CN113573716B - 使用飞燕草色素-3-葡萄糖苷治疗和预防疱疹病毒科的感染 - Google Patents
使用飞燕草色素-3-葡萄糖苷治疗和预防疱疹病毒科的感染 Download PDFInfo
- Publication number
- CN113573716B CN113573716B CN202080021364.1A CN202080021364A CN113573716B CN 113573716 B CN113573716 B CN 113573716B CN 202080021364 A CN202080021364 A CN 202080021364A CN 113573716 B CN113573716 B CN 113573716B
- Authority
- CN
- China
- Prior art keywords
- composition
- subject
- virus
- glucoside
- delphinidin
- 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.)
- Active
Links
- XENHPQQLDPAYIJ-PEVLUNPASA-O delphinidin 3-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC2=C(O)C=C(O)C=C2[O+]=C1C1=CC(O)=C(O)C(O)=C1 XENHPQQLDPAYIJ-PEVLUNPASA-O 0.000 title claims abstract description 192
- 241000700586 Herpesviridae Species 0.000 title abstract description 34
- 208000015181 infectious disease Diseases 0.000 title description 24
- 238000011282 treatment Methods 0.000 title description 19
- 230000002265 prevention Effects 0.000 title description 12
- 241000700605 Viruses Species 0.000 claims abstract description 50
- 230000009385 viral infection Effects 0.000 claims abstract description 35
- 208000036142 Viral infection Diseases 0.000 claims abstract description 33
- 239000000203 mixture Substances 0.000 claims description 127
- 241000700588 Human alphaherpesvirus 1 Species 0.000 claims description 37
- 241001502974 Human gammaherpesvirus 8 Species 0.000 claims description 32
- -1 permeation promoters Substances 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- 230000000699 topical effect Effects 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 230000000202 analgesic effect Effects 0.000 claims description 10
- 239000003963 antioxidant agent Substances 0.000 claims description 7
- 239000000872 buffer Substances 0.000 claims description 6
- 239000003002 pH adjusting agent Substances 0.000 claims description 6
- 239000003755 preservative agent Substances 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 239000003889 eye drop Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000001771 impaired effect Effects 0.000 claims description 4
- 239000000080 wetting agent Substances 0.000 claims description 4
- 230000036737 immune function Effects 0.000 claims description 3
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 3
- 230000001861 immunosuppressant effect Effects 0.000 claims description 3
- 239000003018 immunosuppressive agent Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 239000004480 active ingredient Substances 0.000 claims 1
- 235000010208 anthocyanin Nutrition 0.000 description 88
- 239000004410 anthocyanin Substances 0.000 description 88
- 229930002877 anthocyanin Natural products 0.000 description 88
- 150000004636 anthocyanins Chemical class 0.000 description 81
- 239000000284 extract Substances 0.000 description 66
- 210000004027 cell Anatomy 0.000 description 64
- 235000001466 Ribes nigrum Nutrition 0.000 description 57
- 240000001890 Ribes hudsonianum Species 0.000 description 56
- 235000016954 Ribes hudsonianum Nutrition 0.000 description 56
- 235000017537 Vaccinium myrtillus Nutrition 0.000 description 45
- 244000078534 Vaccinium myrtillus Species 0.000 description 43
- 241001529453 unidentified herpesvirus Species 0.000 description 39
- 235000013399 edible fruits Nutrition 0.000 description 27
- 238000000034 method Methods 0.000 description 25
- 150000001875 compounds Chemical class 0.000 description 24
- 239000003443 antiviral agent Substances 0.000 description 22
- 235000021028 berry Nutrition 0.000 description 21
- 230000000840 anti-viral effect Effects 0.000 description 20
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 19
- 230000000694 effects Effects 0.000 description 15
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 14
- 239000002105 nanoparticle Substances 0.000 description 13
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 12
- 230000003612 virological effect Effects 0.000 description 12
- 229960004150 aciclovir Drugs 0.000 description 11
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 10
- 229920002774 Maltodextrin Polymers 0.000 description 10
- 239000005913 Maltodextrin Substances 0.000 description 10
- 241000700584 Simplexvirus Species 0.000 description 10
- 244000077233 Vaccinium uliginosum Species 0.000 description 10
- VEVZSMAEJFVWIL-UHFFFAOYSA-O cyanidin cation Chemical compound [O+]=1C2=CC(O)=CC(O)=C2C=C(O)C=1C1=CC=C(O)C(O)=C1 VEVZSMAEJFVWIL-UHFFFAOYSA-O 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 229940035034 maltodextrin Drugs 0.000 description 10
- KZMACGJDUUWFCH-UHFFFAOYSA-O malvidin Chemical compound COC1=C(O)C(OC)=CC(C=2C(=CC=3C(O)=CC(O)=CC=3[O+]=2)O)=C1 KZMACGJDUUWFCH-UHFFFAOYSA-O 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 208000024827 Alzheimer disease Diseases 0.000 description 9
- GCPYCNBGGPHOBD-UHFFFAOYSA-N Delphinidin Natural products OC1=Cc2c(O)cc(O)cc2OC1=C3C=C(O)C(=O)C(=C3)O GCPYCNBGGPHOBD-UHFFFAOYSA-N 0.000 description 9
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- 241001593968 Vitis palmata Species 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 238000004113 cell culture Methods 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000008199 coating composition Substances 0.000 description 9
- 235000007242 delphinidin Nutrition 0.000 description 9
- FFNDMZIBVDSQFI-UHFFFAOYSA-N delphinidin chloride Chemical compound [Cl-].[O+]=1C2=CC(O)=CC(O)=C2C=C(O)C=1C1=CC(O)=C(O)C(O)=C1 FFNDMZIBVDSQFI-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 235000016357 Mirtillo rosso Nutrition 0.000 description 8
- 235000017606 Vaccinium vitis idaea Nutrition 0.000 description 8
- 244000077923 Vaccinium vitis idaea Species 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- RKWHWFONKJEUEF-WVXKDWSHSA-O cyanidin 3-O-beta-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CC2=C(O)C=C(O)C=C2[O+]=C1C1=CC=C(O)C(O)=C1 RKWHWFONKJEUEF-WVXKDWSHSA-O 0.000 description 8
- 229960005489 paracetamol Drugs 0.000 description 8
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 208000023275 Autoimmune disease Diseases 0.000 description 7
- 230000003833 cell viability Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 7
- 230000010076 replication Effects 0.000 description 7
- 230000007351 Aβ plaque formation Effects 0.000 description 6
- 241000701022 Cytomegalovirus Species 0.000 description 6
- 206010025323 Lymphomas Diseases 0.000 description 6
- 235000011720 Vaccinium uliginosum Nutrition 0.000 description 6
- 229930014669 anthocyanidin Natural products 0.000 description 6
- 235000008758 anthocyanidins Nutrition 0.000 description 6
- 229930182478 glucoside Natural products 0.000 description 6
- 229940038487 grape extract Drugs 0.000 description 6
- IYRMWMYZSQPJKC-UHFFFAOYSA-N kaempferol Chemical compound C1=CC(O)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 IYRMWMYZSQPJKC-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000006199 nebulizer Substances 0.000 description 6
- ZOQQFMKYEOHRMC-KFOCXKDFSA-N (2r,3r,4r,5r,6s)-2-[[(2r,3s,4s,5r,6s)-6-[5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chromenylium-3-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methoxy]-6-methyloxane-3,4,5-triol;chloride Chemical compound [Cl-].O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(=[O+]C3=CC(O)=CC(O)=C3C=2)C=2C=C(O)C(O)=C(O)C=2)O1 ZOQQFMKYEOHRMC-KFOCXKDFSA-N 0.000 description 5
- ZJWIIMLSNZOCBP-KGDMUXNNSA-N (2s,3r,4s,5r,6r)-2-[5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chromenylium-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;chloride Chemical compound [Cl-].O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CC2=C(O)C=C(O)C=C2[O+]=C1C1=CC(O)=C(O)C(O)=C1 ZJWIIMLSNZOCBP-KGDMUXNNSA-N 0.000 description 5
- 241000271566 Aves Species 0.000 description 5
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- YKRGDOXKVOZESV-WRJNSLSBSA-N Paeoniflorin Chemical compound C([C@]12[C@H]3O[C@]4(O)C[C@](O3)([C@]1(C[C@@H]42)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)C)OC(=O)C1=CC=CC=C1 YKRGDOXKVOZESV-WRJNSLSBSA-N 0.000 description 5
- PLKUTZNSKRWCCA-NQWUONRPSA-O Tulipanin Natural products O(C[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](Oc2c(-c3cc(O)c(O)c(O)c3)[o+]c3c(c(O)cc(O)c3)c2)O1)[C@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 PLKUTZNSKRWCCA-NQWUONRPSA-O 0.000 description 5
- 235000012511 Vaccinium Nutrition 0.000 description 5
- 241000736767 Vaccinium Species 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 235000007336 cyanidin Nutrition 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229960002963 ganciclovir Drugs 0.000 description 5
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 5
- 206010022000 influenza Diseases 0.000 description 5
- 235000009584 malvidin Nutrition 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- YKRGDOXKVOZESV-UHFFFAOYSA-N paeoniflorin Natural products O1C(C)(C2(CC34)OC5C(C(O)C(O)C(CO)O5)O)CC3(O)OC1C24COC(=O)C1=CC=CC=C1 YKRGDOXKVOZESV-UHFFFAOYSA-N 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 241000712461 unidentified influenza virus Species 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- USNPULRDBDVJAO-YRBSALHSSA-O Cyanidin 3-rutinoside Natural products O(C[C@@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](Oc2c(-c3cc(O)c(O)cc3)[o+]c3c(c(O)cc(O)c3)c2)O1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 USNPULRDBDVJAO-YRBSALHSSA-O 0.000 description 4
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 4
- 241000701041 Human betaherpesvirus 7 Species 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 241000712431 Influenza A virus Species 0.000 description 4
- 208000007766 Kaposi sarcoma Diseases 0.000 description 4
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 4
- CWEZAWNPTYBADX-UHFFFAOYSA-N Procyanidin Natural products OC1C(OC2C(O)C(Oc3c2c(O)cc(O)c3C4C(O)C(Oc5cc(O)cc(O)c45)c6ccc(O)c(O)c6)c7ccc(O)c(O)c7)c8c(O)cc(O)cc8OC1c9ccc(O)c(O)c9 CWEZAWNPTYBADX-UHFFFAOYSA-N 0.000 description 4
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 4
- 241000219095 Vitis Species 0.000 description 4
- 235000009754 Vitis X bourquina Nutrition 0.000 description 4
- 235000012333 Vitis X labruscana Nutrition 0.000 description 4
- 235000014787 Vitis vinifera Nutrition 0.000 description 4
- 239000012675 alcoholic extract Substances 0.000 description 4
- 150000001452 anthocyanidin derivatives Chemical class 0.000 description 4
- 238000002832 anti-viral assay Methods 0.000 description 4
- 235000019209 bilberry extract Nutrition 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- YTMNONATNXDQJF-UBNZBFALSA-N chrysanthemin Chemical compound [Cl-].O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC2=C(O)C=C(O)C=C2[O+]=C1C1=CC=C(O)C(O)=C1 YTMNONATNXDQJF-UBNZBFALSA-N 0.000 description 4
- 239000012228 culture supernatant Substances 0.000 description 4
- ADZHXBNWNZIHIX-XYGAWYNKSA-N cyanidin 3-O-rutinoside chloride Chemical compound [Cl-].O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(=[O+]C3=CC(O)=CC(O)=C3C=2)C=2C=C(O)C(O)=CC=2)O1 ADZHXBNWNZIHIX-XYGAWYNKSA-N 0.000 description 4
- 229960000684 cytarabine Drugs 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 210000002919 epithelial cell Anatomy 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229960005102 foscarnet Drugs 0.000 description 4
- 150000008131 glucosides Chemical class 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 201000006747 infectious mononucleosis Diseases 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 4
- 229960001331 keracyanin Drugs 0.000 description 4
- 239000000401 methanolic extract Substances 0.000 description 4
- 201000006417 multiple sclerosis Diseases 0.000 description 4
- 230000001537 neural effect Effects 0.000 description 4
- 229960001179 penciclovir Drugs 0.000 description 4
- 239000000049 pigment Substances 0.000 description 4
- 229920002414 procyanidin Polymers 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 4
- 229960002149 valganciclovir Drugs 0.000 description 4
- 230000029812 viral genome replication Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 3
- 244000178937 Brassica oleracea var. capitata Species 0.000 description 3
- 208000011691 Burkitt lymphomas Diseases 0.000 description 3
- 241000252233 Cyprinus carpio Species 0.000 description 3
- 229940123014 DNA polymerase inhibitor Drugs 0.000 description 3
- UBSCDKPKWHYZNX-UHFFFAOYSA-N Demethoxycapillarisin Natural products C1=CC(O)=CC=C1OC1=CC(=O)C2=C(O)C=C(O)C=C2O1 UBSCDKPKWHYZNX-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 241000283086 Equidae Species 0.000 description 3
- 208000009889 Herpes Simplex Diseases 0.000 description 3
- 208000029433 Herpesviridae infectious disease Diseases 0.000 description 3
- 241000701027 Human herpesvirus 6 Species 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- 241000282553 Macaca Species 0.000 description 3
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 3
- 241001290151 Prunus avium subsp. avium Species 0.000 description 3
- 240000007651 Rubus glaucus Species 0.000 description 3
- 235000011034 Rubus glaucus Nutrition 0.000 description 3
- 235000009122 Rubus idaeus Nutrition 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 235000003095 Vaccinium corymbosum Nutrition 0.000 description 3
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 235000021014 blueberries Nutrition 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 235000019693 cherries Nutrition 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 229920002770 condensed tannin Polymers 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229960004396 famciclovir Drugs 0.000 description 3
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 235000008777 kaempferol Nutrition 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 3
- 235000016709 nutrition Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- HKUHOPQRJKPJCJ-UHFFFAOYSA-N pelargonidin Natural products OC1=Cc2c(O)cc(O)cc2OC1c1ccc(O)cc1 HKUHOPQRJKPJCJ-UHFFFAOYSA-N 0.000 description 3
- 235000006251 pelargonidin Nutrition 0.000 description 3
- YPVZJXMTXCOTJN-UHFFFAOYSA-N pelargonidin chloride Chemical compound [Cl-].C1=CC(O)=CC=C1C(C(=C1)O)=[O+]C2=C1C(O)=CC(O)=C2 YPVZJXMTXCOTJN-UHFFFAOYSA-N 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 238000002627 tracheal intubation Methods 0.000 description 3
- 229940093257 valacyclovir Drugs 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- YDIKCZBMBPOGFT-DIONPBRTSA-N (2s,3r,4s,5s,6r)-2-[5,7-dihydroxy-2-(4-hydroxy-3,5-dimethoxyphenyl)chromenylium-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;chloride Chemical compound [Cl-].COC1=C(O)C(OC)=CC(C=2C(=CC=3C(O)=CC(O)=CC=3[O+]=2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=C1 YDIKCZBMBPOGFT-DIONPBRTSA-N 0.000 description 2
- NGSWKAQJJWESNS-UHFFFAOYSA-N 4-coumaric acid Chemical compound OC(=O)C=CC1=CC=C(O)C=C1 NGSWKAQJJWESNS-UHFFFAOYSA-N 0.000 description 2
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 241000272201 Columbiformes Species 0.000 description 2
- 208000028399 Critical Illness Diseases 0.000 description 2
- 230000004543 DNA replication Effects 0.000 description 2
- OIZFQAFWYYKPMR-PEVLUNPASA-N Delphinidin 3-O-glucoside Natural products O([C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)C=1[C-](c2cc(O)c(O)c(O)c2)[O+]c2c(c(O)cc(O)c2)C=1 OIZFQAFWYYKPMR-PEVLUNPASA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- 235000016623 Fragaria vesca Nutrition 0.000 description 2
- 240000009088 Fragaria x ananassa Species 0.000 description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 2
- 206010019973 Herpes virus infection Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101001033233 Homo sapiens Interleukin-10 Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 2
- 235000011430 Malus pumila Nutrition 0.000 description 2
- 244000070406 Malus silvestris Species 0.000 description 2
- 235000015103 Malus silvestris Nutrition 0.000 description 2
- 240000000982 Malva neglecta Species 0.000 description 2
- 235000000060 Malva neglecta Nutrition 0.000 description 2
- YDIKCZBMBPOGFT-PWUSVEHZSA-N Malvidin 3-galactoside Chemical compound [Cl-].COC1=C(O)C(OC)=CC(C=2C(=CC=3C(O)=CC(O)=CC=3[O+]=2)O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)=C1 YDIKCZBMBPOGFT-PWUSVEHZSA-N 0.000 description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- 206010067152 Oral herpes Diseases 0.000 description 2
- 235000014441 Prunus serotina Nutrition 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
- 206010037779 Radiculopathy Diseases 0.000 description 2
- 244000281247 Ribes rubrum Species 0.000 description 2
- 235000016911 Ribes sativum Nutrition 0.000 description 2
- 235000002355 Ribes spicatum Nutrition 0.000 description 2
- 235000016897 Ribes triste Nutrition 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- UNZIDPIPYUMVPA-UHFFFAOYSA-M Sulpyrine Chemical compound O.[Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 UNZIDPIPYUMVPA-UHFFFAOYSA-M 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 244000151602 Vaccinium ellipticum Species 0.000 description 2
- 244000077036 Vaccinium membranaceum Species 0.000 description 2
- 235000011708 Vaccinium membranaceum Nutrition 0.000 description 2
- 108020000999 Viral RNA Proteins 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940102480 bilberry extract Drugs 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 238000003570 cell viability assay Methods 0.000 description 2
- 229940125507 complex inhibitor Drugs 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- 230000000312 effect on influenza Effects 0.000 description 2
- 230000002996 emotional effect Effects 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- HVQAJTFOCKOKIN-UHFFFAOYSA-N flavonol Natural products O1C2=CC=CC=C2C(=O)C(O)=C1C1=CC=CC=C1 HVQAJTFOCKOKIN-UHFFFAOYSA-N 0.000 description 2
- 150000002216 flavonol derivatives Chemical class 0.000 description 2
- 235000011957 flavonols Nutrition 0.000 description 2
- NWKFECICNXDNOQ-UHFFFAOYSA-N flavylium Chemical compound C1=CC=CC=C1C1=CC=C(C=CC=C2)C2=[O+]1 NWKFECICNXDNOQ-UHFFFAOYSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 2
- 102000052620 human IL10 Human genes 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 150000005828 hydrofluoroalkanes Chemical class 0.000 description 2
- 239000000017 hydrogel Substances 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
- 238000001802 infusion Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000004816 latex Substances 0.000 description 2
- 229920000126 latex Polymers 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- GXPTVXHTZZVLMQ-GCGJSEPQSA-N myrtillin Natural products O[C@H]1O[C@@H](OCC2=C(OC3=CC(=O)C=C(O)C3=C2)c4cc(O)c(O)c(O)c4)[C@H](O)[C@@H](O)[C@@H]1O GXPTVXHTZZVLMQ-GCGJSEPQSA-N 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- 230000002276 neurotropic effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 235000016236 parenteral nutrition Nutrition 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 229960005222 phenazone Drugs 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 150000008442 polyphenolic compounds Chemical class 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- 230000007420 reactivation Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007423 screening assay Methods 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 230000007419 viral reactivation Effects 0.000 description 2
- XFZJEEAOWLFHDH-UHFFFAOYSA-N (2R,2'R,3R,3'R,4R)-3,3',4',5,7-Pentahydroxyflavan(48)-3,3',4',5,7-pentahydroxyflavan Natural products C=12OC(C=3C=C(O)C(O)=CC=3)C(O)CC2=C(O)C=C(O)C=1C(C1=C(O)C=C(O)C=C1O1)C(O)C1C1=CC=C(O)C(O)=C1 XFZJEEAOWLFHDH-UHFFFAOYSA-N 0.000 description 1
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 description 1
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- CWVRJTMFETXNAD-FWCWNIRPSA-N 3-O-Caffeoylquinic acid Natural products O[C@H]1[C@@H](O)C[C@@](O)(C(O)=O)C[C@H]1OC(=O)\C=C\C1=CC=C(O)C(O)=C1 CWVRJTMFETXNAD-FWCWNIRPSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-M 4-Hydroxycinnamate Natural products OC1=CC=C(\C=C\C([O-])=O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-M 0.000 description 1
- JTEGQNOMFQHVDC-RQJHMYQMSA-N 4-amino-1-[(2s,5r)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)SC1 JTEGQNOMFQHVDC-RQJHMYQMSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- AGBXEAQAOHJACV-UHFFFAOYSA-N 7-(2,3-dihydroxypropyl)-1,3-dimethyl-8-(pyridin-3-ylmethyl)purine-2,6-dione Chemical compound OCC(O)CN1C=2C(=O)N(C)C(=O)N(C)C=2N=C1CC1=CC=CN=C1 AGBXEAQAOHJACV-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- DFYRUELUNQRZTB-UHFFFAOYSA-N Acetovanillone Natural products COC1=CC(C(C)=O)=CC=C1O DFYRUELUNQRZTB-UHFFFAOYSA-N 0.000 description 1
- 241000981700 Alcelaphine gammaherpesvirus 2 Species 0.000 description 1
- 241001499808 Allium atrorubens Species 0.000 description 1
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 241000489492 Arisaema Species 0.000 description 1
- 235000007425 Aronia melanocarpa Nutrition 0.000 description 1
- 240000005662 Aronia melanocarpa Species 0.000 description 1
- 241001492313 Ateline alphaherpesvirus 1 Species 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- 208000031462 Bovine Mastitis Diseases 0.000 description 1
- 241000701083 Bovine alphaherpesvirus 1 Species 0.000 description 1
- 241000700585 Bovine alphaherpesvirus 2 Species 0.000 description 1
- 241001492322 Bovine alphaherpesvirus 5 Species 0.000 description 1
- 241000701066 Bovine gammaherpesvirus 4 Species 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- PZIRUHCJZBGLDY-UHFFFAOYSA-N Caffeoylquinic acid Natural products CC(CCC(=O)C(C)C1C(=O)CC2C3CC(O)C4CC(O)CCC4(C)C3CCC12C)C(=O)O PZIRUHCJZBGLDY-UHFFFAOYSA-N 0.000 description 1
- 241000680578 Canid alphaherpesvirus 1 Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241001535104 Caprine alphaherpesvirus 1 Species 0.000 description 1
- 241000252229 Carassius auratus Species 0.000 description 1
- 241001107116 Castanospermum australe Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 235000005976 Citrus sinensis Nutrition 0.000 description 1
- 240000002319 Citrus sinensis Species 0.000 description 1
- 235000006481 Colocasia esculenta Nutrition 0.000 description 1
- 244000205754 Colocasia esculenta Species 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241000371652 Curvularia clavata Species 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 244000000626 Daucus carota Species 0.000 description 1
- 235000002767 Daucus carota Nutrition 0.000 description 1
- 206010073508 Drug reaction with eosinophilia and systemic symptoms Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 241000709661 Enterovirus Species 0.000 description 1
- 208000024658 Epilepsy syndrome Diseases 0.000 description 1
- 208000002877 Epileptic Syndromes Diseases 0.000 description 1
- 241000701081 Equid alphaherpesvirus 1 Species 0.000 description 1
- 241001598169 Equid alphaherpesvirus 3 Species 0.000 description 1
- 241000701089 Equid alphaherpesvirus 4 Species 0.000 description 1
- 241001532692 Equid alphaherpesvirus 8 Species 0.000 description 1
- 241000544856 Equid alphaherpesvirus 9 Species 0.000 description 1
- 241000725578 Equid gammaherpesvirus 2 Species 0.000 description 1
- 241000701040 Equid gammaherpesvirus 5 Species 0.000 description 1
- 241000230501 Equine herpesvirus sp. Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 201000005866 Exanthema Subitum Diseases 0.000 description 1
- 241000701087 Felid alphaherpesvirus 1 Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241001492288 Gallid alphaherpesvirus 3 Species 0.000 description 1
- 235000004101 Gaylussacia dumosa Nutrition 0.000 description 1
- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Natural products O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 208000037952 HSV-1 infection Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 208000001688 Herpes Genitalis Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 241000692870 Inachis io Species 0.000 description 1
- 244000017020 Ipomoea batatas Species 0.000 description 1
- 235000002678 Ipomoea batatas Nutrition 0.000 description 1
- JTPUMZTWMWIVPA-UHFFFAOYSA-O Isopropamide Chemical compound C=1C=CC=CC=1C(C(N)=O)(CC[N+](C)(C(C)C)C(C)C)C1=CC=CC=C1 JTPUMZTWMWIVPA-UHFFFAOYSA-O 0.000 description 1
- GQODBWLKUWYOFX-UHFFFAOYSA-N Isorhamnetin Natural products C1=C(O)C(C)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 GQODBWLKUWYOFX-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000282564 Macaca fuscata Species 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 1
- 208000006758 Marek Disease Diseases 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 241001467058 Murid gammaherpesvirus 4 Species 0.000 description 1
- 241000108638 Murid herpesvirus 68 Species 0.000 description 1
- 241001455073 Murine herpesvirus Species 0.000 description 1
- 208000002033 Myoclonus Diseases 0.000 description 1
- IKMDFBPHZNJCSN-UHFFFAOYSA-N Myricetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC(O)=C(O)C(O)=C1 IKMDFBPHZNJCSN-UHFFFAOYSA-N 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- CWVRJTMFETXNAD-KLZCAUPSSA-N Neochlorogenin-saeure Natural products O[C@H]1C[C@@](O)(C[C@@H](OC(=O)C=Cc2ccc(O)c(O)c2)[C@@H]1O)C(=O)O CWVRJTMFETXNAD-KLZCAUPSSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 240000007377 Petunia x hybrida Species 0.000 description 1
- MOJZMWJRUKIQGL-FWCKPOPSSA-N Procyanidin C2 Natural products O[C@@H]1[C@@H](c2cc(O)c(O)cc2)Oc2c([C@H]3[C@H](O)[C@@H](c4cc(O)c(O)cc4)Oc4c3c(O)cc(O)c4)c(O)cc(O)c2[C@@H]1c1c(O)cc(O)c2c1O[C@@H]([C@H](O)C2)c1cc(O)c(O)cc1 MOJZMWJRUKIQGL-FWCKPOPSSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 235000010401 Prunus avium Nutrition 0.000 description 1
- 240000008296 Prunus serotina Species 0.000 description 1
- 206010037660 Pyrexia Diseases 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
- 238000011529 RT qPCR Methods 0.000 description 1
- 206010037898 Rash vesicular Diseases 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 206010051497 Rhinotracheitis Diseases 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
- 241001312569 Ribes nigrum Species 0.000 description 1
- OVVGHDNPYGTYIT-VHBGUFLRSA-N Robinobiose Natural products O(C[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](C)O1 OVVGHDNPYGTYIT-VHBGUFLRSA-N 0.000 description 1
- 241001412173 Rubus canescens Species 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 241000519995 Stachys sylvatica Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010044302 Tracheitis Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 235000011680 Vaccinium caespitosum Nutrition 0.000 description 1
- 241001409366 Vaccinium caespitosum Species 0.000 description 1
- 235000011681 Vaccinium deliciosum Nutrition 0.000 description 1
- 244000003993 Vaccinium deliciosum Species 0.000 description 1
- 240000001717 Vaccinium macrocarpon Species 0.000 description 1
- 235000012545 Vaccinium macrocarpon Nutrition 0.000 description 1
- 235000011722 Vaccinium ovalifolium Nutrition 0.000 description 1
- 244000000188 Vaccinium ovalifolium Species 0.000 description 1
- 235000002118 Vaccinium oxycoccus Nutrition 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 244000068697 Vitis rotundifolia Species 0.000 description 1
- 235000006359 Vitis rotundifolia var rotundifolia Nutrition 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000012387 aerosolization Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003602 anti-herpes Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 125000000089 arabinosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)CO1)* 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 208000002479 balanitis Diseases 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000021279 black bean Nutrition 0.000 description 1
- 235000019216 blueberry extract Nutrition 0.000 description 1
- 229940055416 blueberry extract Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000004883 caffeic acid Nutrition 0.000 description 1
- 229940074360 caffeic acid Drugs 0.000 description 1
- 230000004094 calcium homeostasis Effects 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 238000012200 cell viability kit Methods 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- CWVRJTMFETXNAD-JUHZACGLSA-N chlorogenic acid Chemical compound O[C@@H]1[C@H](O)C[C@@](O)(C(O)=O)C[C@H]1OC(=O)\C=C\C1=CC=C(O)C(O)=C1 CWVRJTMFETXNAD-JUHZACGLSA-N 0.000 description 1
- 235000001368 chlorogenic acid Nutrition 0.000 description 1
- 229940074393 chlorogenic acid Drugs 0.000 description 1
- FFQSDFBBSXGVKF-KHSQJDLVSA-N chlorogenic acid Natural products O[C@@H]1C[C@](O)(C[C@@H](CC(=O)C=Cc2ccc(O)c(O)c2)[C@@H]1O)C(=O)O FFQSDFBBSXGVKF-KHSQJDLVSA-N 0.000 description 1
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 1
- BMRSEYFENKXDIS-KLZCAUPSSA-N cis-3-O-p-coumaroylquinic acid Natural products O[C@H]1C[C@@](O)(C[C@@H](OC(=O)C=Cc2ccc(O)cc2)[C@@H]1O)C(=O)O BMRSEYFENKXDIS-KLZCAUPSSA-N 0.000 description 1
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000004634 cranberry Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003428 dexibuprofen Drugs 0.000 description 1
- HEFNNWSXXWATRW-JTQLQIEISA-N dexibuprofen Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 description 1
- 229960002783 dexketoprofen Drugs 0.000 description 1
- DKYWVDODHFEZIM-NSHDSACASA-N dexketoprofen Chemical compound OC(=O)[C@@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-NSHDSACASA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical class OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 229940120889 dipyrone Drugs 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000004438 eyesight Effects 0.000 description 1
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 description 1
- 235000001785 ferulic acid Nutrition 0.000 description 1
- 229940114124 ferulic acid Drugs 0.000 description 1
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 229940068517 fruit extracts Drugs 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 150000008195 galaktosides Chemical class 0.000 description 1
- 239000002223 garnet Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 201000004946 genital herpes Diseases 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- IVSXFFJGASXYCL-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=NC=N[C]21 IVSXFFJGASXYCL-UHFFFAOYSA-N 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 229930005346 hydroxycinnamic acid Natural products 0.000 description 1
- 235000010359 hydroxycinnamic acids Nutrition 0.000 description 1
- 230000006951 hyperphosphorylation Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000005562 infectious bovine rhinotracheitis Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000002664 inhalation therapy Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 150000002515 isoflavone derivatives Chemical class 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- 229960001737 isopropamide Drugs 0.000 description 1
- 235000008800 isorhamnetin Nutrition 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 201000009837 laryngotracheitis Diseases 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 201000001268 lymphoproliferative syndrome Diseases 0.000 description 1
- KKSDGJDHHZEWEP-UHFFFAOYSA-N m-hydroxycinnamic acid Natural products OC(=O)C=CC1=CC=CC(O)=C1 KKSDGJDHHZEWEP-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- PCOBUQBNVYZTBU-UHFFFAOYSA-N myricetin Natural products OC1=C(O)C(O)=CC(C=2OC3=CC(O)=C(O)C(O)=C3C(=O)C=2)=C1 PCOBUQBNVYZTBU-UHFFFAOYSA-N 0.000 description 1
- 235000007743 myricetin Nutrition 0.000 description 1
- 229940116852 myricetin Drugs 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 239000002159 nanocrystal Substances 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- PMOWTIHVNWZYFI-UHFFFAOYSA-N o-Coumaric acid Natural products OC(=O)C=CC1=CC=CC=C1O PMOWTIHVNWZYFI-UHFFFAOYSA-N 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229930015721 peonidin Natural products 0.000 description 1
- 235000006404 peonidin Nutrition 0.000 description 1
- OGBSHLKSHNAPEW-UHFFFAOYSA-N peonidin chloride Chemical compound [Cl-].C1=C(O)C(OC)=CC(C=2C(=CC=3C(O)=CC(O)=CC=3[O+]=2)O)=C1 OGBSHLKSHNAPEW-UHFFFAOYSA-N 0.000 description 1
- 229930015717 petunidin Natural products 0.000 description 1
- 235000006384 petunidin Nutrition 0.000 description 1
- QULMBDNPZCFSPR-UHFFFAOYSA-N petunidin chloride Chemical compound [Cl-].OC1=C(O)C(OC)=CC(C=2C(=CC=3C(O)=CC(O)=CC=3[O+]=2)O)=C1 QULMBDNPZCFSPR-UHFFFAOYSA-N 0.000 description 1
- 150000007965 phenolic acids Chemical class 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 206010035114 pityriasis rosea Diseases 0.000 description 1
- 231100000857 poor renal function Toxicity 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- PXWLVJLKJGVOKE-UHFFFAOYSA-N propyphenazone Chemical compound O=C1C(C(C)C)=C(C)N(C)N1C1=CC=CC=C1 PXWLVJLKJGVOKE-UHFFFAOYSA-N 0.000 description 1
- 208000009305 pseudorabies Diseases 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 125000000953 rutinose group Chemical group 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- PMOWTIHVNWZYFI-AATRIKPKSA-N trans-2-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=CC=C1O PMOWTIHVNWZYFI-AATRIKPKSA-N 0.000 description 1
- KKSDGJDHHZEWEP-SNAWJCMRSA-N trans-3-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=CC(O)=C1 KKSDGJDHHZEWEP-SNAWJCMRSA-N 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 1
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0043—Catheters; Hollow probes characterised by structural features
- A61M25/0045—Catheters; Hollow probes characterised by structural features multi-layered, e.g. coated
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
- A61M2025/0042—Microcatheters, cannula or the like having outside diameters around 1 mm or less
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0043—Catheters; Hollow probes characterised by structural features
- A61M2025/0057—Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/04—Liquids
- A61M2202/0468—Liquids non-physiological
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/06—Solids
- A61M2202/064—Powder
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Virology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Alternative & Traditional Medicine (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Anesthesiology (AREA)
- Oncology (AREA)
- Neurosurgery (AREA)
- Communicable Diseases (AREA)
- Neurology (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Biophysics (AREA)
- Ophthalmology & Optometry (AREA)
- Physiology (AREA)
Abstract
本发明涉及用于在受试者中治疗或预防病毒感染的飞燕草色素‑3‑葡萄糖苷(D3G),其中病毒来自疱疹病毒科。
Description
本发明涉及飞燕草色素-3-葡萄糖苷(D3G),用于在受试者中治疗或预防病毒感染,其中病毒来自疱疹病毒科。
花色素苷(anthocyanin)是水溶性液泡色素,取决于周围的pH值,其可以呈现红色、紫色或蓝色。花色素苷属于类黄酮类别,经由苯基丙酸途径合成。它们存在于高等植物的所有组织中,主要存在于花和果实中,并通过添加糖而来源于花色素(anthocyanidin)。花色素苷是黄盐(flavylium salt)的葡萄糖苷。每种花色素苷因此包含三个组成部分:羟基化核心(糖苷配基);糖单元;和抗衡离子。花色素苷是存在于许多花和果实中的天然色素,并且个别花色素苷可作为氯化物盐在市场上买到,例如来自挪威桑内斯的PolyphenolsLaboratories AS(Sandnes,Norway)。自然界中最常见的花色素苷是矢车菊色素(cyanidin)、飞燕草色素(delphinidin)、锦葵色素(malvidin)、天竺葵色素(pelargonidin)、芍药色素(peonidin)和矮牵牛色素(petunidin)的葡萄糖苷。
众所周知,花色素苷,尤其是源自果实摄入的花色素苷,具有广泛的生物活性,包括抗氧化、抗炎、抗微生物和抗癌活性、改善视力、诱导细胞凋亡和神经保护作用。花色素苷的特别合适的果实来源是樱桃、越橘、蓝莓、黑醋栗、红醋栗、葡萄、树莓、草莓和苹果以及蔬菜如红甘蓝。越橘,特别是黑果越橘(Vaccinium myrtillus),和黑醋栗,特别是黑茶藨子(Ribes nigrum)是尤其合适的。
越橘含有多种花色素苷,包括飞燕草色素和矢车菊色素葡萄糖苷,并且包括越橘属(Vaccinium)的几个密切相关的物种,包括黑果越橘(越橘)、笃斯越橘(Vacciniumuliginosum)(笃斯越桔(bog bilberry、bog blueberry、bog whortleberry、boghuckleberry、northern bilberry、ground hurts))、丛生越橘(Vaccinium caespitosum)(矮越橘)、甜越橘(Vaccinium deliciosum)(Cascade越橘)、膜质越橘(Vacciniummembranaceum)(山越橘、黑山越橘、黑越橘、双叶越橘)、椭圆叶越橘(Vacciniumovalifolium)(椭圆叶蓝莓、椭圆叶越桔、山蓝莓、高丛蓝莓)。
黑果越橘的干越橘果实含有高达10%的儿茶素型单宁、原花色素和花色素苷。花色素苷主要是飞燕草色素、矢车菊色素的葡萄糖苷、半乳糖苷或阿拉伯糖苷以及在较小程度上是锦葵色素、芍药色素和矮牵牛色素的葡萄糖苷、半乳糖苷或阿拉伯糖苷(矢车菊色素-3-O-葡萄糖苷(C3G)、飞燕草色素-3-O-葡萄糖苷(D3G)、锦葵色素-3-O-葡萄糖苷(M3G)、芍药色素-3-O-葡萄糖苷和矮牵牛色素-3-O-葡萄糖苷)。黄酮醇包括槲皮素-和山柰酚(kaempferol)-葡萄糖苷。果实还含有其他酚类化合物(例如绿原酸,咖啡酸,邻、间和对香豆酸以及阿魏酸)、柠檬酸和苹果酸以及挥发性化合物。
黑醋栗果实(黑茶藨子)含有高水平的多酚,尤其是花色素苷、酚酸衍生物(羟基苯甲酸和羟基肉桂酸)、黄酮醇(杨梅黄酮、槲皮素、山柰酚和异鼠李素的葡萄糖苷)和原花色素(120至166mg/100g新鲜浆果)。主要的花色素苷是飞燕草色素-3-O-芸香糖苷(D3R)和矢车菊色素-3-O-芸香糖苷(C3R),但也发现了飞燕草色素-3-O-葡萄糖苷和矢车菊色素-3-O-葡萄糖苷(Gafner,Bilberry–Laboratory Guidance Document 2015,BotanicalAdulterants Program)。
EP 1443948 A1涉及一种用于制备包含来自黑醋栗和越橘的提取物的花色素苷混合物的营养补充剂(保健品)的方法。花色素苷是从果皮的饼中提取的,果皮的饼是在黑果越橘和黑茶藨子的果汁压榨过程中产生的废物产物。可以表明,如果口服施用不同花色素苷的组合,特别是包含单糖和二糖花色素苷两者的组合,来替代单个花色素苷,则单个花色素苷的有益效果会增强。据认为,协同效应至少部分源于不同花色素苷的不同溶解度和不同吸收特征。
疱疹病毒科是一大科的DNA病毒,在人中引起的感染和某些疾病,例如口腔疱疹、水痘和传染性单核细胞增多症样综合征。此外,它们可能与严重的病理生理学有关,包括阿尔茨海默病、伯基特淋巴瘤和卡波西肉瘤。潜伏、反复感染也是这组病毒的典型特征,例如全世界超过50%的人口对人巨细胞病毒(hCMV)呈血清阳性。这种无处不在的疱疹病毒是人类广泛感染的原因,尽管在免疫活性宿主中是良性的,但免疫系统不成熟或受损的患者(如AIDS患者或器官移植接受者)遭受危及生命的并发症。
总共已知超过130种疱疹病毒,但已知有9种疱疹病毒引起人类疾病,例如单纯疱疹病毒1和2(HSV-1和HSV-2,也称为HHV1和HHV2)导致口腔和/或生殖器疱疹以及其他单纯疱疹感染,靶向粘膜上皮细胞和神经元潜伏。水痘-带状疱疹病毒(VZV、HHV-3)也靶向粘膜上皮细胞(神经元潜伏)并引起水痘和带状疱疹。埃巴病毒(EBV,HHV-4)靶向B细胞(包括在B细胞中的潜伏)和上皮细胞,并且是传染性单核细胞增多症、伯基特淋巴瘤、AIDS患者的CNS淋巴瘤、移植后淋巴增生综合征(PTLD)、鼻咽癌和HIV相关的毛状白斑的原因。人巨细胞病毒(HCMV、HHV-5)靶向单核细胞和上皮细胞(单核细胞作为潜伏位点)并引起传染性单核细胞增多症样综合征和视网膜炎。人疱疹病毒6A和6B(HHV-6A和HHV-6B)靶向T细胞(包括潜伏位点)并引起第六种疾病(婴儿玫瑰疹或幼儿急疹)。人疱疹病毒7(HHV-7)也靶向T细胞并且是药物诱发的超敏反应综合征、脑病、半惊厥-偏瘫-癫痫综合征、肝炎感染、感染后脊髓神经根病、玫瑰糠疹和HHV-4重新激活的原因,导致“单核细胞增多症样疾病”。卡波西肉瘤相关疱疹病毒(KSHV、HHV-8)靶向淋巴细胞和其他细胞并导致卡波西肉瘤、原发性渗出性淋巴瘤、某些类型的多中心卡斯尔曼病。
疱疹病毒以其在宿主中建立终生感染的能力而闻名,这是通过免疫逃避来实现的。有趣的是,疱疹病毒有许多不同的方式来逃避免疫系统,例如在受感染细胞中模仿人类白细胞介素10(hIL-10)或下调主要组织相容性复合体II(MHC II)。
在过去十年中,人们对疱疹病毒的复制和致病状态有了更好的了解,部分原因是开发了靶向这些病毒的有效抗病毒化合物。虽然这些抗病毒疗法中的一些被认为是安全有效的(阿昔洛韦、喷昔洛韦),但一些具有与之相关的毒性(更昔洛韦和膦甲酸)。阿昔洛韦最严重的副作用是神经毒性,这通常发生在肾功能受损且达到高血清药物浓度的受试者中(Revankar等人,1995)。神经毒性表现为嗜睡、意识模糊、幻觉、震颤、肌阵挛、癫痫发作、锥体外系体征和意识状态改变,在开始疗法的最初几天内出现。这些体征和症状通常会在停用阿昔洛韦后的几天内自行消退。HSV对阿昔洛韦的抗性已成为一个重要的临床问题,尤其是在接受长期疗法的免疫功能受损的患者中(Englund等人,1990)。
在上下文中,令人惊讶地发现,黑醋栗和越橘的提取物,并且特别是在这些提取物中存在的飞燕草素-3-葡萄糖苷介导对疱疹病毒感染和复制的强烈抑制。因此,本发明基于飞燕草素-3-葡萄糖苷作为抗病毒剂在治疗和预防疱疹感染中的用途。因此,通过将抗病毒作用与其对细胞活力的积极影响和无毒性相组合,飞燕草素-3-葡萄糖苷可以成为各种疱疹感染及其相关疾病的重要解决方案。
本发明涉及飞燕草素-3-葡萄糖苷(D3G),用于在受试者中治疗或预防病毒感染,其中病毒来自疱疹病毒科。
飞燕草素-3-葡萄糖苷可如下式所示:
还旨在包括D3G的药学上可接受的多晶型物、前药、异构体、盐和衍生物。
在一个实施方案中,D3G用于治疗或预防病毒感染,其中病毒来自α疱疹病毒亚科或γ疱疹病毒亚科,优选地其中受试者是人。
根据本发明使用的D3G特别用于治疗或预防人类宿主中的病毒感染,所述病毒选自:
单纯疱疹病毒1和2(HSV-1和HSV-2、HHV1和HHV2),
水痘-带状疱疹病毒(VZV,HHV-3),
埃巴病毒(EBV,HHV-4),
人巨细胞病毒(HCMV,HHV-5),
人疱疹病毒6A和6B(HHV-6A和HHV-6B),
人疱疹病毒7(HHV-7),和
卡波西肉瘤相关疱疹病毒(KSHV、HHV-8)。
病毒优选地是HSV-1、EBV、CMV或HHV-8,更优选地是HSV-1和HHV-8,并且D3G优选地阻抑病毒感染。
此外,疱疹病毒代表脑中最常检测到的病原体。在持续的免疫压力下,这些感染在健康宿主中基本上是无症状的。然而,在其他压力源和遗传风险因素的背景下,许多嗜神经性疱疹病毒与中枢神经系统病理学直接相关。有迹象表明嗜神经性疱疹病毒,例如单纯疱疹病毒1(HSV-1)和人疱疹病毒6(HHV-6)导致神经退行性疾病病理学,例如阿尔茨海默病(AD)(Hogestyn等人,Neural Regeneration Research 13(2),211-221,2018)。例如,在与淀粉样斑块相同的区域中发现了单纯疱疹病毒HSV-1。已经表明HSV-1诱导AD相关的病理生理学和病理学,包括神经元产生和淀粉样蛋白β(Aβ)的积累、tau蛋白的过度磷酸化、钙稳态失调和自噬受损(Harris&Harris Frontiers in Aging Neuroscience Vol 10(48),2018)。这表明可以用抗病毒药物治疗或预防AD的可能性。
根据本发明,还进一步优选的是D3G用于治疗或预防以下的病毒感染的用途:
侏猴疱疹病毒1(蛛猴疱疹病毒)、牛疱疹病毒2(引起牛乳房炎和假结节性病)、猕猴(Cercopithecine)疱疹病毒1(也称为疱疹B病毒,在猕猴中引起单纯疱疹样疾病,如果在人中出现症状且未治疗,通常会致命),猴(Macacine)疱疹病毒1,
牛疱疹病毒1(引起牛的传染性牛鼻气管炎、阴道炎、龟头包皮炎和流产)、牛疱疹病毒5(引起牛的脑炎)、水泡疱疹病毒1、山羊疱疹病毒1(引起山羊的结膜炎和呼吸道疾病)、犬疱疹病毒1(引起幼犬的严重出血性疾病)、马疱疹病毒1(引起马的呼吸系统疾病、神经系统疾病/麻痹和自然流产)、马疱疹病毒3(引起马的水疱性媾疹)、马疱疹病毒4(引起马的鼻肺炎)、马疱疹病毒8、马疱疹病毒9、猫疱疹病毒1(引起猫的猫病毒性鼻气管炎和角膜炎)、猪疱疹病毒1(引起基氏病,也称为伪狂犬病),
鹅疱疹病毒1、鸽(Columbiform)疱疹病毒1、禽疱疹病毒2(引起马立克氏病)、禽疱疹病毒3(GaHV-3或MDV-2)、火鸡(Meleagrid)疱疹病毒1(HVT)、孔雀疱疹病毒1,
禽疱疹病毒1(引起鸟类的传染性喉气管炎)、鹦鹉疱疹病毒1(引起鸟类的帕切科病),
猪疱疹病毒2(引起猪的包涵体鼻炎),
狷羚(Alcelaphine)疱疹病毒1(引起牛恶性卡他热)、狷羚疱疹病毒2(引起羚羊和狷羚型MCF)、侏猴(Ateline)疱疹病毒2、牛疱疹病毒4、猕猴(Cercopithecine)疱疹病毒17、马疱疹病毒2(引起马巨细胞病毒感染)、马疱疹病毒5、马疱疹病毒7、日本猕猴鼻病毒,兔(Leporid)疱疹病毒1,鼠疱疹病毒4(鼠γ疱疹病毒-68,MHV-68),
鲤(Cyprinid)疱疹病毒1、2和3(CyHV1、CyHV2和CyHV3)分别在鲤鱼、金鱼和锦鲤中引起疾病。
根据本发明使用的D3G可以包含在组合物中。在一个实施方案中,组合物是红葡萄提取物、越橘提取物、黑醋栗提取物或者其中一种或多种的混合物,其中包含D3G。
在优选实施方案中,黑醋栗是黑茶藨子的果实和/或越橘是黑果越橘的果实。更优选的是,组合物含有重量比为0.5:1至1:0.5的来自黑醋栗和越橘的提取物。在本发明的有利配置中,组合物是来自黑醋栗和越橘的果渣的提取物。
尤其优选的是,组合物包含花色素苷并且花色素苷以至少25重量%、优选地至少30重量%、或至少35重量%、或至少40重量%、或至少45重量%、或至少50重量%的浓度存在于组合物中。
根据本发明优选地,提取物是醇提取物,优选地是甲醇提取物。优选地通过包括以下步骤的工艺生产提取物:
-黑醋栗和/或越橘的提取,
-经由色谱法的纯化,
-将提取物与水混合,和
-混合物的喷雾干燥。
EP1443948中公开了此类工艺的一个实例。
在优选实施方案中,将麦芽糖糊精添加到组合物中。
根据本发明的组合物优选地包含至少三种单糖花色素苷,包括D3G。此外,优选地包含其中糖为阿拉伯糖的至少一种单糖花色素苷或其中二糖为芸香糖的至少一种二糖花色素苷。组合物优选地包含具有至少两个不同糖苷配基、更优选地至少四个糖苷配基的花色素苷。尤其优选地,组合物包含花色素苷,其中糖苷配基单元为矢车菊色素、芍药色素、飞燕草色素、矮牵牛色素、锦葵色素以及任选地天竺葵色素。在一个优选实施方案中,组合物还包含至少一种三糖花色素苷。二糖花色苷比单糖更易溶于水;此外,矢车菊色素和飞燕草色素是水溶性最强的花色素苷。
在本发明的有利实施方案中,除了D3G以外的花色素苷选自矢车菊色素-3-葡萄糖苷、矢车菊色素-3-半乳糖苷、矢车菊色素-3-阿糖胞苷、飞燕草色素-3-半乳糖苷、飞燕草色素-3-阿糖胞苷、矮牵牛色素-3-葡萄糖苷、矮牵牛色素-3-半乳糖苷、矮牵牛色素-3-阿拉伯糖、芍药色素-3-葡萄糖苷、芍药色素-3-半乳糖苷、芍药色素-3-阿拉伯糖、锦葵色素-3-葡萄糖苷、锦葵色素-3-半乳糖苷、锦葵色素-3-阿拉伯糖、矢车菊色素-3-芸香糖苷、飞燕草色素-3-芸香糖苷。花色素苷优选地选自矢车菊色素-3-葡萄糖苷、矢车菊色素-3-芸香糖苷、飞燕草色素-3-葡萄糖苷、飞燕草色素-3-芸香糖苷、矢车菊色素-3-半乳糖苷和飞燕草色素-3-半乳糖苷。
在一个实施方案中,D3G可以包含在具有一种或多种其他花色素苷的组合物中,其中D3G是存在的主要花色素苷,即D3G以比一种或多种其他花色素苷中每一种更大的干重量存在于组合物中。
在进一步的实施方案中,D3G可以包含在花色素苷组合物中,其中花色素苷基本上由D3G组成,例如,在存在其他花色素苷的情况下,这些花色素苷仅以忽略不计的量存在。“基本上由...组成”是指可能存在其他花色素,但这些不会对组合物的基本特征产生实质性影响。
包括D3G的花色素苷可以来自天然来源或合成产品。天然来源优选地选自果实、花、叶、茎和根,优选地紫罗兰花瓣、黑豆种皮。优选地,花色素苷是从选自以下的果实中提取的:阿萨伊果黑醋栗、野樱莓、茄子、血橙、marion黑莓、黑树莓、树莓、野生蓝莓、樱桃、超级李子(queen Garnet plum)、红醋栗、紫玉米(Z.mays L.)、康科德葡萄、诺顿葡萄、麝香葡萄、红甘蓝、冲绳红薯、香芋(Ube)、黑米、红洋葱、黑胡萝卜。花色素苷的特别合适的果实来源是樱桃、越橘、蓝莓、黑醋栗、红醋栗、葡萄、树莓、草莓、黑野樱莓(blackchokeberry)和苹果以及蔬菜如红甘蓝。越橘(特别是黑果越橘)和黑醋栗(特别是黑茶藨子)是特别合适的。进一步优选的是使用富含一种或多种花色素苷的植物作为天然来源,优选地富含飞燕草色素-3-芸香糖苷的植物。
本发明组合物中包含的D3G或其他花色素苷中的抗衡离子可以是任何生理上可耐受的抗衡阴离子,例如氯离子、琥珀酸根、富马酸根、苹果酸根、马来酸根、柠檬酸根、抗坏血酸根、天冬氨酸根、谷氨酸根等。然而优选地,抗衡离子是果酸阴离子,尤其是柠檬酸根,因为这导致产品具有特别令人愉悦的味道。除了花色素苷,包含D3G的组合物还可以理想地包含其他有益或非活性成分,例如维生素(优选地维生素C)、黄酮、异黄酮、抗凝剂(例如麦芽糖糊精、二氧化硅等)、干燥剂等。
优选的是,D3G将以每天每次至少20mg D3G的1至10次口服剂量,优选地每天每次至少20mg花色素苷的3个至6次口服剂量的剂量/方案施用给受试者。
众所周知,当对受试者使用医疗设备时可能会发生病毒感染。当诸如导管或饲管之类的装置要在受试者中保留任意长的时间时尤其如此,例如装置在受试者中的停留时间超过24小时。
因此,在优选的实施方案中,D3G用于与将插入受试者中的医疗装置一起使用,或用于已插入医疗装置的受试者中,任选地其中插入的装置是经皮的或气管内的。在优选的实施方案中,D3G将在医疗装置插入受试者体中的部位施用。还优选的,医疗装置用于气管内插管或肠胃外营养。
在特定的配置中,医疗装置是针、导管、端口、插管装置或管、雾化器、植入物、血管通路导管、脑微导管、经外周插入的中心导管、慢性中心静脉导管、植入端口、急性中心静脉导管、中线导管、短外周静脉内导管或透析导管。
优选的是,医疗装置在受试者中的停留时间超过24小时、超过48小时、超过72小时、超过1周、超过2周、超过3周,优选地其中停留时间超过1周、超过2周或超过3周。
在进一步有利的配置中,包含D3G的组合物将作为肠胃外团注或输注或肠胃外营养溶液施用给受试者。还优选的是使用组合物来稳定危重患者,对于所述危重患者,挽救生命的治疗无效,并且没有可用的最后线治疗(由于缺乏治疗选择)。
根据本发明,D3G将施用给受试者,在靶标隔室中达到至少30μg/ml,优选地至少100μg/ml的浓度。靶标隔室是血液和淋巴,特别是在免疫系统细胞(它们被疱疹病毒科感染)周围的介质,所述细胞优选是外周血单核细胞(PBMC),尤其是B细胞、T细胞、树突细胞。
在一个优选的实施方案中,受试者是人,优选地受试者怀孕或免疫功能受损或正在服用免疫抑制剂或是疱疹病毒科病毒的携带者,优选地其中受试者是单纯疱疹病毒、埃巴病毒或人巨细胞病毒的携带者。
在另一个实施方案中,受试者感染卡波西肉瘤相关疱疹病毒(KSHV,HHV-8),任选地其中受试者是HIV阳性或患有AIDS。
在一个优选的实施方案中,病毒感染是在肝脏或肾脏中。与已知的抗病毒药物相反,测试的浆果提取物和D3G显示出广泛的活性。因此,它可以在诊断出肝脏感染(EBV、CMV或HSV)时使用。由于浆果提取物和D3G不会对肾脏产生毒性,因此也可以在移植后用作预防措施。
本发明的另一方面涉及用于预防或治疗与来自疱疹病毒科的病毒相关的癌症的D3G,任选地其中:
(i)病毒是EBV并且癌症是淋巴瘤(包括霍奇金淋巴瘤和伯基茨淋巴瘤)、鼻咽癌、胃癌或乳腺癌;或者
(ii)病毒是HHV-8并且癌症是卡波西肉瘤、原发性渗出性淋巴瘤、HHV-8相关的多中心卡斯尔曼病或乳腺癌。
本发明的另一方面涉及用于预防或治疗与来自疱疹病毒科的病毒相关的自身免疫性疾病的D3G,任选地其中:
(i)病毒是EBV并且自身免疫性疾病是系统性红斑狼疮(SLE)、类风湿性关节炎(RA)、干燥综合征或多发性硬化症;或者
(ii)病毒是HSV-1并且自身免疫性疾病是多发性硬化症。
在这些方面,D3G或包含D3G的组合物可以如上所述。
根据本发明使用的D3G或包含D3G的组合物优选地用于暴露于身体压力或情绪压力的受试者,或者患有疲劳、抑郁或焦虑的受试者,这可能导致潜伏的疱疹病毒感染的再激活。
此外,组合物可用于预防或治疗阿尔茨海默病。
因此,本发明的另一方面涵盖用于预防或治疗阿尔茨海默病的D3G或包含D3G的组合物,其中组合物减少β-淀粉样蛋白斑块形成,任选地其中组合物通过减少或防止病毒感染来减少β-淀粉样蛋白斑块形成。
病毒感染的减少可以通过对血液样品执行PCR来确定病毒拷贝数的减少而进行评估,病毒拷贝数可用于确定感染是被动的还是主动的。D3G或包含D3G的组合物都可以用于预防病毒感染和预防病毒再激活。
在特定配置中,用于预防或治疗阿尔茨海默病的D3G或包含D3G的组合物减轻脑组织炎症。在这种情况下也可以预防脑炎。
本发明的另一方面是一种局部用组合物,其包含D3G,其中组合物进一步包含适用于施用于皮肤的局部用组合物的药学上可接受的赋形剂,优选地其中药学上可接受的赋形剂包含张力调节剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、pH调节剂、渗透促进剂、表面活性剂和湿润剂中的一种或多种。还优选的是,局部用组合物是唇膏或护唇产品。
本发明的另一方面是一种滴眼液组合物,其包含D3G,其中组合物进一步包含适用于施用于眼的组合物的药学上可接受的赋形剂,优选地其中药学上可接受的赋形剂包含张力调节剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、pH调节剂、渗透促进剂、表面活性剂和湿润剂中的一种或多种。
本发明还涉及
-一种包含镇痛剂和D3G的组合物,优选地其中镇痛剂是布洛芬或扑热息痛(paracetamol)/对乙酰氨基酚(acetaminophen),
-一种用于在受试者中治疗与病毒感染相关的疼痛的组合物,其中病毒来自疱疹病毒科,
-一种包含镇痛剂和D3G的组合制备物,用于同时、单独或顺序地用于医疗,
-一种包含镇痛剂和D3G的局部用组合物,
-一种包含抗病毒剂和D3G的组合物,任选地其中抗病毒剂是阿昔洛韦、更昔洛韦、缬更昔洛韦、膦甲酸、泛昔洛韦、喷昔洛韦、伐昔洛韦或莱特莫韦,
-一种采用局部用组合物或滴眼液形式的组合物,优选地其中抗病毒剂是阿昔洛韦,
-一种包含抗病毒剂和D3G的组合制备物,用于同时、单独或顺序地用于医疗。
组合制备物是包含独立包装的活性组分的制备物,所述活性组分将组合使用,即通过同时、单独或顺序地施用给受试者。
镇痛化合物优选地选自乙酰水杨酸、双氯芬酸、右旋布洛芬、右酮洛芬、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、美洛昔康、萘丁美酮、萘普生、布他酮、吡罗昔康、安替比林(Phenazon)、异丙安替比林(Propyphenazon)、罗非昔布、塞莱昔布、依托昔布、帕瑞昔布、安乃近(Metamizol)、扑热息痛/对乙酰氨基酚。
如上所述的抗病毒剂优选地是疱疹病毒科抗病毒剂。疱疹病毒科抗病毒剂是指可用于治疗或预防疱疹病毒科病毒的感染的试剂,并且其本身可以对抗病毒有活性或可以是在体内代谢为活性剂的前药。后者的示例是缬更昔洛韦,它是更昔洛韦的前药。优选地,疱疹病毒科抗病毒剂是DNA复制的抑制剂,任选地DNA聚合酶抑制剂或DNA终止酶复合物抑制剂。特别地,DNA聚合酶抑制剂是核苷类似物或焦磷酸类似物。在优选的实施方案中,抗病毒剂是阿昔洛韦、更昔洛韦、缬更昔洛韦、膦甲酸、泛昔洛韦、喷昔洛韦、伐昔洛韦或莱特莫韦。
对于上述所有组合物有利的是,D3G或包含D3G的组合物如上文关于医疗用途所述。特别地,除了D3G之外,包含D3G的组合物可以包含一种或多种另外的花色素苷,并且D3G可以以比一种或多种其他花色素苷中的每一种更大的干重量存在于组合物中。备选地,组合物可以是基本上由D3G组成的花色素苷组合物。D3G可以包含在红葡萄提取物、越橘提取物、黑醋栗提取物或者其中两种或更多种的混合物中。优选地,黑醋栗是黑茶藨子的果实和/或越橘是黑果越橘的果实。还优选的是,组合物包含重量比为0.5:1至1:0.5的来自黑醋栗和越橘的提取物。在本发明的一个有利配置中,包含D3G的组合物是来自黑醋栗和越橘的果渣的提取物。特别优选的是,组合物包含花色素苷,花色素苷包括D3G并且花色素苷以至少25重量%、优选地至少30重量%、或至少35重量%、或至少40重量%、或至少45重量%、或至少50重量%的浓度存在于组合物中。根据本发明,优选的是提取物是醇提取物,优选甲醇提取物。
本发明还涉及一种具有抗病毒活性的试剂,用于在受试者中治疗或预防病毒感染,其中病毒来自疱疹病毒科,效力水平为2对数水平,以及涉及无毒的抗病毒剂。
本发明还涉及一种具有抗病毒活性的试剂,用于在受试者中治疗或预防病毒感染,其中病毒来自疱疹病毒科,效力水平为2对数水平,其在哺乳动物细胞、优选地BHK细胞的基于细胞的测定中的杀灭不超过30%、优选地不超过20%、更优选地不超过10%的细胞。
具有抗病毒活性的该试剂优选地包含一种或多种花色素苷,花色素苷选自矢车菊色素-3-葡萄糖苷、矢车菊色素-3-半乳糖苷、矢车菊色素-3-阿糖胞苷、飞燕草色素-3-葡萄糖苷、飞燕草色素-3-半乳糖苷、飞燕草色素-3-阿糖胞苷、矮牵牛色素-3-葡萄糖苷、矮牵牛色素-3-半乳糖苷、矮牵牛色素-3-阿拉伯糖、芍药色素-3-葡萄糖苷、芍药色素-3-半乳糖苷、芍药色素-3-阿拉伯糖、锦葵色素-3-葡萄糖苷、锦葵色素-3-半乳糖苷、锦葵色素-3-阿拉伯糖、矢车菊色素-3-芸香糖苷、飞燕草色素-3-芸香糖苷。花色素苷优选地选自矢车菊色素-3-葡萄糖苷、矢车菊色素-3-芸香糖苷、飞燕草色素-3-葡萄糖苷、飞燕草色素-3-芸香糖苷、矢车菊色素-3-半乳糖苷、飞燕草色素-3-半乳糖苷。
如上所述,本发明还涉及D3G或包含D3G的组合物用于与将插入受试者中的医疗装置一起使用,或用于已插入医疗装置的受试者中,任选地其中装置经由鼻或嘴插入。优选的是,医疗装置是针、导管、端口、插管装置或管、或者雾化器。还优选的是,医疗装置在受试者中的停留时间超过24小时、超过48小时、超过72小时、超过1周、超过2周、超过3周,优选地其中停留时间超过1周、超过2周或超过3周。
本发明还是指一种适合插入受试者中的医疗装置,该医疗装置在装置的外表面上包含涂层组合物,其中涂层组合物包含D3G。优选的是,医疗装置是针、导管、端口、插管装置或管、或者雾化器,优选地其中医疗装置的外表面是塑料的。
涂层组合物可以包含D3G和任选地一种或多种另外的花色素苷,如上所述用于医疗用途方面。D3G可以包含在红葡萄提取物、越橘提取物、黑醋栗提取物或者其中两种或更多种的混合物中。
还优选的是,黑醋栗是黑茶藨子的果实和/或越橘是黑果越橘的果实。还优选的是,组合物包含重量比为0.5:1至1:0.5的来自黑醋栗和越橘的提取物。在本发明的一个有利配置中,组合物是来自黑醋栗和越橘的果渣的提取物。特别优选的是,组合物包含花色素苷并且花色素苷以至少25重量%、优选地至少30重量%、或至少35重量%、或至少40重量%、或至少45重量%、或至少50重量%的浓度存在于组合物中。根据本发明,优选的是提取物是醇提取物,优选甲醇提取物。
本发明还涵盖制造如所述的医疗装置的方法,该方法包括将涂层组合物应用到医疗装置的外表面,任选地其中涂层组合物配制为乳膏、水凝胶乳膏或喷雾。
此外,本发明涉及一种深肺颗粒,其包含含有D3G的组合物,其被分配到个体的更深呼吸道中,以及涉及用于将深肺颗粒分配到个体的更深呼吸道中的装置。
组合物可以包含D3G与纳米颗粒、优选脂质体的制剂。可以吸入此类制剂以最大化纳米颗粒到肺部中的递送。吸入有助于经由口或鼻吸入途径将组合物直接局部递送至肺部。例如,在犬中雾化递送脂质体白细胞介素-2(IL-2)已被证明对骨肉瘤的肺转移有效(Khanna C,Anderson PM,Hasz DE,Katsanis E,Neville M,Klausner JS.Interleukin-2liposome inhalation therapy is safe and effective for dogs with spontaneouspulmonary metastases.Cancer 1997;79:1409–21)。此外,经由纳米颗粒递送抗癌药物已被证明对多种癌症有效且安全。抗癌药物也可以配制成药物纳米晶体,具有高药物载量和最少使用赋型剂(Sharad M,Wei G,Tonglei L,Qi Z,Review:Pulmonary delivery ofnanoparticle chemotherapy for the treatment of lung cancers:challenges andopportunities,Acta Pharmacologica Sinica(2017)38:782–797)。
在优选实施方案中,使用当前可用的吸入装置将包含根据本发明的组合物的纳米颗粒悬浮液雾化成具有适当空气动力学直径的液滴。此类吸入装置优选地选自雾化器和加压计量吸入器(pMDI)。
因此,在有利的配置中,根据本发明的包含D3G的组合物也可以配制为用于雾化器的纳米颗粒悬浮液。此类雾化器将纳米颗粒悬浮液转化为可吸入液滴并且可以用于将组合物递送至深肺而不损害脂质体完整性。替代的配置是指pMDI,它产生悬浮在压缩推进剂(如氢氟烷(HFA))中的药物可吸入小液滴。
本发明还涉及作为干粉的纳米颗粒制剂,其提供比悬浮液更大的长期稳定性。控制纳米颗粒的尺寸是将其配制成可靠、有效的可吸入干粉的关键。纳米颗粒可经由喷雾干燥、冷冻干燥和喷雾冷冻干燥在有/无赋形剂的情况下干燥,以生成稳定且尺寸均匀的可吸入颗粒。
在备选实施方案中,纳米颗粒可与赋形剂共同干燥,这导致在赋形剂基质中形成可吸入纳米颗粒聚集体。可以利用颗粒工程,通过纳米聚集体、大多孔颗粒和其他配制技术,确保将纳米颗粒持续高效地递送到肺部。
本文描述的D3G或包含D3G的组合物的抗来自疱疹病毒科的病毒的活性也可在离体细胞培养和细胞储存的环境中使用,尤其是在细胞疗法用细胞的制备中使用。因此,本发明还提供了一种用于预防或降低离体的一种或多种细胞中病毒感染风险的方法,所述方法包括将一种或多种细胞与包含D3G的组合物接触,任选地所述一种或多种细胞是干细胞或CAR T细胞,任选地其中接触包括使用组合物培养或储存所述一种或多种细胞。特别地,D3G或包含D3G的组合物可以直接添加到细胞或添加到细胞培养基中或添加到另一种组合物中(其随后添加到细胞中)。D3G或包含D3G的组合物可以如上所述用于本发明的其他方面。
项目列表
本发明的优选实施方案总结在以下项目列表中:
1.飞燕草色素-3-葡萄糖苷(D3G),用于在受试者中治疗或预防病毒感染,其中病毒来自疱疹病毒科。
2.根据项目1所述使用的D3G,其中D3G包含在红葡萄提取物、越橘提取物、黑醋栗提取物或者其中两种或更多种的混合物中。
3.根据项目2所述使用的D3G,其中黑醋栗是黑茶藨子的果实和/或越橘是黑果越橘的果实。
4.根据前述项目中任一项所述使用的D3G,其中组合物包含重量比为0.5:1至1:0.5的来自黑醋栗和越橘的提取物。
5.根据前述项目中任一项所述使用的D3G,其中组合物是来自黑醋栗和越橘的果渣的提取物。
6.根据前述项目中任一项所述使用的D3G,其中组合物包含花色素苷并且花色素苷以至少25重量%的浓度存在于组合物中。
7.根据前述项目中任一项所述使用的D3G,其包含在组合物中,其中组合物除了D3G之外还包含一种或多种其他花色素苷,其中D3G以比所述一种或多种其他花色素苷中每一种更大的干重量存在于组合物中。
8.根据前述项目中任一项所述使用的D3G,其包含在主要由D3G组成的花色素苷组合物中。
9.根据前述项目中任一项所述使用的D3G,其中提取物是醇提取物,优选地是甲醇提取物。
10.根据前述项目中任一项所述使用的D3G,其中提取物通过包括以下步骤的方法制备:黑醋栗和/或越橘的提取、经由色谱法的纯化、将提取物与水的混合以及混合物的喷雾干燥。
11.根据前述项目中任一项所述使用的D3G,其中使用包括局部施用至皮肤、嘴唇或眼睛。
12.根据前述项目中任一项所述使用的D3G,其中D3G包含在组合物中,并且其中D3G以至少20重量%的浓度存在于组合物中。
13.根据前述项目中任一项所述使用的D3G,其中病毒来自α疱疹病毒亚科或γ疱疹病毒亚科。
14.根据前述项目中任一项所述使用的D3G,其中病毒是单纯疱疹病毒-1(HSV-1)、单纯疱疹病毒-2(HSV-2)、水痘带状疱疹病毒(VZV)、埃巴病毒(EBV)、巨细胞病毒(CMV)、玫瑰疹病毒或卡波西肉瘤相关疱疹病毒(KSHV、HHV-8),优选地是HSV-1、EBV、CMV和HHV-8,更优选地是HSV-1或HHV-8。
15.根据前述项目中任一项所述使用的D3G,其中组合物阻抑病毒感染。
16.根据前述项目中任一项所述使用的D3G,其中D3G以每天每次至少20mg D3G的1至10次口服剂量、优选地每天每次至少20mg D3G的3至6次口服剂量施用给受试者。
17.根据前述项目中任一项所述使用的D3G,其中D3G将作为肠胃外团注或输注或肠胃外营养溶液施用给受试者,来稳定危重患者。
18.根据前述项目中任一项所述使用的D3G,其中D3G提取物将施用于受试者,在靶标隔室中达到至少30μg/ml、优选地至少100μg/ml的D3G的浓度。
19.根据前述项目中任一项所述使用的D3G,其中受试者是人。
20.根据前述项目中任一项所述使用的D3G,其中受试者是怀孕的。
21.根据前述项目中任一项所述使用的D3G,其中受试者是疱疹病毒科病毒的携带者,优选地其中受试者是单纯疱疹病毒的携带者。
22.根据前述项目中任一项所述使用的D3G,其中受试者是免疫功能受损的。
23.根据前述项目中任一项所述使用的D3G,其中受试者正在服用免疫抑制剂。
24.根据前述项目中任一项所述使用的D3G,其中受试者暴露于身体压力或情绪压力。
25.根据前述项目中任一项所述使用的D3G,其中受试者患有疲劳、抑郁或焦虑。
26.根据前述项目中任一项所述使用的D3G,其中D3G与将插入受试者中的医疗装置一起使用,或者其中受试者已经插入了医疗装置,任选地其中插入的装置是经皮的或气管内的。
27.根据项目26所述使用的D3G,其中组合物将在医疗装置插入受试者中的部位施用。
28.根据项目26或27所述使用的D3G,其中医疗装置用于气管内插管或胃肠外营养。
29.根据项目26至28中任一项所述使用的D3G,其中医疗装置是针、导管、端口、插管装置或管、雾化器、植入物、血管通路导管、脑微导管、经外周插入中心导管、慢性中心静脉导管、植入端口、急性中心静脉导管、中线导管、短外周静脉内导管或透析导管。
30.根据项目26至29中任一项所述使用的D3G,其中医疗装置在受试者中的停留时间超过24小时、超过48小时、超过72小时、超过1周、超过2周、超过3周,优选地其中停留时间超过1周、超过2周或超过3周。
31.根据前述项目中任一项所述使用的D3G,其中受试者感染了卡波西肉瘤相关疱疹病毒(KSHV,HHV-8),任选地其中受试者是HIV阳性或患有AIDS。
32.根据前述项目中任一项所述使用的D3G,其中病毒感染在肝脏或肾脏中。
33.根据前述项目中任一项所述使用的D3G,用于预防或治疗与来自疱疹病毒科的病毒相关的癌症,任选地其中:
(i)病毒是EBV并且癌症为淋巴瘤(包括霍奇金淋巴瘤和伯基特淋巴瘤)、鼻咽癌、胃癌或乳腺癌;或者
(ii)病毒是HHV-8并且癌症是卡波西肉瘤、原发性渗出性淋巴瘤、HHV-8相关的多中心卡斯尔曼病或乳腺癌。
34.根据前述项目中任一项所述的D3G,用于预防或治疗与来自疱疹病毒科的病毒相关的自身免疫性疾病,任选地其中:
(i)病毒是EBV并且自身免疫性疾病是系统性红斑狼疮(SLE)、类风湿性关节炎(RA)、干燥综合征或多发性硬化症;或者
(ii)病毒是HSV-1并且自身免疫性疾病是多发性硬化症。
35.根据前述项目使用的D3G,用于预防或治疗阿尔茨海默病。
36.根据项目35使用的D3G,其中组合物减少β-淀粉样蛋白斑块形成,任选地其中组合物通过减少或预防活性病毒感染来减少β-淀粉样蛋白斑块形成。
37.根据项目35或项目36所述使用的D3G,其减轻脑组织炎症。
38.一种局部用组合物,其包含飞燕草色素-3-葡萄糖苷(D3G),其中组合物进一步包含适用于施用于皮肤的局部用组合物的药学上可接受的赋形剂,优选地其中药学上可接受的赋形剂包含张力调节剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、pH调节剂、渗透促进剂、表面活性剂和湿润剂中的一种或多种。
39.一种滴眼液组合物,其包含飞燕草色素-3-葡萄糖苷(D3G),其中组合物进一步包含适用于施用于眼的组合物的药学上可接受的赋形剂,优选地其中药学上可接受的赋形剂包含张力调节剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、pH调节剂、渗透促进剂、表面活性剂和湿润剂中的一种或多种。
40.一种包含镇痛剂或抗炎症剂以及飞燕草色素-3-葡萄糖苷(D3G)的组合物,优选地其中镇痛剂是布洛芬或扑热息痛/对乙酰氨基酚。
41.根据前述项目使用的组合物,用于治疗受试者中与病毒感染相关的疼痛,其中病毒来自疱疹病毒科。
42.一种组合制备物,其包含镇痛剂和飞燕草色素-3-葡萄糖苷(D3G),用于同时、单独或顺序地用于医疗。
43.一种局部用组合物,其包含镇痛剂和飞燕草色素-3-葡萄糖苷(D3G)。
44.根据项目38至43中任一项所述的组合物,其中组合物包含花色素苷并且花色素苷以至少25重量%的浓度存在于组合物中。
45.一种适合插入受试者中的医疗装置,所述医疗装置在装置的外表面上包含涂层组合物,其中涂层组合物包含飞燕草色素-3-葡萄糖苷(D3G)。
46.根据项目45所述的医疗装置,其中医疗装置是针、导管、端口、插管装置或管、雾化器、植入物、血管通路导管、脑微导管、经外周插入的中心导管、慢性中心静脉导管、植入端口、急性中心静脉导管、中线导管、短外周静脉内导管或透析导管,优选地其中医疗装置的外表面是塑料的。
47.一种制造根据项目45或项目46所述的医疗装置的方法,所述方法包括将涂层组合物应用到医疗装置的外表面,任选地其中涂层组合物配制为乳膏、水凝胶乳膏或喷雾。
48.一种包含抗病毒剂和飞燕草色素-3-葡萄糖苷(D3G)的组合物,其中抗病毒剂是疱疹病毒科抗病毒剂,优选地其中抗病毒剂是DNA复制的抑制剂,任选地其中抗病毒剂是DNA聚合酶抑制剂或DNA终止酶复合物抑制剂。
49.根据项目48所述的组合物,其中抗病毒剂是阿昔洛韦、更昔洛韦、缬更昔洛韦、膦甲酸、泛昔洛韦、喷昔洛韦、伐昔洛韦或莱特莫韦。
50.根据项目48或49所述的组合物,其采用局部用组合物或滴眼液的形式,优选地其中抗病毒剂是阿昔洛韦。
51.一种组合制备物,其包含抗病毒剂和飞燕草色素-3-葡萄糖苷(D3G),用于同时、单独或顺序地用于医疗。
52.一种用于预防或降低离体的一种或多种细胞内病毒感染风险的方法,包括将所述一种或多种细胞与包含飞燕草色素-3-葡萄糖苷(D3G)的组合物接触,任选地其中所述一种或多种细胞是干细胞或CAR T细胞,任选地其中接触包括使用组合物培养或储存所述一种或多种细胞。
53.一种在有需要的受试者中治疗或预防病毒感染的方法,包括向受试者施用有效量的D3G,其中病毒来自疱疹病毒科。
54.一种在有需要的受试者中阻抑病毒感染或预防病毒再激活的方法,包括向受试者施用有效量的D3G,其中病毒剂来自疱疹病毒科。
55.一种用于预防受试者中的与装置相关的病毒感染的方法,包括:(a)将装置插入受试者中并在装置的插入部位施用有效量的D3G;和/或(b)将有效量的D3G应用于装置的外表面并将装置插入受试者中,
其中病毒来自疱疹病毒科。
56.一种在有需要的受试者中治疗或预防与来自疱疹病毒科的病毒相关的癌症的方法,包括向受试者施用有效量的D3G。
57.一种在有需要的受试者中治疗或预防与来自疱疹病毒科的病毒相关的自身免疫性疾病的方法,包括向受试者施用有效量的D3G。
58.一种在有需要的受试者中减少β-淀粉样斑块形成和/或减轻脑组织炎症的方法,包括向受试者施用有效量的D3G,任选地其中组合物通过减少或防止来自疱疹病毒科的病毒的感染来减少β-淀粉样斑块形成和/或减轻脑组织炎症。
59.根据项目53至58中任一项所述的方法,其中D3G或包含D3G的组合物如项目2至10中任一项所定义。
60.根据项目53至59中任一项所述的方法,其中病毒如项目14所定义。
61.根据项目53至60中任一项所述的方法,其中D3G或包含D3G的组合物将如项目16或18项所定义施用。
62.根据项目53至61中任一项所述的方法,其中受试者如项目19至25中任一项所定义。
实施例
本研究中使用的浆果提取物组合物(865;Evonik Nutrition&CareGmbH,Darmstadt,德国)是一种膳食补充剂,由从黑醋栗(黑茶藨子)和越橘(黑果越橘)分离的17种纯化的花色素苷(矢车菊色素、芍药色素、飞燕草色素、矮牵牛色素和锦葵色素的所有葡萄糖苷)组成。
865产品中每种花色素苷的相对含量如下:33.0%的矢车菊色素的3-O-b-芸香糖苷、3-O-b-葡萄糖苷、3-O-b-半乳糖苷和3-O-b-阿拉伯糖苷;58.0%的飞燕草色素的3-O-b-芸香糖苷、3-O-b-葡萄糖苷、3-O-b-半乳糖苷和3-O-b-阿拉伯糖苷;2.5%的矮牵牛色素的3-O-b-葡萄糖苷、3-O-b-半乳糖苷和3-O-b-阿拉伯糖苷;2.5%的芍药色素的3-O-b-葡萄糖苷、3-O-b-半乳糖苷和3-O-b-阿拉伯糖苷;3.0%的锦葵色素的3-O-b-葡萄糖苷、3-O-b-半乳糖苷和3-O-b-阿拉伯糖苷。
矢车菊色素和飞燕草色素的3-O-b-葡萄糖苷至少占总花色素苷的40–50%。
所用浆果提取物中含有的主要花色素苷是矢车菊色素-3-葡萄糖苷、矢车菊色素-3-芸香糖苷、飞燕草色素-3-葡萄糖苷、飞燕草色素-3-芸香糖苷、矢车菊色素-3-半乳糖苷和飞燕草色素-3-半乳糖苷。
除上述花色素苷外,产品还含有麦芽糖糊精(占组合物的约40重量%)和柠檬酸(以保持花色素苷的稳定性)。柠檬酸花色素苷的量是组合物的至少25重量%。组合物从黑醋栗和越橘通过包括以下步骤的方法制备:黑醋栗和越橘的醇提取、经由色谱法的纯化、将提取物与柠檬酸麦芽糖糊精和水的混合以及混合物的喷雾干燥。产品组合物包含重量比为约1:1混合的黑醋栗和越橘的提取物。
材料:
表1:用于测量细胞存活和代谢的材料
表2:用于测量细胞存活和代谢的装置
装置 | 供应商 |
Centro LB 960微孔板光度仪 | Berthold Technologies,(德国) |
表3:用于抗病毒测定的材料
表4:用于抗病毒测定的装置
方法:
测试化合物制备:
将所有测试化合物溶解并稀释在细胞培养基中。花色素苷的总量在865和单一花色素苷或单一浆果提取物(考虑到/>865除花色素外还含有麦芽糖糊精)之间进行标准化(例如,500μg/mL的/>865对应于对于单一测试化合物测试的150μg/mL花色素苷)。培养基用作病毒抑制或细胞毒性的对照。
细胞活力测定:
通过RealTime-GloTM MT细胞活力测定(Cat.No.G9712,Promega,德国)测量细胞活力。BHK细胞与逐渐降低量的溶解在DMEM中的化合物一起孵育。只具有DMEM的孔作为对照。根据制造商的说明书添加MT细胞活力底物和荧光素酶。测定一式三份执行。3天后,用Centro LB 960微孔板光度计(Berthold Technologies,德国)测量发光信号。1h后的发光值设置为1并确定随时间的变化。
抗病毒测定:
疱疹病毒感染:
BHK细胞与浓度逐渐降低的溶解的测试化合物孵育约1h。所有浓度均在黑色96孔板(PerkinElmer)上通过六个独立重复进行分析。细胞用编码GFP的野生型HSV-1病毒感染并孵育两天。感染两天后,使用带有光学细胞培养板的PerkinElmer Ensight系统对HSV-1感染的细胞和表达GFP的细胞进行直接计数。仪器由人工计数控制。相应地执行对于HHV8的抗病毒测定。
为了不仅分析感染的病毒进入和病毒复制的早期阶段,还分析病毒复制的后期阶段,相应地调整了测试测定。BHK细胞与测试化合物一起孵育,并随后用HSV-1进行感染。感染后两天收集上清液,离心去除脱离的细胞并用于感染BHK细胞。再过两天后,使用Ensight系统对受感染的细胞进行定量。
从第一次鉴定到现在,使用复制测定经由体外或细胞培养中的筛选测定对抗病毒化合物进行最初鉴定。甚至通过体外酶筛选试验鉴定的化合物的活性需要在基于细胞培养的测定中进行验证。这些测定是鉴定和验证抗病毒活性的现有技术方法,因为它们允许对病毒复制的抑制进行定量并确保化合物的细胞摄取。例如,治疗HSV-1的金标准阿昔洛韦是通过筛选海绵中的抗病毒物质得到鉴定的(Elion等人,1977Selectivity of action ofan antiherpetic agent,9-(2-hydroxyethoxymethyl)guanine.PNAS 74.5716)。后来,阿昔洛韦抑制疱疹病毒科其他成员的抗病毒活性也在基于细胞培养的测定中得以展示(AKESSON-JOHANSSON等人,1990Inhibition of Human Herpesvirus 6 Replicationby9-[4-Hydroxy-2-(Hydroxymethyl)Butyl]Guanine(2HM-HBG)and Other AntiviralCompounds.AAC 34.2417)。此外,所有用作抗HIV-1的临床药物的化合物,例如3TC和洛匹那韦(ABT-378),最初都经过体外测试以证明它们的抗病毒作用(Coates等人,1992.TheSeparated Enantiomers of 2'-Deoxy-3'-Thiacytidine(BCH 189)Both Inhibit HumanImmunodeficiency Virus Replication In Vitro.AAC 36.202;Sham等人1998.ABT-378,aHighly Potent Inhibitor of the Human Immunodeficiency Virus Protease.AAC42.3218)。
流感基因组测定:
MDCK细胞接种于48孔板中。24h后加入测试化合物,并随后用甲型流感病毒感染细胞。所有感染一式三份执行。感染后三天收获细胞培养物上清液并以2000rpm离心以去除脱离的细胞并分析分泌到上清液中的病毒。根据制造商手册,使用Roche HP病毒核酸试剂盒从200μl细胞培养上清液中分离病毒RNA。使用5μl洗脱的RNA和RTqPCR模块甲型流感试剂盒(Cat.No.07 792 182 001,Roche)与/>多重RNA病毒主试剂盒(Cat.No..07 083 173 001,Roche)组合来测定病毒基因组拷贝数。所有PCR反应均使用Roche LightCycler96 qPCR 20从RNA中一式三份执行。用各自的循环仪软件(RocheLightCycler96应用软件V1.1)确定Cq值。具有1000个基因组拷贝的模块甲型流感试剂盒的内标作为阳性对照。通过遵循MIQE指南确保质量。
实施例1:浆果提取物对细胞活力的影响
为了排除细胞毒性和不良副作用,使用RealTime-GloTM MT细胞活力测定试剂盒测定BHK细胞(96孔板:650个细胞/孔)在测试化合物存在下的细胞活力。该测定测量细胞内ATP含量,并因此提供有关细胞活力和代谢的信息。在一式三份测定中用逐渐减少的化合物浓度孵育细胞。随后,添加MT细胞活力底物和酶两者,并且1h后测量荧光素酶活性。三天后测量发光,并根据培养基对照孔的平均值进行标准化。这些补偿导致培养基对照的值为1,并且小于1的值表明与适当的对照相比,细胞数量更少或代谢活性降低。
图1显示了865对BHK2细胞的活力的影响。将三天后测量的荧光素酶活性的增加针对与培养基孵育的对照细胞的增加标准化。误差条代表标准偏差。
865在任何分析浓度下都不对细胞生长或代谢活动产生负面影响,表明化合物在这些浓度下是无毒的。
实施例2:
865对单纯疱疹病毒1的抗病毒作用
BHK细胞与浓度逐渐降低的865或与不含麦芽糖糊精的865预孵育。将不含麦芽糖糊精的材料的浓度调整为含糖产品的0.6倍,以补偿/>865中40%的麦芽糖糊精含量。因此,使用了浓度相当的花色素苷。随后以2.5的感染复数用编码GFP的HSV感染细胞,并在感染后一天使用PerkinElmer Ensight系统对受感染的表达GFP的细胞进行计数。/>865和不含麦芽糖糊精的浆果提取物类似物在/>865浓度>0.250μg/mL均能将病毒感染阻抑约2个对数步长(logsteps)。观察到的病毒感染性的这种抑制作用在常见的抗病毒药物化合物范围内,并且表明单纯疱疹是黑醋栗和越橘的浆果提取物(例如/>865)的主要靶标。对不含麦芽糖糊精的浆果提取物类似物的分析表明150μg/mL的活性物质浓度(对应于250μg/mL865)足以阻抑HSV。因此,不需要糖作为药物摄取的潜在辅助因子。
图2显示单纯疱疹病毒1是865介导的对病毒感染的阻抑作用(对数级)的主要靶标。BHK2细胞用/>865或不含麦芽糖糊精的浆果提取物类似物进行处理,并随后用编码GFP的HSV-1进行感染。
实施例3: 865对甲型流感病毒的抗病毒作用(比较)/>
分析了865和单一花色素苷对甲型流感病毒的复制的影响。MDCK细胞与测试化合物孵育,并随后用血清型A流感病毒患者来源的分离株进行感染。所有反应均一式三份执行。三天后收获细胞培养上清液,并从200μL细胞培养上清液中分离病毒基因组RNA。使用/>模块甲型流感试剂盒(Roche)通过RTqPCR确定病毒载量。RTqPCR中包括具有1000个流感基因组拷贝的阳性对照。所有RTqPCR反应一式三份执行。
所有测试材料,包括865,在上清液中都显示出与阴性对照相似的病毒量,只有微小的差异表明没有一种组分抑制流感病毒的复制。
图3显示流感病毒的复制不受865影响。MDCK细胞用/>865预处理,感染流感病毒(血清型A)。分离病毒RNA并通过RTqPCR定量病毒RNA(Cq值;注意:较低的Cq值对应于较高的病毒载量)。
结果显示865对甲型流感病毒没有影响,证实了黑醋栗和越橘的浆果提取物分别对特定病毒或病毒家族的抗病毒作用的特异性。其他化合物作为单一的花色素苷也没有展示对流感病毒复制有任何影响。
实施例4:浆果提取物对单纯疱疹病毒1的抗病毒作用
由于865是越橘和黑醋栗提取物的组合物,因此分析了两种提取物是否都含有对抗HSV-1有活性的化合物。BHK细胞与500、250和125mg/mL的/>865、越橘或黑醋栗提取物孵育,然后用HSV-1进行感染。感染后两天收集上清液,离心去除脱离的细胞并用于感染BHK细胞。再过两天后,使用PerkinElmer Ensight系统对受感染的细胞进行定量。计算来自六个独立孔的受感染的细胞的平均值。误差条显示标准偏差。
除865外,两种提取物均显示出病毒抑制作用,表明越橘和黑醋栗提取物中均存在活性化合物。但与/>865直接比较,越橘和黑醋栗提取物对HSV-1病毒感染的阻抑程度低于/>865,尽管尤其是越橘提取物甚至含有比865高约10%的花色素苷。尤其是像500μg/mL越橘和黑醋栗提取物的更高浓度达到了约1.5个对数级的病毒感染减少,而/>865令人惊讶地达到了2-3个对数级。受感染的细胞的绝对值甚至更加强调了效果的显著性,/>865将受感染的细胞的数量从约100万个减少至~300个(减少至~0.3%),而单一提取物仅减少约90000个受感染的细胞下降至2200-3500个(减少至~3%)。
图4显示了来自越橘和黑醋栗的浆果提取物介导的对病毒感染的阻抑作用(对数级)。BHK细胞用黑醋栗或越橘提取物处理,并随后用编码GFP的HSV-1进行感染。
实施例5:花色素苷对单纯疱疹病毒1的抗病毒作用
为了进一步鉴定865的活性化合物,我们测试了几种已知的花色素苷。C3G、D3Gal或Pet3G均不抑制HSV-1,而D3G降低了病毒感染性,如/>865提供了D3G是活性HSV-1抑制剂的证据。
图5显示D3G(而不是C3G、D3Gal或Pet3G)介导对病毒感染的阻抑作用(对数级)。BHK细胞用花色素苷处理,并随后用编码GFP的HSV-1进行感染。
实施例6:
865、浆果提取物和花色素苷对疱疹病毒8/HHV8的抗病
毒作用
细胞与不同浓度的865、浆果提取物类似物、越橘提取物、黑醋栗提取物或单一花色素苷进行预孵育。再次调整材料的浓度至相同水平的花色素苷。无处理或仅麦芽糖糊精作为对照。随后用编码GFP的HHV-8感染细胞,并在感染两天后使用PerkinElmer Ensight系统对受感染的表达GFP的细胞进行计数。/>865(两个不同批次)和不含麦芽糖糊精的浆果提取物类似物显著阻抑病毒传染性高达2个数量级。病毒传染性的这种抑制作用表明疱疹病毒8和疱疹病毒科是/>865的靶标。对不含麦芽糖糊精的浆果提取物类似物和麦芽糖糊精对照的分析再次证实不需要糖部分作为药物摄取的潜在辅助因子。
图6显示疱疹病毒8是865介导的对病毒感染的阻抑作用(对数级)的靶标。BHK2细胞用/>865、不含麦芽糖糊精的浆果提取物类似物、越橘提取物、黑醋栗提取物、单一花色素苷或麦芽糖糊精进行处理,并随后用编码GFP的HHV-8进行感染。
除了865之外,越橘和黑醋栗的两种单一浆果提取物均显示出病毒抑制作用并且表明越橘提取物和黑醋栗提取物中都存在活性化合物。但与/>865直接比较,越橘和黑醋栗提取物再次以比/>865更小的程度阻抑HHV-8病毒感染(尽管尤其是越橘提取物甚至含有比/>865多约10%的花色素苷),显示在865混合物中提取物的协同作用。受感染的细胞的绝对值再次强调了效果的显著性,/>865将受感染的细胞的数量从约250万个减少至~25000个(减少至1%),而单一提取物仅将受感染的细胞减少至~60000-80000个(减少至2.8%)。并且,D3G可以再次被鉴定为/>865中的活性成分。
实施例7:替代D3G来源对单纯疱疹病毒1和疱疹病毒8的抗病毒作用
此外,对已知富含D3G的红葡萄提取物作为替代D3G来源使用前面实施例中描述的方法进行了分析。结果表明,来自红葡萄的提取物也将受感染的细胞的数量减少了大约2个数量级。这些数据再次强化了D3G作为抗HSV-1的活性物质的结论。
图7显示作为替代D3G来源的红葡萄提取物介导了对HSV-1感染的阻抑作用(对数级)。BHK细胞用花色素苷进行处理,并然后用编码GFP的HSV-1进行感染。
此外,使用前面实施例中描述的方法并使用疱疹病毒8作为靶标,将源自红葡萄提取物的D3G作为替代D3G进行了分析。结果表明,来自865的D3G以及来自红葡萄的D3G显著减少了受感染的细胞的数量。这些数据再次强化了D3G作为对抗来自疱疹病毒科的病毒的活性物质的结论。
图8显示从不同来源分离的D3G介导了对病毒感染的阻抑作用(对数级)。BHK细胞用花色素苷进行处理,随后用编码GFP的HHV-8进行感染。
图9显示了人疱疹病毒(HHV)的系统发育树。EBV:埃巴病毒;HSV:单纯疱疹病毒;VZV:水痘带状疱疹病毒;CMV:巨细胞病毒。(Raphael Borie,Jacques Cadranel,AmélieGuihot,Anne Geneviève Marcelin,Lionel Galicier,Louis-Jean Couderc:Pulmonarymanifestations of human herpesvirus-8during HIV infection,EuropeanRespiratory Journal 2013 42:1105-1118)。从系统发育树中可以明显看出,所测试的人疱疹病毒位于系统发育树的不同分支,涵盖了γ疱疹病毒、α疱疹病毒和β疱疹病毒的成员。因此,可以预期浆果提取物的抗病毒活性覆盖整个疱疹病毒科。
Claims (12)
1.飞燕草色素-3-葡萄糖苷(D3G)在制备用于在受试者中治疗或预防病毒感染的药物组合物中的用途,其中所述D3G是所述药物组合物的唯一活性成分,并且所述病毒是单纯疱疹病毒-1,即HSV-1;或卡波西肉瘤相关疱疹病毒,即KSHV/HHV-8。
2.根据权利要求1所述的用途,其中所述用途包括局部施用至皮肤、嘴唇或眼睛。
3.根据权利要求1所述的用途,其中D3G包含在组合物中,并且其中D3G以至少20重量%的浓度存在于组合物中。
4.根据权利要求1所述的用途,其中D3G以每天每次至少20mg D3G的1至10次口服剂量施用给受试者。
5.根据权利要求4所述的用途,其中D3G以每天每次至少20mg D3G的3至6次口服剂量施用给受试者。
6.根据权利要求1所述的用途,其中受试者是人。
7.根据权利要求6所述的用途,其中受试者怀孕或免疫功能受损或者受试者正在服用免疫抑制剂。
8.根据权利要求1所述的用途,其中所述药物组合物是包含飞燕草色素-3-葡萄糖苷(D3G)的局部用组合物,并且其中所述局部用组合物进一步包含适用于施用于皮肤的局部用组合物的药学上可接受的赋形剂。
9.根据权利要求8所述的用途,其中药学上可接受的赋形剂包括张力调节剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、pH调节剂、渗透促进剂、表面活性剂和湿润剂中的一种或多种。
10.根据权利要求8所述的用途,其中所述局部用组合物还包含镇痛剂。
11.根据权利要求1所述的用途,其中所述药物组合物是包含飞燕草色素-3-葡萄糖苷(D3G)的滴眼液组合物,其中所述滴眼液组合物进一步包含适用于施用于眼的组合物的药学上可接受的赋形剂。
12.根据权利要求11所述的用途,其中药学上可接受的赋形剂包括张力调节剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、pH调节剂、渗透促进剂、表面活性剂和湿润剂中的一种或多种。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP19166083 | 2019-03-29 | ||
EP19166083.6 | 2019-03-29 | ||
PCT/EP2020/058659 WO2020201058A1 (en) | 2019-03-29 | 2020-03-27 | Treatment and prevention of infections by herpesviridae with delphinidin-3-glucoside |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113573716A CN113573716A (zh) | 2021-10-29 |
CN113573716B true CN113573716B (zh) | 2024-06-04 |
Family
ID=66041161
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080021364.1A Active CN113573716B (zh) | 2019-03-29 | 2020-03-27 | 使用飞燕草色素-3-葡萄糖苷治疗和预防疱疹病毒科的感染 |
CN202080023425.8A Active CN113613660B (zh) | 2019-03-29 | 2020-03-27 | 包含花色素苷组合物和抗病毒剂的组合制备物 |
CN202080023424.3A Active CN113631176B (zh) | 2019-03-29 | 2020-03-27 | 用于预防和/或治疗由疱疹病毒科引起的病毒感染的含有浆果提取物的制备物 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080023425.8A Active CN113613660B (zh) | 2019-03-29 | 2020-03-27 | 包含花色素苷组合物和抗病毒剂的组合制备物 |
CN202080023424.3A Active CN113631176B (zh) | 2019-03-29 | 2020-03-27 | 用于预防和/或治疗由疱疹病毒科引起的病毒感染的含有浆果提取物的制备物 |
Country Status (8)
Country | Link |
---|---|
US (3) | US20220175809A1 (zh) |
EP (3) | EP3946400A1 (zh) |
JP (3) | JP2022533518A (zh) |
KR (3) | KR20210145207A (zh) |
CN (3) | CN113573716B (zh) |
AU (3) | AU2020253038A1 (zh) |
CA (3) | CA3131593A1 (zh) |
WO (3) | WO2020201050A1 (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024097158A1 (en) * | 2022-11-01 | 2024-05-10 | Ramirez Christina M | Viral prophylaxis treatment methods and pre-exposure prophylaxis kits |
CN115581702A (zh) * | 2022-12-12 | 2023-01-10 | 汤臣倍健股份有限公司 | 芍药素-3-o-阿拉伯糖苷在制备药物或保健食品的应用 |
WO2024148202A1 (en) * | 2023-01-04 | 2024-07-11 | Nse Products, Inc. | Metabolic health promoting compositions |
US11944742B1 (en) * | 2023-06-08 | 2024-04-02 | Microneb Tech Holdings, Inc. | Apparatus, methods, and systems for administering a medication to an animal |
CN116138248A (zh) * | 2023-02-22 | 2023-05-23 | 西北农林科技大学 | 一种奶绵羊精液冷冻保存用稀释液的制备方法及其应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000212092A (ja) * | 1999-01-27 | 2000-08-02 | Yanai Yoshiaki | 抗ウイルス・抗菌剤 |
WO2003039569A1 (en) * | 2001-11-09 | 2003-05-15 | Medpalett Pharmaceuticals As | Process for the preparation of anthocyanin-containaing products |
US20030149252A1 (en) * | 2000-08-31 | 2003-08-07 | Gourdin Gerald T | Efficient method for producing compositions enriched in total phenols |
CN103189065A (zh) * | 2010-10-11 | 2013-07-03 | 因德纳有限公司 | 用于治疗上呼吸道病症的制剂 |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5211944A (en) * | 1990-10-12 | 1993-05-18 | Shaman Pharmaceuticals, Inc. | Proanthocyanidin polymers having antiviral activity and methods of obtaining same |
JP3672340B2 (ja) * | 1994-07-11 | 2005-07-20 | エーザイ株式会社 | ブドウ色素を含有する飼料 |
WO1997041137A1 (en) * | 1996-04-17 | 1997-11-06 | Unifob | Use of anthocyanidin and anthocyanidin derivatives |
US7306815B2 (en) * | 2000-08-31 | 2007-12-11 | Phenolics, Llc | Compositions enriched in phenolic compounds and methods for producing the same |
WO2006076387A2 (en) * | 2005-01-11 | 2006-07-20 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, Centers For Disease Control And Prevention | Cyanidin-3-glucoside as an anti-neoplastic agent |
AU2006344708A1 (en) * | 2005-07-08 | 2008-03-20 | Magellan Companies, Inc. | Polymer coatings containing phytochemical agents and methods for making and using same |
US8802128B2 (en) * | 2006-06-23 | 2014-08-12 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
EP2117506A2 (en) * | 2006-12-13 | 2009-11-18 | Stephen M. Tuel | Methods of making pharmaceutical components for customized drug products |
KR100832240B1 (ko) * | 2007-04-11 | 2008-05-28 | 경상대학교산학협력단 | 검정콩 껍질로부터 추출한 안토시아닌을 함유하는 창상치료용 의약 조성물 |
WO2009069130A2 (en) * | 2007-11-27 | 2009-06-04 | Ramot At Tel-Aviv University Ltd. | New adjuvant |
WO2009111300A2 (en) * | 2008-02-29 | 2009-09-11 | Smith & Nephew, Inc. | Gradient coating for biomedical applications |
JP5347599B2 (ja) * | 2008-03-28 | 2013-11-20 | 大正製薬株式会社 | アントシアニンを含有するエアゾール用外用組成物 |
EP2493479A4 (en) * | 2009-10-30 | 2013-04-17 | Chimerix Inc | METHOD FOR THE TREATMENT OF VIRUS DISEASES |
JP2014001292A (ja) * | 2012-06-18 | 2014-01-09 | Wakamoto Co Ltd | アントシアニン含有水性組成物 |
TW201406382A (zh) * | 2012-08-09 | 2014-02-16 | Tci Co Ltd | 具視網膜保護功能之複方組成物及應用 |
KR101351062B1 (ko) * | 2012-11-21 | 2014-01-22 | 경상대학교산학협력단 | 검정콩 추출물을 포함하는 퇴행성 뇌신경 질환 치료 또는 예방용 조성물 |
ES2917425T3 (es) * | 2013-06-07 | 2022-07-08 | Shrivastava Remi | Una composición para aplicación tópica que comprende glicerol y taninos |
JP6434267B2 (ja) * | 2014-09-30 | 2018-12-05 | 小林製薬株式会社 | カプセル剤 |
CN109563156A (zh) * | 2016-07-26 | 2019-04-02 | 波利化学公司 | 抗体和抗病毒剂的抗hsv协同活性 |
EP3946403A1 (en) * | 2019-03-29 | 2022-02-09 | Evonik Operations GmbH | Preparations containing berry extracts for use in treating cancer |
-
2020
- 2020-03-27 WO PCT/EP2020/058651 patent/WO2020201050A1/en unknown
- 2020-03-27 CN CN202080021364.1A patent/CN113573716B/zh active Active
- 2020-03-27 EP EP20713020.4A patent/EP3946400A1/en active Pending
- 2020-03-27 CA CA3131593A patent/CA3131593A1/en active Pending
- 2020-03-27 WO PCT/EP2020/058662 patent/WO2020201060A1/en unknown
- 2020-03-27 JP JP2021557507A patent/JP2022533518A/ja active Pending
- 2020-03-27 AU AU2020253038A patent/AU2020253038A1/en active Pending
- 2020-03-27 US US17/598,557 patent/US20220175809A1/en active Pending
- 2020-03-27 KR KR1020217034675A patent/KR20210145207A/ko active Search and Examination
- 2020-03-27 CN CN202080023425.8A patent/CN113613660B/zh active Active
- 2020-03-27 AU AU2020252112A patent/AU2020252112A1/en active Pending
- 2020-03-27 WO PCT/EP2020/058659 patent/WO2020201058A1/en unknown
- 2020-03-27 CA CA3131585A patent/CA3131585A1/en active Pending
- 2020-03-27 CA CA3131609A patent/CA3131609A1/en active Pending
- 2020-03-27 KR KR1020217034678A patent/KR20210145209A/ko active Search and Examination
- 2020-03-27 EP EP20713900.7A patent/EP3946402A1/en active Pending
- 2020-03-27 AU AU2020252068A patent/AU2020252068A1/en active Pending
- 2020-03-27 US US17/598,587 patent/US20220175720A1/en active Pending
- 2020-03-27 JP JP2021557508A patent/JP7523460B2/ja active Active
- 2020-03-27 US US17/598,647 patent/US20220184164A1/en active Pending
- 2020-03-27 CN CN202080023424.3A patent/CN113631176B/zh active Active
- 2020-03-27 EP EP20713021.2A patent/EP3946401A1/en active Pending
- 2020-03-27 JP JP2021553311A patent/JP2022524772A/ja active Pending
- 2020-03-27 KR KR1020217034676A patent/KR20210145208A/ko active Search and Examination
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000212092A (ja) * | 1999-01-27 | 2000-08-02 | Yanai Yoshiaki | 抗ウイルス・抗菌剤 |
US20030149252A1 (en) * | 2000-08-31 | 2003-08-07 | Gourdin Gerald T | Efficient method for producing compositions enriched in total phenols |
WO2003039569A1 (en) * | 2001-11-09 | 2003-05-15 | Medpalett Pharmaceuticals As | Process for the preparation of anthocyanin-containaing products |
CN103189065A (zh) * | 2010-10-11 | 2013-07-03 | 因德纳有限公司 | 用于治疗上呼吸道病症的制剂 |
Non-Patent Citations (2)
Title |
---|
Brain health and anthocyanins-a new road to explore;佚名;《Agro Food Industry hi-tech》;20160831;第27卷(第4期);第16-17页,第16页右栏第2段,第17页左栏第2段 * |
Knox YM et al..Activity of anthocyanins from fruit extract of Ribes nigrum L against influenza A and B viruses.《Acta Virologica》.2001,第45卷(第4期),209-215. * |
Also Published As
Publication number | Publication date |
---|---|
JP2022533518A (ja) | 2022-07-25 |
JP2022540273A (ja) | 2022-09-15 |
WO2020201060A1 (en) | 2020-10-08 |
AU2020252112A1 (en) | 2021-11-25 |
WO2020201058A1 (en) | 2020-10-08 |
EP3946400A1 (en) | 2022-02-09 |
JP2022524772A (ja) | 2022-05-10 |
CA3131593A1 (en) | 2020-10-08 |
KR20210145207A (ko) | 2021-12-01 |
KR20210145209A (ko) | 2021-12-01 |
US20220175720A1 (en) | 2022-06-09 |
WO2020201050A1 (en) | 2020-10-08 |
CA3131609A1 (en) | 2020-10-08 |
AU2020252068A1 (en) | 2021-11-25 |
EP3946402A1 (en) | 2022-02-09 |
US20220184164A1 (en) | 2022-06-16 |
US20220175809A1 (en) | 2022-06-09 |
CN113631176A (zh) | 2021-11-09 |
CA3131585A1 (en) | 2020-10-08 |
CN113613660A (zh) | 2021-11-05 |
CN113573716A (zh) | 2021-10-29 |
CN113631176B (zh) | 2024-02-06 |
EP3946401A1 (en) | 2022-02-09 |
KR20210145208A (ko) | 2021-12-01 |
AU2020253038A1 (en) | 2021-11-25 |
CN113613660B (zh) | 2024-02-06 |
JP7523460B2 (ja) | 2024-07-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113573716B (zh) | 使用飞燕草色素-3-葡萄糖苷治疗和预防疱疹病毒科的感染 | |
KR102265798B1 (ko) | 코로나 바이러스에 연관된 감염의 치료를 위한 항바이러스 조성물 | |
US20230302075A1 (en) | Preparations containing berry extracts for use in the prophylaxis and/or treatment of viral infections caused by coronaviridae | |
ITRM20000294A1 (it) | Metodo di estrazione di prodotti ad attivita' farmaceutica da piante spermatofite, prodotti cosi' ottenuti e loro impiego in medicina, in pa | |
WO2020201055A1 (en) | Preparations containing berry extracts for use in the prophylaxis and/or treatment of viral infections caused by pneumoviridae | |
KR20160046782A (ko) | 레드비트 추출물을 이용한 방사선에 의한 면역조혈기능 장해 방호용 조성물 | |
Serkedjieva et al. | Protective efficacy of an aerosol preparation, obtained from Geranium sanguineum L., in experimental influenza infection | |
US20230398168A1 (en) | Use of effective part extract of monochasma savatieri in preparation of drug for treating inflammatory disease or tumor | |
US20170340689A1 (en) | Titrated extracts of cynara scolymus for use in the treatment of mesothelioma | |
CN114377027A (zh) | 白头翁皂苷B4在制备治疗或预防SARS-CoV-2的药物的用途 | |
KR101682156B1 (ko) | 레드비트 추출물을 이용한 방사선에 의한 면역조혈기능 장해 방호용 조성물 | |
US20200289593A1 (en) | Spirulina carotenoid complex | |
US12076357B2 (en) | Preparations containing berry extracts for use in the prophylaxis and/or treatment of viral infections caused by Paramyxoviridae | |
US20220184163A1 (en) | Preparations containing berry extracts for use in the prophylaxis and/or treatment of viral infections caused by paramyxoviridae | |
US20200289412A1 (en) | Bioenhanced spirulina lozenge formulation | |
KR20160095358A (ko) | 우고닌 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 헤르페스 바이러스 감염 질환의 예방 또는 치료용 약학적 조성물 | |
PL234670B1 (pl) | Zastosowanie wyciągu z liści miłorzębu japońskiego Ginkgo biloba |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |