CN111686239A - 抗真菌化合物的应用 - Google Patents
抗真菌化合物的应用 Download PDFInfo
- Publication number
- CN111686239A CN111686239A CN201910182059.XA CN201910182059A CN111686239A CN 111686239 A CN111686239 A CN 111686239A CN 201910182059 A CN201910182059 A CN 201910182059A CN 111686239 A CN111686239 A CN 111686239A
- Authority
- CN
- China
- Prior art keywords
- fatty liver
- antifungal
- liver disease
- icz
- fcz
- 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.)
- Granted
Links
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 35
- 230000000843 anti-fungal effect Effects 0.000 title claims abstract description 33
- 150000001875 compounds Chemical class 0.000 title claims abstract description 20
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims abstract description 48
- 229960004130 itraconazole Drugs 0.000 claims abstract description 48
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 229960004884 fluconazole Drugs 0.000 claims abstract description 47
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims abstract description 45
- 229960004740 voriconazole Drugs 0.000 claims abstract description 43
- 239000003814 drug Substances 0.000 claims abstract description 28
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 claims abstract description 24
- 108010020326 Caspofungin Proteins 0.000 claims abstract description 21
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims abstract description 21
- 229960003034 caspofungin Drugs 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 21
- 235000013305 food Nutrition 0.000 claims abstract description 8
- 230000036541 health Effects 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 19
- 208000030159 metabolic disease Diseases 0.000 claims description 18
- 208000008589 Obesity Diseases 0.000 claims description 17
- 235000020824 obesity Nutrition 0.000 claims description 17
- 208000010706 fatty liver disease Diseases 0.000 claims description 10
- 206010019668 Hepatic fibrosis Diseases 0.000 claims description 9
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 8
- 208000026594 alcoholic fatty liver disease Diseases 0.000 claims description 7
- 201000001421 hyperglycemia Diseases 0.000 claims description 5
- 230000003902 lesion Effects 0.000 claims description 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 2
- 229930183010 Amphotericin Natural products 0.000 claims 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 claims 1
- 229940009444 amphotericin Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 22
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 abstract description 20
- 229960003942 amphotericin b Drugs 0.000 abstract description 20
- 201000010099 disease Diseases 0.000 abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 230000002503 metabolic effect Effects 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 210000004369 blood Anatomy 0.000 description 33
- 239000008280 blood Substances 0.000 description 33
- 241000699670 Mus sp. Species 0.000 description 25
- 230000000968 intestinal effect Effects 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- 230000037396 body weight Effects 0.000 description 13
- 210000004185 liver Anatomy 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 12
- 239000008103 glucose Substances 0.000 description 12
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 12
- 229960003105 metformin Drugs 0.000 description 12
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 206010012601 diabetes mellitus Diseases 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 238000011160 research Methods 0.000 description 9
- 206010019708 Hepatic steatosis Diseases 0.000 description 8
- 230000003345 hyperglycaemic effect Effects 0.000 description 8
- 150000002632 lipids Chemical class 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 208000004930 Fatty Liver Diseases 0.000 description 6
- 108010028554 LDL Cholesterol Proteins 0.000 description 6
- 230000001476 alcoholic effect Effects 0.000 description 6
- 239000003429 antifungal agent Substances 0.000 description 6
- 231100000283 hepatitis Toxicity 0.000 description 6
- 208000006454 hepatitis Diseases 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 231100000240 steatosis hepatitis Toxicity 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 206010002091 Anaesthesia Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000037005 anaesthesia Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 235000020888 liquid diet Nutrition 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 241000233866 Fungi Species 0.000 description 4
- 108010023302 HDL Cholesterol Proteins 0.000 description 4
- 206010022489 Insulin Resistance Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 4
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 210000005229 liver cell Anatomy 0.000 description 4
- 230000003908 liver function Effects 0.000 description 4
- 210000005228 liver tissue Anatomy 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 3
- 108010082126 Alanine transaminase Proteins 0.000 description 3
- 208000001145 Metabolic Syndrome Diseases 0.000 description 3
- 108090000340 Transaminases Proteins 0.000 description 3
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 239000002702 enteric coating Substances 0.000 description 3
- 238000009505 enteric coating Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 235000009200 high fat diet Nutrition 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 102000014898 transaminase activity proteins Human genes 0.000 description 3
- -1 triglyceride lipid Chemical class 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 208000002353 alcoholic hepatitis Diseases 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 238000002224 dissection Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 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
- 239000003921 oil Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 2
- 210000003934 vacuole Anatomy 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 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
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 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
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 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
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000012004 Ghrelin Human genes 0.000 description 1
- 101800001586 Ghrelin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101001077604 Homo sapiens Insulin receptor substrate 1 Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021024 Hypolipidaemia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100025087 Insulin receptor substrate 1 Human genes 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
- 208000032420 Latent Infection Diseases 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 101100001708 Mus musculus Angptl4 gene Proteins 0.000 description 1
- 101100181592 Mus musculus Lep gene Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000012871 anti-fungal composition Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 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
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037771 disease arising from reactivation of latent virus Diseases 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000012666 negative regulation of transcription by glucose Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 210000005037 parasympathetic nerve Anatomy 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000013424 sirius red staining Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004548 suspo-emulsion Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Gastroenterology & Hepatology (AREA)
- Nutrition Science (AREA)
- Mycology (AREA)
- Polymers & Plastics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Food Science & Technology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Child & Adolescent Psychology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了抗真菌化合物在制备治疗和/或预防代谢相关疾病药物或食品中的应用，所述的抗真菌化合物包括卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑。通过本发明的抗真菌药物及其药用盐制备的抑制剂、药物、食品或保健品无毒副作用，治疗效果显著。
Description
技术领域
本发明涉及抗真菌化合物新型治疗技术领域。
背景技术
代谢疾病是由于体内代谢紊乱而发生的疾病的总称。代谢疾病通常是由碳水化合物、脂质、蛋白质、维生素、电解质、水等的失衡而引起的。代谢疾病的实例包括肥胖症、高血糖、高血脂症、动脉硬化症、高血压、非酒精性脂肪性肝病等。随着社会的发展，人们生活水平的不断提高和饮食结构的调整，饮食呈富余化趋势，导致代谢类疾病的发病率不断提高，其中以高血糖以及高血脂最引人关注，目前全世界糖尿病人数为2亿人左右，并以惊人的速度每年递增。中国糖尿病人数为4千万，占世界糖尿病人群总数的1/5。另外，因血脂升高导致的动脉粥样硬化、冠心病等心血管疾病发病率逐年升高，并有年轻化趋势。降血糖、降血脂药物已经成为药物研究的重点之一。
随着微生物组计划的启动，肠道菌群与人体健康的关系受到广泛重视，以肠道菌群变化为切入点探讨代谢综合征的治疗和预防已成为研究热点。研究表明肠道元基因组与人体基因组相互作用，借助于神经递质、代谢产物、免疫信号、甚至基因表达等作用方式，调控许多疾病的发生和发展，如癌症、肥胖、糖尿病、非酒精性脂肪肝、心血管疾病、神经性病变等。肠道菌群是生活在我们机体内的特殊微生物，参与宿主的能量代谢,调控脂类、糖类、蛋白质类物质在肠道中的吸收。当菌群结构失调时，血液里内毒素LPS的浓度会增加，LPS进入循环系统，识别结合蛋白，促进CD14和TLR4的表达和炎症因子的产生，诱导肌肉和脂肪IRS1的丝氨酸磷酸化，继而阻断胰岛素在外周组织的传导，造成胰岛素抵抗。此外，肠道菌群失衡，会产生大量乙酸，激活副交感神经，促进胰岛素分泌，释放饥饿素，使能量摄入失衡，同时肠道fiaf基因表达受到抑制，造成脂肪堆积和肥胖。肠道菌群在代谢综合征的两个核心症状胰岛素抵抗和肥胖的发生发展中都发挥着非常重要的作用，已被证实是代谢综合征的元凶，或者是代谢类疾病的潜伏感染源。
但目前关于肠道菌群对代谢性疾病影响的研究主要集中在肠道细菌上，而肠道中另外一类重要共生者-肠道真菌对代谢性疾病的作用目前尚不清晰，有部分对于人体的研究表明肥胖及脂肪肝患者的肠道真菌发生了改变，但肠道真菌在肥胖、糖尿病、脂肪肝等代谢性疾病中的作用目前并不清楚，肠道真菌的干扰对代谢性疾病的影响尚无研究报道。我们发现卡泊芬净、两性霉素B、氟康唑、伊曲康唑及伏立康唑等抗真菌药物均可以显著改善糖尿病、高血脂、脂肪肝等代谢病疾病，证明了口服抗真菌药物对于代谢性疾病治疗的新用途。
发明内容
本发明提供了抗真菌化合物在制备治疗和/或预防代谢相关疾病药物或食品中的应用，所述的抗真菌化合物包括卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑。
进一步地，所述的代谢性疾病包括肥胖、高血糖、高血脂、非酒精性脂肪性肝病和酒精性脂肪肝病。
更进一步地，所述的非酒精性脂肪性肝病包括：单纯脂肪性病变的脂肪性肝病、非酒精性脂肪肝炎的脂肪性肝病、肝纤维化的脂肪性肝病。
通过本发明的抗真菌化合物及其药用盐制备的抑制剂、药物、食品或保健品无毒副作用，治疗效果显著。
附图说明
图1是非酒精性脂肪性肝病的肝脏观察和组织病理切片图。
图2是红色胶原纤维形成网状结构图。
图3是酒精性脂肪性肝病的肝脏观察和组织病理切片图。
具体实施方式
发明人经过广泛而深入的研究和实验，发现抗真菌药物卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑具有预防和治疗代谢相关疾病(包括肥胖、高血糖、高血脂、非酒精性脂肪性肝病)的作用，将含有卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑的单一化合物或组合物饲喂实验对象，发现均能够抑制体重增加，降低血糖，降低血脂、改善非酒精性脂肪性肝病、缓解非酒精性脂肪肝炎及肝纤维化症状，有效减轻糖尿病及肥胖等代谢性疾病病症。在此基础上完成本发明。
本发明提供了抗真菌药物在治疗和预防代谢相关疾病方面的用途。受试动物摄入高脂肪的食物，卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑均具有抑制该受试动物体重增加的能力。根据本发明的一个优选例，经卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑来治疗的被喂以可导致肥胖的高脂肪食物的C57BL/6J小鼠以及肥胖模型ob/ob小鼠，与未受治疗的对照组相比，可保持体重无任何增加，且有助于血糖、血脂下降，非酒精性脂肪性肝病症状的改善。因此，所述化合物能够用以预防和治疗肥胖及由肥胖引起的疾病如糖尿病、非酒精性脂肪性肝病等。
本发明还提供了一种组合物，优选地，为药物组合物。所述组合物包括有效量的卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑及其组合。
本发明药物组合物可以以药物片剂，针剂或胶囊的任一种形式给药，所述药物制剂包括赋形剂、药物允许的媒介和载体，这些物质可根据给药途径进行选择。本发明中的药物制剂可进一步包含辅助的活性组分。
乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮(PVP)、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁或矿物油等都可用作本发明中药物组合物的载体、赋形剂或稀释剂等。
此外，本发明的药物组合物可进一步包括润滑剂、润湿剂、乳化剂、悬乳液稳定剂、防腐剂、甜味剂和香料等。本发明的药物组合物可通过多种公知的方法以肠衣制剂生产，以便于药物组合物的活性成分即微生物能顺利通过胃而不被胃酸所破坏。
本发明的组合物可制成肠衣片供口服使用。本申请中的术语-“肠衣”包括所有常规药物允许使用的包衣，这些包衣不被胃酸降解，但在小肠中能充分分解并快速释放出本发明的微生物。本发明的肠衣能在合成胃酸如pH＝1的HCl溶液中36-38℃维持2小时以上，并优选在合成肠液如pH＝7.0的缓冲液中在1.0小时内分解。
本发明的肠衣以每片约16-30mg进行包衣，较佳地16-25mg，更佳地16-20mg进行包衣。本发明中肠衣厚度为5-100μm，理想的厚度为20-80μm.肠衣成分自己公开知晓的常规聚合物。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
抗真菌化合物对肥胖、糖尿病模型小鼠ob/ob血糖、血脂及体重影响
材料：被测化合物为卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)，每种药物选择三个灌胃剂量，分别为10mg/kg、50mg/kg、100mg/kg体重，频率为每日一次。
Ob/ob小鼠购自中国医学科学院北京协和医学院动物研究所，温度20-24摄氏度，恒湿50-60％，光照12小时(8:00-20:00)，隔音，自由摄食、饮水，适应环境一周后进行实验。血糖试纸(罗氏公司)、血糖仪(罗氏公司)、血清总胆固醇TC试剂盒(批号20131112)，低密度脂蛋白LDL-C试剂盒(批号20140114)，高密度脂蛋白HDL-C试剂盒(批号20140413)，甘油三酯TG试剂盒(批号20131226)购自南京建成生物工程研究所。
方法：雄性C57小鼠6-8周，体重30-32，10只，作为正常对照组(1)，雄性ob/ob小鼠6-8周，体重38-42，测定空腹血糖，依据血糖值和体重情况平均分组：(2)模型对照组，(3)Cas 10mg/kg，(4)Cas 50mg/kg，(5)Cas 100mg/kg，(6)Amp 10mg/kg，(7)Amp 50mg/kg，(8)Amp 100mg/kg，(9)FCZ 10mg/kg，(10)FCZ 50mg/kg，(11)FCZ 100mg/kg，(12)ICZ 10mg/kg，(13)ICZ 50mg/kg，(14)ICZ 100mg/kg，(15)VCZ 10mg/kg，(16)VCZ 50mg/kg，(17)VCZ100mg/kg，每组8只，连续给药5周。模型对照组给予等量的水。对照组和模型组给予等量的生理盐水。末次给药后，取血，4摄氏度3000rpm离心，测定血清总胆固醇TC，低密度脂蛋白LDL-C，甘油三酯TG。
结果：与对照组和模型组比较，卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)在不同剂量下均可以剂量依赖的显著控制体重，从第1周起即可降低自由饮食血糖及禁食(4小时)血糖，改善小鼠血脂情况，结果见表1-4。
表1抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对高血糖小鼠ob/ob的体重影响
表2抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对高血糖小鼠ob/ob的自由饮食血糖影响
表3抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对高血糖小鼠ob/ob的禁食血糖影响
表4抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对高血糖小鼠ob/ob的血脂影响
实施例2
抗真菌化合物对非酒精性脂肪性肝病的影响
材料：被测化合物为卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)，剂量选定为有效剂量50mg/kg，频率为每日一次。
雄性SPF级Wister大鼠60只，体重180-220g，购自维通利华实验动物中心。温度20-24摄氏度，恒湿50-60％，光照12小时(8:00-20:00)，隔音，自由摄食、饮水，适应环境一周后进行实验。血清总胆固醇TC试剂盒(批号20131112)，低密度脂蛋白LDL-C试剂盒(批号20140114)，高密度脂蛋白HDL-C试剂盒(批号20140413)，甘油三酯TG试剂盒(批号20131226)，谷草转氨酶ALT试剂盒(批号20131006)购自南京建成生物工程研究所。
方法：雄性SPF级Wister大鼠随机分组：(1)正常组；(2)模型对照组；(3)Cas 50mg/kg；(4)Amp 50mg/kg；(5)FCZ 50mg/kg；(6)ICZ 50mg/kg；(7)ICZ 100mg/kg；(8)VCZ 50mg/kg，每组10只。正常组大鼠标准饲料喂养，其余组大鼠每天喂食胆碱缺乏饲料(高脂饲料)，检测大鼠摄食量及体重。胆碱缺乏饲料喂养会诱发肝脏细胞变性、肝炎及肝损伤，同时血脂水平升高并诱发胰岛素抵抗，是常用的啮齿类动物脂肪肝的造模方法。
高脂饮食喂养8周后，给药组开始给药，连续给药4周。正常组和模型对照组给予等量的水。给药四周后，麻醉处死大鼠，取肝组织和血。
测定指标：1)肝脏指数。
2)测定血清总胆固醇、高密度脂蛋白、低密度脂蛋白及甘油三酯含量。
3)测定谷丙转氨酶、谷草转氨酶、羟脯氨酸含量，利用elisa试剂盒检测肝炎及肝纤维化TGFβ1及TNFα含量。
4)肝脏组织切片：末次给药后，麻醉处死，冰上取肝脏，并迅速放入福尔马林中固定，准备组织切片。
实验结果，与正常对照组比较，模型组肝指数显著升高，给予抗真菌药后各组能显著降低非酒精性脂肪性肝病大鼠的肝指数。同时模型组的TC、LDL-C、TG均显著升高，HDL-C显著降低，提示本模型造成明显的血脂紊乱，与模型组相比，给予五种抗真菌药物后均可降低非酒精性脂肪性肝病大鼠的血脂，同时还能改善肝功能，降低血浆ALT的含量，降低非酒精性脂肪肝炎指标TNFα及肝纤维化指标TGFβ1水平。
表5抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对非酒精性肝脏脂肪性病变的影响
表6抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对非酒精性肝炎及肝纤维化的影响
结合解剖时对肝脏大体的肉眼观察和组织病理切片的油红染色发现(图1)，模型组大鼠肝细胞内均有大量大小不等的脂肪空泡，形成脂肪肝，同时，天狼猩红染色发现模型组大鼠肝脏纤维化情况明显，红色胶原纤维形成网状结构(图2)。而卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)组中大鼠肝细胞内的甘油三酯脂滴及肝脏纤维化情况基本消失。
结果表明卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)均可以有效防治由于肥胖引起的的非酒精性脂肪性肝病。
实施例3
抗真菌化合物对酒精性脂肪性肝病的影响
材料：被测化合物为卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)，剂量选定为有效剂量50mg/kg，频率为每日一次。
C57BL/6J(9weeks，♂，SPF级)小鼠随机分成7组，每组12只，分组情况如下：(1)正常对照组Lieber-DeCarli对照液体饲料喂养(给予与给药组相同剂量的蒸馏水)；(2)模型组Lieber-DeCarli酒精液体饲料喂养(给予与给药组相同剂量的蒸馏水)；(3)卡泊芬净(Cas)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；(4)两性霉素B(Amp)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；(5)氟康唑(FCZ)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；(6)伊曲康唑(ICZ)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；(7)伏立康唑(VCZ)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；连续给药4周。正常组和模型对照组给予等量的水。给药四周后，麻醉处死大鼠，取肝组织和血。
测定指标：1)肝脏指数。
2)测定血清总胆固醇、高密度脂蛋白、低密度脂蛋白及甘油三酯含量。
3)测定谷丙转氨酶、谷草转氨酶、羟脯氨酸含量，利用elisa试剂盒检测肝炎及肝纤维化TGFβ1及TNFα含量。
4)肝脏组织切片：末次给药后，麻醉处死，冰上取肝脏，并迅速放入福尔马林中固定，准备组织切片。
实验结果，与正常对照组比较，给予液体酒精饲料组小鼠肝指数显著升高，给予抗真菌药后各组能显著降低酒精性脂肪性肝病小鼠的肝指数。同时模型组的TC、LDL-C、TG均显著升高，HDL-C显著降低，提示本模型造成明显的血脂紊乱，与模型组相比，给予五种抗真菌药物后均可降低酒精性脂肪性肝病小鼠的血脂，同时还能改善肝功能，降低血浆ALT的含量，降低非酒精性脂肪肝炎指标TNFα及肝纤维化指标TGFβ1水平。
表5抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对酒精性肝脏脂肪性病变的影响
表6抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对酒精性肝炎及肝纤维化的影响
结合解剖时对肝脏大体的肉眼观察和组织病理切片的油红染色发现(图3)，模型组小鼠肝细胞内均有大量大小不等的脂肪空泡，形成脂肪肝。而卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)组中大鼠肝细胞内的甘油三酯脂滴基本消失。
结果表明卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)均可以有效防治由于酒精诱导的酒精性脂肪性肝病。
实施例4
抗真菌化合物与代谢性疾病治疗药物组合物对高血糖小鼠ob/ob血糖、体重、血脂及肝功能的影响
二甲双胍是目前临床上首选的降糖药物，主要通过降低肝糖输出，减少肠道对糖的吸收，增加外周血糖的摄取和利用，达到提高胰岛素的敏感性的作用，本发明中抗真菌药物与一线治疗药物组织使用可以显著增强其治疗效果。
材料：被测化合物为卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)的有效剂量50mg/kg以及二甲双胍(100mg/kg)的联合用药。
Ob/ob小鼠购自中国医学科学院北京协和医学院动物研究所，温度20-24摄氏度，恒湿50-60％，光照12小时(8:00-20:00)，隔音，自由摄食、饮水，适应环境一周后进行实验。血糖仪为德国罗氏公司产品。
方法：雄性C57小鼠6-8周，体重30-32，10只，作为正常对照组(1)；
雄性ob/ob小鼠6-8周，体重38-42g，测定空腹血糖，依据血糖值和体重情况平均分组：
(2)模型对照组；
(3)卡泊芬净(Cas)50mg/kg；
(4)两性霉素B(Amp)50mg/kg；
(5)氟康唑(FCZ)50mg/kg；
(6)伊曲康唑(ICZ)50mg/kg；
(7)伏立康唑(VCZ)50mg/kg；
(8)二甲双胍(Met)100mg/kg；
(9)卡泊芬净(Cas)50mg/kg+二甲双胍(Met)100mg/kg；
(10)两性霉素B(Amp)50mg/kg+二甲双胍(Met)100mg/kg；
(11)氟康唑(FCZ)50mg/kg+二甲双胍(Met)100mg/kg；
(12)伊曲康唑(ICZ)50mg/kg+二甲双胍(Met)100mg/kg；
(13)伏立康唑(VCZ)50mg/kg+二甲双胍(Met)100mg/kg；
每组8只，连续给药5周。模型对照组给予等量的水。
抗真菌药物与二甲双胍的组合效果：
测定指标：1)对体重和血糖的影响：给药第7天、14天、21天、28天、35天称量体重并记录，给药后尾尖取血测血糖值(见表5)。
4)末次给药后，麻醉处死，取血，4摄氏度3000rpm离心，测定血清总胆固醇TC，低密度脂蛋白LDL-C，甘油三酯TG，谷丙转氨酶、谷草转氨酶。
实验结果表明抗真菌药物对高血糖小鼠的代谢紊乱的治疗效果在与二甲双胍联用后更为显著，可以用于制备治疗II型糖尿病、降血脂、肥胖的药物或与其它药物合用治疗II型糖尿病、肥胖、高血脂或在治疗过程中/后起辅助作用。
表9抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)与二甲双胍组合物对高血糖小鼠ob/ob血糖与体重的影响
与对照组和模型组比较，抗真菌药及组合物可以显著改善小鼠血脂情况，对小鼠血清ALT也有很好的逆转作用，提示可以保护高血脂造成的肝损伤结果见表10。
表10.抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)与二甲双胍组合物对高血糖小鼠ob/ob的血脂和肝功能影响
Claims (3)
1.抗真菌化合物及其药用盐在制备预防和/或治疗代谢性疾病药物、保健品或食品中的应用，其特征在于，
所述的抗真菌化合物包括：卡泊芬净、两性霉素、氟康唑、伊曲康唑、伏立康唑。
2.根据权利要求1所述的的应用，其特征在于，
所述的代谢性疾病包括肥胖、高血糖、高血脂、非酒精性脂肪性肝病和酒精性脂肪肝病。
3.根据权利要求2所述的应用，其特征在于，
所述的非酒精性脂肪性肝病包括：单纯脂肪性病变的脂肪性肝病、非酒精性脂肪肝炎的脂肪性肝病、肝纤维化的脂肪性肝病。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910182059.XA CN111686239B (zh) | 2019-03-11 | 2019-03-11 | 抗真菌化合物的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910182059.XA CN111686239B (zh) | 2019-03-11 | 2019-03-11 | 抗真菌化合物的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111686239A true CN111686239A (zh) | 2020-09-22 |
| CN111686239B CN111686239B (zh) | 2021-12-24 |
Family
ID=72474713
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910182059.XA Active CN111686239B (zh) | 2019-03-11 | 2019-03-11 | 抗真菌化合物的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111686239B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117551596A (zh) * | 2024-01-11 | 2024-02-13 | 云南大学 | 一种解除土壤对生防真菌抑菌作用的方法 |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050031544A1 (en) * | 2003-08-07 | 2005-02-10 | Njemanze Philip Chidi | Receptor mediated nanoscale copolymer assemblies for diagnostic imaging and therapeutic management of hyperlipidemia and infectious diseases |
| US20050049208A1 (en) * | 2003-09-03 | 2005-03-03 | Kaufmann Doug A. | Method of treating and method of preventing diabetes |
| CN101405003A (zh) * | 2006-03-17 | 2009-04-08 | Cv医药有限公司 | 利用a2b腺苷受体拮抗剂预防和治疗肝病的方法 |
| CN101522196A (zh) * | 2006-08-07 | 2009-09-02 | 博士伦公司 | 用组合的分离的糖皮质激素受体激动剂和抗感染剂治疗感染及其后遗症 |
| CN101951936A (zh) * | 2008-02-26 | 2011-01-19 | 康奈尔大学 | 用于防止和治疗急性肾损伤的方法 |
| CN103189374A (zh) * | 2010-08-12 | 2013-07-03 | 杏林制药株式会社 | 非酒精性脂肪肝炎的预防或治疗剂 |
| CN106581680A (zh) * | 2015-10-16 | 2017-04-26 | 山东亨利医药科技有限责任公司 | 一种降低药物吸收受食物影响的药物组合物 |
-
2019
- 2019-03-11 CN CN201910182059.XA patent/CN111686239B/zh active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050031544A1 (en) * | 2003-08-07 | 2005-02-10 | Njemanze Philip Chidi | Receptor mediated nanoscale copolymer assemblies for diagnostic imaging and therapeutic management of hyperlipidemia and infectious diseases |
| US20050049208A1 (en) * | 2003-09-03 | 2005-03-03 | Kaufmann Doug A. | Method of treating and method of preventing diabetes |
| CN101405003A (zh) * | 2006-03-17 | 2009-04-08 | Cv医药有限公司 | 利用a2b腺苷受体拮抗剂预防和治疗肝病的方法 |
| CN101522196A (zh) * | 2006-08-07 | 2009-09-02 | 博士伦公司 | 用组合的分离的糖皮质激素受体激动剂和抗感染剂治疗感染及其后遗症 |
| CN101951936A (zh) * | 2008-02-26 | 2011-01-19 | 康奈尔大学 | 用于防止和治疗急性肾损伤的方法 |
| CN103189374A (zh) * | 2010-08-12 | 2013-07-03 | 杏林制药株式会社 | 非酒精性脂肪肝炎的预防或治疗剂 |
| CN106581680A (zh) * | 2015-10-16 | 2017-04-26 | 山东亨利医药科技有限责任公司 | 一种降低药物吸收受食物影响的药物组合物 |
Non-Patent Citations (1)
| Title |
|---|
| 李同林等: "伏立康唑联合卡泊芬净序贯治疗拟诊侵袭性肺真菌病患者的疗效", 《湖南师范大学学报（医学版）》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117551596A (zh) * | 2024-01-11 | 2024-02-13 | 云南大学 | 一种解除土壤对生防真菌抑菌作用的方法 |
| CN117551596B (zh) * | 2024-01-11 | 2024-03-29 | 云南大学 | 一种解除土壤对生防真菌抑菌作用的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111686239B (zh) | 2021-12-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11058703B2 (en) | Application of triacetyl-3-hydroxyphenyladenosine in preparation of pharmaceutical drug for preventing or treating non-alcoholic fatty liver disease | |
| CN111686239B (zh) | 抗真菌化合物的应用 | |
| CN107468683B (zh) | 土木香内酯及其衍生物在制备预防和治疗脂肪肝损伤药物中的用途 | |
| CN112494471A (zh) | 胆固醇酯合成酶acat1抑制剂在制备用于预防/治疗非酒精性脂肪肝药物中的应用 | |
| CN107737136A (zh) | 一种药物组合物在预防和/或治疗高脂血症与降血糖中的用途 | |
| US20190247343A1 (en) | Use of fenofibric acid in the treatment of hepatic diseases | |
| CN112955132A (zh) | 用于预防或治疗肥胖或非酒精性脂肪性肝炎的包含氢醌衍生物的药物组合物 | |
| CN108420890B (zh) | 一种具有降血脂作用的组合物及其制备方法 | |
| KR101461252B1 (ko) | 지방간 또는 비알코올성 지방성 간염의 예방 및/또는 치료를 위한 의약 | |
| CN103800352A (zh) | 一种抗非酒精性脂肪性肝病的中药有效成分复方制剂及应用 | |
| CN106727480B (zh) | Fex-3在制备抗肥胖症药物中的应用 | |
| US20210338700A1 (en) | Pharmaceutical use of anemoside b4 against acute gouty arthritis | |
| CN109045070A (zh) | 一种防治非酒精性脂肪肝病的组合物 | |
| CN108261412A (zh) | 益母草碱在制备胰岛素增敏剂中的用途 | |
| US8349373B1 (en) | Dietary supplement for use in a weight loss program | |
| CN111202775A (zh) | 一种治疗非酒精性脂肪性肝病的药物及其制备方法 | |
| CN109260217A (zh) | 3`-脱氧次黄嘌呤核苷在制备用于多种疾病药品、食品或保健品中的应用 | |
| CN112641779B (zh) | Gw441756在制备预防和/或治疗脂肪肝药物中的应用 | |
| CN112691089B (zh) | 1-苯基-1-丙醇在制备治疗高血脂和/或糖尿病药物中的应用 | |
| CN111714522A (zh) | 拟杆菌及其应用 | |
| KR101613252B1 (ko) | 아르기나아제 억제제를 함유하는 비만 및 지방간 예방 또는 치료용 조성물 | |
| KR101572311B1 (ko) | 2-아미노-2-노보네인카르복실산을 함유하는 비만 예방 또는 치료용 조성물 | |
| WO2022135461A1 (zh) | Magl抑制剂在制备预防或治疗脂肪性肝病药物中的用途 | |
| TWI797455B (zh) | 安卓錠化合物用於預防或治療非酒精性脂肪肝病的用途 | |
| CN115531406A (zh) | 芒柄花苷在制备预防或治疗脂肪肝药物中的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |