)C1=CC=CC(I)=C1C(=O)NC(C)(C)CS(C)(=O)=O ZGNITFSDLCMLGI-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 230000007760 free radical scavenging Effects 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 230000036397 gastrointestinal physiology Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 210000004195 gingiva Anatomy 0.000 description 1
- 201000011560 gingival overgrowth Diseases 0.000 description 1
- 230000004914 glial activation Effects 0.000 description 1
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 1
- 230000004022 gliogenesis Effects 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 210000004884 grey matter Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000035931 haemagglutination Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000014752 hemophagocytic syndrome Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000005745 host immune response Effects 0.000 description 1
- 230000007236 host immunity Effects 0.000 description 1
- 102000046824 human IL1RN Human genes 0.000 description 1
- 102000047008 human IL21R Human genes 0.000 description 1
- 102000052611 human IL6 Human genes 0.000 description 1
- LKLASFRCXLTNMY-FCXRPNKRSA-N hydrazinocurcumin Chemical class C1=C(O)C(OC)=CC(\C=C\C2=NNC(\C=C\C=3C=C(OC)C(O)=CC=3)=C2)=C1 LKLASFRCXLTNMY-FCXRPNKRSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 229950001392 ilodecakin Drugs 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015266 indolent plasma cell myeloma Diseases 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000010661 induction of programmed cell death Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 208000037801 influenza A (H1N1) Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229940074383 interleukin-11 Drugs 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- 108040006858 interleukin-6 receptor activity proteins Proteins 0.000 description 1
- 229940096397 interleukin-8 Drugs 0.000 description 1
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 230000003910 liver physiology Effects 0.000 description 1
- 230000006738 locomotor deficit Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 231100000516 lung damage Toxicity 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000006386 memory function Effects 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 208000005871 monkeypox Diseases 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 230000023105 myelination Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 230000022666 negative regulation of interleukin-17 production Effects 0.000 description 1
- 208000037971 neglected tropical disease Diseases 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 230000014537 nerve growth factor production Effects 0.000 description 1
- 230000009251 neurologic dysfunction Effects 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 208000015015 neurological dysfunction Diseases 0.000 description 1
- 230000019581 neuron apoptotic process Effects 0.000 description 1
- 230000004693 neuron damage Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 230000003557 neuropsychological effect Effects 0.000 description 1
- 230000000508 neurotrophic effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000002640 oxygen therapy Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000009038 pharmacological inhibition Effects 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000015323 positive regulation of phagocytosis Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000007112 pro inflammatory response Effects 0.000 description 1
- 230000001536 pro-arrhythmogenic effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000007342 reactive astrogliosis Effects 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 210000001567 regular cardiac muscle cell of ventricle Anatomy 0.000 description 1
- 230000034394 regulation of mitosis Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 208000037974 severe injury Diseases 0.000 description 1
- 208000010721 smoldering plasma cell myeloma Diseases 0.000 description 1
- 239000002047 solid lipid nanoparticle Substances 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 108010035597 sphingosine kinase Proteins 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000003107 structure activity relationship analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 102000014898 transaminase activity proteins Human genes 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 230000007332 vesicle formation Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/48—Other medical applications
- A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
-
- 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
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
-
- 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
Definitions
- the present invention relates in general to the field of infectious diseases and disease conditions that trigger a cytokine cascade, and more particularly, to the use of compositions that reduce the cytokine cascade.
- the inventors argue that, in contrast to current allogeneic cell therapy protocols where T-cells in the graft mediate the beneficial graft vs. tumor (GVT) and detrimental graft vs. host (GVH) effects, the allogeneic cells of the invention stimulate host T-cells to mediate the "mirror" of these effects.
- the highly activated allogeneic cells of the invention are said to stimulate host immunity in a complete HLA mis-matched setting in patients that have not had a prior bone marrow transplant or received chemotherapy and/or radiation conditioning regimens.
- compositions and methods for inhibiting vascular permeability relate to compounds, compositions and methods for inhibiting vascular permeability and pathologic angiogenesis.
- These inventors teach methods for producing and screening compounds and compositions capable of inhibiting vascular permeability and pathologic angiogenesis. It is said that the compositions described are useful in, methods of inhibiting vascular permeability and pathologic angiogenesis, including methods of inhibiting vascular permeability and pathologic angiogenesis induced by specific angiogenic, permeability and inflammatory factors, such as, for example VEGF, FGF and thrombin.
- United States Patent No. 7,479,498, issued to Keller, is entitled “Treatments for viral infections” and relates to improved methods and compositions for treating viral infections and other diseases and conditions that induce a cytokine storm. It is further said that the invention relates to novel compositions comprising quercetin, and an anti-convulsant, such as phenytoin, in combination with multivitamins as an anti-viral composition and methods of use thereof.
- United States Patent Application No. 20100075329 filed by O'Toole, et al., is entitled “Methods For Predicting Production Of Activating Signals By Cross-Linked Binding Proteins” and relates to human binding proteins and antigen-binding fragments thereof that specifically bind to the human interleukin-21 receptor (IL21R), and uses therefore.
- the invention is said to include methods to predict whether the binding proteins of the invention may take on agonistic activities in vivo and produce a cytokine storm.
- the invention is said to provide methods for determining whether an anti-IL21R binding protein is a neutralizing anti-IL21R binding protein, based on the identification of several IL21 -responsive genes.
- the binding proteins can act as antagonists of IL21R activity, thereby modulating immune responses in general, and those mediated by IL21R in particular.
- the present invention includes a method of ameliorating symptoms or treating one or more adverse reactions triggered by a widespread release of cytokines in a subject comprising the steps of: identifying the subject in need of amelioration of symptoms or treatment of one or more infectious diseases or disease conditions that trigger a widespread release of cytokines; and administering one or more pharmaceutical compositions comprising a therapeutically effective amount of a lipid dissolved or dispersed in a suitable aqueous or non- aqueous medium sufficient to reduce the level of cytokines in the subject.
- the widespread release of cytokines is caused by one or more infectious diseases selected from at least one of viral, bacterial, fungal, helminthic, protozoan, or hemorrhagic infectious agents.
- the one or more infectious diseases is selected from at least one of infection with a Rhinovirus, Coronavirus, Paramyxoviridae, Orthomyxoviridae, Adenovirus, Parainfluenza Virus, Metapneumovirus, Respiratory Syncytial Virus, Influenza virus, Arenaviridae, Filoviridae, Bunyaviridae, Flaviviridae, Rhabdoviridae virus, Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue, yellow fever, Rift Valley fever, Omsk hemorrhagic fever virus, Kyasanur Forest, Junin, Machupo, Sabia, Guanarito, Garissa, Ilesha, or Lassa fever viruses.
- a Rhinovirus Coronavirus
- Paramyxoviridae Orthomyxoviridae
- Adenovirus Parainfluenza Virus
- Metapneumovirus Metapneum
- the one or more disease conditions is selected from at least one of cachexia, septic shock syndrome, a chronic inflammatory response, septic shock syndrome, traumatic brain injury, cerebral cytokine storm, graft versus host disease (GVHD), autoimmune diseases, multiple sclerosis, acute pancreatitis, or hepatitis.
- the one or more disease conditions is an adverse reaction caused by the treatment with anti-CD 19 Chimeric Antigen Receptor (CAR) T cells or antitumor cell therapy, activated dendritic cells, activated macrophages, or activated B cells.
- CAR Chimeric Antigen Receptor
- the composition further comprises a curcumin extract, curcumin, curcuminoids disposed in a lipid, wherein the curcuminoids are selected from at least one of Ar-tumerone, methylcurcumin, demethoxy curcumin, bisdemethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, l,7-bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione (curcuminl), l,7-bis(piperonyl)-l,6-heptadiene-3,5-dione (piperonyl curcumin) l,7-bis(2- hydroxy naphthyl)-l,6-heptadiene-2,5-dione (2-hydroxyl naphthyl curcumin) and 1,1- bis(phenyl
- the lipid or the phospholipid is selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), Dipalmitoylphosohatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG), phosphatidylcholine, lysolecithin, lysophosphatidylethanolamine, lysoDMPC, lysoDMPG, lysoDSPG, lysoDPPC, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine, cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol,
- the therapeutically effective amount comprises 50 nM/kg, 10 to 100 nM/kg, 25 to 75 nM/kg, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM/kg of body weight of the subject.
- the composition comprises an active agent, and has a ratio of lipid phospholipids to active agent of 3:1, 1:1, 0.3:1, and 0.1:1.
- the diseases is rheumatoid arthritis, psoriasis, multiple sclerosis, relapsing multiple sclerosis, or inflammatory bowel disease.
- the present invention includes a composition for ameliorating symptoms or treating one or more adverse reactions triggered by an infectious disease or a disease condition that trigger a widespread release of cytokines in a subject comprising a therapeutically effective amount of a lipid or a lysophosphatidyl dissolved or dispersed in a suitable aqueous or non- aqueous medium.
- the one or more infectious diseases are selected from at least one of viral, bacterial, fungal, helminthic, protozoan, or hemorrhagic infectious agents.
- the one or more infectious diseases is selected from at least one of infection with a Rhinovirus, Coronavirus, Paramyxoviridae, Orthomyxoviridae, Adenovirus, Parainfluenza Virus, Metapneumovirus, Respiratory Syncytial Virus, Influenza Virus, Arenaviridae, Filoviridae, Bunyaviridae, Flaviviridae, Rhabdoviridae virus, Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue, yellow fever, Rift Valley fever, Omsk hemorrhagic fever virus, Kyasanur Forest, Junin, Machupo, Sabia, Guanarito, Garissa, Ilesha, or Lassa fever viruses.
- a Rhinovirus Coronavirus
- Paramyxoviridae Orthomyxoviridae
- Adenovirus Parainfluenza Virus
- Metapneumovirus Respiratory
- the one or more disease conditions is selected from at least one of cachexia, septic shock syndrome, a chronic inflammatory response, septic shock syndrome, traumatic brain injury, cerebral cytokine storm, graft versus host disease (GVHD), autoimmune diseases, multiple sclerosis, acute pancreatitis, or hepatitis.
- the curcumin extract, curcuminoids or synthetic curcumin are disposed in a lipid.
- the or the lysophosphatidyl is selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG),
- Dipalmitoylphosohatidylcholine DPPC
- disteroylphosphatidylglycerol DSPG
- dipalmitoylphosphatidylglycerol DMPG
- phosphatidylcholine lysolecithin
- lysophosphatidylethanolamine lysoDMPC
- lysoDMPG lysoDMPG
- lysoDSPG lysoDPPC
- phosphatidylserine phosphatidylinositol
- sphingomyelin phosphatidylethanolamine
- cardiolipin phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl- phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate
- the biodegradable polymer is selected from the group consisting of polyesters, polylactides, polyglycolides, polycaprolactones, poly anhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), copolymers, terpolymers, and combinations or mixtures thereof.
- the composition adapted for intravenous, sub-cutaneous, intramuscular, or intraperitoneal injection in the subject.
- the composition further comprises a curcumin or curcuminoids are selected from at least one of Ar-tumerone, methylcurcumin, demethoxy curcumin, bisdemethoxycurcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, l,7-bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5- dione (curcuminl), l,7-bis(piperonyl)-l,6-heptadiene-3,5-dione (piperonyl curcumin) l,7-bis(2- hydroxy naphthyl)-!, 6-heptadiene-2,5-dione (2-hydroxyl naphthyl curcumin)
- the present invention includes a method of determining if a candidate drug causes an amelioration of symptoms or treats one or more adverse reactions triggered by an infectious disease or a disease condition that trigger a widespread release of cytokines in a subject, the method comprising: (a) administering an amount of the candidate drug in combination with empty liposomes, and a placebo to a second subset of the patients, wherein the candidate drug is provided in an amount effective to reduce or prevent the overall level of cytokines in the subject; (b) measuring the level of cytokines in the subject from the first and second set of patients; and (c) determining if the candidate drug in combination with empty liposomes ameliorates symptoms or treats one or more adverse reactions triggered by infectious diseases or disease conditions that trigger a widespread release of cytokines is statistically significant as compared to any reduction occurring in the subset of patients that took the placebo, wherein a statistically significant reduction indicates that the candidate drug is useful in treating a disease state while also reducing or eliminating the overall level of cytokines in
- the present invention includes a method of ameliorating symptoms or treating a cytokine storm caused by a therapeutic agent in a subject comprising the steps of: identifying the subject in need of amelioration of symptoms or treatment of the cytokine storm caused by a therapeutic agent; and administering one or more pharmaceutical compositions comprising a therapeutically effective amount of a curcumin extract, curcuminoids or synthetic curcumin and derivatives thereof, or empty liposomes, dissolved or dispersed in a suitable aqueous or non-aqueous medium sufficient to reduce the level of cytokines in the subject.
- FIGS. 1A and IB show the percent inhibition and percent viability, respectively, achieved with liposomal curcumin in HeFa cells.
- FIGS. 2A and 2B show the percent inhibition and percent viability, respectively, using solid S-curcumin curcumin in HeFa cells.
- FIGS. 3A and 3B show the percent inhibition and percent viability, respectively, comparing liposomal curcumin and solid curcumin in HeFa cells.
- FIG. 4 A is a graph that shows the effect of liposomal curcumin on liver function during sepsis, including asparate aminotransferase (AST) and alanine aminotransferase (AST) levels.
- AST asparate aminotransferase
- AST alanine aminotransferase
- FIGS. 4B to 4D are graphs that show the effect of liposomal curcumin during sepsis on kidney function measuring Creatine, Neutrophil gelatinase-associated lipocalin (NGAL) and Blood Urea Nitrogen (BUN).
- NGAL Neutrophil gelatinase-associated lipocalin
- BUN Blood Urea Nitrogen
- FIGS. 4E and 4F are graphs that show the effect of liposomal curcumin during sepsis on heart function for c-Troponin and the percent ejection fraction. Liposomal curcumin showed a decrease in cardiac damage when compared to the standard of care and equaled the standard of care in percent ejection fraction.
- FIG. 4G is a graph that shows the effect of liposomal curcumin during sepsis on overall survival. Liposomal curcumin showed a higher survival time versus the standard of care treatment.
- cytokine storm refers to the dysregulated of pro-inflammatory cytokines leading to disease has been referred to as a "cytokine storm,” “cytokine release syndrome” or "inflammatory cascade”. Often, a cytokine storm or cascade is referred to as being part of a sequence because one cytokine typically leads to the production of multiple other cytokines that can reinforce and amplify the immune response. Generally, these pro- inflammatory mediators have been divided into two subgroups: early mediators and late mediators.
- infectious diseases commonly associated with a “cytokine storm” include but at not limited to, malaria, avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS).
- Certain specific infectious agents include but are not limited to: infectious diseases is selected from at least one of Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue, yellow fever, Rift Valley fever, Omsk hemorrhagic fever virus, Kyasanur Forest, Junin, Machupo, Sabia, Guanarito, Garissa, Ilesha, or Fassa fever viruses.
- Other viruses can include rhinovirus, coronavirus, paramyxoviridae, Orthomyxoviridae, adenovirus, parainfluenza virus, metapneumovirus, respiratory syncytial virus or influenza virus.
- cytokine storm Disease conditions commonly associated with a “cytokine storm” include but at not limited to: sepsis, systemic inflammatory response syndrome (SIRS), cachexia, septic shock syndrome, traumatic brain injury (e.g., cerebral cytokine storm), graft versus host disease (GVHD), or the result of treatment with activated immune cells, e.g., IF-2 activated T cells, T cells activated with anti-CD 19 Chimeric Antigen Receptor (CAR) T cells.
- SIRS systemic inflammatory response syndrome
- cachexia e.g., cerebral cytokine storm
- GVHD graft versus host disease
- activated immune cells e.g., IF-2 activated T cells, T cells activated with anti-CD 19 Chimeric Antigen Receptor (CAR) T cells.
- CAR Chimeric Antigen Receptor
- a cytokine storm is a healthy systemic expression of a vigorous immune system.
- the present invention can be used to reduce or eliminate some or most of an exaggerated immune response caused by, e.g., rapidly proliferating and highly activated T-cells or natural killer (NK) cells that results in the release of the “cytokine storm” that can include more than 150 inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors).
- cytokine storm can include more than 150 inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors).
- pro-inflammatory cytokines such as Tumor Necrosis Factor-a, Interleukin- 1, and Interkeukin-6
- anti-inflammatory cytokines such as Interleukin- 10, and Interleukin- 1 receptor antagonist (IF- 1RA)
- IF- 1RA Interleukin- 1 receptor antagonist
- a cytokine storm can result in permanent lung damage and, in many cases, death.
- the end stage symptoms of the cytokine storm include but are not limited to: hypotension; tachycardia; dyspnea; fever; ischemia or insufficient tissue perfusion; uncontrollable hemorrhage; severe metabolism dysregulation; and multisystem organ failure.
- Deaths from infectious diseases such as Ebola virus infection are not caused by the virus itself, but rather, the cytokine storm that causes uncontrollable hemorrhaging; severe metabolism dysregulation; hypotension; tachycardia; dyspnea; fever; ischemia or insufficient tissue perfusion; and multisystem organ failure.
- the term “Curcumin (diferuloyl methane; l,7-bis(4-hydroxy-3- methoxyphenyl)-l,6-heptadiene-3,5-dione)” is a naturally occurring compound which is the main coloring principle found in the rhizomes of the plant Curcuma longa (U.S. Pat. No. 5,679,864 (Krackov et al.)).
- the synthetic curcumin is 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96% pine diferuloylmethane.
- curcumin and curcuminoids include, e.g., Ar-tumerone, methylcurcumin, demethoxy curcumin, bisdemethoxy curcumin, sodium curcuminate, dibenzoylmethane, acetylcurcumin, feruloyl methane, tetrahydrocurcumin, l,7-bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione (curcuminl), l,7-bis(piperonyl)- l,6-heptadiene-3,5-dione (piperonyl curcumin) l,7-bis(2-hydroxy naphthyl)-l,6-heptadiene-2,5- dione (2-hydroxyl naphthyl curcumin) and l,l-bis(phenyl)-l,3,8,10 undecatetraene-5,7-dione.
- liposome refers to a capsule wherein the wall or membrane thereof is formed of lipids, especially phospholipid, with the optional addition therewith of a sterol, especially cholesterol.
- the liposomes are empty liposomes and can be formulated from a single type of phospholipid or combinations of phospholipids.
- the empty liposomes or lipid can further include one or more surface modifications, such as proteins, carbohydrates, glycolipids or glycoproteins, and even nucleic acids such as aptamers, thio- modified nucleic acids, protein nucleic acid mimics, protein mimics, stealthing agents, etc.
- the composition also comprises an active agent in or about the liposome or lipid and the composition has a ratio of lipids to active agent of 3:1, 1:1, 0.3:1, and 0.1:1.
- lipid refers to amphiphilic biomolecules that are soluble in nonpolar solvents. Lipids are capable of liposome formation, vesicle formation, micelle formation, emulsion formation, and are substantially non-toxic when administrated at the necessary concentrations as liposomes.
- the lipid composition of the present invention can include, e.g., dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), Dipalmitoylphosohatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG), phosphatidylcholine, lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine, cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl
- the term “in vivo ” refers to being inside the body.
- the term “in vitro” as used in the present application is to be understood as indicating an operation carried out in a non living system.
- the term “treatment” refers to the treatment of the conditions mentioned herein, particularly in a patient who demonstrates symptoms of the disease or disorder.
- treating refers to any administration of a compound of the present invention and includes (i) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology) or (ii) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
- controlling includes preventing treating, eradicating, ameliorating or otherwise reducing the severity of the condition being controlled.
- the terms “effective amount” or “therapeutically effective amount” described herein means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
- the therapeutically effective amount comprises 50 nM/kg, 10 to 100 nM/kg, 25 to 75 nM/kg, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM/kg of body weight of the subject.
- administering should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP), and the like; enteral or parenteral, transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
- oral dosage forms such as tablets, capsules, syrups, suspensions, and the like
- injectable dosage forms such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP), and the like
- enteral or parenteral, transdermal dosage forms including creams, jellies, powders, or patches
- buccal dosage forms inhalation powder
- intravenous administration includes injection and other modes of intravenous administration.
- the curcumin formulation of the present invention may comprise one or more optional pharmaceutical excipients, diluents, extended or controlled release agents, lubricants, preservatives or any combination thereof, and once solubilized may be added to injectable anti diabetic medications or administered in a schedule depending upon the release kinetics of the curcumin formulation.
- a large number of biodegradable polymers may be used in the formulation of the present invention.
- Non-limiting examples of these polymers include polysesters, polylactides, polyglycolides, polycaprolactones polyanhydrides, polyamides, polyurethanes, polyesteramides, polydiaxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybuterates, polyhydroxyvalerates, polyalkelene oxalates, polyalkylene succinates, poly(malic)acid, poly(amino)acids, copolymers, terpolymers, and combinations or mixtures thereof.
- Specific polymers that may be used include an acrylic acid, a vinylpyrolidinome, a N- isopropylacrylamide or combinations and modifications thereof.
- the synthesized curcumin that is used includes curcumin, curcumin analogues, curcumin derivatives and any modifications thereof.
- the terminal stage of Ebola and other viral diseases is often the onset of cytokine storm, the massive overproduction of cytokines by the body’s immune system.
- the present invention includes the treatment of infectious agents that trigger a cytokine storm, such as Ebola virus, with curcumin actions to suppress cytokine release and cytokine storm.
- curcumin blocks cytokine release, most importantly the key pro- inflammatory cytokines, interleukin- 1, interleukin-6 and tumor necrosis factor-a. Curcumin’ s suppression of cytokine release correlates with clinical improvement in experimental models of disease conditions where cytokine storm plays a significant role in mortality. Thus, curcumin can be used to treat the cytokine storm of patients with Ebola. In certain examples, intravenous formulations allow achievement of therapeutic blood levels.
- Cytokine storm can occur after a wide variety of infectious and non-infectious stimuli.
- cytokine storm numerous cytokines, both pro-inflammatory (IL-1, IL-6, TNF-a) and anti-inflammatory (IL-10), are released, resulting in hypotension, hemorrhage, and, ultimately, multi-organ failure.
- IL-1, IL-6, TNF-a pro-inflammatory
- IL-10 anti-inflammatory
- the term “cytokine storm” is most associated with the 1918 H1N1 influenza pandemic and the more recent cases of bird flu H5N1 infection 3 5 .
- viruses can include rhinovirus, coronavirus, paramyxoviridae, Orthomyxoviridae, adenovirus, parainfluenza virus, metapneumovirus, respiratory syncytial virus or influenza virus.
- Curcumin has been shown to inhibit the release of numerous cytokines. Abe et al showed that curcumin suppresses IL-Ib, IL-8, TNF-a, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-la (MIP-la) release from monocytes and macrophages 14 . Jain et al., showed that curcumin markedly reduced the release of IL-6, IL-8, TNF-a and MCP-1 from monocytes that had been cultured in a high glucose environment 15 .
- Curcumin 15 has been reported to block the release of IL-6 in rheumatoid synovial fibroblasts 16 , of IL-8 in human esophageal epithelial cells 17 and alveolar epithelial cells 18 , and of IL-1 in bone marrow stromal cells 19 , colonic epithelial cells 20 and human articular chondrocytes 21 . Curcumin also prevents release of IL-2 , IL-12 , Interferon-g and many other key cytokines (Tables 1 and 2).
- EXAMPLE 1 Curcumin Cytokine Suppression Correlates with Clinical Improvement in Conditions Associated with Cytokine Storm.
- Curcumin has positive effects on numerous disease conditions in patients and in animal systems.
- Avasarala et al reported on curcumin’s effects on cytokine expression and disease progression in a mouse model of viral-induced acute respiratory distress syndrome.
- Curcumin reduced the expression of key cytokines IL-6, IL-10, interferon g and MCP-1, and this correlated with a marked decrease in inflammation and reduction in fibrosis 27 .
- Yu et al showed curcumin’s suppression of TNF-a levels was associated with decreased pancreatic injury in an acute pancreatitis mouse model 28 .
- Curcumin has been shown to have activity against numerous viruses, including, Coronavirus, HIV-1, HIV-2, HSV, HPV, HTLV-1, HBV, HCV, and Japanese encephalitis virus 31 .
- the virus can include rhinovirus, coronavirus, paramyxoviridae, Orthomyxoviridae, adenovirus, parainfluenza virus, metapneumo virus, respiratory syncytial virus or influenza virus.
- curcumin has been shown to have specific activity against the H1N1 virus in culture 32 33 , although cytokine levels were not measured in these two studies. Most importantly, curcumin has been shown to stimulate the SOCS proteins 34 . These proteins have been shown to be crucial in protecting against severe cytokine storm in mice infected with influenza virus 35 .
- Curcumin s activity in suppressing multiple cytokines, and its activity in experimental models of diseases and conditions associated with cytokine storm, suggest it may be useful in the treatment of patients with Ebola and cytokine storm. Curcumin is poorly absorbed from the intestinal tract; however intravenous formulations may allow therapeutic curcumin blood levels to be achieved in patients diagnosed with cytokine storm. Clinical status and levels of important cytokines, such as IL-Ib, IL-6 and TNF-a, should be monitored carefully when patients are treated with curcumin. [0042] Table 1: Curcumin Effect on Interleukins
- Liposomes and Liposomal-Curcumin were prepared as a 6 mg/ml solutions. Curcumin (solid) was solubilized in DMSO at 6mg/ml. All three compounds were tested in EBOV infection assay with two cell lines Hela and HFF-1. There were two sets for studies done with different dilution strategy.
- FIGS. 1A and IB show the percent inhibition and percent viability, respectively, achieved with liposomal curcumin in HeLa cells.
- FIGS. 2A and 2B shows the percent inhibition and percent viability, respectively, using solid S-curcumin curcumin in HeLa cells. Similar results were obtained with the same study using HFF-1 cells.
- FIGS. 3A and 3B show the percent inhibition and percent viability, respectively, comparing liposomal curcumin and solid curcumin in HeLa cells. Similar results were obtained with the same study using HFF-1 cells.
- Pro-Inflammatory Cytokines in the Causation of The Prolonged QT Interval Role of the Ceramide and Sphingosine-1 Phosphate Pathways.
- QT prolongation was noted as a side effect of the cytokine, interferon g, and QT prolongation has been seen after treatment with interleukin- 18.
- Patients with inflammatory diseases, such as rheumatoid arthritis, psoriasis and inflammatory bowel disease have a high incidence of QT prolongation, and die more frequently secondary to this complication.
- TNF-a and other cytokines have been shown to cause increased production of ROS.
- the effects of TNF-a could be blocked by administration of an anti-TNF-a antibody or by an anti-oxidant.
- IL-Ib and IL-6 have been shown to increase the L-type Ca(2 + ) current (ICaL), and this effect can be blocked by aspirin or indomethacin.
- the close link between phospholipidosis and prolonged QT provides another hint of the importance of these cytokines. 77% of the agents that can cause phospholipidosis also are hERG channel blockers.
- Phospholipidotic cells have been shown to secrete large amounts of TNF-a and IL-6 after LPS stimulation. It has also been speculated that the mechanism of damage from drug-induced phospholipidosis is accumulation of ceramides. Numerous studies have shown that cytokines such as interferon g, IL-Ib and TNF-a increase sphingomyelinase activation, and increase production of ceramides, which are known to suppress hERG current. It is also known that sphingolipids mediate ROS signaling. Ceramides are metabolized to sphingosine and fatty acids, and sphingosine is phosphorylated by sphingosine kinases to form sphingosine-1 phosphate.
- cytokines such as interferon g, IL-Ib and TNF-a increase sphingomyelinase activation, and increase production of ceramides, which are known to suppress hERG current. It is also known that
- Ceramides and sphingosine-1 phosphate have opposite effects, ceramides causing apoptosis and sphingosine-1 phosphate promoting cell survival.
- Fingolimod a sphingosine analogue (which has both agonist and antagonist effects on the sphingosine-1 phosphate- 1 receptor), is used to treat patients with relapsing multiple sclerosis, causes QT prolongation through inhibition of the hERG current, as well as fatal ventricular arrhythmias.
- studies in the mouse model of influenza-induced cytokine storm have shown sphingosine-1 phosphate- 1 signaling to be the primary pathway for activation of the cytokine storm.
- the cytokine storm was reversed by a sphingosine analogue through feedback inhibition of cytokines, with marked reductions in TNF- a, IL-la, IL-6, MCP-1, interferon a and MIP-la, and clinical improvement seen.
- the survival of the mice in the study was much higher with the sphingosine analogue than with anti-viral therapy.
- agents found clinically to be suppressors of QT prolongation progestins, statins, liposomal curcumin, resveratrol, anti-oxidants, are also strong suppressors of these inflammatory cytokines.
- TNF-a administration causes a decrease in the rapid component of the delayed rectifier potassium current (IKr), in the slow component of the delayed rectifier current (IKs) and in the transient outward current (Ito).
- IKr delayed rectifier potassium current
- IKs slow component of the delayed rectifier current
- Ito transient outward current
- ROS reactive oxygen species
- the present inventors have recognized that the list of agents which cause both cytokine suppression and shortening of the previously prolonged QT interval is strikingly similar to the list of agents that have been shown in animal models to reduce cytokine levels and secondary brain inflammation and also reduce the degree of brain damage.
- the present invention can be used to target those diseases that increase ceramide production, thus shifting the balance from the sphingosine-1 -phosphate (SIP) pathway (protective), to the ceramide pathway (destructive).
- SIP sphingosine-1 -phosphate
- the present inventors have shown, in both in vitro and in vivo models, that Liposomal Curcumin and EU8120 reduce IL-Ib, IL-6, TNF-a, MCP-1, MIP-1 and Rantes. Liposomes have also been shown, in other models, to compete for the enzyme sphingomyelinase and to reduce levels of ceramides, thus also shifting the ceramide/SlP balance toward SIP.
- LPS-induced cytokine storm produces QTc prolongation, which is prevented by an anti inflammatory lipid.
- QTc prolongation There is increasing evidence that excess levels of pro-inflammatory cytokines play a major role in the pathogenesis of the prolonged QT syndrome.
- blockers such as tocilizumab (IL-6), or anti-cytokine antibodies (TNFa) contribute to a shortening of the previously -prolonged QT interval.
- EU8120 a lipid blend shown to prevent IKr- channel block by a variety of hERG blockers
- QTc prolongation was limited to 5 ms after 2 hours, and completely prevented at 1 and 4 hours post- LPS.
- Plasma levels of TNFa, IL1 b, and IL-6 were significantly lower in EU8120-administered animals.
- This example demonstrates that EU8120 suppresses QTc prolongation via an anti inflammatory cytokine -effect and not by any interaction with the active agent (LPS).
- LPS active agent
- the present invention can use the compositions to treat the cytokine storm disorders using synthetic curcumin (S-curcumin).
- S-curcumin synthetic curcumin
- Curcumin is the active principle of the turmeric plant, which has been synthesized to near purity (99.2%). It is formulated with liposomes, polymers, or PLGM to render it capable of being administered intravenously as a bolus or as a continuous infusion over 1-72 hours in combination with other active agents. Curcumin has antioxidant and anti-inflammatory activity, and can block autonomous intracellular signaling pathways abnormally responsive to extracellular growth factors, uncontrolled proliferation of cells and fibrosis-associated and tissue degenerative conditions. Specifically, Curcumin reacts negatively with components of key signaling pathways commanding proliferation, metabolism, survival and death.
- Curcumin as an extract of turmeric root is available to researchers as a mixture of three curcuminoids and to the public as a food supplement or spice according to the FDA.
- the extract is 79.2% curcumin (diferuloylmethane), 18.27% demethoxycurcumin, and 2.53 % bisdemethoxycurcumin.
- Synthesized curcumin is GMP grade 99.2% pure diferuloylmethane produced for non human experimental study and future Phase I clinical trials. There are obvious differences between the C3 three component extract and the single component synthesized S-curcumin that extend to discernable analytic, physicochemical, and biological characteristics.
- the diferuloylmethane is 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96% pure diferuloylmethane.
- the present invention relates to synthetic curcumin (S-curcumin) and compares the properties and the activity of S-curcumin with liposomal curcumin, NANOCURC ® , and PLGA- curcumin (hereinafter C3 -complex).
- Liposomal curcumin The initial studies of liposomal curcumin were done using material bought as the complex. 6 7 Studies with S-curcumin are Mach CM, et al (2009) 8 and Mach CM et al (20 lO) 9 [0066] NANOCURC ® : The initial study of Nanocurc® was done using product bought as the complex Savita Bisht et al (2007) 10 used a non-sabinsa source. Since then studies with S-curcumin are used in the remainder of Nanocurc® publications. 11 13
- PLGA-curcumin The initial studies of PLGA-curcumin were done using product manufactured as the C3 -complex. 14-18 Studies included PLGA -curcumin C3 complex and PLGA- S-curcumin pharmacokinetic studies in rat brains.
- FIG. 4A is a graph that shows the effect of liposomal curcumin on liver function during sepsis, including aspartate aminotransferase (AST) and alanine aminotransferase (AST) levels in a mouse model system. The results show the effectiveness of liposomal curcumin compared to the standard of care in sepsis for age matched controls. Liposomal curcumin showed a higher effectiveness when compared to the standard of care for AST and ALT.
- FIGS. 4B to 4D are graphs that show the effect of liposomal curcumin during sepsis on kidney function for glomerular filtration rate (GFR) by measuring Creatine, Neutrophil gelatinase-associated lipocalin (NGAL) which measures the progression of chronic kidney disease, and Blood Urea Nitrogen which measures the kidney’s ability to remove urea from blood, respectively.
- Liposomal curcumin showed a higher effectiveness is preserving kidney function when compared to the standard of care, in particular, and importantly with NGAL which measures the progression of chronic kidney disease.
- FIGS. 4E and 4F are graphs that show the effect of liposomal curcumin during sepsis on heart function for c-Troponin, which measures cardia tissue damage and the percent ejection fraction, which measures the efficacy with which the left ventricle (or right ventricle) pumps blood with each heartbeat.
- Liposomal curcumin showed a decrease in cardiac damage when compared to the standard of care and equaled the standard of care in percent ejection fraction.
- FIG. 4G is a graph that shows the effect of liposomal curcumin during sepsis on overall survival. Liposomal curcumin showed a higher survival time versus the standard of care treatment.
- Brain damage after traumatic brain injury is a two-stage process: the injury caused by the initial insult is followed by a stage of inflammation where a great deal of additional damage may occur.
- This inflammation begins within minutes of the initial insult and can continue for months or years, and results from a complex series of metabolic processes involving marked increases in cytokines, particularly the pro-inflammatory cytokines, interleukin- 1b, interleukin-6 and tumor necrosis factor-a. Levels of these cytokines may increase thousands of times more than the corresponding levels in serum. Strategies to control the levels of these pro- inflammatory cytokines and to reduce the cytokine-induced brain damage are discussed. There is extensive evidence from experiments in animal models that suppression of cytokines is effective in ameliorating neurologic damage after TBI. However, the efficacy of this approach remains to be proven in patient trials.
- Cytokine storm also known as 'cytokine release syndrome,' can occur after infection with malaria [1], SARS [2], dengue [3], leptospirosis [4], Lassa fever [5], gram-negative sepsis [6] as well as with numerous other infectious diseases (7-10] Cytokine storm is a major cause of death in patients with Ebola [11-13] Patients with cytokine storm may experience increased vascular permeability, severe hemorrhage and multi organ failure, which may ultimately be the cause of a fatal outcome [8, 13, 14] Marked increases in systemic cytokine levels, of both pro -inflammatory and anti-inflammatory cytokines, are seen.
- Cytokine storm is also a recognized complication of treatment with the commonly-used antineoplastic agent rituximab [22], as well as of treatment with the monoclonal antibodies, tositumomab, alemtuzumab, muromonab and blinatumomab [23] Elevated levels of cytokines are found and are thought to be an important cause of the pathology in many neurological conditions, including Alzheimer’s disease [24], Parkinson’s disease [25], autism [26], and multiple sclerosis [27], as well as in the acute phase of Guillian-Barre syndrome [28, 29] .
- TBI represents a major health problem in the United States, with 1.7 million cases, 275 000 hospitalizations and 52 000 deaths each year [34], and neuropsychiatric sequalae are common, especially after severe injury [35]
- ILj-Ib interleukin
- IL-6 tumour necrosis factor
- TNF tumour necrosis factor
- IL-6 is not usually detectable in CSF, or is detectable in only very low concentrations (1-23 pg/ml) [37, 38]
- CSF levels of IL-6 as high as 35 500 pg/ml were seen after severe TBI [38, 39]
- These IL-6 levels were 40-100x greater than the corresponding levels in the serum of these patients [40]
- Kushi et al reported very large increases in both IL-6 and IL-8, measured on admission, at 24 hours, at 72 hours and at 168 hours after severe TBI in 22 patients.
- IL-6 values at these times in the CSF were 15 241, 97384, 548 225 and 336 500 pg/ml compared to 102, 176, 873, 3 059 pg/ml in the blood, a 'storm' of cytokines mostly localized to the brain.
- average IL-6 CSF values were lower, but still much greater than in the peripheral blood: 5 376, 3 565, 328 and 764 pg/ml compared to 181, 105, 37 and 26 pg/ml in the blood [41] Similar differences were seen for IL-8.
- IL-8 levels in the CSF are normally very low (5-72 pg/ml) [37]
- Kushi et al reported CSF IL-8 levels that were consistently elevated thousands of times more than normal levels or comparable levels in the peripheral blood [41]
- IL-6 and IL-8 blood levels that remained markedly elevated after 72 hours correlated with a worse prognosis and high fatality rate.
- Helmy et al found marked elevations of multiple cytokines, including IL-la, IL-Ib, IL-6, IL-8, IL-10, monocyte chemotactic protein (MCP-1) and macrophage inflammatory protein-la (MIP-la), in brain extracellular fluid after severe TBI in 12 patients.
- MCP-1 monocyte chemotactic protein
- MIP-la macrophage inflammatory protein-la
- Interleukin- 1 The IL-1 family is a group of 11 cytokines which are intimately involved in the body’s response to injury or infection [48, 49], and which also play a key role in tumour angiogenesis [50] and stimulation of cancer stem cells [51]
- the most important cytokines of the IL-1 group are IL-Ib, IL-1 a and the IL-1 receptor antagonist, IL-1RA, but the IL-1 group also includes the pro-inflammatory cytokines IL-18, IL-33 and IL-36, as well as several less well- studied cytokines.
- the key cytokine IL-Ib is a protein produced by activated macrophages.
- IL-1RA IL-1RA
- Yang et al showed that the cerebral damage caused by middle cerebral artery occlusion in mice was reduced in those animals that were previously transfected with an adenoviral vector to induce IL-1RA overexpression
- Jones et al showed that a single intracerebroventricular dose of IL-1RA administered to mice at the time of TBI reduced lesion volume, resulted in functional improvement and caused a major decrease in nitric oxide synthase-2 -positive cells in the lesion [63-Jones].
- Sanderson et al studied the effect of systemically-administered IL-1RA to Sprague Dawley rats after TBI.
- Hasturk et al showed IL-1RA reduced tissue IL-Ib levels and increased levels of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase in rats after TBI [65] .
- Other groups have reported similar results [66, 67] .
- IL-1RA Human recombinant IL-IRA has been a standard medication for patients with rheumatoid arthritis for several years, and its use has been investigated in a number of diseases where increased cytokines play a role in the destructive process, including diabetes [70], heart failure [71], multiple myeloma [72] and sepsis [73]
- IL-IRA In a randomized phase II trial of patients with acute stroke, there was less loss of cognitive function in patients treated with IL-IRA compared to the control group
- Helmy et al conducted a phase II controlled trial of this agent in 20 patients with severe TBI, and were able to conclude that IL-IRA does cross the blood-brain barrier and is safe in this population [75] They were unable to conclude that IL-IRA administration resulted in therapeutic benefit in these patients [75] While many of these results seem promising, however, the efficacy of IL-IRA may be limited, as it directly blocks only
- TNF-a Tumor necrosis factor-a.
- This cytokine plays an important role in the body’s response to infections and to cancer. Since the report on TNF-a by Helson et al in 1975 [77], aberrant TNF-a function has been reported in numerous diseases, including conditions as diverse as diabetes [78], cardiovascular disease [79], inflammatory bowel disease [80] and Alzheimer’s disease [81] TNF blockers, such as infliximab, etanercept, and adalimumab, are standard therapies for patients with rheumatoid arthritis, ankylosing spondylitis and psoriasis.
- TNF-a is thought to have both beneficial and detrimental effects in patients with TBI [46] .
- results in experimental models suggest that these effects are mostly detrimental, especially when excessive levels of this cytokine are produced.
- Knoblach et al reported the correlation of TNF levels and the degree of brain injury and neurological impairment in rats after experimental TBI, with the highest levels of TNF at 1-4 hours after injury in rats with the most severe brain injury [82] .
- studies with the TNF-blocker, etanercept have consistently shown reduction of brain damage in these animals after administration of this agent.
- TNF blockers have been studied extensively in animal models, little work has been done to assess the potential efficacy of these agents in patients with TBI [92] Tobinick et al reviewed the medical records of 617 patients with stroke and 12 with TBI who had been treated with etanercept. Marked improvement in neurological function was observed, even for patients treated more than 10 years after the initial insult. The investigators concluded that this supported the view that long-term inflammation, perhaps lasting many years, was a major cause of neurological impairment in these patients [93] However, the small number of patients in the TBI group and the lack of a control group make the data in this report difficult to interpret, as it is not clear that TNF blockade was responsible for the observed improvement.
- TNF blockers may have substantial toxicity.
- TNF blockers target only a single cytokine, and since the use of these agents is contradicted in combination with IL-1 antagonists, the use of these blockers may not be the most effective strategy in treatment of these patients.
- Interleukin-6 A third major pro-inflammatory cytokine is IL-6.
- IL-6 A third major pro-inflammatory cytokine is IL-6.
- TNF-a elevated levels of IL-6 have been thought to have a role in the causation of numerous diseases, and like TNF-a, IL-6 is thought to have beneficial as well as harmful effects after TBI [94] Indeed, IL-6 appears to have both a beneficial and a deleterious role in a number of neurological conditions [95]
- IL-6 plays a key role in induction of nerve growth factor by astrocytes, and thus in the repair of the injured brain [39]
- Ley et al reported that IL-6 knockout mice demonstrated reduced neurological function after TBI compared to normal mice, again suggesting IL-6 is necessary for neuronal recovery.
- the IL-6 knockout mice did, however, show significantly elevated levels of IL-Ib [96]
- the neuroprotective role of IL-6 was also suggested in a study of frontal lobe parenchymal IL-6 levels in patients after severe TBI. Markedly elevated IL-6 levels were found in survivors compared to those who died, while levels of IL-Ib were not different
- Anti-inflammatory cytokines such as IL-4, IL-10, IL-11 IL-13 and transforming growth factor (TGF)-[L can also be markedly elevated in inflammatory conditions.
- TGF transforming growth factor
- One of the major functions of these cytokines is to inhibit synthesis of pro- inflammatory cytokines
- IL-10 is the most important anti-inflammatory cytokine, and IL- 10 levels are markedly elevated in the brain and CSF after TBI [54, 108]
- IL-10 is known to also have pro-inflammatory functions [107], its main effect after TBI appears to be primarily protective against inflammatory damage.
- Kumar et al studied cytokine levels in 87 patients with severe TBI over a twelve-month period and found that patients with an elevated IL- 6/IL-10 ratio at six months had a poor prognosis [109]
- BBis et al showed IL-10 blocks caspase- 3 and reduces neuronal death after exposure of rat cerebellar granule cells in culture to toxic doses of glutamate [110]
- Knoblach et al showed that either intravenous or subcutaneous administration of IL-10 after experimental TBI in rats could reduce synthesis of IL-1 and enhance neurological recovery in the animals. Intracerebroventricular administration was not effective, however [111].
- mice deficient in IL-10 failed to respond to the beneficial effects of hyperbaric oxygen treatment after TBI (112- X. Chen 2013).
- Bethea et al showed that IL-10 reduced TNF-a production and improved motor function after spinal cord injury in rats [113]
- Similar neuroprotective effects of IL-10 were also seen in other studies of experimental spinal cord injury [114, 115] This suggests another approach to the treatment of TBI in patients might be administration of an anti-inflammatory cytokine like IL-10.
- Trials of recombinant human IL- 10 (ilodecakin) have been done in a number of diseases. However, results have so far been disappointing [116]
- progestins It is well known, from studies in animal systems, that progestins can reduce neuronal damage after TBI [117-121] A major mechanism for the neuroprotection seen with progestins is the ability of these agents to suppress pro-inflammatory cytokines. Cutler et al showed that progesterone given to aged male rats after TBI reduced brain levels of IL-6 at 24, 48 and 72 hours. Decreased levels of NF-KB and COX-2 were also seen, and the rats demonstrated improved motor skills, decreased cerebral edema and decreased mortality (122 -Cutler). He et al reported that intraperitoneal administration of progesterone could reduce IL-Ib and TNF-a at 3 hours after injury.
- Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are used to inhibit cholesterol production in the liver. These drugs are widely utilized clinically in patients with hypercholesterolemia. Statins are also known to have marked anti-inflammatory effects. Chen et al showed that lovastatin pre-administered to rats with experimental TBI caused marked decreases in IL-Ib and TNF-a in the areas of brain injury at 6 hours and at 96 hours post injury.
- this trial included only 8 rosuvastatin patients and 13 controls, while 21 of the 43 assessed TBI patients were deemed ineligible.
- Sanchez-Aquilar et al reported that the rosuvastatin patients had a dramatic decrease in plasma levels of TNF-a compared to placebo and an improvement in disability scores. No effect was seen on IL-Ib, IL-6 or IL-10 [139]
- Rasras et al investigated the effects of a similar agent, simuvastatin, in a randomized trial of 66 patients with severe TBI; however, no difference was found between the treated and the control groups [140] [0095] Tetracyclines.
- Tetracyclines have been shown, in animal models, to suppress inflammation and better outcomes in several neurological conditions.
- minocycline could reduce IL-Ib and IL-6 expression and microglial and macrophage activation in mice after TBI. Neurological functioning was better at day 1 in treated mice, although there was no difference between treated mice and controls at day 4 [141] Later studies by this same group did show, however, comparative improvement in the minocycline group by 6 weeks [142]
- Shanchez Mejia et al reported that minocycline given to mice after TBI reduced IL-Ib by inhibiting caspase-1 activation, resulting in improved neurological function and decreased lesion volume in the treated animals [143]
- Lee et al showed that minocycline given to rats after spinal cord injury reduced TNF-a, increased IL-10, reduced neuronal cell death and improved motor function
- Yrjanheikki reported that either doxycycline or minocycline could reduce mRNA induction of IL-Ib converting enzyme and protect
- Cyclosporine is a potent, immunosuppressant drug. Because of its wide-ranging effects on cytokines [162-165], and activity in animal models [166], it has been studied in trials of patients with TBI. However, a randomized, placebo-controlled, trial of this agent in patients with TBI showed no activity [167] A formulation of cyclosporine (neurostat) continues to be investigated in patients with TBI and other neurological conditions, although a recent report showed neurostat had no neuroprotective activity in acute ischemic stroke [168]
- TBI pro-inflammatory cytokines
- Carprofen a COX-2 inhibitor, which is currently used to treat arthritis in dogs and other animals, was found to markedly reduce IL-Ib and IL-6, and to improve neurological functioning in mice after TBI
- Triptolide a diterpenoid epoxide, which has anti-cancer activity in animal models, was found to suppress IL-Ib, IL-6 and TNF-a, to increase IL-10 levels and to reduce neuronal apoptosis in Sprague-Dawley rats after experimental TBI
- TSG-6 TNF-a stimulated gene/protein 6
- MIP-la pro-inflammatory cytokines
- Watanabe et al showed that administration of this agent to mice after TBI
- the brain damage after TBI may be markedly worsened during a succeeding phase of brain inflammation.
- Dining this phase massive increases occur in the levels of key cytokines, particularly IL-Ib, IL-6 and TNF-a, a 'cerebral cytokine storm' where levels may increase thousands of times compared to their corresponding levels in serum.
- cytokines particularly IL-6 and TNF-a
- IL-6 and TNF-a may have beneficial actions, evidence suggests excessive levels are harmful, since numerous studies in animal models have shown blockade of these cytokines can reduce brain injury.
- suppression of pro-inflammatory cytokines can limit the secondary damage caused by neuro-inflammation after TBI.
- the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
- “comprising” may be replaced with “consisting essentially of’ or “consisting of’.
- the phrase “consisting essentially of’ requires the specified integer(s) or steps as well as those that do not materially affect the character or function of the claimed invention.
- the term “consisting” is used to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method/process step or a limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), propertie(s), method/process steps or limitation(s)) only.
- words of approximation such as, without limitation, “about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present.
- the extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature.
- a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ⁇ 1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
- compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
- Clark IA Alieva LM
- Budd AC Budd AC
- Cowden WB Understanding the role of inflammatory cytokines in malaria and related diseases. Travel Med Infect Dis 2008, 6:67-81.
- IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA 2003;100:2645-2650.
- Antagonism of the interleukin- 1 receptor following traumatic brain injury in the mouse reduces the number of nitric oxide synthase-2-positive cells and improves anatomical and functional outcomes. Eur J Neurosci 2005;22:72-78.
- Genovese MC Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2014;50:1412- 1419.
- Opal SM DePalo VA. Anti-inflammatory cytokines. Chest 2000;117:1162-1172.
- CE Agoston DV.
- Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury.
- Senol N Vietnameseroglu M. Melatonin reduces traumatic brain injury-induced oxidative stress in the cerebral cortex and blood of rats. Neural Regen Res 2014;9: 1112-1116.
- HY Cyclosporine differentially regulates interleukin- 10, interleukin- 15, and tumor necrosis factor a production by rheumatoid synoviocytes. Arthritis Rheum 2002;46:42-51.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Cell Biology (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Urology & Nephrology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pathology (AREA)
- Physics & Mathematics (AREA)
- Developmental Biology & Embryology (AREA)
- Zoology (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Microbiology (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Toxicology (AREA)
- Biophysics (AREA)
- Heart & Thoracic Surgery (AREA)
- Medical Informatics (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/945,195 US20200360300A1 (en) | 2014-12-31 | 2020-07-31 | Suppression of Cytokine Release and Cytokine Storm |
PCT/US2021/041403 WO2022026170A1 (en) | 2020-07-31 | 2021-07-13 | Suppression of cytokine release and cytokine storm |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4188398A1 true EP4188398A1 (en) | 2023-06-07 |
Family
ID=80036956
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP21850964.4A Pending EP4188398A1 (en) | 2020-07-31 | 2021-07-13 | Suppression of cytokine release and cytokine storm |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP4188398A1 (ja) |
JP (1) | JP2023536833A (ja) |
KR (1) | KR20230026468A (ja) |
CN (1) | CN116710123A (ja) |
AU (1) | AU2021315452A1 (ja) |
CA (1) | CA3189374A1 (ja) |
MX (1) | MX2023001145A (ja) |
TW (1) | TW202207907A (ja) |
WO (1) | WO2022026170A1 (ja) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2875470C (en) * | 2012-06-14 | 2021-01-12 | Universitaet Bern | Tailored liposomes for the treatment of bacterial infections |
US10286065B2 (en) * | 2014-09-19 | 2019-05-14 | Board Of Regents, The University Of Texas System | Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds |
US10739353B2 (en) * | 2014-12-31 | 2020-08-11 | Signpath Pharma, Inc. | Suppression of cytokine release and cytokine storm |
US20200360300A1 (en) * | 2014-12-31 | 2020-11-19 | Signpath Pharma, Inc. | Suppression of Cytokine Release and Cytokine Storm |
US10898483B2 (en) * | 2015-12-23 | 2021-01-26 | Moonshot Pharma Llc | Methods for inducing an immune response by promoting premature termination codon read-through |
-
2021
- 2021-07-13 CN CN202180058955.0A patent/CN116710123A/zh not_active Withdrawn
- 2021-07-13 MX MX2023001145A patent/MX2023001145A/es unknown
- 2021-07-13 JP JP2023505892A patent/JP2023536833A/ja active Pending
- 2021-07-13 KR KR1020237002192A patent/KR20230026468A/ko active Search and Examination
- 2021-07-13 WO PCT/US2021/041403 patent/WO2022026170A1/en active Application Filing
- 2021-07-13 AU AU2021315452A patent/AU2021315452A1/en active Pending
- 2021-07-13 TW TW110125635A patent/TW202207907A/zh unknown
- 2021-07-13 CA CA3189374A patent/CA3189374A1/en active Pending
- 2021-07-13 EP EP21850964.4A patent/EP4188398A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
KR20230026468A (ko) | 2023-02-24 |
TW202207907A (zh) | 2022-03-01 |
CA3189374A1 (en) | 2022-02-03 |
JP2023536833A (ja) | 2023-08-30 |
AU2021315452A1 (en) | 2023-02-02 |
CN116710123A (zh) | 2023-09-05 |
MX2023001145A (es) | 2023-03-06 |
WO2022026170A1 (en) | 2022-02-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10739353B2 (en) | Suppression of cytokine release and cytokine storm | |
US20200360300A1 (en) | Suppression of Cytokine Release and Cytokine Storm | |
Arora et al. | Macrophages: Their role, activation and polarization in pulmonary diseases | |
US11622961B2 (en) | Combination therapies for treating cancer | |
Babu et al. | Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention | |
JP2023521051A (ja) | 1’-シアノ置換カルバヌクレオシド類似体の吸入製剤 | |
US11179412B2 (en) | Methods of treating conditions involving elevated inflammatory response | |
CA3164734A1 (en) | Engineered platelets for targeted delivery of a therapeutic agent | |
JP2015199747A (ja) | 病原体に対する哺乳類先天性免疫抵抗性の刺激のための組成物 | |
Guan et al. | Dysregulated chemokine signaling in cystic fibrosis lung disease: a potential therapeutic target | |
Li et al. | Signaling pathways in macrophages: molecular mechanisms and therapeutic targets | |
KR20220158030A (ko) | 급성 폐손상 치료용 5-아미노-2,3-디히드로-1,4-프탈라진디온 | |
CN111655267A (zh) | 预防或治疗鼻病毒感染的药物 | |
JP2024528731A (ja) | 眼癌転移を予防するためのイブジラスト | |
HRP960070A2 (en) | Use of quinoxaline and protease inhibitors in a composition for the treatment of aids and/or hiv infections | |
Wang et al. | Mechanisms of PANoptosis and relevant small-molecule compounds for fighting diseases | |
O Ulgen et al. | The role of minocycline in ischemia-reperfusion injury: a comprehensive review of an old drug with new implications | |
Yang et al. | Discovery of novel aporphine alkaloid derivative as potent TLR2 antagonist reversing macrophage polarization and neutrophil infiltration against acute inflammation | |
EP4188398A1 (en) | Suppression of cytokine release and cytokine storm | |
CN115052602A (zh) | 5-胺基-2,3-二氢-1,4-酞嗪二酮在治疗罕见的慢性发炎性肺病中的用途 | |
US20230263768A1 (en) | Water-soluble artesunate-based therapy for coronavirus infection | |
TWI737974B (zh) | 用於治療增生性失調的劑量方案 | |
US20210205325A1 (en) | Methods of treating a subject having an infectious disease | |
Liu et al. | Pyroptosis in health and disease: mechanisms, regulation and clinical perspective | |
CN116600797A (zh) | 用于治疗急性呼吸衰竭和/或急性呼吸窘迫综合征的包含四氢大麻酚的组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20230118 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) |