CN116829157A - Application of polyanionic fiber diglycoside compound - Google Patents
Application of polyanionic fiber diglycoside compound Download PDFInfo
- Publication number
- CN116829157A CN116829157A CN202180080201.5A CN202180080201A CN116829157A CN 116829157 A CN116829157 A CN 116829157A CN 202180080201 A CN202180080201 A CN 202180080201A CN 116829157 A CN116829157 A CN 116829157A
- Authority
- CN
- China
- Prior art keywords
- acute respiratory
- respiratory distress
- distress syndrome
- compound
- covid
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 15
- 239000000835 fiber Substances 0.000 title description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims abstract description 59
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims abstract description 59
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims abstract description 59
- 208000025721 COVID-19 Diseases 0.000 claims abstract description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
- 201000010099 disease Diseases 0.000 claims abstract description 26
- 208000024891 symptom Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000002158 endotoxin Substances 0.000 claims description 30
- 229920006008 lipopolysaccharide Polymers 0.000 claims description 30
- 206010035664 Pneumonia Diseases 0.000 claims description 21
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 206010038687 Respiratory distress Diseases 0.000 claims description 12
- 238000001802 infusion Methods 0.000 claims description 12
- 208000015181 infectious disease Diseases 0.000 claims description 11
- 206010021143 Hypoxia Diseases 0.000 claims description 10
- 206010040047 Sepsis Diseases 0.000 claims description 10
- 208000000059 Dyspnea Diseases 0.000 claims description 9
- 206010013975 Dyspnoeas Diseases 0.000 claims description 9
- 208000034486 Multi-organ failure Diseases 0.000 claims description 9
- 206010040070 Septic Shock Diseases 0.000 claims description 9
- 206010001053 acute respiratory failure Diseases 0.000 claims description 9
- 230000007954 hypoxia Effects 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 claims description 9
- 201000004193 respiratory failure Diseases 0.000 claims description 9
- 230000036303 septic shock Effects 0.000 claims description 9
- 208000010718 Multiple Organ Failure Diseases 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 238000001990 intravenous administration Methods 0.000 claims description 7
- 206010037660 Pyrexia Diseases 0.000 claims description 6
- 230000008816 organ damage Effects 0.000 claims description 6
- 206010010904 Convulsion Diseases 0.000 claims description 5
- 206010014523 Embolism and thrombosis Diseases 0.000 claims description 5
- 208000032140 Sleepiness Diseases 0.000 claims description 5
- 206010041349 Somnolence Diseases 0.000 claims description 5
- 239000000872 buffer Substances 0.000 claims description 5
- 230000036461 convulsion Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000004089 microcirculation Effects 0.000 claims description 5
- 210000002345 respiratory system Anatomy 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 4
- 239000008363 phosphate buffer Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000008351 acetate buffer Substances 0.000 claims description 2
- 239000007981 phosphate-citrate buffer Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 2
- 241001465754 Metazoa Species 0.000 description 61
- 238000012360 testing method Methods 0.000 description 54
- 210000004072 lung Anatomy 0.000 description 39
- 239000000523 sample Substances 0.000 description 22
- 210000004369 blood Anatomy 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 238000001514 detection method Methods 0.000 description 15
- 239000012530 fluid Substances 0.000 description 14
- 108010033040 Histones Proteins 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 11
- 241001678559 COVID-19 virus Species 0.000 description 10
- 241000711573 Coronaviridae Species 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- 230000006872 improvement Effects 0.000 description 10
- 210000000265 leukocyte Anatomy 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 9
- 230000001575 pathological effect Effects 0.000 description 8
- 210000002381 plasma Anatomy 0.000 description 8
- 238000004820 blood count Methods 0.000 description 7
- 230000006378 damage Effects 0.000 description 7
- 208000014674 injury Diseases 0.000 description 7
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 6
- 108010082126 Alanine transaminase Proteins 0.000 description 6
- 108010074051 C-Reactive Protein Proteins 0.000 description 6
- 102100032752 C-reactive protein Human genes 0.000 description 6
- 206010015548 Euthanasia Diseases 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 6
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 239000007928 intraperitoneal injection Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 230000005856 abnormality Effects 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 210000000621 bronchi Anatomy 0.000 description 5
- 210000004969 inflammatory cell Anatomy 0.000 description 5
- -1 pH adjusters Substances 0.000 description 5
- 210000003437 trachea Anatomy 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 4
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 4
- 230000003187 abdominal effect Effects 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 229960002725 isoflurane Drugs 0.000 description 4
- 230000002685 pulmonary effect Effects 0.000 description 4
- 239000008354 sodium chloride injection Substances 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- 101100243025 Arabidopsis thaliana PCO2 gene Proteins 0.000 description 3
- 238000001295 Levene's test Methods 0.000 description 3
- 208000004852 Lung Injury Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 206010069363 Traumatic lung injury Diseases 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000004868 gas analysis Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 231100000515 lung injury Toxicity 0.000 description 3
- 210000002751 lymph Anatomy 0.000 description 3
- 238000005399 mechanical ventilation Methods 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 238000002663 nebulization Methods 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 230000036285 pathological change Effects 0.000 description 3
- 231100000915 pathological change Toxicity 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 208000013220 shortness of breath Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 208000006083 Hypokinesia Diseases 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010028748 Nasal obstruction Diseases 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 210000000702 aorta abdominal Anatomy 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000001043 capillary endothelial cell Anatomy 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 208000037888 epithelial cell injury Diseases 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 239000002906 medical waste Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000007190 Chlamydia Infections Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose 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)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 description 1
- 206010013647 Drowning Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 206010028470 Mycoplasma infections Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010035737 Pneumonia viral Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000010868 animal carcass Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 208000034526 bruise Diseases 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000028512 chlamydia infectious disease Diseases 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004704 glottis Anatomy 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004276 hyalin Anatomy 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 208000037806 kidney injury Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000017804 lesions in lung Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000008383 multiple organ dysfunction Effects 0.000 description 1
- 208000037891 myocardial injury Diseases 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 230000007119 pathological manifestation Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 210000003456 pulmonary alveoli Anatomy 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000000534 thyroid cartilage Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 208000009421 viral pneumonia Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Toxicology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application of the polyanionic cellobioside compound is shown in a formula II in the preparation of a medicament for treating 2019-nCoV infection-induced related diseases or symptoms. The compound is safe, can obviously improve related diseases or symptoms caused by 2019-nCoV infection, and can achieve treatment effect on acute respiratory distress syndrome caused by other reasons.
Description
The present application claims priority from Chinese patent application 202011384873.9 with the filing date 2020/12/1. The present application incorporates the entirety of the above-mentioned chinese patent application.
The application relates to application of a polyanionic cellobioside compound.
The new coronavirus pneumonia (Corona Virus Disease, 2019) is a new acute respiratory infectious disease, is caused by SARS-CoV-2 (also known as 2019-nCoV), and has been caused to infect more than 2 hundred million people worldwide by the current time since the bottom of 12 months in 2019, and has become a global serious public health event at present, and has great influence on the world.
According to the new diagnosis and treatment scheme (revised eighth edition) of coronavirus pneumonia released in 2021 in China, the pneumonia infected by 2019 new coronavirus can be classified into light, common, heavy and dangerous according to the degree of illness. The light clinical symptoms are mild, only low fever, slight hypodynamia and the like, and no pneumonia is caused. The common type has symptoms such as fever, respiratory tract and the like (cough, pharyngalgia, nasal obstruction, shortness of breath, hypodynamia and the like), and the symptoms of pneumonia can be seen in imaging. Heavy subjects show dyspnea, shortness of breath, hypoxia, somnolence and convulsion; severe patients may rapidly progress to acute respiratory distress syndrome, sepsis, septic shock and multiple organ failure, and even die.
Pathological studies of acute respiratory distress syndrome have found that numerous proteins and various inflammatory cells, predominantly neutrophils, are present in the edema fluid in the alveolar and pulmonary interstitium. Activation and recruitment of neutrophils is thought to play a role in the progression of acute respiratory distress syndrome.
After a patient is infected with a novel coronavirus, because the virus injury and the immune injury caused by inflammation are interwoven, clinical pathological manifestations mainly comprising lung injury and affected by multiple organs of the whole body can appear, especially severe patients, and the patients are represented by acute respiratory distress syndrome and can develop into sepsis, septic shock, multiple organ failure and even death. For epidemic prevention and control, effective vaccines and antiviral drugs are needed for prevention and control, and "life-saving drugs" for treating immune injury of organisms caused by virus infection are also urgently needed.
Disclosure of Invention
The application aims to solve the technical problem that the existing medicine for treating acute respiratory distress syndrome and novel coronavirus pneumonia has a single structure, and therefore, the application provides application of a polyanion fiber diglycoside compound. The compound is safe, can obviously improve related diseases or symptoms caused by 2019-nCoV infection, and can achieve treatment effect on acute respiratory distress syndrome caused by other reasons.
The first aspect of the application provides the use of a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl-beta-cellobiose heptasodium salt) for the manufacture of a medicament for the treatment of a disease or disorder associated with 2019-nCoV infection;
the "2019-nCoV" refers to a 2019 novel coronavirus named by world health organization, and is also called SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). 2019-nCoV described in the application comprises various strains, such as all strains recorded by NCBI or GISAID (global shared influenza data initiative), particularly important variants with strong transmissibility, pathogenicity or immune evasion, such as WHO specified Alpha, beta, gamma, delta, eta, iota, kappa, lambda or Omicron variants, and important variants specified later.
The 2019-nCoV infection related diseases or conditions described by the application include, but are not limited to: one or more of symptoms of pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disturbance, acute respiratory distress syndrome, acute respiratory failure, sepsis, septic shock, multiple organ failure, fever, respiratory tract (cough, pharyngalgia, nasal obstruction, shortness of breath, debilitation, etc.), dyspnea, somnolence and convulsion; preferably, wherein the pneumonia is a covd-19, more preferably a heavy or critical covd-19. Further, the acute respiratory distress syndrome may be a lipopolysaccharide-initiated acute respiratory distress syndrome.
It will be appreciated by those skilled in the art that there may be differences in the definition and identification of the clinical typing of the covd-19 by different countries or organizations, and that the present application includes all of the clinical typing of heavy or critical covd-19 (expressed in english as Severe covd-19 or Severe covd-19 pneumaria) defined by different countries or organizations, for example, in our country "new coronavirus pneumonia diagnosis and treatment scheme (trial eighth edition revision).
As used herein, "COVID-19" refers to pneumonia caused by infection with 2019-nCoV.
Organ damage includes, but is not limited to: one or more of lung injury, kidney injury, myocardial injury, and liver injury. The lung injury may include: lung capillary endothelial cell injury and/or alveolar epithelial cell injury.
The pathological basis of the acute respiratory distress syndrome is diffuse alveolar injury, and the pathological characteristic is that capillary endothelial cells of lung tissues are widely damaged by inflammation, so that exudation of capillaries is increased; and alveolar epithelial cell injury, resulting in increased lung permeability, alveolar and pulmonary interstitial filling with protein-rich pulmonary edema fluid, hyaline membrane formation, and inflammatory cell infiltration, resulting in severe deregulation of the ventilation/blood ratio. Acute respiratory distress syndrome is manifested clinically as respiratory distress and refractory hypoxemia, pulmonary imaging presents as a non-uniform exudative lesion, the early stages of which are generally considered to be acute lung injury, and moderate or severe are referred to as acute respiratory distress syndrome.
Sepsis generally refers to a life-threatening multiple organ dysfunction caused by an inflammatory response of the body to infection (e.g., 2019-nCoV) that is overactive throughout the body, further developing septic shock and multiple organ failure; the multi-organ failure includes, but is not limited to: lung failure, kidney failure and liver failure.
The application also provides an application of the pharmaceutical composition in preparing medicines;
the pharmaceutical composition comprises a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl-beta-cellobiose heptasodium salt) and pharmaceutically acceptable auxiliary materials;
the medicine is used for treating 2019-nCoV infection-induced related diseases or symptoms.
Further, the 2019-nCoV infection-induced related disease or disorder is as described above, such as heavy or critical type COVID-19, and also such as lipopolysaccharide-induced acute respiratory distress syndrome.
The pharmaceutical compositions may be formulated for administration by solid or liquid forms, including but not limited to: injection (e.g., subcutaneous, intramuscular, intravenous, or epidural), mucosal, transdermal, or topical administration, nasal or oral inhalation administration, and ocular administration.
Pharmaceutically acceptable excipients in the art include, but are not limited to: diluents, fillers, disintegrants, wetting agents, lubricants, pH adjusters, buffers, colorants, flavorants, preservatives or other conventional additives.
In one embodiment of the present application, the pharmaceutical composition may be an injectable pharmaceutical composition. Further, the pharmaceutical composition for injection may be prepared in the form of a powder or a concentrated solution (it will be understood by those skilled in the art that the powder and the concentrated solution are generally sterile) which may be dissolved or dispersed in a pharmaceutically acceptable carrier for clinical use. The pharmaceutically acceptable carrier may be a solvent or dispersion medium including, but not limited to: water, ringer's solution, isotonic saline, phosphate buffer, ethanol or polyols, and the like.
In some embodiments of the application, the concentrated solution has a pH of about 7.0 to about 8.0, further 7.4 to about 7.6, and still further 7.5, and the pH is adjusted by adding a buffer selected from the group consisting of phosphate buffer, citrate buffer, and acetate buffer.
In some embodiments of the application, the concentration of the compound of formula II in the concentrated solution may be 50-500mg/mL, further 60-100mg/mL, preferably 65-85mg/mL, more preferably 68-80mg/mL (e.g., 70 mg/mL), and may be administered by intravenous infusion after dilution according to the clinical protocol, which dilution may be performed using the following reagents: water, ringer's solution, isotonic saline, and the like.
In some embodiments, the concentrated solution may be infused at a rate of 15 to 120mg/hr, preferably 20 to 90mg/hr, for example, at the time of clinical use (i.e. diluted solution of the concentrated solution): 25mg/hr, 30mg/hr, 35mg/hr, 40mg/hr, 45mg/hr, 50mg/hr, 55mg/hr, 58.3mg/hr, 60mg/hr, 65mg/hr, 70mg/hr, 75mg/hr, 80mg/hr, 87.5mg/hr or 90mg/hr; infusion times may be 1-120hr, for example: 2hr, 4hr, 6hr, 8hr, 10hr, 12hr, 24hr, 36hr, 48hr, 60hr, 72hr, 84hr, 96hr, 108hr, etc. The numerical values include intermediate values of all point values.
In some embodiments of the application, the pharmaceutical composition may be administered directly to the airway of a subject in the form of an aerosol or by nebulization. For use as an aerosol, the solution or suspension of the pharmaceutically acceptable composition of the application may be packaged in a pressurized aerosol container together with a suitable propellant, for example a hydrocarbon propellant such as propane, butane or isobutane, and conventional adjuvants. Such compositions may also be administered in non-pressurized form, for example in a nebulizer or atomizer.
The application also provides in a third aspect the use of a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl- β -cellobiose heptasodium salt) in the manufacture of a medicament for the treatment of acute respiratory distress syndrome or acute respiratory failure;
further, the acute respiratory distress syndrome may be an acute respiratory distress syndrome induced by infection or an acute respiratory distress syndrome induced by lipopolysaccharide, and may be an acute respiratory distress syndrome induced by 2019-nCoV infection.
In a fourth aspect the application also provides a method of treating a disease or condition associated with 2019-nCoV infection as described above, comprising administering to a patient a therapeutically effective amount of a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl- β -cellobioside heptasodium salt);
further, the 2019-nCoV infection may cause related diseases or conditions such as COVID-19, and also such as heavy or critical COVID-19.
Further, the 2019-nCoV infection may be associated with a disease or condition such as acute respiratory distress syndrome or acute respiratory failure, and may be associated with acute respiratory distress syndrome caused by lipopolysaccharide.
Preferably, intravenous continuous infusion is used, the infusion rate may be 15 to 120mg/hr, preferably 20 to 90mg/hr, for example: 25mg/hr, 30mg/hr, 35mg/hr, 40mg/hr, 45mg/hr, 50mg/hr, 55mg/hr, 58.3mg/hr, 60mg/hr, 65mg/hr, 70mg/hr, 75mg/hr, 80mg/hr, 87.5mg/hr or 90mg/hr; infusion times may be 1-120hr, for example: 2hr, 4hr, 6hr, 8hr, 10hr, 12hr, 24hr, 36hr, 48hr, 60hr, 72hr, 84hr, 96hr, 108hr, etc. The numerical values include intermediate values of all point values.
The present application also provides in a fifth aspect a method of treating acute respiratory distress syndrome or acute respiratory failure comprising administering to a patient a therapeutically effective amount of a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl- β -cellobioside heptasodium salt);
further, the acute respiratory distress syndrome may be an acute respiratory distress syndrome induced by infection or an acute respiratory distress syndrome induced by lipopolysaccharide, and may be an acute respiratory distress syndrome induced by 2019-nCoV infection.
Acute respiratory distress syndrome is a non-cardiac clinical syndrome which can be caused by various causes and mainly shows progressive dyspnea and refractory hypoxia, has high incidence rate and large harm, and is a major difficult problem to be solved in clinical treatment. The etiology of acute respiratory distress syndrome is numerous and can be divided into intrapulmonary causes: bacterial or viral pneumonia (including coronavirus pneumonia), aspiration of gastric contents, lung bruise, toxic aspiration, drowning, etc., and extrapulmonary causes: sepsis, pancreatitis, severe trauma, massive blood transfusion, burns, etc., but the common pathological basis is diffuse alveolar injury, and clinical manifestations are mainly characterized by progressive respiratory distress and refractory hypoxia. Pathological studies of acute respiratory distress syndrome have long found that there are a large number of proteins and a variety of inflammatory cells in the oedema fluid that accumulate in the alveoli and pulmonary interstitium, with neutrophils being the dominant factor.
In some embodiments of the application, the acute respiratory distress syndrome is an infectious or non-infectious acute respiratory distress syndrome; such infections include, but are not limited to, viral, bacterial, fungal, mycoplasma or chlamydia infections. Such bacteria include, but are not limited to, streptococcus pneumoniae, staphylococcus or Klebsiella pneumoniae. Such viruses include, but are not limited to, influenza virus, parainfluenza virus, or coronavirus (e.g., 2019-nCoV). Such fungi include, but are not limited to, actinomycetes.
In some embodiments, the application further provides a method of treating acute respiratory distress syndrome comprising administering to a patient a therapeutically effective amount of a polyanionic cellobiose compound of formula II. Preferably, intravenous continuous infusion is used, the infusion rate may be 15 to 120mg/hr, preferably 20 to 90mg/hr, for example: 25mg/hr, 30mg/hr, 35mg/hr, 40mg/hr, 45mg/hr, 50mg/hr, 55mg/hr, 58.3mg/hr, 60mg/hr, 65mg/hr, 70mg/hr, 75mg/hr, 80mg/hr, 87.5mg/hr or 90mg/hr; infusion times may be 1-120hr, for example: 2hr, 4hr, 6hr, 8hr, 10hr, 12hr, 24hr, 36hr, 48hr, 60hr, 72hr, 84hr, 96hr, 108hr, etc. The numerical values include intermediate values of all point values.
The term "C 1-6 Alkyl "denotes straight-chain or branched alkyl having the specifically indicated number of carbon atoms (for example one, two, three, four, five or six carbon atoms), for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2,3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl.
The term "therapeutically effective amount" refers to an amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by one skilled in the art.
The term "treatment" refers to any of the following conditions: (1) alleviating one or more biological manifestations of a disease; (2) Interfere with one or more points in the biological cascade that trigger the disease; (3) Slowing the progression of one or more biological manifestations of the disease.
The term "patient" refers to any animal, preferably a mammal, most preferably a human, that has been or is about to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present application can be obtained.
The reagents and materials used in the present application are commercially available.
The application has the positive progress effects that: the compound of the formula II is safe, can obviously improve related diseases or symptoms caused by 2019-nCoV infection, and can achieve treatment effect on acute respiratory distress syndrome caused by other reasons.
FIG. 1 is a graph showing the effect of a compound of formula II on the extent of inflammatory lesions in lung tissue in rats in a model of acute respiratory distress syndrome.
The present application will be described in further detail with reference to examples, but should not be construed as being limited thereto. The reagents or equipment used below are all commercial varieties, and are operated according to the specification unless otherwise specified, and are not described herein.
Example 1 evaluation of the Effect of Compounds of formula II on treatment of acute respiratory distress syndrome
Animal species: male Sprague-Dawley rats (SD rats)
Animal grade: SPF stage
Age at the beginning of modeling: 6-8 weeks old.
Body weight at the beginning of molding: 195-270 g.
1.1 grouping and modeling of animals:
grouping animals: randomly dividing 56 qualified male animals into a normal control group, a model control group, a low-dose group of the test sample, a medium-dose group of the test sample and a high-dose group of the test sample according to the weight measured before grouping; the normal control group had 8, and the remaining groups were 12/group.
Test batch: the test was performed in two batches. Batch 1 was the first half of the animals per group and batch 2 was the second half of the animals per group. Model construction, drug administration, index detection and the like of animals in each batch are uniform.
Model construction:
the animals of group D0 were given lipopolysaccharide (0.8 mg/kg, 400. Mu.L/kg) by intraperitoneal injection by extracting a molding agent (lipopolysaccharide, LPS) according to their body weights.
D1: after 16h (+ -30 min) intraperitoneal injection, isoflurane was inhaled for anaesthesia and lipopolysaccharide (5 mg/kg, 1000. Mu.L/kg) was given intratracheal nebulization to each group of animals.
Intraperitoneal injection of Lipopolysaccharide (LPS): according to the recently weighed animal body weight, the amount of lipopolysaccharide administered to each animal was withdrawn using a disposable microinjector, and lipopolysaccharide was administered by intraperitoneal injection. The lipopolysaccharide volume is held to an integer position and is aspirated according to the upper graduation value when the lipopolysaccharide volume is between the two graduation capacity lines.
Nebulized Lipopolysaccharide (LPS) in the airways: the animal isoflurane is inhaled for anesthesia, then the animal isoflurane is fixed on a rat fixer placed at 45 degrees, a small animal anesthesia pharyngoscope is used for pressing the root of an animal tongue, a glottis is exposed, a lung micro liquid atomizer needle head (blunt) for extracting quantitative Lipopolysaccharide (LPS) solution is gently inserted into a trachea, then a piston is quickly pushed, the LPS solution is atomized into lungs, the needle head is quickly pulled out, the animal is taken down from the fixer, and the head is rotated upwards and leftwards and rightwards, so that the LPS is uniformly distributed on each lung lobe as much as possible. The lipopolysaccharide volume is held to the 1-position after the decimal, and is sucked according to the upper graduation value when the lipopolysaccharide volume is between the two graduation capacity lines.
1.2 sample dosage and method
After animal model construction, the test and control substances were administered according to the following table. The details are given in the following table:
the test sample was a compound of formula II (1-O-methyl 2,2', 3',4', 6' -hepta-O-sulfonyl-beta-cellobioside heptasodium salt), the compound of formula II was prepared as a stock solution of 70mg/mL (the solvent was phosphate buffer solution of pH 7.5), and before administration, 70mg/mL of the stock solution was diluted to a test sample solution of 1mg/mL, 5mg/mL, 20mg/mL using sodium chloride injection.
The normal control group and the model control group were given sodium chloride injection by intravenous injection.
TABLE 1 dosing amounts
Route of administration: group 1 to group 5: tail vein injection.
Frequency and time of administration: group 1 to group 5: d1, D2: 9:00-10:30 am, 13:00-14:30, 16:00-17:30; d3 (dosing 2 times): 8:30-10:00 am, 11:00-12:30 am.
1.3 test observations and data collection
1.3.1 general clinical observations
Animals were observed 2 times daily during quarantine and dosing (1 each of morning and afternoon). The content is observed: mental state, behavioral activity, death, respiration, secretion, fecal behavior, and other abnormalities.
1.3.2 body weight
Weighing animals on the day of modeling and on the day of administration of the test sample before receiving and grouping; animals were also weighed when death or euthanasia was found.
1.3.3 survival
After planned euthanasia, the ratio of the number of animals surviving each group to the total number of animals in each group during the test period was calculated.
Survival (%) = number of animals surviving group/total number of animals group x 100%.
1.3.4 blood gas detection
Detection time: d3 after the end of the last 1 dose for about 2 hours
Sample collection: anesthesia is carried out by injecting chloral hydrate (350 mg/kg,100 mg/mL) into the abdominal cavity, the abdominal midline is longitudinally cut, the abdominal aorta is separated, about 0.5mL of arterial blood is collected by adopting an arterial hemostix, the hemostix is rubbed by the syringe in the palm and turned upside down for 5 seconds respectively, and the hemostix cannot be pulled back to carry out uniform blood mixing treatment.
The detection method comprises the following steps: after arterial blood collection, the needle is gently inserted into the blood injection opening of the test card, blood is slowly pushed in, the sample filling pipe is filled up, when the blood reaches the sample filling position, sample filling is stopped, the cover is buckled, the blood automatically enters the test tube, the test card is inserted into the blood gas analyzer, and the test result is waited.
Detecting the index: PO2 (mmHg), PCO2 (mmHg), pH, sO2%.
1.3.5 plasma histone concentration assay
D3, about 1mL each of abdominal aortic blood and venous blood was collected separately and loaded into a sampling tube for anticoagulation of sodium citrate. After blood sample collection, wet ice is temporarily stored, centrifugation is carried out at 3000rpm at 4 ℃ within 2 hours, separated blood plasma is respectively filled in a freezing tube marked with arterial blood plasma and venous blood plasma, freezing is carried out at-70 ℃, and after the test, plasma histone concentration is detected according to the steps required by the kit.
1.3.6 blood cell counts
D3 collecting main abdominal venous blood 1mL, and loading it into EDTA-K containing solution 2 Sampling tubes for anticoagulant. By usingBlood counts were performed with a 2120 series hematology analyzer. The detection parameter indexes are as follows:
blood cell count
1.3.7 Lung lavage fluid (BALF) detection
Sample collection: after euthanasia of the animals, the neck and chest skin and tissue is cut to expose the trachea, bronchi and lungs, the right lung bronchi are isolated and ligated. The suture line is penetrated under the trachea, a 1/2 incision is made between the tracheal cartilage rings at a proper position under the thyroid cartilage, the tracheal cannula is slowly inserted into the left bronchus along the incision to the airway, and the cannula and the trachea are tightly fixed at a proper position in the incision centripetal direction by the penetrated suture line. 3mL of PBS buffer is sucked by a syringe and slowly injected, alveolar lavage is carried out, the lavage is repeatedly carried out for 3 times, each time of rinsing stays for about 10s, and the lavage liquid is collected in a centrifuge tube with proper capacity (not less than 2.1mL and finally based on the actual collection amount).
BALF processing: the collected lavage fluid was kept 2mL (excess treated as medical waste) per animal and centrifuged at about 2000rpm at 4℃for 10min. The supernatant was dispensed into 2 tubes and kept at below-70℃until use (after the test was completed, the consignor was sent or otherwise treated). The pellet was resuspended in 1mL PBS buffer for total white blood cell count and differential count.
And (3) detecting the concentration of the lavage fluid histone: and (3) after the test is finished, carrying out the detection of the histone concentration of the lung lavage fluid according to the steps required by the kit on the supernatant of the lung lavage fluid.
Leukocyte classification detection: the resuspended lung lavage fluid was subjected to white blood cell count and classification using a fully automatic blood cell analyzer.
1.3.8 euthanasia of animals
All animals were anesthetized by intraperitoneal injection of chloral hydrate (350 mg/kg,100 mg/mL) and euthanized by abdominal aortic exsanguination according to AVMA Guidelines for the Euthanasia of Animals:2013 Edition (the American Veterinary Medical Association, 2013). After the moribund animals were anesthetized with isoflurane, the abdominal aorta was exsanguinated to effect euthanasia.
1.3.9 histopathological examination
General observations: all animals in each group (including dead, moribund euthanized animals) were dissected and tissues were preserved. The animals were found to die in a dead time, stored in a refrigerator at 2-8℃, and dissected as soon as possible within 24 hours. After dissecting and leaving the tissue, the animal carcasses are treated according to medical waste.
During necropsy, animals were observed for abnormalities in the lungs, trachea and bronchi. The right lung middle leaf was cut and used to calculate the wet/dry weight ratio. The remaining right lung tissue and bronchi were fixed in 10% neutral buffered formalin solution, paraffin embedded, sectioned, pelleted, HE stained for pathological morphological observation of lung tissue, and the lung tissue was pathologically examined using standard terminology for diagnosis and classification according to 4-grade method (mild, moderate, severe).
1.3.10 Lung wet to Dry weight ratio
The surface of the tissue of the right lung is wiped clean with paper towel, and the foreign matters such as blood, tissue fluid and the like are weighed, then the tissue of the right lung is placed in a 60 ℃ oven for 72 hours for weighing again, and the wet/dry weight ratio is calculated.
Lung wet dry weight ratio = leaf wet weight/dry weight in right lung
1.3.11 data acquisition and statistical analysis
And (3) data acquisition: the data is collected by adopting a system generation and manual recording mode.
Data analysis: the data were processed using statistical software SPSS 13.0 and or GraphPad Prism 5. All statistical analyses were performed using a two-tailed analysis, with the statistical level set at P.ltoreq.0.05. Each index is expressed as "mean ± standard deviation" and analyzed as follows: firstly, carrying out uniformity Test on data by using a level's Test, and if the data are uniform (P > 0.05), carrying out one-way analysis of variance (ANOVA); if the analysis of variance is significant (P.ltoreq.0.05), dunnett's multiple comparisons are made of the differences between the model control group and the other groups. If the result of the level's Test is significant (P.ltoreq.0.05), a Kruskal-wallis nonparametric Test is performed. If the Kruskal-wallis nonparametric test results are significant (P.ltoreq.0.05), the Mann-Whitney U test is further used for pairwise comparison.
1.4 experimental results
And (3) molding: microscopic observation shows pathological changes such as alveolar space, blood vessel, alveolar wall inflammatory cell infiltration/alveolar wall interval thickening, intra-alveolar hemorrhage (with or without hemoglobin crystallization) and the like of the animal in the model control group; in the lung lavage of the model control group animals, WBC, neut and histone are respectively increased from 0.32+/-0.22, 0.04+/-0.02 and 0.039+/-0.012 of the normal control group to 9.41+/-2.01, 5.17+/-1.90 and 0.835+/-0.380; the wet-dry ratio of the lung is increased from 1.17+/-0.09 of the normal control group to 2.26+/-0.51; PO2 and sO2% are respectively reduced from 103.3+/-5.9 and 98.4+/-0.5 to 77.5+/-11.4 and 95.3+/-2.5 of the normal control group; and the indexes all have statistical differences. In summary, under the present test conditions, intraperitoneal injection in combination with intra-airway nebulization of the modeling agent Lipopolysaccharide (LPS) was considered successful in constructing an acute respiratory distress syndrome model.
Survival rate: no animal death was observed during the test, and the survival rate of each group of animals was 100%. Data details see the attached table: table 6.
Lung lavage fluid detection: the total number of white blood cells and the average value of classification indexes in the lung lavage fluid of the low, medium and high dose groups of animals of the test sample are respectively reduced to (2.88+/-1.50), (0.91+/-0.45) and (0.59+/-0.49) compared with the average value (9.41+/-2.01) of the WBC indexes of the model control group; compared with the mean value (5.17+/-1.90) of the Neut index of the model control group, the Neut index is respectively reduced to (1.45+/-1.13), (0.50+/-0.43) and (0.30+/-0.26); the Lymph and Mono index mean value is also obviously lower; and all have statistical differences. Data details see the attached table: table 2.
And (3) blood gas analysis and detection: the mean values of the blood gas analysis indexes of the animals in the low, medium and high dose groups of the test sample are respectively increased to (88.4+/-8.6), (90.3+/-6.4) and (92.3+/-9.2) compared with the mean value of the PO2 index of the model control group (77.5+/-11.4), respectively increased to (97.2+/-1.1), (97.4+/-0.8) and (97.3+/-1.2) compared with the mean value of the sO2 index of the model control group (95.3+/-2.5), and have statistical differences; no statistical difference was seen between PCO2 and pH index. Data details see the attached table: table 3.
And (3) histone detection: comparing the histone index mean value of the low, medium and high dose animals of the test sample with the histone index mean value (0.835+/-0.380) of the lung lavage fluid of the model control group, respectively reducing the mean value to (0.686+/-0.452), (0.415+/-0.445) and (0.449+/-0.606), wherein the medium and high dose animals of the test sample have statistical differences; compared with the mean value (0.164+/-0.093) of the arterial plasma histone index of the model control group, the mean value is respectively reduced to (0.126+/-0.039), (0.117+/-0.062) and (0.091+/-0.035), and the high-dose group of the test sample has statistical difference; compared with the mean value (0.074+/-0.019) of the model control group intravenous plasma histone index, the mean value is respectively reduced to (0.073+/-0.046), (0.057+/-0.008) and (0.049+/-0.009), and the statistical difference exists between the medium-dose group and the high-dose group of the test sample. Data details see the attached table: table 4.
Lung wet-dry ratio detection: compared with a model control group (2.26+/-0.51), the mean value of lung wet-dry ratio indexes of the animals in the low, medium and high dose groups of the test sample is respectively reduced to (1.97+/-0.33), (1.85+/-0.20) and (1.61+/-0.43), and the average value of lung wet-dry ratio indexes of the animals in the low, medium and high dose groups of the test sample has statistical differences. Data details see the attached table: table 5.
Blood cell count: compared with corresponding indexes of animals in a model control group, the average value of the indexes of WBC, lymph, PLT and the like of the animals in low, medium and high dose groups of the test sample is increased, the average value of the indexes of Neut, mono, LUC and the like is reduced, and the statistical difference exists. Data details see the attached table: table 7.
And (3) pathology detection: in this test, pulmonary inflammation was observed in model animals, and the inflammation was mainly expressed as: neutrophil-dominated inflammatory cells (alveolar space, blood vessels, alveolar walls), thickening of alveolar wall spaces, intra-alveolar hemorrhage (with or without hemoglobin crystallization). The animal of the administration group has the inflammation degree obviously lower than that of the model control group, which indicates that the test sample reduces the inflammation degree, the animal of each administration group has the dose relation, and the pathological change degree of the inflammation gradually reduces along with the increase of the dose. See the drawings for details: FIG. 1 (1, normal control animals showed no pathological changes in the histopathological examination of the lung, and therefore, not shown in the figure; 2, the number of lung lobes for pathological examination per group = the number of animals per group (12) ×the number of lung lobes for pathological examination per animal (3 lobes: upper right lobe, lower right lobe, and minor lobes), each group was 36 lobes).
TABLE 2 total and score of white blood cells in lung lavage fluid (BALF) from rats model for acute respiratory distress syndromeInfluence of classn＝8/12)
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. the level's Test WBC, neut, lymph, mono index was non-uniform and was statistically analyzed using the Kruskal-wallis nonparametric Test.
TABLE 3 influence on blood gas analysis in rats model of acute respiratory distress syndromen＝8/12)
| Group of | PH | PCO2(mmHg) | PO2(mmHg) | sO 2 ％ |
| Normal control group | 7.477±0.054 | 34.33±3.02 | 103.3±5.9* | 98.4±0.5* |
| Model control group | 7.437±0.033 | 37.14±4.31 | 77.5±11.4 | 95.3±2.5 |
| Test article low dose group | 7.463±0.052 | 36.26±4.86 | 88.4±8.6* | 97.2±1.1* |
| Dose group in test article | 7.450±0.035 | 36.23±4.09 | 90.3±6.4* | 97.4±0.8* |
| High dose group of test articles | 7.437±0.045 | 37.20±3.70 | 92.3±9.2* | 97.3±1.2* |
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. levene's Test for sO 2 % index inhomogeneities were statistically analyzed using the Kruskal-wallis nonparametric test.
TABLE 4 influence of rat histone on acute respiratory distress syndrome modeln＝8/12；Median)
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. the Levene's Test examined non-uniform lung lavage histone and venous plasma histone index, and the Kruskal-wallis nonparametric Test was used for statistical analysis.
TABLE 5 influence on the lung wet to dry ratio of rats in the model of acute respiratory distress syndromen＝8/12)
| Group of | Wet to dry ratio |
| Normal control group | 1.17±0.09* |
| Model control group | 2.26±0.51 |
| Test article low dose group | 1.97±0.33 |
| Dose group in test article | 1.85±0.20* |
| High dose group of test articles | 1.61±0.43* |
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. the Levene's Test tests that the lung wet to dry ratio index was not uniform, and the Kruskal-wallis nonparametric Test was used for statistical analysis.
TABLE 6 effect on survival of rats in acute respiratory distress syndrome model
| Group of | Modeling animal number (only) | Group memory number of living animals (only) | Survival (%) |
| Normal control group | 8 | 8 | 100.0 |
| Model control group | 12 | 12 | 100.0 |
| Test article low dose group | 12 | 12 | 100.0 |
| Dose group in test article | 12 | 12 | 100.0 |
| High dose group of test articles | 12 | 12 | 100.0 |
Remarks: 1. survival (%) = number of animals surviving group/total number of animals group x 100%.
TABLE 7 influence on the blood cell count of rats in the model of acute respiratory distress syndromen＝8/12)
Note that: 1. number of animals: 8 normal control groups and 12 other groups; 2. compared with the model control group, "x" indicates that p is less than or equal to 0.05; 3. the level's Test Neut, mono, LUC, HCT, PLT index was non-uniform and was statistically analyzed using the Kruskal-wallis nonparametric Test.
EXAMPLE 2 clinical study of Compounds of formula II
The present study is a randomized, open-label, multicenter clinical study aimed at evaluating the safety and efficacy of continuous infusion of compounds of formula II in patients with severe 2019 coronavirus Pneumonia (sever covd-19 Pneumonia). The subjects will be randomized into three cohorts at a 2:2:1 ratio, receiving continuous infusion of the compound of formula II, at 58.3mg/hr or 87.5mg/hr for 3 days (72 hours), or receiving appropriate standard of care (placebo as 0.9% sodium chloride injection). All subjects in the compound of formula II treatment group will also receive standard of care as background treatment.
The compound of formula II was prepared as a sterile concentrated solution (70 mg/mL, phosphate buffer pH 7.5 in a solvent) and placed in a 10mL glass bottle equipped with a rubber stopper and a sealing cap, and stored under refrigeration at 2℃to 8 ℃. Immediately before use, the preparation is diluted by normal saline for injection and is prepared according to a clinical scheme for intravenous infusion administration.
The placebo for this study was 0.9% sodium chloride injection provided in the form of individual glass penicillin bottles with the same label, 10mL each, and stored under the same conditions as the study medication, refrigerated at 2-8 ℃. Placebo must be administered following the same procedure and instructions as the compound of formula II.
The present study explored: 1) Occurrence rate of adverse events and serious adverse events; 2) Adverse events lead to treatment termination rates; 3) An electrocardiographic abnormality; 4) Laboratory checking for anomalies; 5) Vital signs and physical examination abnormalities various adverse event occurrences, including symptoms or abnormal signs and laboratory examination abnormalities. Changes in PaO2/FiO2 after 1) administration compared to baseline; 2) Changes in biological indicators such as c-reactive protein (CRP), alanine Aminotransferase (ALT), lactate Dehydrogenase (LDH), etc. after administration as compared to baseline; 3) Changes in SOFA score after dosing compared to baseline; 4) A time of life within 30 days; 5) Survival time after off-line within 30 days; 6) Hospitalization time within 30 days; 7) ICU hospital stay within 30 days; 8) Invasive mechanical ventilation time was within 30 days.
The above-mentioned index detection is conventional in the art, and those skilled in the art know how to obtain the detection index.
Few adverse events or severe adverse reactions associated with the test agents were found in the clinical study. After administration of the compound of formula II, the patient has improved clinical symptoms, including an improvement in one or more of the biological or clinical indicators shown below: biological indicators such as C-reactive protein (CRP), alanine Aminotransferase (ALT), lactate Dehydrogenase (LDH) or PaO2/FiO2 are improved (or restored to normal levels), sequential organ failure assessment Score (SOFA) is reduced (e.g., to 1 or 0), use of mechanical ventilation and reduced time to use, reduced hospitalization time or ICU hospitalization time, and reduced mortality, etc.
The improvement or restoration of PaO2/FiO2 to normal levels may reflect some improvement or alleviation of the patient's respiratory condition (e.g., symptoms such as respiratory distress, hypoxia, acute respiratory distress syndrome, etc.). Improvement of C-reactive protein (CRP), improvement of Lactate Dehydrogenase (LDH) may reflect improvement of the patient's degree of infection (e.g., symptoms such as sepsis, septic shock, etc.), and decrease of SOFA score may reflect improvement of the patient's organ injury or failure to some extent. Improvement in alanine Aminotransferase (ALT) may reflect to some extent improvement in liver injury. The reduction of hospital stays, reduction of ICU hospital stays, reduction of use time of mechanical ventilation, prolongation of ventilator free survival, and the like, may reflect, to some extent, overall improvement or therapeutic effects of the patient on the associated diseases or conditions caused by 2019-nCoV infection (including pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disorders, acute respiratory distress syndrome, sepsis, septic shock, multiple organ failure, and the like).
The clinical research results show that the compound of the formula II has good safety and has therapeutic effect on related diseases or symptoms caused by 2019-nCoV infection.
While embodiments of the present application have been shown and described, it will be understood that the above embodiments are illustrative and not to be construed as limiting the application, and that variations, modifications, alternatives, and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the application. The scope of the application is defined by the appended claims.
Claims (15)
- Use of a compound of formula II in the manufacture of a medicament for the treatment of a disease or condition associated with 2019-nCoV infection;
- the use of claim 1, wherein the 2019-nCoV infection causes related diseases or conditions including, but not limited to: pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disturbance, acute respiratory distress syndrome, acute respiratory failure, sepsis, septic shock, multiple organ failure, fever, respiratory tract and other symptoms, dyspnea, somnolence and convulsion.
- The application of claim 2, wherein the application satisfies one or both of the following conditions:a) The pneumonia is COVID-19; preferably, the COVID-19 is a heavy or critical COVID-19;b) The acute respiratory distress syndrome may be lipopolysaccharide-initiated acute respiratory distress syndrome.
- Use of a pharmaceutical composition in the manufacture of a medicament;the pharmaceutical composition comprises a compound of a formula II and pharmaceutically acceptable auxiliary materials;the medicine is used for treating 2019-nCoV infection-induced related diseases or symptoms.
- The use according to claim 4, wherein the pharmaceutical composition is a pharmaceutical composition for injection; preferably, the pharmaceutical composition for injection is in the form of a powder or a concentrated solution.
- The use according to claim 5, wherein the pH of the concentrated solution is 7.0 to 8.0, preferably 7.4 to 7.6, further 7.5.
- The use according to claim 6, wherein the concentrated solution is pH adjusted by adding a buffer selected from the group consisting of phosphate buffer, citrate buffer and acetate buffer.
- The use of claim 4, wherein the 2019-nCoV infection causes related diseases or conditions including, but not limited to: pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disturbance, acute respiratory distress syndrome, acute respiratory failure, sepsis, septic shock, multiple organ failure, fever, respiratory tract and other symptoms, dyspnea, somnolence and convulsion.
- The application of claim 8, wherein the application satisfies one or both of the following conditions:c) The pneumonia is COVID-19; preferably, the COVID-19 is a heavy or critical COVID-19;d) The acute respiratory distress syndrome may be lipopolysaccharide-initiated acute respiratory distress syndrome.
- The use according to any one of claims 5 to 9, wherein the concentration of the compound of formula II in the concentrated solution is 50-500mg/mL, further 60-100mg/mL, preferably 65-85mg/mL, more preferably 68-80mg/mL.
- The use according to claim 10, wherein the injectable pharmaceutical composition is administered by intravenous continuous infusion at a rate of 15 to 120mg/hr for a period of 1 to 120hr.
- Use of a compound of formula II in the manufacture of a medicament for the treatment of acute respiratory distress syndrome or acute respiratory failure;the acute respiratory distress syndrome can be acute respiratory distress syndrome caused by infection or acute respiratory distress syndrome caused by lipopolysaccharide, and can also be acute respiratory distress syndrome caused by 2019-nCoV infection.
- A method of treating a 2019-nCoV infection-associated disease or disorder comprising administering to a patient a therapeutically effective amount of a compound of formula II;wherein the 2019-nCoV infection causes related diseases or conditions including but not limited to: pneumonia, organ damage, respiratory distress, hypoxia, thrombosis and embolism, microcirculation disturbance, acute respiratory distress syndrome, acute respiratory failure, sepsis, septic shock, multiple organ failure, fever, respiratory tract and other symptoms, dyspnea, somnolence and convulsion.
- The method of claim 13, wherein the application satisfies one or both of the following conditions:e) The pneumonia is COVID-19; preferably, the COVID-19 is a heavy or critical COVID-19;f) The acute respiratory distress syndrome may be lipopolysaccharide-initiated acute respiratory distress syndrome.
- A method of treating acute respiratory distress syndrome or acute respiratory failure comprising administering to a patient a therapeutically effective amount of a compound of formula II;the acute respiratory distress syndrome can be acute respiratory distress syndrome caused by infection or acute respiratory distress syndrome caused by lipopolysaccharide, and can also be acute respiratory distress syndrome caused by 2019-nCoV infection.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2020113848739 | 2020-12-01 | ||
| CN202011384873 | 2020-12-01 | ||
| PCT/CN2021/134613 WO2022116981A1 (en) | 2020-12-01 | 2021-11-30 | Application of polyanionic cellobioside compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116829157A true CN116829157A (en) | 2023-09-29 |
Family
ID=81853837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180080201.5A Pending CN116829157A (en) | 2020-12-01 | 2021-11-30 | Application of polyanionic fiber diglycoside compound |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN116829157A (en) |
| WO (1) | WO2022116981A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG11202109032SA (en) * | 2019-02-25 | 2021-09-29 | Univ Australian National | Compounds for treating and preventing net associated complications |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09183789A (en) * | 1995-10-31 | 1997-07-15 | Sanwa Kagaku Kenkyusho Co Ltd | New sulfated and phosphated sugar derivative, its production and use |
| ES2710857T3 (en) * | 2010-12-01 | 2019-04-29 | Univ Australian National | Use of polyanions to inhibit the cytotoxic activity of histones in the treatment of sepsis |
| JP7359396B2 (en) * | 2017-12-15 | 2023-10-11 | ジ・オーストラリアン・ナショナル・ユニヴァーシティ | Compounds for treating and preventing pathologies mediated by extracellular histones |
| WO2019113646A1 (en) * | 2017-12-15 | 2019-06-20 | Griffith University | Sulfation method |
| SG11202109032SA (en) * | 2019-02-25 | 2021-09-29 | Univ Australian National | Compounds for treating and preventing net associated complications |
-
2021
- 2021-11-30 WO PCT/CN2021/134613 patent/WO2022116981A1/en active Application Filing
- 2021-11-30 CN CN202180080201.5A patent/CN116829157A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022116981A1 (en) | 2022-06-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20170143674A1 (en) | Use of Glutaryl Histamine for the Treatment of Respiratory Tract Diseases | |
| WO2021249561A1 (en) | Therapeutic use of of cell-free fat extract for pulmonary diseases | |
| CN116829157A (en) | Application of polyanionic fiber diglycoside compound | |
| CN111514137A (en) | Application of compound in preparation of medicine for treating acute lung injury | |
| CN111388492B (en) | Application of Jasurolignoside in preparation of medicine for treating and/or preventing lung injury | |
| CN111329870B (en) | Application of Yadanzigan in preparing medicine for treating and/or preventing lung injury | |
| Berenguer et al. | Treatment of deep mycoses with liposomal amphotericin B | |
| WO2022227513A1 (en) | Medication for treating lung injury | |
| CN111494392A (en) | Composition for treating acute lung injury and application thereof | |
| WO2022028375A1 (en) | Therapeutic use of cell-free fat extract solution for pulmonary diseases | |
| WO2022095715A1 (en) | Use of cell-free fat extract for treating ulcerative colitis | |
| WO2022236585A1 (en) | Use of hyaluronic acid in preparation of medication for treating pulmonary fibrosis | |
| WO2022236599A1 (en) | Use of hyaluronic acid for preparing medicament for treating acute respiratory distress syndrome | |
| CN114191424A (en) | Pharmaceutical composition and application thereof in preparation of medicine for treating acute lung injury | |
| CN114129705B (en) | Application of polypeptide in medicine for preventing and treating pneumonia | |
| CN113559100B (en) | Composition for treating lung injury and application thereof | |
| CN108096242B (en) | Traditional Chinese medicine composition for treating chronic obstructive pulmonary disease | |
| CN114288284B (en) | Application of philippine in preparing medicine for preventing and treating acute pneumonia | |
| CN109394776B (en) | Traditional Chinese medicine component formula for treating diffuse interstitial pulmonary fibrosis and application thereof | |
| WO2021209003A1 (en) | Prevention and treatment of organ injuries | |
| Abeysekera et al. | Fatal pulmonary haemorrhage following adenovirus infection | |
| CN108096240B (en) | Traditional Chinese medicine composition for treating pulmonary fibrosis | |
| Samimi et al. | OJVRTM | |
| CN114984022A (en) | Use of ceftazidime or a pharmaceutically acceptable salt thereof in the treatment of AECOPD | |
| Sierra Rodriguez | Airway Deposition of Nebulized Voriconazole in Horses |
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 |