CN114641285A - 包含植物提取物的配方 - Google Patents
包含植物提取物的配方 Download PDFInfo
- Publication number
- CN114641285A CN114641285A CN202180005862.1A CN202180005862A CN114641285A CN 114641285 A CN114641285 A CN 114641285A CN 202180005862 A CN202180005862 A CN 202180005862A CN 114641285 A CN114641285 A CN 114641285A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- andrographolide
- derivative
- antiviral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 38
- 238000009472 formulation Methods 0.000 title description 16
- 239000000419 plant extract Substances 0.000 title description 5
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 claims abstract description 54
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 claims abstract description 50
- HSTZMXCBWJGKHG-UHFFFAOYSA-N (E)-piceid Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=CC(C=CC=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-UHFFFAOYSA-N 0.000 claims abstract description 49
- 229960003764 polydatin Drugs 0.000 claims abstract description 49
- HSTZMXCBWJGKHG-CUYWLFDKSA-N trans-piceid Polymers O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(\C=C\C=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-CUYWLFDKSA-N 0.000 claims abstract description 49
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 48
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 claims abstract description 41
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229940096998 ursolic acid Drugs 0.000 claims abstract description 39
- 208000036142 Viral infection Diseases 0.000 claims abstract description 33
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 23
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 23
- 244000118350 Andrographis paniculata Species 0.000 claims abstract description 22
- 239000000284 extract Substances 0.000 claims abstract description 22
- 235000009008 Eriobotrya japonica Nutrition 0.000 claims abstract description 13
- 239000003443 antiviral agent Substances 0.000 claims abstract description 11
- 208000025721 COVID-19 Diseases 0.000 claims abstract description 7
- 244000061508 Eriobotrya japonica Species 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims description 91
- 150000001875 compounds Chemical class 0.000 claims description 66
- 241000700605 Viruses Species 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 33
- 230000009385 viral infection Effects 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 24
- 241000711573 Coronaviridae Species 0.000 claims description 23
- 208000015181 infectious disease Diseases 0.000 claims description 23
- -1 andrographolide glycosides Chemical class 0.000 claims description 18
- 230000002265 prevention Effects 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 9
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- AIGAZQPHXLWMOJ-UHFFFAOYSA-N Tanshinone I Chemical compound C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 241000712461 unidentified influenza virus Species 0.000 claims description 6
- 208000003322 Coinfection Diseases 0.000 claims description 5
- 241000709661 Enterovirus Species 0.000 claims description 5
- 241000351643 Metapneumovirus Species 0.000 claims description 5
- 208000002606 Paramyxoviridae Infections Diseases 0.000 claims description 5
- 241000709664 Picornaviridae Species 0.000 claims description 5
- 241000725643 Respiratory syncytial virus Species 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims description 5
- 241000701161 unidentified adenovirus Species 0.000 claims description 5
- 241000196324 Embryophyta Species 0.000 claims description 4
- 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 claims description 4
- 244000153955 Reynoutria sachalinensis Species 0.000 claims description 4
- 235000003202 Reynoutria sachalinensis Nutrition 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 4
- 244000178231 Rosmarinus officinalis Species 0.000 claims description 3
- 235000007303 Thymus vulgaris Nutrition 0.000 claims description 3
- 240000002657 Thymus vulgaris Species 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229930182470 glycoside Natural products 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 239000001585 thymus vulgaris Substances 0.000 claims description 3
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 claims description 2
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 claims description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 2
- HARGZZNYNSYSGJ-UHFFFAOYSA-N 1,2 dihydrotanshinquinone Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)CO1 HARGZZNYNSYSGJ-UHFFFAOYSA-N 0.000 claims description 2
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 claims description 2
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 claims description 2
- YGCYRQKJYWQXHG-RDNQFMDVSA-N 4-[2-[(1r,4as,5r,8as)-5,8a-dimethyl-2-methylidene-5-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]-3,4,4a,6,7,8-hexahydro-1h-naphthalen-1-yl]ethyl]-2h-furan-5-one Chemical compound C([C@@]1(C)[C@H]2CCC(=C)[C@@H](CCC=3C(OCC=3)=O)[C@]2(C)CCC1)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O YGCYRQKJYWQXHG-RDNQFMDVSA-N 0.000 claims 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 claims description 2
- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 claims 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 claims description 2
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 claims description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 2
- GVKKJJOMQCNPGB-JTQLQIEISA-N Cryptotanshinone Chemical compound O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1[C@@H](C)CO2 GVKKJJOMQCNPGB-JTQLQIEISA-N 0.000 claims description 2
- GVKKJJOMQCNPGB-UHFFFAOYSA-N Cryptotanshinone Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)CO2 GVKKJJOMQCNPGB-UHFFFAOYSA-N 0.000 claims description 2
- HARGZZNYNSYSGJ-JTQLQIEISA-N Dihydrotanshinone I Chemical compound C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2[C@@H](C)CO1 HARGZZNYNSYSGJ-JTQLQIEISA-N 0.000 claims description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 2
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 claims description 2
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 claims description 2
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 claims description 2
- ZSBXGIUJOOQZMP-UHFFFAOYSA-N Isomatrine Natural products C1CCC2CN3C(=O)CCCC3C3C2N1CCC3 ZSBXGIUJOOQZMP-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 claims description 2
- ZSBXGIUJOOQZMP-JLNYLFASSA-N Matrine Chemical compound C1CC[C@H]2CN3C(=O)CCC[C@@H]3[C@@H]3[C@H]2N1CCC3 ZSBXGIUJOOQZMP-JLNYLFASSA-N 0.000 claims description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 claims description 2
- IPQKDIRUZHOIOM-UHFFFAOYSA-N Oroxin A Natural products OC1C(O)C(O)C(CO)OC1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IPQKDIRUZHOIOM-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 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 claims description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 2
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 2
- 229930183118 Tanshinone Natural products 0.000 claims description 2
- HYXITZLLTYIPOF-UHFFFAOYSA-N Tanshinone II Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 claims description 2
- RNSASHBZNLJPDG-MCLZGWMTSA-N [(3s,4e)-4-[2-[(1r,4as,5r,6r,8as)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1h-naphthalen-1-yl]ethylidene]-5-oxooxolan-3-yl] 5-(dithiolan-3-yl)pentanoate Chemical compound O([C@H]1\C(C(OC1)=O)=C/C[C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)C(=O)CCCCC1CCSS1 RNSASHBZNLJPDG-MCLZGWMTSA-N 0.000 claims description 2
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 claims description 2
- 229960004238 anakinra Drugs 0.000 claims description 2
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 claims description 2
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 2
- 229960004099 azithromycin Drugs 0.000 claims description 2
- IKIIZLYTISPENI-ZFORQUDYSA-N baicalin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IKIIZLYTISPENI-ZFORQUDYSA-N 0.000 claims description 2
- AQHDANHUMGXSJZ-UHFFFAOYSA-N baicalin Natural products OC1C(O)C(C(O)CO)OC1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 AQHDANHUMGXSJZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960003321 baicalin Drugs 0.000 claims description 2
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 claims description 2
- 229960003677 chloroquine Drugs 0.000 claims description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 2
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 claims description 2
- 235000012754 curcumin Nutrition 0.000 claims description 2
- 239000004148 curcumin Substances 0.000 claims description 2
- 229940109262 curcumin Drugs 0.000 claims description 2
- MEEPUSVTMHGIPC-UHFFFAOYSA-N deoxyandrographiside Natural products OC1CCC2(C)C(CCC=3C(OCC=3)=O)C(=C)CCC2C1(C)COC1OC(CO)C(O)C(O)C1O MEEPUSVTMHGIPC-UHFFFAOYSA-N 0.000 claims description 2
- 229960003957 dexamethasone Drugs 0.000 claims description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 2
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims description 2
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 claims description 2
- CVOQYKPWIVSMDC-UHFFFAOYSA-L dipotassium;butanedioate Chemical compound [K+].[K+].[O-]C(=O)CCC([O-])=O CVOQYKPWIVSMDC-UHFFFAOYSA-L 0.000 claims description 2
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 claims description 2
- 229960002768 dipyridamole Drugs 0.000 claims description 2
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 claims description 2
- 229950008454 favipiravir Drugs 0.000 claims description 2
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 claims description 2
- 229960000556 fingolimod Drugs 0.000 claims description 2
- 229950009614 gimsilumab Drugs 0.000 claims description 2
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 claims description 2
- 239000001685 glycyrrhizic acid Substances 0.000 claims description 2
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 claims description 2
- 229960004949 glycyrrhizic acid Drugs 0.000 claims description 2
- 235000019410 glycyrrhizin Nutrition 0.000 claims description 2
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims description 2
- 229960002897 heparin Drugs 0.000 claims description 2
- 229920000669 heparin Polymers 0.000 claims description 2
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 claims description 2
- 229940025878 hesperidin Drugs 0.000 claims description 2
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960004171 hydroxychloroquine Drugs 0.000 claims description 2
- 229960004525 lopinavir Drugs 0.000 claims description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 2
- 229960004773 losartan Drugs 0.000 claims description 2
- IQPNAANSBPBGFQ-UHFFFAOYSA-N luteolin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(O)C(O)=C1 IQPNAANSBPBGFQ-UHFFFAOYSA-N 0.000 claims description 2
- LRDGATPGVJTWLJ-UHFFFAOYSA-N luteolin Natural products OC1=CC(O)=CC(C=2OC3=CC(O)=CC(O)=C3C(=O)C=2)=C1 LRDGATPGVJTWLJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000009498 luteolin Nutrition 0.000 claims description 2
- 229930014456 matrine Natural products 0.000 claims description 2
- 229960004584 methylprednisolone Drugs 0.000 claims description 2
- HTNPEHXGEKVIHG-QCNRFFRDSA-N molnupiravir Chemical compound C(OC(=O)C(C)C)[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C(=O)N=C(NO)C=C1 HTNPEHXGEKVIHG-QCNRFFRDSA-N 0.000 claims description 2
- BBGWVUQBIGGVLS-UHFFFAOYSA-N neoandrographolide Natural products CC1(COC2OC(CO)C(O)C(O)C2O)C(O)CCC3(C)C(CCC4=C(O)COC4=O)C(=C)CCC13 BBGWVUQBIGGVLS-UHFFFAOYSA-N 0.000 claims description 2
- YGCYRQKJYWQXHG-UHFFFAOYSA-N neoandrographoside Natural products C1CCC2(C)C(CCC=3C(OCC=3)=O)C(=C)CCC2C1(C)COC1OC(CO)C(O)C(O)C1O YGCYRQKJYWQXHG-UHFFFAOYSA-N 0.000 claims description 2
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 claims description 2
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 claims description 2
- 229960003752 oseltamivir Drugs 0.000 claims description 2
- GGHMUJBZYLPWFD-CUZKYEQNSA-N patchouli alcohol Chemical compound C1C[C@]2(C)[C@@]3(O)CC[C@H](C)[C@@H]2C[C@@H]1C3(C)C GGHMUJBZYLPWFD-CUZKYEQNSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical compound OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- CJWHWKXAABCWLT-UHFFFAOYSA-L potassium;sodium;butanedioate Chemical compound [Na+].[K+].[O-]C(=O)CCC([O-])=O CJWHWKXAABCWLT-UHFFFAOYSA-L 0.000 claims description 2
- 229960001285 quercetin Drugs 0.000 claims description 2
- 235000005875 quercetin Nutrition 0.000 claims description 2
- GGHMUJBZYLPWFD-UHFFFAOYSA-N rac-patchouli alcohol Natural products C1CC2(C)C3(O)CCC(C)C2CC1C3(C)C GGHMUJBZYLPWFD-UHFFFAOYSA-N 0.000 claims description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 2
- 229960000329 ribavirin Drugs 0.000 claims description 2
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 2
- 229960000311 ritonavir Drugs 0.000 claims description 2
- AZEZEAABTDXEHR-UHFFFAOYSA-M sodium;1,6,6-trimethyl-10,11-dioxo-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-2-sulfonate Chemical compound [Na+].C12=CC=C(C(CCC3)(C)C)C3=C2C(=O)C(=O)C2=C1OC(S([O-])(=O)=O)=C2C AZEZEAABTDXEHR-UHFFFAOYSA-M 0.000 claims description 2
- 229960004556 tenofovir Drugs 0.000 claims description 2
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 2
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 claims description 2
- 229960005342 tranilast Drugs 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 241001071917 Lithospermum Species 0.000 claims 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 claims 1
- 230000003612 virological effect Effects 0.000 abstract description 11
- 240000001341 Reynoutria japonica Species 0.000 abstract description 6
- 235000018167 Reynoutria japonica Nutrition 0.000 abstract description 6
- 210000004027 cell Anatomy 0.000 description 32
- 241001678559 COVID-19 virus Species 0.000 description 25
- 230000014509 gene expression Effects 0.000 description 17
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 12
- 102100035765 Angiotensin-converting enzyme 2 Human genes 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 10
- 210000003501 vero cell Anatomy 0.000 description 10
- 241000315672 SARS coronavirus Species 0.000 description 9
- 241001092070 Eriobotrya Species 0.000 description 8
- 241000282339 Mustela Species 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 241000008904 Betacoronavirus Species 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000002648 combination therapy Methods 0.000 description 6
- 230000000120 cytopathologic effect Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 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
- 240000004530 Echinacea purpurea Species 0.000 description 4
- 241000241413 Propolis Species 0.000 description 4
- 238000002123 RNA extraction Methods 0.000 description 4
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 4
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 4
- 239000011149 active material Substances 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000007859 condensation product Substances 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 235000014134 echinacea Nutrition 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 229940069949 propolis Drugs 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 235000021283 resveratrol Nutrition 0.000 description 4
- 229940016667 resveratrol Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000606750 Actinobacillus Species 0.000 description 3
- 241000004176 Alphacoronavirus Species 0.000 description 3
- 102000053723 Angiotensin-converting enzyme 2 Human genes 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 241001461743 Deltacoronavirus Species 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- 241000008920 Gammacoronavirus Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 101710167605 Spike glycoprotein Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000012054 celltiter-glo Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000034217 membrane fusion Effects 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 238000003757 reverse transcription PCR Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- RASMOUCLFYYPSU-UHFFFAOYSA-N 2-amino-5-(3,4-dimethoxyphenyl)-6-methylpyridine-3-carbonitrile Chemical compound C1=C(OC)C(OC)=CC=C1C1=CC(C#N)=C(N)N=C1C RASMOUCLFYYPSU-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- FUDDLSHBRSNCBV-UHFFFAOYSA-N 4-hydroxyoxolan-2-one Chemical compound OC1COC(=O)C1 FUDDLSHBRSNCBV-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 235000006491 Acacia senegal Nutrition 0.000 description 2
- 241000589291 Acinetobacter Species 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 241000223836 Babesia Species 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000606660 Bartonella Species 0.000 description 2
- 241000588807 Bordetella Species 0.000 description 2
- 241000589562 Brucella Species 0.000 description 2
- 241001453380 Burkholderia Species 0.000 description 2
- 241000589876 Campylobacter Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241001533384 Circovirus Species 0.000 description 2
- 241000193403 Clostridium Species 0.000 description 2
- 241000195493 Cryptophyta Species 0.000 description 2
- 241000194033 Enterococcus Species 0.000 description 2
- 241000588698 Erwinia Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241000589601 Francisella Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000224466 Giardia Species 0.000 description 2
- 241000224467 Giardia intestinalis Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000588748 Klebsiella Species 0.000 description 2
- 241000589248 Legionella Species 0.000 description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 description 2
- 241000222722 Leishmania <genus> Species 0.000 description 2
- 241000186781 Listeria Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 2
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 2
- 244000022198 Mirabilis jalapa Species 0.000 description 2
- 235000009053 Mirabilis jalapa Nutrition 0.000 description 2
- 241000588621 Moraxella Species 0.000 description 2
- 241000588771 Morganella <proteobacterium> Species 0.000 description 2
- 241000588653 Neisseria Species 0.000 description 2
- 241000187654 Nocardia Species 0.000 description 2
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 2
- 241000606860 Pasteurella Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 241000223960 Plasmodium falciparum Species 0.000 description 2
- 241000223801 Plasmodium knowlesi Species 0.000 description 2
- 241000223821 Plasmodium malariae Species 0.000 description 2
- 241001505293 Plasmodium ovale Species 0.000 description 2
- 241000223810 Plasmodium vivax Species 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- 241000588768 Providencia Species 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 241000242678 Schistosoma Species 0.000 description 2
- 241000607720 Serratia Species 0.000 description 2
- 241000607768 Shigella Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 241000122971 Stenotrophomonas Species 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000223777 Theileria Species 0.000 description 2
- 241000223996 Toxoplasma Species 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 241000589886 Treponema Species 0.000 description 2
- 241000224526 Trichomonas Species 0.000 description 2
- 241000223104 Trypanosoma Species 0.000 description 2
- 241000607598 Vibrio Species 0.000 description 2
- 108020000999 Viral RNA Proteins 0.000 description 2
- 241000607734 Yersinia <bacteria> Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 201000008680 babesiosis Diseases 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 239000013553 cell monolayer Substances 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000001010 compromised effect Effects 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229940085435 giardia lamblia Drugs 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 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 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 238000002941 microtiter virus yield reduction assay Methods 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 229940118768 plasmodium malariae Drugs 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- HSTZMXCBWJGKHG-OWOJBTEDSA-N 2-[3-hydroxy-5-[(e)-2-(4-hydroxyphenyl)ethenyl]phenoxy]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC1C(O)C(O)C(CO)OC1OC1=CC(O)=CC(\C=C\C=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-OWOJBTEDSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 101800000535 3C-like proteinase Proteins 0.000 description 1
- 101800002396 3C-like proteinase nsp5 Proteins 0.000 description 1
- IADBQAOIOMKMLD-YHQHWJDSSA-N 6-amino-3-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-hydroxy-1H-pyrimidin-2-one Chemical compound C1=CC(N)(O)NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IADBQAOIOMKMLD-YHQHWJDSSA-N 0.000 description 1
- IDVQGNMSSHPZSJ-UHFFFAOYSA-N 7-methylsulfanyl-3-nitro-6h-[1,2,4]triazolo[5,1-c][1,2,4]triazin-4-one Chemical compound N1=C([N+]([O-])=O)C(=O)N2NC(SC)=NC2=N1 IDVQGNMSSHPZSJ-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
- 241001519451 Abramis brama Species 0.000 description 1
- 239000004229 Alkannin Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000606646 Anaplasma Species 0.000 description 1
- 241000746375 Andrographis Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000008924 Bafinivirus Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- VWDXGKUTGQJJHJ-UHFFFAOYSA-N Catenarin Natural products C1=C(O)C=C2C(=O)C3=C(O)C(C)=CC(O)=C3C(=O)C2=C1O VWDXGKUTGQJJHJ-UHFFFAOYSA-N 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 241000862448 Chlorocebus Species 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 241000502280 Clitocybe Species 0.000 description 1
- 241000224483 Coccidia Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000001528 Coronaviridae Infections Diseases 0.000 description 1
- 241000004175 Coronavirinae Species 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000192700 Cyanobacteria Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 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 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 208000000655 Distemper Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 239000010282 Emodin Substances 0.000 description 1
- RBLJKYCRSCQLRP-UHFFFAOYSA-N Emodin-dianthron Natural products O=C1C2=CC(C)=CC(O)=C2C(=O)C2=C1CC(=O)C=C2O RBLJKYCRSCQLRP-UHFFFAOYSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- ZWQVYZXPYSYPJD-RYUDHWBXSA-N Glu-Gly-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZWQVYZXPYSYPJD-RYUDHWBXSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- YOOXNSPYGCZLAX-UHFFFAOYSA-N Helminthosporin Natural products C1=CC(O)=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O YOOXNSPYGCZLAX-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000638154 Homo sapiens Transmembrane protease serine 2 Proteins 0.000 description 1
- 244000309467 Human Coronavirus Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 235000010676 Ocimum basilicum Nutrition 0.000 description 1
- 240000007926 Ocimum gratissimum Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101800004803 Papain-like protease Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000218657 Picea Species 0.000 description 1
- 241000218595 Picea sitchensis Species 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000010362 Protozoan Infections Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 244000184734 Pyrus japonica Species 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 239000013614 RNA sample Substances 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 101710153041 Replicase polyprotein 1a Proteins 0.000 description 1
- 101710151619 Replicase polyprotein 1ab Proteins 0.000 description 1
- NTGIIKCGBNGQAR-UHFFFAOYSA-N Rheoemodin Natural products C1=C(O)C=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1O NTGIIKCGBNGQAR-UHFFFAOYSA-N 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 108091005634 SARS-CoV-2 receptor-binding domains Proteins 0.000 description 1
- 241000059486 Sabo virus Species 0.000 description 1
- 244000151637 Sambucus canadensis Species 0.000 description 1
- 235000018735 Sambucus canadensis Nutrition 0.000 description 1
- 241001678561 Sarbecovirus Species 0.000 description 1
- 101100316897 Severe acute respiratory syndrome coronavirus 2 E gene Proteins 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000008923 Torovirinae Species 0.000 description 1
- 241000711517 Torovirus Species 0.000 description 1
- 240000000851 Vaccinium corymbosum Species 0.000 description 1
- 235000003095 Vaccinium corymbosum Nutrition 0.000 description 1
- 240000001717 Vaccinium macrocarpon Species 0.000 description 1
- 235000012545 Vaccinium macrocarpon Nutrition 0.000 description 1
- 235000017537 Vaccinium myrtillus Nutrition 0.000 description 1
- 235000002118 Vaccinium oxycoccus Nutrition 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 108070000030 Viral receptors Proteins 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 101150054399 ace2 gene Proteins 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 235000019232 alkannin Nutrition 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001745 anti-biotin effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- SWJRLTOYMKAFKN-UHFFFAOYSA-N azanium 2-(2,5-diphenyl-1H-tetrazol-1-ium-3-yl)-4,5-dimethyl-1,3-thiazole dibromide Chemical compound [Br-].[NH4+].CC=1N=C(SC1C)N1N([NH2+]C(=N1)C1=CC=CC=C1)C1=CC=CC=C1.[Br-] SWJRLTOYMKAFKN-UHFFFAOYSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 235000007123 blue elder Nutrition 0.000 description 1
- 235000021014 blueberries Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 208000014058 canine distemper Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 210000004922 colonic epithelial cell Anatomy 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000004634 cranberry Nutrition 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- ZVTDLPBHTSMEJZ-UPZRXNBOSA-N danoprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCC[C@H](C(N1C[C@@H](C[C@H]1C(=O)N2)OC(=O)N1CC2=C(F)C=CC=C2C1)=O)NC(=O)OC(C)(C)C)NS(=O)(=O)C1CC1 ZVTDLPBHTSMEJZ-UPZRXNBOSA-N 0.000 description 1
- 229950002891 danoprevir Drugs 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000002355 dual-layer Substances 0.000 description 1
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 1
- 229960001971 ebastine Drugs 0.000 description 1
- 229940045811 echinacea purpurea extract Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 235000007124 elderberry Nutrition 0.000 description 1
- RHMXXJGYXNZAPX-UHFFFAOYSA-N emodin Chemical compound C1=C(O)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O RHMXXJGYXNZAPX-UHFFFAOYSA-N 0.000 description 1
- VASFLQKDXBAWEL-UHFFFAOYSA-N emodin Natural products OC1=C(OC2=C(C=CC(=C2C1=O)O)O)C1=CC=C(C=C1)O VASFLQKDXBAWEL-UHFFFAOYSA-N 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 235000008995 european elder Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011832 ferret model Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 235000019674 grape juice Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000007407 health benefit Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 239000012676 herbal extract Substances 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 235000008777 kaempferol Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 229940045335 menthol 2 mg/ml Drugs 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 238000010232 migration assay Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 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 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- PKUBGLYEOAJPEG-UHFFFAOYSA-N physcion Natural products C1=C(C)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O PKUBGLYEOAJPEG-UHFFFAOYSA-N 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011897 real-time detection Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000020095 red wine Nutrition 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 208000011479 upper respiratory tract disease Diseases 0.000 description 1
- 150000003675 ursolic acids Chemical class 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 230000007502 viral entry Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Images
Classifications
-
- 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)
- A61K36/19—Acanthaceae (Acanthus family)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K31/365—Lactones
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
-
- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- 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)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- 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)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
-
- 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)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
-
- 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)
- A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
-
- 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)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medical Informatics (AREA)
- Engineering & Computer Science (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本申请涉及包含穿心莲内酯,熊果酸和虎杖苷的抗病毒组合物及其在治疗病毒和细菌感染(包括COVID‑19)中的用途。还公开了穿心莲内酯和熊果酸的组合,或穿心莲内酯和虎杖苷的组合。或者,使用穿心莲(用其穿心莲内酯),枇杷(用其熊果酸)和虎杖(用其虎杖苷)的提取物。该组合还可以包含包括单克隆抗体在内的其他抗病毒剂。
Description
技术领域
本发明一般涉及可用于治疗或预防病毒和细菌感染的包含植物提取物的组合和组合物。
背景技术
冠状病毒是一个大的病毒家族,通常会引起轻度到中度的上呼吸道疾病,如普通感冒。然而,近些年在动物宿主中出现了新型冠状病毒,可引起严重和广泛的疾病和死亡。严重急性呼吸综合征冠状病毒(SARS-CoV)和中东呼吸综合征冠状病毒(MERS-CoV)引起具有高死亡率的严重呼吸道疾病。
严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)是全球COVID-19大流行的病原体。2019年底中国湖北省首次报告了SARS-CoV-2。继2002/2003年SARS爆发和2012年MERS流行之后,COVID-19是21世纪第三次显著爆发(Yang,T.,et al.J.Autoimmun.,2020,109,102434;Da Costa,V.G.et al.Arch.Virol.,2020,165(7),1517-1526)。截至2020年9月20日,全球有30369778例确诊病例,948795例确诊死亡病例(https://covid19.who.int)。
SARS-CoV、MERS-CoV和SARS-CoV-2属于冠状病毒科和β冠状病毒属。SARS-CoV-2是一种球形、包膜、单链正义RNA病毒,与SAR-CoV基因组的同源性约为79.6%。病毒粒子由核酸和核衣壳蛋白组成,形成螺旋状的核衣壳。脂质包膜上镶嵌着结构蛋白,结构蛋白包括细胞膜(M)糖蛋白、包膜(E)蛋白和刺突(S)糖蛋白。病毒感染是由S糖蛋白与宿主细胞表面受体之间的相互作用引起的。S糖蛋白被细胞丝氨酸蛋白酶TMPRSS2裂解成S1和S2亚基,负责受体识别和膜融合。膜融合允许将病毒基因组释放到细胞质中,然后进行RNA复制。
在冠状病毒科的其他病毒中观察到S糖蛋白通过接触位于细胞表面的特定宿主受体来介导病毒进入。宿主-客体识别是病毒特异性的,特异性由病毒嗜性和发病机制决定(Ou,X.,et al.Nat.Commun,2020,11(1),1620;Walls,A.C.,et al.Cell,2020,181(2),281-292)。SARS-CoV和SARS-CoV-2均通过宿主细胞膜上的血管紧张素转换酶2(ACE2)受体进入宿主细胞。病毒与宿主细胞的膜融合在结合后被激活,病毒RNA随后被释放到细胞质中,形成感染(Hoffmann,M.,et al.Cell,2020,181(2),271-280).
冠状病毒的特点是具有已知最大的RNA病毒基因组,范围约为26至32kb(Song,Z.et al.Viruses,2019,11(1)59;Anand,K.,et al.Science,2003,300(5626),1763-1767),并包含至少6个开放阅读框(Chen,Y.,et al.J Med Virol,2020,92(4),418-423;Gordon,D.E.et al.Nature,2020,10.1038)。主要的阅读框ORF 1ab,编码两种重叠的多蛋白(pp1a和pp1ab),它们被主蛋白酶(Mpro)和木瓜蛋白酶样蛋白酶(PLpro)切割成16种非结构蛋白(Ullrich,S.and Nitsche,C.Bioorganic&Medicinal Chemistry Letters,2020,30(17),127377)。
目前,获得批准用于治疗SARS,MERS或COVID-19等人类冠状病毒或潜在致命威胁的人畜共患冠状病毒疾病的治疗方法很少。因此,有必要开发用于包括冠状病毒感染在内的病毒感染的有力且有效的治疗方法。
发明概述
提供了一种用于治疗病毒感染的新型抗病毒组合、组合物和方法。
因此,在一个方面,本发明提供一种抗病毒组合,其包含选自穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐、以及虎杖苷或其衍生物或其药学上可接受的盐中的两种或更多种化合物。
在另一方面,本发明提供了一种药物组合物,其包含根据本发明的抗病毒组合和至少一种药学上可接受的载体或稀释剂。
在一个方面中,本发明提供一种包含穿心莲(Andrographis paniculata)提取物、连同熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐的药物组合物。
在另一方面,本发明提供一种在有其需要的对象中治疗或预防病毒感染的方法,包括向对象施用有效量的根据本发明的抗病毒组合或药物组合物。
在另一方面,本发明提供一种在有其需要的对象中治疗或预防细菌感染的方法,包括向对象施用有效量的根据本发明的抗病毒组合或药物组合物。
在另一方面,本发明提供了一种根据本发明的抗病毒组合或药物组合物,其用于治疗或预防病毒感染。
在另一方面,本发明提供了一种根据本发明的组合或药物组合物,其用于治疗或预防细菌感染。
在阅读以下详细描述后,结合所附实施案例和权利要求,本发明的这些和其他方面对于本领域技术人员将变得更加明显。
附图简要说明
本发明将仅参考以下非限制性附图以示例方式进行描述,其中:
图1举例说明穿心莲内酯(UP-A)、虎杖苷(UP-P)和熊果酸(UP-U)对Vero(AGM)细胞中ACE2 mRNA表达的影响。细胞与这些化合物一起培养48小时。通过定量逆转录酶RT-PCT测定ACE2表达。数据显示为平均值±SEM。*与平板对照组相比p<0.05。
图2举例说明穿心莲内酯(UP-A)和虎杖苷(UP-P)对Vero(AGM)细胞和人肺上皮(A549)细胞中ACE2 mRNA表达的影响。细胞与这些化合物一起培养24小时。通过定量逆转录酶RT-PCT测定ACE2表达。数据显示平均值±SEM。*与平板对照组相比p<0.05。
图3举例说明在每天用穿心莲内酯(UP-A)和虎杖苷(UP-P)(1μM)处理三天后的72小时,通过ELISA在CACO-2细胞的细胞裂解液中ACE2蛋白的表达。数据显示平均值±SEM;*p<0.05。
发明详述
联合疗法在HIV感染的治疗中已经确立,在因耐药性导致的其他病毒感染的治疗中同时也作为一种对抗其他难治的病毒感染的手段也开始出现。美国卫生和公众服务部发布的治疗指南规定,实现病毒抑制需要使用联合疗法,即来源于至少两种或更多种药物类别的几种药物。
出于这种考虑,设想包含某些植物提取物的联合疗法将为治疗病毒感染提供一种新的治疗方案。植物源性天然产物在新型治疗剂的开发中起着至关重要的作用。它们被建议通过靶向病毒受体(Chang&Woo,2003;Keyaerts,et al.2007)、病毒整合(Kim etal.2010)、逆转录(Zhang et al.2014)、病毒复制和病毒蛋白翻译(Mansouri et al.2009)用来对抗病毒感染。具体而言,已发现包含选自穿心莲内酯或其衍生物、或其药学上可接受的盐,熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物、或其药学上可接受的盐中的两种或更多种化合物的组合具有良好的抗病毒活性。
因此,在一个实施方案中,本发明提供了一种抗病毒组合,其包含选自穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐、以及虎杖苷或其衍生物或其药学上可接受的盐中的两种或更多种化合物。
如本文所使用的,术语“组合”指的是组合物或试剂盒,其中上文定义的组合成员可以不独立或独立地给药,或使用区别剂量的组合成员的不同固定组合,即,同时或在不同时间点给药。其后组合成员可以例如同时施用或按时间顺序交错施用,即在不同的时间点以相同或不同的时间间隔施用试剂盒的任一成员。组合中待施用的组合成员的总量的比例可以例如为了应对待治疗的患者亚群的需求或者单个患者的需求而变化,单个患者的不同需求可能归因于患者的年龄、性别、体重等。
在一个实施方案中,设想抗病毒组合将包含穿心莲内酯或其衍生物或其药学上可接受的盐,以及熊果酸或其药学上可接受的盐。在另一个实施方案中,设想抗病毒组合包含穿心莲内酯或其衍生物或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。在另一实施方案中,设想抗病毒组合将包含熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。在又一个实施方案中,设想抗病毒组合包含穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。
穿心莲内酯是一种具有以下结构的内酯二萜:
穿心莲内酯(3-[2-[十氢-6-羟基-5-(羟甲基)-5,8a-二甲基-2-亚甲基-1-萘烯基]亚乙基]二氢-4-羟基-2(3H)-呋喃酮)
穿心莲内酯在穿心莲[通常被称为穿心莲(Creat)或绿印度当药(greenchiretta)]的叶子中含量非常丰富,一种原产于印度和斯里兰卡的草本植物。穿心莲因其药用作用在南亚和东南亚广泛种植,穿心莲提取物和穿心莲内酯已发现多种用途,例如,作为抗炎、抗肿瘤和抗高血糖剂。
有利的是,穿心莲内酯在亚洲的传统医学中被广泛使用,被认为是食用安全的。
熊果酸是一种五环三萜化合物,具有以下结构:
熊果酸(1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-羟基-1,2,6a,6b,9,9,12a-七甲基-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-十四氢-1H-苉-4a-羧酸)
它存在于许多植物中,包括枇杷(Eriobotrya japonica)、团花(Cadamba)、紫茉莉(Mirabillis jalapa),以及苹果的蜡质层和许多水果和草本植物如迷迭香、百里香、罗勒、越橘、蔓越莓、接骨木花和薄荷中。
虎杖苷(虎杖甙)是一种芪类甙(stilbenoid glucoside),是葡萄汁中发现的主要白藜芦醇。可以在北美云杉(Picea sitchensis)树皮中发现虎杖苷,也可以从虎杖(Reynoutria japonica)中分离出虎杖苷。虎杖苷具有结构:
虎杖苷(2-[3-羟基-5-[(E)-2-(4-羟基苯基)乙烯基]苯氧基]-6-(羟甲基)恶烷-3,4,5-三醇)
虎杖苷及其衍生物,白藜芦醇,被证明用作抗氧化剂,并且是与红酒的健康益处相关联的化合物。虎杖苷和白藜芦醇也同样被提出具有抗增殖和抗炎作用(Cheng,S.D.etal.PLoS ONE,8(1):e54505).
此处,虎杖苷已被确定为一种靶向Mpro的化合物。初步的计算机和酶学研究表明虎杖苷是靶向Mpro的有望候选药物。
在一个实施方案中,抗病毒组合和组合物包含穿心莲内酯衍生物。如上所述,穿心莲内酯来源于从穿心莲叶。除了穿心莲内酯,还发现了几种衍生物具有有益的治疗性质。此类衍生物包括但不限于:
14-去氧-二去氢穿心莲内酯;
14-脱羟穿心莲内酯-12-磺酸钠盐;
14-α-硫辛酰穿心莲内酯;
穿心莲内酯苷;
新穿心莲内酯苷元(andrograpanin);
14-去羟基-11,12-二去氢穿心莲内酯-3,19-双(琥珀酸)钾盐;
14-去羟基-11,12-二去氢穿心莲内酯-3,19-双(琥珀酸)钾钠盐;
(R)-((1R,5aS,6R,9aS)-1,5a-二甲基-7-亚甲基-3-氧代-6-((E)-2-(2-氧代-2,5-二氢呋喃-3-基)乙烯基)十氢-1H-苯并[c]氮杂(azapin)-1-基)2-氨基-3-苯丙酸酯;
2-((1R,5R,6R,8aS)-6-羟基-5-(羟甲基)-5,8a-二甲基-2-亚甲基十氢萘-1-基)苯甲酸乙酯;
(1S,2R,4aS,5R,8aS)-1-甲酰胺-1,4a-二甲基-6-亚甲基-5-((E)-2-(2-氧代-2,5-二氢呋喃-3-基)乙烯基)十氢萘-2-基5-((R)-1,2-戊酸酯;
(1S,2R,4aS,5R,8aS)-1-甲酰胺-1,4a-二甲基-6-亚甲基-5-((E)-2-(2-氧代-2,5-二氢呋喃-3-基)乙烯基)十氢萘-2-基-2-硝基苯甲酸酯;及
(S)-(1S,2R,4aS,5R,8aS)-1-甲酰胺-1,4a-二甲基-6-亚甲基-5-((E)-2-(2-氧代-2,5-二氢呋喃-3-基)乙烯基)十氢萘-2-基-2-氨基-3-苯丙酸酯。
在另一实施方案,抗病毒组合和组合物包含熊果酸衍生物。这类衍生物包括白藜芦醇。
应理解,本发明化合物可以以多种等效互变异构形式存在。为清楚起见,已将化合物描述为单一互变异构体,尽管所有此类互变异构体形式均被认为在本发明范围内。
应注意,本发明的一些化合物的结构包括不对称碳原子。因此,应当理解,由这种不对称性产生的异构体(例如,所有对映体、立体异构体、旋转异构体、互变异构体、非对映体或外消旋体)包括在本发明的范围内。本发明在其范围内包括所有这些立体异构体形式,或者是分离的(例如,在对映体分离中),或者是组合的(包括外消旋混合物和非对映体混合物)。
因此,本发明还涉及相对于氨基酸残基的不对称中心呈基本上纯立体异构形式的化合物,例如大于约90%de,如95%至97%de,或大于99%de,以及其混合物,包括外消旋混合物。技术人员将认识到,有多种技术可用于生产以外消旋、对映体富集或对映异构体形式的本发明的非手性化合物。例如,化合物的对映体富集或对映体纯形式可以通过立体选择性合成和/或通过使用色谱或选择性重结晶技术来制备。
本发明的化合物可以是结晶形式或溶剂化物(例如水合物),并且这两种形式都在本发明的范围内。术语“溶剂化物”是由溶质(在本发明中为本发明化合物)和溶剂形成的可变化学计量比的复合物。此类溶剂优选不干扰溶质的生物活性。例如,溶剂可以是水、丙酮、乙醇或乙酸。溶剂化方法在本领域内是众所周知的。
如果化合物包含可被质子化或去质子化(例如在生理pH下)的一个或多个官能团,则该化合物可制备或分离成药学上可接受的盐。应了解,化合物在给定pH值下可为两性离子。如本文所使用的,表述“药学上可接受的盐”系指给定化合物的盐,其中该盐适合作为药物施用。此类盐可在化学合成期间制备,例如,分别通过酸或碱与胺或羧酸基团的反应制备。化合物的药学上可接受的盐也可从药草提取物中分离。
药学上可接受的酸加成盐可由无机酸和有机酸制备。无机酸的实例包括盐酸、氢溴酸、硫酸、硝酸、磷酸等。有机酸的实例包括乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、丁二酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。例如,本发明化合物的无环部分中的氮原子可与酸发生反应以形成酸加成盐。
药学上可接受的碱加成盐可由无机碱和有机碱制备。来自无机碱的相应反离子包括钠、钾、锂、铵、钙和镁盐。有机碱包括伯胺、仲胺和叔胺、经取代胺(包括天然存在的取代胺)和环胺,包括异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二甲氨基乙醇、氨丁三醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴胺、胆碱、甜菜碱、乙二胺、氨基葡萄糖、N-烷基葡糖胺、可可碱、嘌呤、哌嗪、哌啶和N-乙基哌啶。例如,当本发明化合物具有膦酸基团时,该化合物可与碱发生反应以形成碱加成盐。
酸/碱加成盐比相应的游离酸/碱形式更易溶于水溶剂。
本发明还提供一种药物组合物,其包含根据本发明的抗病毒组合以及至少一种药学上可接受的载体或稀释剂。因此,在一个实施方案中,药物组合物将包含穿心莲内酯或其衍生物或其药学上可接受的盐,以及熊果酸或其药学上可接受的盐。在另一个实施方案中,药物组合物将包含穿心莲内酯或其衍生物或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。在另一实施方案,药物组合物将包含熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。在又一实施方案中,药物组合物将包含穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。
术语“组合物”旨在包括以包封材料作为载体的活性成分的制剂,以得到其中活性成分(具有或不具有其他载体)被载体包围的胶囊。
在另一实施方案中,药物组合物将包含选自穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐、以及虎杖苷或其衍生物或其药学上可接受的盐中的两种或更多种化合物,以及一种或更多种附加治疗剂。在一个实施方案中,所述一种或更多种附加治疗剂为抗病毒剂。上文提供了合适的抗病毒剂。
在另一实施方案中,抗病毒组合和组合物包含一种或更多种附加治疗剂。在一个实施方案中,所述一种或更多种附加治疗剂为抗病毒剂。
术语“抗病毒剂”是指任意目前已知的用于治疗病毒感染的治疗性化合物。合适的抗病毒剂包括但不限于:瑞德西韦、地塞米松、瑾司鲁单抗(gimsilumab)、沙利单抗、、托珠单抗、阿那白滞素、鲁索替尼、巴瑞替尼、菲卓替尼、氯喹、羟化氯喹、洛匹那韦、利托那韦、法匹拉韦、EIDD-2801、巴瑞替尼、甲基强的松龙、肝素、锌、阿比朵尔/乌米诺韦、地瑞拉韦、奥司他韦、恩曲他滨、替诺福韦、巴洛沙韦玛波西酯、丹诺普韦、双嘧达莫、芬戈莫德、氯沙坦、阿奇霉素、利巴韦林、特力阿扎维林(triazavirin)、曲尼司特、依巴斯汀、槲皮素、甘草酸、黄芩苷、广藿香醇、木犀草素、橙皮苷、大黄素、山奈酚、木质素、白桦脂酸、丹参酮、隐丹参酮、二氢丹参酮I、丹参酮IIA、姜黄素、紫草素和苦参碱。
在另一个实施方案中,提供了一种药物组合物,其包含穿心莲提取物、连同熊果酸或其药学上可接受的盐、虎杖苷或其衍生物或其药学上可接受的盐。如上所述,穿心莲内酯是来源于穿心莲中的几种化合物之一,已被发现具有有益的治疗性质,包括抗病毒和抗炎活性。
在另一个实施方案中,熊果酸或其药学上可接受的盐和/或虎杖苷,或其衍生物或其药学上可接受的盐也以植物提取物的形式提供。因此,在一个实施方案中,本发明提供了一种药物组合物,其包含穿心莲提取物,以及选自枇杷、迷迭香和百里香的植物提取物,和/或虎杖提取物。
本发明的抗病毒组合和组合物可用于治疗和/或预防一系列病毒感染。如本文所使用的,治疗可包括减轻或改善与正在治疗的病毒感染相关联的症状、疾病或状况,包括降低病毒感染的严重性和/或频率。如本文所使用的,预防可包括预防或延迟与病毒感染相关的特定症状、疾病或状况的发生、抑制其进展、或完全停止或逆转其发生或进展。
因此,在一个实施方案中,本发明提供了一种在有其需要的对象中治疗或预防病毒感染的方法,包括向患者施用有效量的本发明的抗病毒组合或药物组合物。
在一个实施方案中,该方法将包括向对象施用有效量的穿心莲内酯或其衍生物或其药学上可接受的盐,以及熊果酸或其药学上可接受的盐。在另一实施方案中,该方法将包括向对象施用有效量的穿心莲内酯或其衍生物或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。在另一个实施方案中,该方法将包括向对象施用有效量的熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。在又一实施方案中,该方法将包括向对象施用有效量的穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。
在另一实施方案中,该方法将包含向对象施用有效量的选自穿心莲内酯或其衍生物、或其药学上可接受的盐,熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物,或其药学上可接受的盐中的两种或更多种的化合物和一种或更多种附加治疗剂。在一个实施方案中,一种或更多种附加治疗剂为抗病毒剂。上文提供了合适的抗病毒剂。
本发明还提供了一种用于治疗或预防病毒感染的抗病毒组合或药物组合物。
在另一实施方案中,本发明提供穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐、以及虎杖苷或其衍生物或其药学上可接受的盐中的两种或更多种用于制造治疗或预防病毒感染的药物中的用途。
术语“病毒”是指已知会在宿主中引起感染的任何病毒。在一个实施方案中,病毒选自小核糖核酸病毒、冠状病毒、流感病毒、副流感病毒、呼吸道合胞病毒、腺病毒、肠道病毒和偏肺病毒组成的组。本领域技术人员将熟悉小核糖核酸病毒、冠状病毒、流感病毒、副流感病毒、呼吸道合胞病毒、腺病毒、肠道病毒和偏肺病毒的合适抗原。
在一个实施方案中,病毒属于冠状病毒科(Coronaviridae)。冠状病毒科通常分为冠状病毒亚科(Coronavirinae)和环曲病毒亚科(Torovirinae),再进一步分为六个属:α冠状病毒、β冠状病毒、γ冠状病毒、δ冠状病毒、环曲病毒(Torovirus)和白鳊鱼病毒(Bafinivirus)。虽然α冠状病毒和β冠状病毒属的病毒主要感染哺乳动物,但γ冠状病毒感染鸟类,在哺乳动物和鸟类宿主中都发现了δ冠状病毒属的成员(Phan et al.,VirusEvol.2018;4(2):vey035)。
本领域技术人员将熟悉冠状病毒科的合适病毒,其说明性示例包括:α勒托病毒(Alphaletovirus)(e.g.,Bukhari et al.;Virology.2018;524:160-171)和冠状病毒(e.g.,Fehr and Perlman;Coronaviruses.2015;1282:1–23)。因此,在本文公开的一个实施方案中,病毒选自α勒托病毒和冠状病毒。在一个实施方案中,病毒是冠状病毒。在本文公开的实施方案中,冠状病毒选自α冠状病毒、β冠状病毒、δ冠状病毒和γ冠状病毒。在一个实施方案中,冠状病毒为β冠状病毒。本领域技术人员将熟悉合适的β-冠状病毒,其示例包括沙贝病毒(Sarbecovirus)。在一个实施方案中,β-冠状病毒是沙贝病毒。本领域技术人员将熟悉沙贝病毒,其说明性示例包括:严重急性呼吸综合征相关冠状病毒、严重急性呼吸综合征冠状病毒(SARS-CoV)和严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。在一个实施方案中,沙贝病毒选自严重急性呼吸综合征相关冠状病毒SARS-CoV和SARS-CoV-2。在一个实施方案中,沙贝病毒为SARS-CoV-2。在一个实施方案中,SARS-CoV-2由NCBI登录号NC_045512的核酸序列编码。
在一个实施方案中,病毒感染由选自以下的病毒引起:小核糖核酸病毒、冠状病毒、流感病毒、副流感病毒、呼吸道合胞病毒、腺病毒、肠道病毒、和偏肺病毒。在优选实施方案中,病毒为冠状病毒。在优选实施方案中,冠状病毒是SARS-CoV-2。
除了治疗、减轻或预防病毒感染外,如本文所描述的穿心莲内酯、熊果酸和虎杖苷的组合可有益于治疗或预防微生物和细菌感染,包括继发性微生物或细菌感染。例如,患有严重急性呼吸综合征的患者疾病进展的一个主要后果是继发性细菌感染。在武汉SARS-CoV-2流行期间,至少七分之一的COVID-19患者被发现患有继发性细菌感染,50%的死亡病例是由未经治疗或无法治疗的细菌感染引起的,大多数病例发生在肺部(Zhou,F.etal.Lancet,2020,395,1054-1062)。
因此,在一个实施方案中,提供了一种在有其需要的对象中治疗或预防细菌感染的方法,其包括向对象施用有效量的本发明的抗病毒组合或药物组合物。在一个实施方案中,细菌感染是病毒感染的继发性感染。
在本文所公开的另一实施方案中,提供了穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐、以及虎杖苷或其衍生物或其药学上可接受的盐中的两种或更多种在制造用于治疗或预防细菌感染的药物中的用途。在一个实施方案中,细菌感染是病毒感染的继发性感染。
继发性细菌感染通常发生在患者初次感染病原体期间或之后,并与高发病率和死亡率相关(Mallia,P.,et al.Am.J.Respir.Crit.Care Med.2012,186,1117-1124)。大约5000万人死于1918-1919年西班牙流感大流行期间的细菌合并感染(Kash,J.C.和Taubenberger,J.K.Am.J.Patrol.2015,185,1528-1536)。由于原发性感染无法对两种病原体作出适当反应,免疫系统受损,从而促进了继发性细菌感染。
术语“微生物”包括藻类、细菌、真菌和原生动物等类别内的任何微生物或分类相关宏观生物。细菌感染可由选自革兰氏阴性细菌属的一种或更多种中的一个或更多个物种引起,如:不动杆菌(Acinetobacter);放线杆菌(Actinobacillus);巴尔通体(Bartonella);博德特菌(Bordetella);布鲁氏菌(Brucella);伯克霍尔德菌(Burkholderia);弯曲杆菌(Campylobacter);蓝藻(Cyanobacteria);肠杆菌(Enterobacter);欧文氏菌(Erwinia);大肠杆菌(Escherichia);弗朗西斯菌(Francisella);幽门螺杆菌(Helicobacter);嗜血杆菌(Hemophilus);克雷伯菌(Klebsiella);军团菌(Legionella);莫拉菌属(Moraxella);摩根菌属(Morganella);分枝杆菌(Mycobacterium);奈瑟菌(Neisseria);巴氏杆菌(Pasteurella);变形杆菌(Proteus);普罗维登斯菌属(Providencia);假单胞菌(Pseudomonas);沙门氏菌(Salmonella);沙雷氏菌(Serratia);志贺氏菌(Shigella);寡养单胞菌(Stenotrophomonas);密螺旋体(Treponema);弧菌(Vibrio);和耶尔森氏菌(Yersinia)。具体示例包括但不限于由幽门螺杆菌和泌尿致病性大肠杆菌引起的感染。
细菌感染可由选自革兰氏阳性细菌属的一种或更多种中的一个或多个物种引起,如:放线杆菌(Actinobacteria);芽孢杆菌(Bacillus);梭菌(Clostridium);棒状杆菌(Corynebacterium);肠球菌(Enterococcus);李斯特菌(Listeria);诺卡氏菌(Nocardia);葡萄球菌(Staphylococcus)和链球菌(Streptococcus)。
原生动物感染包括但不限于利什曼原虫(Leishmania)、弓形虫(Toxoplasma)、疟原虫(Plasmodia)(被认为是疟疾感染的病原体)、泰勒虫(Theileria)、无浆体(Anaplasma)、贾第虫(Giardia)、三毛滴虫(Tritrichomonas)、锥虫(Trypanosoma)、血吸虫(Schistosoma)、球虫(Coccidia)和巴贝虫(Babesia)引起的感染。具体的例子包括恶性疟原虫(Plasmodium falciparum)、间日疟原虫(Plasmodium vivax)、三日疟原虫(Plasmodium malariae)、诺氏疟原虫(Plasmodium knowlesi)、卵形疟原虫(Plasmodiumovale)和蓝氏贾第鞭毛虫(Giardia lamblia)。
术语“对象”旨在包括哺乳动物例如人类、狗、牛、马、猪、羊、山羊、猫、小鼠、兔子、大鼠和转基因非人类动物等生物体。在某些实施方案中,对象是人类,例如,患有微生物感染、有风险患有微生物感染或潜在地可能患有微生物感染的人类。在另一实施方案中,对象是细胞。
“施用”是指向对象或患者递送两种或更多种治疗性化合物。在一个实施方案中,给药为合用给药以使得在治疗过程中两种或更多种治疗性化合物一起递送。在一个实施方案中,两种或更多种的治疗性化合物共同配制成单一剂型或“组合剂量单位”,或单独配制并随后组合成组合剂量单位,通常作为单层或双层片剂或胶囊口服施用。
在一个实施方案中,以每种化合物的有效量向有需要的人类患者施用选自穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐以及虎杖苷或其衍生物或其药学上可接受的盐中的两种或更多种化合物,每种化合物的有效量为独立地每天每种化合物约0.1mg至约1000mg。在一个实施方案中,组合治疗的有效量为独立地每天每种化合物约0.5mg至约200mg。在一个实施方案中,组合治疗的有效量为独立地每天每种化合物约1mg至约100mg。在其他实施方案中,组合治疗的有效量为对于每种成分,每天约1毫克、约3毫克、约5毫克、约10毫克、约15毫克、约18毫克、约20毫克、约30毫克、约40毫克、约60毫克、约80毫克、约100毫克、约200毫克或约500毫克。
共同施用也可以包括施用成分药,例如选自穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐的化合物中的两种或更多种。选自穿心莲内酯或其衍生物、或其药学上可接受的盐、熊果酸或其药学上可接受的盐、以及虎杖苷或其衍生物、或其药学上可接受的盐中的两种或更多种化合物的这种组合可在每次施用的合理时间段内(例如,约1分钟至24小时)同时或顺序(一个接一个)施用,这取决于每种药剂或组合的药代动力学和/或药效学性质。共同施用还可涉及使用固定组合进行的处理,其中处理方案的药剂可组合在固定剂量或组合剂量介质中,例如固体、液体或气溶胶。在一个实施方案中,可以使用试剂盒施用药物或药物组分。
本发明的抗病毒组合和组合物主要用于口服施用,以使活性化合物能够递送到目标或感染部位,如呼吸系统。本领域技术人员可使用常规方法容易地确定本发明化合物的适当制剂。
虽然活性化合物可以单独施用,但可以优选将其呈现为药物制剂。用于兽用和人类用途的制剂包括如本文所定义的至少两种活性化合物,以及一种或更多种可接受的载体和任选的其他治疗成分,特别是如本文所述的那些附加治疗成分。载体必须是“可接受的”,即与制剂的其他成分相容且对其接受者生理无害。
所有制剂都将任选地包含辅料,如《药用辅料手册》(1986年)中规定的那些。辅料包括抗坏血酸和其他抗氧化剂、螯合剂(如EDTA)、碳水化合物(如葡聚糖、羟基烷基纤维素、羟基烷基甲基纤维素、硬脂酸等)。制剂的pH范围为约3至约11,但通常为约7至10。
这些制剂可以方便地以单位剂型呈现,并且可以通过药学领域中众所周知的任何方法制备。技术和制剂通常可以在雷明顿制药科学(Mack Publishing Co.,Easton,PA)中找到。此类方法包括使活性成分与构成一种或多种辅助成分的载体结合的步骤。一般而言,通过将活性成分均匀且紧密地与液体载体或精细分离的固体载体或两者结合,然后,如有必要,对产品进行成型来制备制剂。
适于口服施用的制剂可呈现为离散单元,例如每种含有预定量的活性成分的胶囊、扁囊剂或片剂;作为粉末或颗粒剂;作为水性或非水性液体中的溶液或悬浮液;或作为水包油液体乳剂或水包油液体乳剂。活性成分也可作为丸剂、干药糖剂或糊剂施用。
本发明的化合物可通过从加压分配器或容器中以气溶胶喷雾的形式吸入施用,所述加压分配器或容器包含诸如二氧化碳气体、二氯二氟甲烷、氮气、丙烷或其他合适气体或气体组合的推进剂。也可使用喷雾器施用所述化合物。
水悬浮液含有与适于制备水悬浮液的辅料相混合的活性材料。此类辅料包括悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和金合欢胶,以及分散剂或润湿剂,例如天然磷脂(例如卵磷脂),环氧烷烃与脂肪酸的缩合产物(例如,硬脂酸聚氧乙烯酯),环氧乙烷与长链脂肪醇的缩合产物(例如,十七烷氧基乙氧基十六醇),环氧乙烷与衍生自脂肪酸和己糖醇酐的部分酯的缩合产物(例如,聚氧乙烯山梨醇酐单油酸酯)。水悬浮液还可能含有一种或多种防腐剂,如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或更多种着色剂、一种或更多种调味剂和一种或更多种甜味剂,如蔗糖或糖精。
适合于通过添加水制备水悬浮液的可分散粉末和颗粒提供了与分散剂或润湿剂、悬浮剂和一种或更多种防腐剂混合的活性成分。合适的分散剂或润湿剂和悬浮剂的示例如上所述。还可能存在其他辅料,例如甜味剂、调味剂和着色剂。
油悬浮液可通过将活性成分悬浮在植物油(如花生油、橄榄油、芝麻油或椰子油)或矿物油(如液体石蜡)中来配制。口服悬浮液可以含有增稠剂,如蜂蜡、硬石蜡或十六醇。可添加甜味剂(如上文所述的那些)和调味剂,以提供可口的口服制剂。可通过添加抗坏血酸等抗氧化剂来保存这些组合物。
药物组合物也可以是水包油乳剂的形式。油相可以是植物油,如橄榄油或花生油,矿物油如液体石蜡,或这些的混合物。合适的乳化剂包括天然存在的树胶,如金合欢树胶和黄蓍胶,天然存在的磷脂,如大豆卵磷脂,来自脂肪酸和己糖醇酸酐的酯或部分酯,如山梨醇单油酸酯,以及这些部分酯与环氧乙烷的缩合产物,如聚氧乙烯山梨醇酐单油酸酯。乳剂还可含有甜味剂和调味剂。糖浆剂和酏剂可以用甜味剂如甘油、山梨醇或蔗糖配制。此类制剂还可包含镇痛剂、防腐剂、调味剂或着色剂。
片剂是通过压缩或模压制成的,可选地含有一种或更多种辅助成分。可通过在适当的机器中压缩任选地与粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂混合的自由流动形式(如粉末或颗粒)的活性成分来制备压制片。模制片剂可通过在适当的机器中模制用惰性液体稀释剂润湿的粉末状活性成分的混合物来制备。片剂可任选地被包衣或刻痕,并且任选地被配制以提供活性成分的缓慢或受控释放。
包含了活性成分及药学上可接受的无毒的适用于片剂生产的辅料而成的片剂是可接受的。这些辅料可以是惰性稀释剂,例如碳酸钙或碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,如玉米淀粉或褐藻酸;粘合剂,如淀粉、明胶或阿拉伯胶;和润滑剂,如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者可以通过包括微胶囊化在内的已知技术包衣以延迟胃肠道中的崩解和吸附从而在更长时间内提供持续作用,例如,可以使用诸如单硬脂酸甘油酯或双硬脂酸甘油酯之类的延时材料,或者使用蜡。药片可以是咀嚼片。
如果需要,根据本发明的抗病毒组合和组合物可以制备成肠胃外剂型,包括适合于静脉、鞘内或硬膜外递送的剂型。适于注射使用的药物形式包括无菌注射溶液或分散体,以及用于临时制备无菌注射溶液的无菌粉末。它们在制造和储存条件下应该是稳定的,并可在对抗还原或氧化以及微生物(诸如细菌或真菌)的污染作用下保存。
用于可注射溶液或分散体的溶剂或分散介质可包含用于化合物的任何常规溶剂或载体系统,并且可包含例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)、其适当混合物和植物油。可以通过,例如使用诸如卵磷脂的涂层、在分散体的情况下保持所需的粒径以及通过使用表面活性剂来保持适当的流动性。必要时可通过加入各种抗细菌剂和抗真菌剂(例如,对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)来防止微生物的作用。在许多情况下,优选包括调节渗透压的试剂,例如糖或氯化钠。优选地,用于注射的制剂将与血液等渗。可注射组合物的延长吸收可通过在组合物中使用延迟吸收剂(例如单硬脂酸铝和明胶)来实现。适合注射使用的药物形式可通过任何适当途径递送,包括静脉内、肌肉内、脑内、鞘内、硬膜外的注射或输注。
肠内制剂可通过与适当的基质(例如乳化基质或水溶性基质)混合而制备成栓剂的形式。本发明的化合物也可以局部、鼻内、阴道内、眼内等给药,但不是必须的。
以剂量单位形式配制组合物尤其有利,便于施用和统一用药。本文使用的剂量单位形式是指适合作为待治疗受试者的单一剂量的物理离散单位;每个单位包含预定量的活性物质,其与所需的药学上可接受的载体联合经计算可产生所需的治疗效果。
本发明新型剂量单位形式的规范是规定的并直接取决于(a)活性材料的独特特性和要达到的特定治疗效果,以及(b)如本文详细披露的,合成活性材料的工艺所固有的局限性,所述活性材料用于治疗患有身体健康受到损害的疾病的活体受试者中的疾病。
如上所述,主要活性成分可与适当的药学上可接受的载体以剂量单位形式复合,用于方便和有效地以治疗有效量施用。例如,单位剂量形式可以以0.25μg至约200mg的量包含一种或更多种活性化合物。以比例表示,活性化合物可以以约0.25μg/mL至约200mg/mL载体的浓度存在。对于含有补充活性成分的组合物,通过参考所述成分的常用剂量和给药方式来确定剂量。
除非上下文另有要求,否则在整个说明书和随后的权利要求中,“包括”一词及其变体,将理解为包含所陈述的整数或步骤或一组整数或步骤,但不排除任何其他整数或步骤或一组整数或步骤。
本说明书中对任何先前出版物(或从中获得的信息)或任何已知事项的引用,不是也不应被视为承认或供认或任何形式的暗示该先前出版物(或从中获得的信息)或已知事项构成本说明书所涉及领域的公共常识的一部分。
现在将参考一些具体实施例和附图来描述本发明。然而,应当理解,以下描述的特殊性并不能取代本文前面描述的本发明的一般性。
实施例1:抗病毒活性的体外评估
方法:(改编自Tilmanis et al.Antiviral Therapy 2017,147,142-8;Dowall etal.Viruses,2016)
细胞和病毒:
SARS-CoV-2在Vero细胞中生长,等分并储存在-80℃下。所选化合物的抗病毒活性在带有Vero细胞单层的96孔板中进行评估,标准病毒浓度为100TCID50/孔或其他指定的感染复数(MOI)。
阶段1A–抗病毒活性
试验化合物:
制备供试化合物的储备溶液,分装并冻存于-20℃。为了进行试验,解冻一份等分试样,通过以下方法制备连续两倍稀释液:在孔中加入等体积介质后,从40μM至0.078μM直到达到20μM至0.039μM终浓度。
几种化合物需要在二甲基亚砜(DMSO)溶液中制备。当应用于细胞时,DMSO的最高浓度不超过0.05%。
抗病毒试验:
筛选试验:
在PC3实验室中将介质从96孔板的孔中移除。
方法:
将SARS-CoV-2以100TCID50(组织培养感染剂量50%)以50μl加入三复孔。其他的孔模拟感染(使用50μl培养基),一组孔不含化合物也不含病毒(使用50μl培养基)。
在室温下吸附1小时后,培养液被移除,用PBS清洗孔1次,每孔加入100μl培养基。“无化合物无病毒”的孔加入额外的100μl培养基。
100μl经稀释的化合物以40μM至0.078μM的浓度加入到相关的孔中;三个有病毒的和模拟感染的孔,“无化合物无病毒”的孔原样保持。培养皿在37℃下培养3天。
在感染后第3天,通过显微镜评估细胞是否存在SARS-CoV-2诱导的细胞病变效应。CPE被记录后,来自有病毒的孔的上清液被收集。140μl用于RNA提取和病毒基因组定量的RT-PCR,100μl放在Vero细胞(新鲜或冷冻)的96孔板上用于病毒滴定,其余的300+μl被冷冻在-80℃下,直到TCID50操作时。
确认试验:
在PC3实验室中,从96孔板的内孔移除介质。由于边缘效应,外围孔保留下来并添加介质。这样每个板上留下横向6个孔,纵向10个孔。
方法:
SARS-CoV-2以100TCID50(组织培养感染剂量50%)以50μl添加到三复孔。其他的孔模拟感染(使用50μl培养基),一组孔不含化合物也不含病毒(使用50μl培养基)。
在室温下吸附1小时后,培养液被移除,用PBS清洗孔1次,每孔加入100μl培养基。“无化合物无病毒”的孔加入额外的100μl培养基。
100μl经稀释的化合物以40μM至0.078μM的浓度加入到相关的孔中;三个有病毒的和模拟感染的孔,“无化合物无病毒”的孔原样保持。培养皿在37℃下培养3天。
在感染后第3天,通过显微镜评估细胞是否存在SARS-CoV-2诱导的细胞病变效应。从每个病毒感染的孔和1个模拟感染的孔中分别收集140μl上清液用于RNA提取和病毒基因组定量的RT-PCR。来自每个病毒感染孔和1个模拟感染孔的剩余体积被滴定在96孔板的Vero细胞上(新鲜或冷冻)。
第1B阶段-细胞毒性试验
显示出抗病毒活性的化合物在浓度<20μM的情况下进行细胞毒性评估。细胞毒性的评估采用CellTiterGlo细胞活力测定法(CTG;Promega,USA)和MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化铵;MP Biomedical,USA)检测,然后培养皿在37℃下培养3天。
按照制造商的说明书进行CTG分析,并使用FLUOstar Optima发光计(德国BMGLabtech)测量发光。
MTT试验程序基于先前描述的方法(Mosmann,15,1983)。简单地说,细胞单层在37℃、1mg/mL MTT存在下培养4小时。去除上清液并添加200μl异丙醇(Sigma,USA)以溶解产生的紫色甲臜。使用Multiskan Ascent读板仪(Thermo Fisher,USA)测量570nm处吸光度。
对于两种细胞毒性读数,使用非线性回归分析(GraphPad Prism,美国)确定化合物的50%细胞毒性浓度(CC50;与纯细胞对照相比,使细胞活力降低50%的化合物浓度)。
第2阶段-抗病毒活性,验证性试验
细胞迁移试验
验证性试验:
将在Vero细胞筛选中显示出有效果前景的化合物转向验证性筛选,使用在气液界面(ALI)生长的正常人支气管上皮(NHBE)细胞
NHBE细胞在ACDP组织培养实验室ALI处分化6-8周。
方法:
在PC4实验室中在24孔transwell培养板与中,将NHBE细胞与MOI为0.01的SARS-CoV-2孵育,三复孔。
在室温下吸附1小时后,将培养液移除,用PBS清洗孔一次。
根据Vero细胞筛选的结果,将100μl经稀释的化合物以三个不同的浓度加入到相关的孔中。培养皿在37℃培养3天。
在感染后第3天,通过显微镜评估细胞是否存在SARS-CoV-2诱导的细胞病变效应。从每个感染的孔中收集140μl上清液用于RNA提取和用于病毒基因组定量RT-PCR。另外的50μl用于通过Cytotox 96非放射性细胞毒性(Promega)评估细胞毒性。来自每个病毒感染孔的剩余体积在96孔板中的Vero细胞(新鲜或冷冻)上进行滴定以检测TCID50。
实施例2:动物研究
研究:
利用SARS-CoV-2的雪貂模型,这项工作评估两项研究中抗病毒候选药物的疗效。作为标准畜牧业要求的一部分,雪貂最初被安置在Werribee动物中心,它们将在注册前接受犬瘟热疫苗(CDV)的首次注射和加强针,清洗期超过六周。然后,雪貂被转移到该机构的ACDP国家设施,并在接种SARS-CoV-2候选疫苗前适应一周。每项研究由8只性别均等的雪貂组成一个测试组。每项研究都有两只雄性和两只雌性对照者接受生理盐水。在病毒攻击之前,对所有雪貂进行预采样,以进行基线血液学、临床化学和血清学检查。此外,在雪貂接受SARS-CoV-2(10^5TCID_50)鼻内攻击之前,收集直肠和口腔拭子以及鼻腔冲洗液。检测雪貂的临床症状,并在攻击后两周内每2-3天收集一次直肠和口腔拭子以及鼻腔冲洗液,以进行病毒学评估。监测雪貂的发烧、嗜睡和烦躁、减少与其他雪貂/饲养员互动的兴趣、腹泻以及任何呼吸道疾病的迹象,包括打喷嚏、咳嗽、流鼻涕、呼吸用力增加或呼吸困难。在第一次观察到任何中度或重度临床症状时或在研究结束时(第21天)人道地处死动物。采集终末血样,尸检时收集一组组织,并评估是否存在SARS-CoV-2。
实施例3:制剂
本发明的代表性制剂提供如下:
KBD喷雾:
枇杷提取物
相当于枇杷(干叶)12mg/mL
蜂胶200mg/mL
虎杖提取物
相当于虎杖(干根)250mg/mL
A+KBD喷雾:
枇杷提取物
相当于枇杷(干叶)34.5mg/mL
蜂胶100mg/mL
虎杖提取物相当于虎杖(干根)56mg/mL
穿心莲提取物
相当于穿心莲(干)2.8mg/mL
薄荷醇2mg/mL
KBD咀嚼片:
虎杖提取物
相当于虎杖(干根)25g
枇杷提取物
相当于枇杷(干叶)4.5g
紫锥菊(Echinacea purpurea)提取物
相当于紫锥菊(干草药)840mg
蜂胶250mg
KBD硬胶囊:
紫锥菊提取物
相当于紫锥菊(干草)840mg
虎杖提取物
相当于虎杖(干根)3g
穿心莲提取物
相当于穿心莲(干草)1.63g
枇杷提取物
相当于枇杷(干叶)2.25g
蜂胶200mg
维生素D3 5mcg(200IU)
实施例4:Vero细胞中的抗病毒活性
方法:
24孔培养皿中的Vero细胞用体积为100μl的1000TCID50(0.005MOI)的SARS-CoV-2(Vic 01)在室温下感染1小时。移除培养液,替换为以单独或组合方式的500μl连续稀释的化合物,在37℃和5%的CO2下培养3天。对照组包括既不接受病毒也不接受药物的细胞对照和浓度与受试药物最高浓度相同的载体的载体对照。NHC(β-D-N4-羟基胞苷)被用作检测中的阳性对照。第3天,通过显微镜检查孔是否存在细胞病变效应(CPE)。从复孔中收集上清液,汇集并储存在-80℃下,直到样品在96孔板中的Vero细胞上滴定感染性病毒,并提取病毒RNA。用SARS-CoV-2E基因特异性引物对提取的RNA样本进行RT-PCR分析。GraphPad Prism用于生成图表,并根据TCID50数据计算IC50值。
结论:
表1.第3天时的显微镜检查
使用GraphPadprism绘制病毒滴定数据,计算得出单独使用穿心莲的IC50为3.251μM。.对于穿心莲和虎杖苷的组合,IC50降低至2.475μM。对于穿心莲、虎杖苷和熊果酸的组合,IC50进一步降低至1.406μM。因此,化合物穿心莲单独以及与虎杖苷和熊果酸组合显示出抗SARS-CoV-2的抗病毒活性。
实施例5:化合物对ACE2表达的影响
方法:
体外试验使用在MCDB 131培养基(含10%FCS和10mM谷氨酰胺、EGF和氢化可的松)中培养的人结肠上皮细胞(Caco-2)和在αMEM培养基中培养的非洲绿猴(Chlorocebus sp)衍生的VeroE6细胞。这些细胞系具有ACE2的内源性高表面表达,并可在体外被SARS-CoV感染。细胞在24孔板中培养至80%融合,然后用含有0-10μM的穿心莲内酯、虎杖苷和熊果酸的新鲜培养基处理,重复8次。1-3天后,在Trizol中刮取细胞进行RNA提取。从提取的RNA合成cDNA,并使用基于累积荧光实时检测的TaqMan系统(ABI Prism 7700,Perkin Elmer Inc.)通过定量实时RT-PCR评估ACE2mRNA的基因表达。基因表达相对于18S mRNA归一化,并报告出与未处理样本中表达水平相比的倍数变化,未处理样本中的表达水平被赋予任意值1.0。
为了测量ACE2蛋白,Caco-2细胞被在冰冷的RIPA缓冲液中从每个孔刮取下来用于ELISA分析。为了测定Caco-2细胞中ACE2的量,根据制造商的协议,对样品使用血管紧张素转换酶2(ACE2)ELISA试剂盒(中国湖北武汉库萨比奥,目录号:CSB-E17204m)进行测试。简而言之,用样品稀释剂加载每个样品,二复孔。根据提供的标准溶液制备标准曲线。将0,6.25,12.5,25,50,100,200和400pg/mL的标准品加入一系列孔中,二复孔。加入样品稀释剂,使每个标准品孔的最终体积达到250mL。向每个孔中加入100mL提供的生物素抗体(1x),然后在洗涤步骤后加入100mL HRP抗生物素抗体(1x)。在终点模式下以Ex/Em=570/540nm进行扫描之前,在CLARIOstarPlus Multi-Mode Microplate Reader(德国,奥尔滕贝格,BMG Labtech)上将板置于震动模式,以确保正确混合。
结果:
从图1可以看出,穿心莲内酯(UP-A)在48小时时显著降低了Vero(AGM)细胞中ACE2mRNA的表达,在最低剂量1μM时效果最大。熊果酸(UP-U)以剂量依赖性方式在较小程度上即可降低ACE2 mRNA的表达。虎杖苷(UP-P)对ACE2 mRNA表达无明显影响。
图2验证了穿心莲内酯(UP-A)降低ACE2 mRNA表达的有效性,并说明在人肺上皮(A549)细胞中也观察到类似的效果。最大效应出现在24小时,48小时减少,72小时减弱。这表明可能需要多次给药,这对于可能被代谢的化合物来说并不意外。剂量反应表明,1μM穿心莲内酯达到最大反应,在0.5μM以下观察到疗效损失,在较高剂量下活性没有实质性增加。
ACE2基因表达的减少与图3所示数据一致,经ELISA测定,与UP-P对比,在使用1μM穿心莲内酯(UP-A)治疗72小时后,CACO-2细胞中的ACE2蛋白水平降低。这些数据表明,UP-A的抗病毒活性至少部分是由于ACE2的细胞表面表达减少,值得注意的是ACE2是SARS-CoV-2受体结合域(RBD)的假定受体。
Claims (26)
1.一种抗病毒组合,其包含选自穿心莲内酯或其衍生物或其药学上可接受的盐,熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐中的两种或更多种化合物。
2.根据权利要求1的抗病毒组合,其包含穿心莲内酯或其衍生物或其药学上可接受的盐,以及熊果酸或其药学上可接受的盐。
3.根据权利要求1的抗病毒组合,其包含穿心莲内酯或其衍生物或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。
4.根据权利要求1的抗病毒组合,其包含熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。
5.根据权利要求1的抗病毒组合,其包含穿心莲内酯或其衍生物或其药学上可接受的盐,熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐。
6.根据权利要求1至5中任一项所述的抗病毒组合,其中穿心莲内酯的衍生物选自:
14-去氧-二去氢穿心莲内酯;
14-脱羟穿心莲内酯-12-磺酸钠盐;
14-α-硫辛酰穿心莲内酯;
穿心莲内酯苷;
新穿心莲内酯苷元;
14-去羟基-11,12-二去氢穿心莲内酯-3,19-双(琥珀酸)钾盐;
14-去羟基-11,12-二去氢穿心莲内酯-3,19-双(琥珀酸)钾钠盐;
(R)-((1R,5aS,6R,9aS)-1,5a-二甲基-7-亚甲基-3-氧代-6-((E)-2-(2-氧代-2,5-二氢呋喃-3-基)乙烯基)十氢-1H-苯并[c]氮杂-1-基)2-氨基-3-苯丙酸酯;
2-((1R,5R,6R,8aS)-6-羟基-5-(羟甲基)-5,8a-二甲基-2-亚甲基十氢萘-1-基)苯甲酸乙酯;
(1S,2R,4aS,5R,8aS)-1-甲酰胺-1,4a-二甲基-6-亚甲基-5-((E)-2-(2-氧代-2,5-二氢呋喃-3-基)乙烯基)十氢萘-2-基5-((R)-1,2-戊酸酯;
(1S,2R,4aS,5R,8aS)-1-甲酰胺-1,4a-二甲基-6-亚甲基-5-((E)-2-(2-氧代-2,5-二氢呋喃-3-基)乙烯基)十氢萘-2-基-2-硝基苯甲酸酯;和
(S)-(1S,2R,4aS,5R,8aS)-1-甲酰胺-1,4a-二甲基-6-亚甲基-5-((E)-2-(2-氧代-2,5-二氢呋喃-3-基)乙烯基)十氢萘-2-基-2-氨基-3-苯丙酸酯。
7.根据权利要求1至6中的任一项的抗病毒组合,其进一步包含一种或更多种附加治疗剂。
8.根据权利要求7的抗病毒组合,其中所述一种或更多种附加治疗剂是抗病毒剂。
9.根据权利要求8的抗病毒组合,其中所述一种或更多种附加抗病毒剂选自瑞德西韦、地塞米松、瑾司鲁单抗(gimsilumab)、沙利单抗、托珠单抗、阿那白滞素、鲁索替尼、巴瑞替尼、菲卓替尼、氯喹、羟化氯喹、洛匹那韦、利托那韦、法匹拉韦、EIDD-2801、巴瑞替尼、甲基强的松龙、肝素、锌、阿比朵尔/乌米诺韦、地瑞拉韦、奥司他韦、恩曲他滨、替诺福韦、巴洛沙韦玛波西酯、丹诺普韦、双嘧达莫、芬戈莫德、氯沙坦、阿奇霉素、利巴韦林、特力阿扎维林(triazavirin)、曲尼司特、依巴斯汀、槲皮素、甘草酸、黄芩苷、广藿香醇、木犀草素、橙皮苷、大黄素、山奈酚、木质素、白桦脂酸、丹参酮、隐丹参酮、二氢丹参酮I、丹参酮IIA、姜黄素、紫草素和苦参碱。
10.一种药物组合物,其包含根据权利要求1至9中任一项的抗病毒组合和至少一种药学上可接受的载体或稀释剂。
11.一种药物组合物,其包含穿心莲提取物,连同熊果酸或其药物上可接受的盐,以及虎杖苷或其衍生物或药物上可接受的盐。
12.一种药物组合物,其包含穿心莲提取物,连同选自枇杷、迷迭香和百里香的植物的提取物,和/或虎杖提取物。
13.根据权利要求10至12中任一项的药物组合物,其中所述组合物配制为用于口服施用。
14.一种在有其需要的对象中治疗或预防病毒感染的方法,其包括向对象施用有效量的权利要求1至9中任一项的抗病毒组合,或权利要求10至13中任一项的药物组合物。
15.根据权利要求14所述的方法,其中病毒选自小核糖核酸病毒、冠状病毒、流感病毒、副流感病毒、流感病毒、呼吸道合胞病毒、腺病毒、肠道病毒和偏肺病毒。
16.根据权利要求14或15所述的方法,其中病毒感染是COVID-19。
17.一种在有其需要的对象中治疗或预防细菌感染的方法,其包括向对象施用有效量的权利要求1至9中任一项的抗病毒组合,或权利要求10至13中的任一项的药物组合物。
18.根据权利要求17所述的方法,其中细菌感染是病毒感染的继发感染。
19.根据权利要求1至9中任一项所述的抗病毒组合,或根据权利要求10至13中任一项所述的药物组合物,其用于治疗或预防病毒感染。
20.根据权利要求19所述的权利要求1至9中任一项的抗病毒组合,或根据权利要求10至13中任一项的药物组合物,其用于治疗或预防病毒感染,其中病毒选自小核糖核酸病毒、冠状病毒、流感病毒、副流感病毒、呼吸道合胞病毒、腺病毒、肠道病毒和偏肺病毒。
21.根据权利要求19或20所述的根据权利要求1至9中任一项的抗病毒组合,或根据权利要求10至13中的任一项的药物组合物,其用于治疗或预防病毒感染,其中病毒感染为COVID-19。
22.根据权利要求1至9中任一项的抗病毒组合,或根据权利要求10至13中任一项的药物组合物,其用于治疗或预防细菌感染。
23.根据权利要求22所述的权利要求1至9中任何一项的抗病毒组合,或根据权利要求10至13中任何一项的药物组合物,其用于治疗或预防细菌感染,其中细菌感染是病毒感染的继发感染。
24.穿心莲内酯或其衍生物或其药学上可接受的盐、熊果酸或其药学上可接受的盐,以及虎杖苷或其衍生物或其药学上可接受的盐中的两种或更多种在制备用于治疗或预防病毒感染的药物中的用途。
25.根据权利要求1至9中任一项的组合在制备用于治疗或预防病毒感染的药物中的用途。
26.根据权利要求1至9中任一项的组合在制备用于治疗或预防细菌感染的药物中的用途。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2020903493A AU2020903493A0 (en) | 2020-09-28 | Formulations comprising botanical extracts | |
AU2020903493 | 2020-09-28 | ||
AU2020903527 | 2020-09-30 | ||
AU2020903527A AU2020903527A0 (en) | 2020-09-30 | Formulations comprising botanical extracts | |
AU2021901178 | 2021-04-21 | ||
AU2021901178A AU2021901178A0 (en) | 2021-04-21 | Formulations comprising botanical extracts | |
PCT/AU2021/051126 WO2022061420A1 (en) | 2020-09-28 | 2021-09-28 | Formulations comprising botanical extracts |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114641285A true CN114641285A (zh) | 2022-06-17 |
Family
ID=78610645
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180005862.1A Pending CN114641285A (zh) | 2020-09-28 | 2021-09-28 | 包含植物提取物的配方 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20230372290A1 (zh) |
EP (1) | EP4216945A1 (zh) |
JP (1) | JP2023544454A (zh) |
CN (1) | CN114641285A (zh) |
AU (2) | AU2021106876A4 (zh) |
CA (1) | CA3193951A1 (zh) |
WO (1) | WO2022061420A1 (zh) |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1548081A (zh) * | 2003-05-20 | 2004-11-24 | 邓大勇 | 一种治疗病毒性肺炎的药物 |
US20060172021A1 (en) * | 2005-01-10 | 2006-08-03 | Moffett Scott A | Herbal compositions for the prevention or treatment of symptoms of stress and infection |
CN104173713A (zh) * | 2014-09-12 | 2014-12-03 | 钟召凤 | 一种预防小儿病毒性发热的药物组合物及其制备方法 |
CN104815283A (zh) * | 2015-03-28 | 2015-08-05 | 繁昌县智融中药材专业合作社 | 一种治疗病毒性肝炎的中药 |
CN105833034A (zh) * | 2016-05-26 | 2016-08-10 | 张晓燕 | 一种治疗哮喘的中药组合物 |
CN108125297A (zh) * | 2018-01-22 | 2018-06-08 | 孙显林 | 一种功能性口罩 |
-
2021
- 2021-08-24 AU AU2021106876A patent/AU2021106876A4/en not_active Ceased
- 2021-09-28 JP JP2023543247A patent/JP2023544454A/ja active Pending
- 2021-09-28 AU AU2021346951A patent/AU2021346951A1/en active Pending
- 2021-09-28 CN CN202180005862.1A patent/CN114641285A/zh active Pending
- 2021-09-28 US US18/246,931 patent/US20230372290A1/en active Pending
- 2021-09-28 CA CA3193951A patent/CA3193951A1/en active Pending
- 2021-09-28 EP EP21870605.9A patent/EP4216945A1/en active Pending
- 2021-09-28 WO PCT/AU2021/051126 patent/WO2022061420A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
EP4216945A1 (en) | 2023-08-02 |
WO2022061420A1 (en) | 2022-03-31 |
JP2023544454A (ja) | 2023-10-23 |
US20230372290A1 (en) | 2023-11-23 |
AU2021346951A1 (en) | 2023-05-18 |
AU2021106876A4 (en) | 2021-11-25 |
CA3193951A1 (en) | 2022-03-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112472691A (zh) | 一种抗冠状病毒的没食子酸组合物及其应用 | |
CN111759851B (zh) | 单宁酸在制备抗冠状病毒的药物方面的应用 | |
KR101317318B1 (ko) | 신종인플루엔자, 조류인플루엔자, 일반 및 독감감기, sars 바이러스 억제 효능을 갖는 오배자 추출물 또는 이로부터 분리된 화합물을 유효성분으로 함유하는 약학 조성물 | |
US20230302075A1 (en) | Preparations containing berry extracts for use in the prophylaxis and/or treatment of viral infections caused by coronaviridae | |
CA2746437C (en) | Composition for the prevention and treatment of viral infections | |
CN112912074A (zh) | Egcg-棕榈酸酯组合物及其使用方法 | |
Shin et al. | Comparison of anti-influenza virus activity and pharmacokinetics of oseltamivir free base and oseltamivir phosphate | |
CN114641285A (zh) | 包含植物提取物的配方 | |
WO2022228651A1 (en) | Pyruvate esters for the treatment of viral diseases | |
KR20230021009A (ko) | 항바이러스 치료로서의 아젤라스틴 | |
CN113197886A (zh) | 双黄连制剂在抗病毒感染中的应用 | |
EP3960173A1 (en) | Enterovirus inhibitor | |
US10993981B2 (en) | Compositions for treatment of follicular tonsillitis using an emulsion based on rosemary extract and oregano essential oil | |
WO2022232337A2 (en) | Composition and method for treating covid-19 | |
CN115515597A (zh) | 地尔硫卓和病毒聚合酶抑制剂的组合 | |
IT202000026566A1 (it) | Combinazioni di antivirali e antimicrobici naturali, loro uso e formulazioni che le contengono | |
KR20110090293A (ko) | 황련 추출물을 포함하는 치주질환용 조성물 |
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 |