JP2019503983A - 高血糖症を処置する方法 - Google Patents
高血糖症を処置する方法 Download PDFInfo
- Publication number
- JP2019503983A JP2019503983A JP2018521403A JP2018521403A JP2019503983A JP 2019503983 A JP2019503983 A JP 2019503983A JP 2018521403 A JP2018521403 A JP 2018521403A JP 2018521403 A JP2018521403 A JP 2018521403A JP 2019503983 A JP2019503983 A JP 2019503983A
- Authority
- JP
- Japan
- Prior art keywords
- verapamil
- pharmaceutically acceptable
- acceptable salt
- use according
- pharmaceutical composition
- 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
- 201000001421 hyperglycemia Diseases 0.000 title abstract description 13
- SGTNSNPWRIOYBX-HHHXNRCGSA-N dexverapamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCC[C@@](C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-HHHXNRCGSA-N 0.000 claims abstract description 114
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 62
- 238000011282 treatment Methods 0.000 claims abstract description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 40
- 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 claims description 76
- 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 claims description 57
- 239000008103 glucose Substances 0.000 claims description 57
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 40
- 229960003105 metformin Drugs 0.000 claims description 39
- 239000008194 pharmaceutical composition Substances 0.000 claims description 35
- -1 treragliptin Chemical compound 0.000 claims description 32
- 108090001061 Insulin Proteins 0.000 claims description 31
- 102000004877 Insulin Human genes 0.000 claims description 31
- 229940125396 insulin Drugs 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 26
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 21
- 239000003472 antidiabetic agent Substances 0.000 claims description 17
- 229940126904 hypoglycaemic agent Drugs 0.000 claims description 17
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 15
- 229940123208 Biguanide Drugs 0.000 claims description 14
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 claims description 14
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 14
- 229940100389 Sulfonylurea Drugs 0.000 claims description 14
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 14
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 claims description 13
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 12
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 11
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000004026 insulin derivative Substances 0.000 claims description 10
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 10
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 238000007918 intramuscular administration Methods 0.000 claims description 8
- 238000001990 intravenous administration Methods 0.000 claims description 8
- 238000007920 subcutaneous administration Methods 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical group O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 7
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 7
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 claims description 7
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical group C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 claims description 7
- DVJAMEIQRSHVKC-BDAKNGLRSA-N Dutogliptin Chemical compound OB(O)[C@@H]1CCCN1C(=O)CN[C@H]1CNCC1 DVJAMEIQRSHVKC-BDAKNGLRSA-N 0.000 claims description 7
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 claims description 7
- 108010011459 Exenatide Proteins 0.000 claims description 7
- ZWPRRQZNBDYKLH-VIFPVBQESA-N Gemigliptin Chemical compound C([C@@H](N)CC(=O)N1CC2=C(C(=NC(=N2)C(F)(F)F)C(F)(F)F)CC1)N1CC(F)(F)CCC1=O ZWPRRQZNBDYKLH-VIFPVBQESA-N 0.000 claims description 7
- 108010057186 Insulin Glargine Proteins 0.000 claims description 7
- FYZPCMFQCNBYCY-WIWKJPBBSA-N Insulin degludec Chemical compound CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC(O)=O)C(O)=O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC FYZPCMFQCNBYCY-WIWKJPBBSA-N 0.000 claims description 7
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 claims description 7
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 claims description 7
- 108010019598 Liraglutide Proteins 0.000 claims description 7
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical group C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims description 7
- QLXKHBNJTPICNF-QMCAAQAGSA-N Sergliflozin etabonate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)OCC)O[C@H]1OC1=CC=CC=C1CC1=CC=C(OC)C=C1 QLXKHBNJTPICNF-QMCAAQAGSA-N 0.000 claims description 7
- ZXOCGDDVNPDRIW-NHFZGCSJSA-N Tofogliflozin Chemical compound O.C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 ZXOCGDDVNPDRIW-NHFZGCSJSA-N 0.000 claims description 7
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 claims description 7
- 229960002632 acarbose Drugs 0.000 claims description 7
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 claims description 7
- 229960001667 alogliptin Drugs 0.000 claims description 7
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 claims description 7
- 229950009977 anagliptin Drugs 0.000 claims description 7
- LDXYBEHACFJIEL-HNNXBMFYSA-N anagliptin Chemical compound C=1N2N=C(C)C=C2N=CC=1C(=O)NCC(C)(C)NCC(=O)N1CCC[C@H]1C#N LDXYBEHACFJIEL-HNNXBMFYSA-N 0.000 claims description 7
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims description 7
- 229940093265 berberine Drugs 0.000 claims description 7
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims description 7
- 229960004111 buformin Drugs 0.000 claims description 7
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 claims description 7
- 229960001713 canagliflozin Drugs 0.000 claims description 7
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 claims description 7
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 claims description 7
- 229950009226 ciglitazone Drugs 0.000 claims description 7
- 229960003834 dapagliflozin Drugs 0.000 claims description 7
- QQKNSPHAFATFNQ-UHFFFAOYSA-N darglitazone Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCC(=O)C(C=C1)=CC=C1CC1SC(=O)NC1=O QQKNSPHAFATFNQ-UHFFFAOYSA-N 0.000 claims description 7
- 229950006689 darglitazone Drugs 0.000 claims description 7
- 229950003693 dutogliptin Drugs 0.000 claims description 7
- 229960003345 empagliflozin Drugs 0.000 claims description 7
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 claims description 7
- 229950002375 englitazone Drugs 0.000 claims description 7
- 229960001519 exenatide Drugs 0.000 claims description 7
- 229960002458 gemigliptin Drugs 0.000 claims description 7
- 229960004580 glibenclamide Drugs 0.000 claims description 7
- 229960000346 gliclazide Drugs 0.000 claims description 7
- 229960004346 glimepiride Drugs 0.000 claims description 7
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 claims description 7
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 claims description 7
- 229960001381 glipizide Drugs 0.000 claims description 7
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims description 7
- 108010050259 insulin degludec Proteins 0.000 claims description 7
- 229960002869 insulin glargine Drugs 0.000 claims description 7
- 229950000991 ipragliflozin Drugs 0.000 claims description 7
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 claims description 7
- 229960002397 linagliptin Drugs 0.000 claims description 7
- 229960002701 liraglutide Drugs 0.000 claims description 7
- MQYXUWHLBZFQQO-QGTGJCAVSA-N lupeol Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C MQYXUWHLBZFQQO-QGTGJCAVSA-N 0.000 claims description 7
- PKGKOZOYXQMJNG-UHFFFAOYSA-N lupeol Natural products CC(=C)C1CC2C(C)(CCC3C4(C)CCC5C(C)(C)C(O)CCC5(C)C4CCC23C)C1 PKGKOZOYXQMJNG-UHFFFAOYSA-N 0.000 claims description 7
- PKWDZWYVIHVNKS-UHFFFAOYSA-N netoglitazone Chemical compound FC1=CC=CC=C1COC1=CC=C(C=C(CC2C(NC(=O)S2)=O)C=C2)C2=C1 PKWDZWYVIHVNKS-UHFFFAOYSA-N 0.000 claims description 7
- 229950001628 netoglitazone Drugs 0.000 claims description 7
- 229960003243 phenformin Drugs 0.000 claims description 7
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 claims description 7
- 229960005095 pioglitazone Drugs 0.000 claims description 7
- 229950011516 remogliflozin etabonate Drugs 0.000 claims description 7
- UAOCLDQAQNNEAX-ABMICEGHSA-N remogliflozin etabonate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)OCC)O[C@H]1OC1=NN(C(C)C)C(C)=C1CC1=CC=C(OC(C)C)C=C1 UAOCLDQAQNNEAX-ABMICEGHSA-N 0.000 claims description 7
- 229960004586 rosiglitazone Drugs 0.000 claims description 7
- 229960004937 saxagliptin Drugs 0.000 claims description 7
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 claims description 7
- 108010033693 saxagliptin Proteins 0.000 claims description 7
- 229950000378 sergliflozin etabonate Drugs 0.000 claims description 7
- 229960004034 sitagliptin Drugs 0.000 claims description 7
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims description 7
- 229950000034 teneligliptin Drugs 0.000 claims description 7
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 claims description 7
- 229950006667 tofogliflozin Drugs 0.000 claims description 7
- 229960001641 troglitazone Drugs 0.000 claims description 7
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 claims description 7
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 claims description 7
- 229960001254 vildagliptin Drugs 0.000 claims description 7
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 claims description 7
- 229960001729 voglibose Drugs 0.000 claims description 7
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 229960003948 insulin detemir Drugs 0.000 claims description 6
- UGOZVNFCFYTPAZ-IOXYNQHNSA-N levemir Chemical compound CCCCCCCCCCCCCC(=O)NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=2C=CC=CC=2)C(C)C)CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)CSSC[C@H](NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC2=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CSSC1)C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 UGOZVNFCFYTPAZ-IOXYNQHNSA-N 0.000 claims description 6
- 229960001110 miglitol Drugs 0.000 claims description 6
- 239000006187 pill Substances 0.000 claims description 6
- 239000006188 syrup Substances 0.000 claims description 6
- 235000020357 syrup Nutrition 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940122069 Glycosidase inhibitor Drugs 0.000 claims 2
- 239000003316 glycosidase inhibitor Substances 0.000 claims 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 33
- 238000000034 method Methods 0.000 abstract description 19
- 208000035475 disorder Diseases 0.000 abstract description 15
- 208000004104 gestational diabetes Diseases 0.000 abstract description 8
- 229960001722 verapamil Drugs 0.000 description 60
- 210000004369 blood Anatomy 0.000 description 49
- 239000008280 blood Substances 0.000 description 49
- 241000699670 Mus sp. Species 0.000 description 35
- 230000000694 effects Effects 0.000 description 20
- 201000010099 disease Diseases 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 16
- DOQPXTMNIUCOSY-UHFFFAOYSA-N [4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-[2-(3,4-dimethoxyphenyl)ethyl]-methylazanium;chloride Chemical compound [H+].[Cl-].C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 DOQPXTMNIUCOSY-UHFFFAOYSA-N 0.000 description 14
- 239000003981 vehicle Substances 0.000 description 14
- SGTNSNPWRIOYBX-MHZLTWQESA-N (S)-verapamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCC[C@](C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-MHZLTWQESA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 9
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 7
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 108091005995 glycated hemoglobin Proteins 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 6
- 238000007917 intracranial administration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 150000001467 thiazolidinediones Chemical class 0.000 description 6
- 101150046735 LEPR gene Proteins 0.000 description 5
- 101150063827 LEPROT gene Proteins 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 206010022489 Insulin Resistance Diseases 0.000 description 4
- 241000282887 Suidae Species 0.000 description 4
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
- 150000004283 biguanides Chemical class 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 238000001361 intraarterial administration Methods 0.000 description 4
- 239000012669 liquid formulation Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229950010728 trelagliptin Drugs 0.000 description 4
- IWYJYHUNXVAVAA-OAHLLOKOSA-N trelagliptin Chemical compound C=1C(F)=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 IWYJYHUNXVAVAA-OAHLLOKOSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000020925 non fasting Nutrition 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000011870 unpaired t-test Methods 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 206010054805 Macroangiopathy Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- 239000011358 absorbing material Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 230000003143 atherosclerotic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 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 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 230000003345 hyperglycaemic effect Effects 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- CHHXEZSCHQVSRE-UHFFFAOYSA-N lobeglitazone Chemical compound C1=CC(OC)=CC=C1OC1=CC(N(C)CCOC=2C=CC(CC3C(NC(=O)S3)=O)=CC=2)=NC=N1 CHHXEZSCHQVSRE-UHFFFAOYSA-N 0.000 description 2
- 229950007685 lobeglitazone Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 210000004923 pancreatic tissue Anatomy 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000031872 Body Remains Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 102000034534 Cotransporters Human genes 0.000 description 1
- 108020003264 Cotransporters Proteins 0.000 description 1
- 206010068271 Cystic fibrosis related diabetes Diseases 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 238000009083 HbA1C assay kit Methods 0.000 description 1
- 208000018565 Hemochromatosis Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 101000986786 Homo sapiens Orexin/Hypocretin receptor type 1 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 108050000742 Orexin Receptor Proteins 0.000 description 1
- 102000008834 Orexin receptor Human genes 0.000 description 1
- 108050001089 Orexin receptor 2 Proteins 0.000 description 1
- 102100028141 Orexin/Hypocretin receptor type 1 Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033649 Pancreatitis chronic Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 208000001280 Prediabetic State Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000808 adrenergic beta-agonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000006399 behavior Effects 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
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 208000003611 congenital autoimmune diabetes mellitus Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- DOQPXTMNIUCOSY-HZPIKELBSA-N dexverapamil hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CCN(C)CCC[C@@](C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 DOQPXTMNIUCOSY-HZPIKELBSA-N 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000010030 glucose lowering effect Effects 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000003230 hygroscopic agent Substances 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000006362 insulin response pathway Effects 0.000 description 1
- 230000004155 insulin signaling pathway Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000011542 limb amputation Methods 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 206010062198 microangiopathy Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000006082 mold release agent Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004848 polyfunctional curative Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 102000004052 somatostatin receptor 2 Human genes 0.000 description 1
- 108090000586 somatostatin receptor 2 Proteins 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 208000023516 stroke disease Diseases 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 201000005665 thrombophilia Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 238000009736 wetting Methods 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
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- 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
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Obesity (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
Abstract
【選択図】図3
Description
便宜上、明細書、実施例、および添付の請求項に使用されている特定の用語をここに集めている。別様に定義されない限り、本明細書に用いられるすべての技術用語および科学用語は、本発明が属する技術分野の通常の当業者によって一般的に理解されるものと同じ意味を有する。
ベラパミル(例、2−(3,4−ジメトキシフェニル)−5−[2−(3,4−ジメトキシフェニル)エチル−メチルアミノ]−2−プロパン−2−イルペンタンニトリル)は、さまざまな医薬的効能を有する公知の薬物である。伝統的に、ベラパミルはたとえば高血圧症などの冠疾患を処置するために用いられる。この化合物は不斉中心を有するため、光学鏡像異性体に分離され得る。(S)−鏡像異性体は、カルシウムチャネル拮抗薬活性の大部分を有することが公知であるのに対し、(R)−鏡像異性体はソマトスタチン受容体2に対するアゴニスト活性と、オレキシン受容体1および2、ドーパミンD2L受容体、ナトリウムおよびカルシウムチャネルに対する拮抗薬活性とを有することが公知である(国際公開第2011/057471A1号を参照)。したがって、(R)−鏡像異性体はヒト対象におけるこれらの受容体に関係する疾患または状態を処置するための薬物として有用である。
材料
(R)−(+)−ベラパミルHCl、(S)−(−)−ベラパミルHCl、およびラセミ混合物は、それぞれセンター・ラボラトリーズ社(Center Laboratories Inc)(台北(Taipei)、台湾(Taiwan)、R.O.C.)が提供したものである。グルコメーターは、アボット(Abbott)(USA)より購入した。グルコースアッセイキットは、デンカ生研株式会社(Denka Seiken Co.Ltd)(東京(Tokyo)、日本(Japan))より購入した。インスリンおよびメトホルミンは、どちらもシグマアルドリッチ(Sigma−Aldrich)(USA)からのものであり、HbA1cアッセイキットは富士レビオ(Fujirebio)(日本)からのものであった。
野生型(Wide−type)オスC57BL/6マウス(各体重約20〜25g)、インスリン非依存型真性糖尿病(NIDDM)オスdb/dbマウス(C57BLKS/J lar− +Leprdb/+Leprdb、各体重約45±10g)およびdb/m+(C57BLKS/J Lar−m+/+Leprdb)マウスを本研究に用いた。
野生型(Wide−type)オスC57BL/6マウスに、ストレプトゾトシン(STZ:streptozotocin、40mg/Kg/日を5日間、1日目から5日目)を複数回腹腔内注射することによって、糖尿病にした。6日目に160mg/dLより高い平均血糖値を示したマウスを、以後の研究のために選択した。媒体または指定用量のテスト化合物(すなわちベラパミルHClのラセミ形(VPM:verapamil、bid)、(R)−(+)−ベラパミルHCl(R−VPM、bid)、または(S)−(−)−ベラパミルHCl(S−VPM、bid))を、各マウスに6日目から1日2回経口的に与え、49日目まで44日間続けた。インスリン処置する動物に対しては、血糖測定の90分前にインスリンを皮下投与した。6、15、および25日目に非絶食時血糖値を測定し、40日目および50日目に空腹時血糖(すなわち12hr絶食後の絶食後血糖値)を測定した。
NIDDMマウスおよびdb/m+マウス(シャム対照)を少なくとも1週間順化し、次いで6hr絶食後の平均血糖値が≧350mg/dlであるときに処置のためにグループ化した。指定用量のテスト化合物(すなわちベラパミルHClのラセミ形(VPM、bid)、(R)−(+)−ベラパミルHCl(R−VPM、bid)、(S)−(−)−ベラパミルHCl(S−VPM、bid)、メトホルミン(1日1回)、またはR−VPM(bid)とメトホルミン(Met:metformin、1日1回)との組み合わせ)を各マウスに1日目から経口投与し、45日目までの44連続日(実施例1.2)または43日目までの42連続日(実施例2)だけ続けた。指定日に、6hr絶食後の血糖および糖化ヘモグロビン(HbA1c)レベルを測定した。研究期間中に各テスト動物の体重も測定した。
平均±平均の標準誤差(SEM:standard error of the mean)として結果を表した。物質処置および媒体処置グループの統計的比較のために、独立スチューデントt検定または1元ANOVAに続くダネット検定を用いた。+P<0.05、対媒体対照(db/m+)、*P<0.05、対媒体対照(db/dbまたはSTZ誘導マウス)、#P<0.05、対メトホルミン(db/db)における差を有意とみなす。スチューデントの対応のないt検定による「Met」および「媒体対照(db/db)」の比較:有意性を実線で示し、傾向を破線で示す。
この実施例においては、「材料および方法」セクションに記載した手順に従って、STZ誘導糖尿病動物におけるラセミベラパミルHCl(VPM)、(R)−(+)−ベラパミルHCl(R−VPM)、または(S)−(−)−ベラパミルHCl(S−VPM)の効果を評価した。結果を図1に示す。
この実施例においては、インスリン抵抗性およびその後の糖尿病表現型の進行を引き起こすインスリンシグナル伝達カスケードの軽度の欠陥を有して生まれたNIDDMマウスを用いることによって、血糖値に対するラセミベラパミルHCl(VPM)、(R)−(+)−ベラパミルHCl(R−VPM)、または(S)−(−)−ベラパミルHCl(S−VPM)の効果を評価した。比較のために、シャム対照として5匹のdb/m+(C57BLKS/J Lar− m+/+Leprdb)マウスのグループを用いた。6hr絶食動物の血糖値を0日目(処置前)、ならびに15、30、および45日目に測定した。結果を図2に示す。
図3を参照すると、予想どおり、メトホルミンはNIDDMマウスの血糖値を15、29、および43日目に低下でき、高用量(すなわち30mg/Kg、bidまたは50mg/Kg、bid)の(R)−(+)−ベラパミルHCl(R−VPM)も同様であった。より驚くべきことに、R−VPMおよびメトホルミンの併用処置は、単独では血糖値低下に効果のない用量である低用量R−VPM(すなわち15mg/Kg、bid)を投与した場合にも血糖値低下に対する相乗効果を示した。
本研究においては、別の一般的指標である、ある持続時間にわたる平均血糖値を反映する糖化ヘモグロビン(HbA1c)も測定した。HbA1cは、身体全体に酸素を運ぶ赤血球内のタンパク質であるヘモグロビンが血中のグルコースと結合して「糖化」されるときに発生する。ヒト体内の赤血球は再生まで約8〜12週間残存するため、HbA1cのレベルはこうした期間の平均血糖値の全体像を与える。
Claims (52)
- 真性糖尿病および/または真性糖尿病に関係する障害の処置のための薬物を製造するための、(R)−(+)−ベラパミルまたはその薬学的に許容できる塩の使用。
- 前記(R)−(+)−ベラパミルまたはその薬学的に許容できる塩は、結晶形態である、請求項1に記載の使用。
- 前記(R)−(+)−ベラパミルは塩酸塩として存在する、請求項2に記載の使用。
- 前記薬物は血糖低下剤をさらに含む、請求項1に記載の使用。
- 前記血糖低下剤はグルカゴン様ペプチド1(GLP−1)受容体アゴニスト、ジペプチジルペプチダーゼ4(DPP−4)阻害剤、インスリン、インスリン類似体、ビグアナイド、スルホニルウレア、チアゾリジンジオン(TZD)、ナトリウム・グルコース共輸送体2(SGLT2)阻害剤、またはα−グリコシダーゼ阻害剤である、請求項4に記載の使用。
- 前記GLP−1受容体アゴニストはリラグルチド、エクセナチド、アルビグルチド、またはLY2189265である、請求項5に記載の使用。
- 前記DPP−4阻害剤はグリプチンである、請求項5に記載の使用。
- 前記グリプチンは、シタグリプチン、ビルダグリプチン、サキサグリプチン、リナグリプチン、ゲミグリプチン、アナグリプチン、テネリグリプチン、アログリプチン、トレラグリプチン、デュトグリプチン、オマリグリプチン、ベルベリン、およびルペオールからなる群より選択される、請求項7に記載の使用。
- 前記インスリン類似体はグラルギン、デグルデク、またはデテミルである、請求項5に記載の使用。
- 前記ビグアナイドはメトホルミン、フェンホルミン、またはブホルミンである、請求項5に記載の使用。
- 前記スルホニルウレアはグリベンクラミド、グリクラジド、グリメピリド、またはグリピジドである、請求項5に記載の使用。
- 前記TZDはピオグリタゾン、ロシグリタゾン、ロベグリタゾン、シグリタゾン、ダルグリタゾン、エングリタゾン、ネトグリタゾン、リボグリタゾン、またはトログリタゾンである、請求項5に記載の使用。
- 前記SGLT2阻害剤はダパグリフロジン、エンパグリフロジン、カナグリフロジン、イプラグリフロジン、トホグリフロジン、セルグリフロジンエタボネート、レモグリフロジンエタボネート、またはエルツグリフロジンである、請求項5に記載の使用。
- 前記α−グリコシダーゼ阻害剤はアカルボース、ミグリトール、またはボグリボースである、請求項5に記載の使用。
- 前記薬物は経口、静脈内、筋肉内、皮下、経粘膜、または直腸内投与に対して好適である、請求項1に記載の使用。
- 経口投与のための前記薬物は、錠剤、丸剤、顆粒、粉末、溶液、懸濁物、シロップ、またはカプセルとして提供される、請求項15に記載の使用。
- 前記薬物は15〜1,000mg/日の量で投与される、請求項15に記載の使用。
- 前記薬物は25〜800mg/日の量で投与される、請求項17に記載の使用。
- 真性糖尿病および/または真性糖尿病に関係する障害を処置するための医薬組成物であって、有効量の(R)−(+)−ベラパミルまたはその薬学的に許容できる塩と、薬学的に許容できる担体とを含む、医薬組成物。
- 前記(R)−(+)−ベラパミルまたはその薬学的に許容できる塩は、結晶形態である、請求項19に記載の医薬組成物。
- 前記(R)−(+)−ベラパミルは塩酸塩として存在する、請求項20に記載の医薬組成物。
- 血糖低下剤をさらに含む、請求項19に記載の医薬組成物。
- 前記血糖低下剤はグルカゴン様ペプチド1(GLP−1)受容体アゴニスト、ジペプチジルペプチダーゼ4(DPP−4)阻害剤、インスリン、インスリン類似体、ビグアナイド、スルホニルウレア、チアゾリジンジオン(TZD)、ナトリウム・グルコース共輸送体2(SGLT2)阻害剤、またはα−グリコシダーゼ阻害剤である、請求項22に記載の医薬組成物。
- 前記GLP−1受容体アゴニストはリラグルチド、エクセナチド、アルビグルチド、またはLY2189265である、請求項23に記載の医薬組成物。
- 前記DPP−4阻害剤はグリプチンである、請求項23に記載の医薬組成物。
- 前記グリプチンは、シタグリプチン、ビルダグリプチン、サキサグリプチン、リナグリプチン、ゲミグリプチン、アナグリプチン、テネリグリプチン、アログリプチン、トレラグリプチン、デュトグリプチン、オマリグリプチン、ベルベリン、およびルペオールからなる群より選択される、請求項25に記載の医薬組成物。
- 前記インスリン類似体はグラルギン、デグルデク、またはデテミルである、請求項23に記載の医薬組成物。
- 前記ビグアナイドはメトホルミン、フェンホルミン、またはブホルミンである、請求項23に記載の医薬組成物。
- 前記スルホニルウレアはグリベンクラミド、グリクラジド、グリメピリド、またはグリピジドである、請求項23に記載の医薬組成物。
- 前記TZDはピオグリタゾン、ロシグリタゾン、ロベグリタゾン、シグリタゾン、ダルグリタゾン、エングリタゾン、ネトグリタゾン、リボグリタゾン、またはトログリタゾンである、請求項23に記載の医薬組成物。
- 前記SGLT2阻害剤はダパグリフロジン、エンパグリフロジン、カナグリフロジン、イプラグリフロジン、トホグリフロジン、セルグリフロジンエタボネート、レモグリフロジンエタボネート、またはエルツグリフロジンである、請求項23に記載の医薬組成物。
- 前記α−グリコシダーゼ阻害剤はアカルボース、ミグリトール、またはボグリボースである、請求項23に記載の医薬組成物。
- 前記医薬組成物は経口、静脈内、筋肉内、皮下、経粘膜、または直腸内投与に対して好適である、請求項19に記載の医薬組成物。
- 経口投与に対して好適な前記医薬組成物は、錠剤、丸剤、顆粒、粉末、溶液、懸濁物、シロップ、またはカプセルとして提供される、請求項33に記載の医薬組成物。
- 前記(R)−(+)−ベラパミルまたはその薬学的に許容できる塩は、前記医薬組成物中に15〜1,000mgの量で存在する、請求項19に記載の医薬組成物。
- 前記(R)−(+)−ベラパミルまたはその薬学的に許容できる塩は、前記医薬組成物中に25〜800mgの量で存在する、請求項35に記載の医薬組成物。
- 真性糖尿病および/または真性糖尿病に関係する障害の処置における使用のための、(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記(R)−(+)−ベラパミルまたはその薬学的に許容できる塩は、結晶形態である、請求項37に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記(R)−(+)−ベラパミルは塩酸塩として存在する、請求項37に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記処置は、15〜1,000mg/日の量の(R)−(+)−ベラパミルまたはその薬学的に許容できる塩を処置を必要とする対象に投与するステップを含む、請求項37に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記処置は、25〜800mg/日の量の(R)−(+)−ベラパミルまたはその薬学的に許容できる塩を処置を必要とする前記対象に投与するステップを含む、請求項40に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記処置はさらに、血糖低下剤を処置を必要とする前記対象に投与するステップを含む、請求項40に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記血糖低下剤はグルカゴン様ペプチド1(GLP−1)受容体アゴニスト、ジペプチジルペプチダーゼ4(DPP−4)阻害剤、インスリン、インスリン類似体、ビグアナイド、スルホニルウレア、チアゾリジンジオン(TZD)、ナトリウム・グルコース共輸送体2(SGLT2)阻害剤、またはα−グリコシダーゼ阻害剤である、請求項42に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記GLP−1受容体アゴニストはリラグルチド、エクセナチド、アルビグルチド、またはLY2189265である、請求項43に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記DPP−4阻害剤はグリプチンである、請求項43に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記グリプチンは、シタグリプチン、ビルダグリプチン、サキサグリプチン、リナグリプチン、ゲミグリプチン、アナグリプチン、テネリグリプチン、アログリプチン、トレラグリプチン、デュトグリプチン、オマリグリプチン、ベルベリン、およびルペオールからなる群より選択される、請求項45に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記インスリン類似体はグラルギン、デグルデク、またはデテミルである、請求項43に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記ビグアナイドはメトホルミン、フェンホルミン、またはブホルミンである、請求項43に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記スルホニルウレアはグリベンクラミド、グリクラジド、グリメピリド、またはグリピジドである、請求項25に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記TZDはピオグリタゾン、ロシグリタゾン、ロベグリタゾン、シグリタゾン、ダルグリタゾン、エングリタゾン、ネトグリタゾン、リボグリタゾン、またはトログリタゾンである、請求項43に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記SGLT2阻害剤はダパグリフロジン、エンパグリフロジン、カナグリフロジン、イプラグリフロジン、トホグリフロジン、セルグリフロジンエタボネート、レモグリフロジンエタボネート、またはエルツグリフロジンである、請求項43に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
- 前記α−グリコシダーゼ阻害剤はアカルボース、ミグリトール、またはボグリボースである、請求項43に記載の使用のための(R)−(+)−ベラパミルまたはその薬学的に許容できる塩。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662339131P | 2016-05-20 | 2016-05-20 | |
US62/339,131 | 2016-05-20 | ||
PCT/CN2017/084746 WO2017198177A1 (en) | 2016-05-20 | 2017-05-17 | Method of treating hyperglycemia |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020032083A Division JP2020100651A (ja) | 2016-05-20 | 2020-02-27 | 高血糖症を処置する方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019503983A true JP2019503983A (ja) | 2019-02-14 |
JP6692903B2 JP6692903B2 (ja) | 2020-05-13 |
Family
ID=60326464
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018521403A Active JP6692903B2 (ja) | 2016-05-20 | 2017-05-17 | 高血糖症を処置する方法 |
JP2020032083A Pending JP2020100651A (ja) | 2016-05-20 | 2020-02-27 | 高血糖症を処置する方法 |
JP2022002081A Active JP7266327B2 (ja) | 2016-05-20 | 2022-01-11 | 高血糖症を処置する方法 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020032083A Pending JP2020100651A (ja) | 2016-05-20 | 2020-02-27 | 高血糖症を処置する方法 |
JP2022002081A Active JP7266327B2 (ja) | 2016-05-20 | 2022-01-11 | 高血糖症を処置する方法 |
Country Status (15)
Country | Link |
---|---|
US (2) | US9980935B2 (ja) |
EP (1) | EP3413886A4 (ja) |
JP (3) | JP6692903B2 (ja) |
KR (3) | KR102200664B1 (ja) |
CN (2) | CN108430467B (ja) |
AU (1) | AU2017267006B2 (ja) |
BR (1) | BR112018073688A2 (ja) |
CA (2) | CA3003319C (ja) |
HK (1) | HK1254471A1 (ja) |
IL (1) | IL262994B2 (ja) |
MX (1) | MX2018013943A (ja) |
RU (2) | RU2020140694A (ja) |
SG (1) | SG11201809899RA (ja) |
TW (1) | TWI659738B (ja) |
WO (1) | WO2017198177A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022231357A1 (en) * | 2021-04-29 | 2022-11-03 | Ildong Pharmaceutical Co., Ltd. | Pharmaceutical composition comprising gpr40 agonist and sglt-2 inhibitor |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108430467B (zh) * | 2016-05-20 | 2021-06-22 | 晟德大药厂股份有限公司 | (r)-(+)-维拉帕米用于治疗高血糖的用途及其药学组合物 |
US10639292B2 (en) | 2018-04-20 | 2020-05-05 | Center Laboratories, Inc. | Method of treating hyperglycemia |
EP3981401A1 (en) * | 2020-10-06 | 2022-04-13 | InSphero AG | Pharmaceutical combination for the treatment and/or prevention of diabetes comprising a calcium channel blocking agent and an incretin mimetic |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012528170A (ja) * | 2009-05-27 | 2012-11-12 | ブリストル−マイヤーズ スクイブ カンパニー | 別の抗糖尿病薬を用いた先の治療に抵抗性を有する2型糖尿病患者をsglt2阻害剤およびその組成物を用いて治療する方法 |
JP2013032359A (ja) * | 2005-06-03 | 2013-02-14 | Mitsubishi Tanabe Pharma Corp | 医薬の併用およびその用途 |
JP2013510872A (ja) * | 2009-11-13 | 2013-03-28 | ブリストル−マイヤーズ スクイブ カンパニー | 低質量のメトホルミン製剤 |
US20130210911A1 (en) * | 2009-11-10 | 2013-08-15 | Center Laboratories, Inc. | Method and composition for treating a disease or condition related to orexin receptor 1, orexin receptor 2, somatostatin receptor 2 or dopamine d2l receptor |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9616549D0 (en) * | 1996-08-06 | 1996-09-25 | Chiroscience Ltd | Therapeutic product and its use |
US20030092765A1 (en) * | 2001-11-15 | 2003-05-15 | John Kelly | Treatment of abnormal increases in gastrointestinal motility with (R)-verapamil |
RU2338521C1 (ru) * | 2007-02-28 | 2008-11-20 | Илья Николаевич Медведев | Способ быстрого снижения активности тромбопластиногенерации у лиц с метаболическим синдромом |
EP2405934B1 (en) * | 2009-03-12 | 2014-03-26 | Nordic Bioscience A/S | Treatment of diabetes and metabolic syndrome |
CN101869708A (zh) * | 2009-04-24 | 2010-10-27 | 北京奥萨医药研究中心有限公司 | 含有钙通道阻滞剂和双胍类降糖药物的药物组合物及其用途 |
EP2573088A1 (en) * | 2011-09-26 | 2013-03-27 | Prous Institute for Biomedical Research, S.A. | Pyrano[3,2-c]benzopyran-6(2h)-one derivatives and uses thereof |
WO2015142865A2 (en) * | 2014-03-17 | 2015-09-24 | Massachusetts Institute Of Technology | Metakaryocidal treatments |
US9950995B2 (en) * | 2014-10-29 | 2018-04-24 | Center Laboratories, Inc. | Crystal forms of verapamil hydrochloride |
CN108430467B (zh) * | 2016-05-20 | 2021-06-22 | 晟德大药厂股份有限公司 | (r)-(+)-维拉帕米用于治疗高血糖的用途及其药学组合物 |
-
2017
- 2017-05-17 CN CN201780003723.9A patent/CN108430467B/zh active Active
- 2017-05-17 KR KR1020187012063A patent/KR102200664B1/ko active IP Right Grant
- 2017-05-17 MX MX2018013943A patent/MX2018013943A/es unknown
- 2017-05-17 AU AU2017267006A patent/AU2017267006B2/en active Active
- 2017-05-17 CA CA3003319A patent/CA3003319C/en active Active
- 2017-05-17 CA CA3114057A patent/CA3114057A1/en not_active Abandoned
- 2017-05-17 CN CN202110545191.XA patent/CN113384571A/zh active Pending
- 2017-05-17 RU RU2020140694A patent/RU2020140694A/ru not_active Application Discontinuation
- 2017-05-17 SG SG11201809899RA patent/SG11201809899RA/en unknown
- 2017-05-17 EP EP17798740.1A patent/EP3413886A4/en not_active Withdrawn
- 2017-05-17 KR KR1020207037511A patent/KR20210000757A/ko not_active Application Discontinuation
- 2017-05-17 JP JP2018521403A patent/JP6692903B2/ja active Active
- 2017-05-17 WO PCT/CN2017/084746 patent/WO2017198177A1/en active Application Filing
- 2017-05-17 US US15/597,200 patent/US9980935B2/en active Active
- 2017-05-17 KR KR1020217031124A patent/KR102423967B1/ko active IP Right Grant
- 2017-05-17 BR BR112018073688-0A patent/BR112018073688A2/pt not_active IP Right Cessation
- 2017-05-17 TW TW106116239A patent/TWI659738B/zh active
- 2017-05-17 RU RU2018139578A patent/RU2739255C2/ru active
-
2018
- 2018-04-20 US US15/957,956 patent/US10278943B2/en active Active
- 2018-10-23 HK HK18113557.8A patent/HK1254471A1/zh unknown
- 2018-11-13 IL IL262994A patent/IL262994B2/en unknown
-
2020
- 2020-02-27 JP JP2020032083A patent/JP2020100651A/ja active Pending
-
2022
- 2022-01-11 JP JP2022002081A patent/JP7266327B2/ja active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013032359A (ja) * | 2005-06-03 | 2013-02-14 | Mitsubishi Tanabe Pharma Corp | 医薬の併用およびその用途 |
JP2012528170A (ja) * | 2009-05-27 | 2012-11-12 | ブリストル−マイヤーズ スクイブ カンパニー | 別の抗糖尿病薬を用いた先の治療に抵抗性を有する2型糖尿病患者をsglt2阻害剤およびその組成物を用いて治療する方法 |
US20130210911A1 (en) * | 2009-11-10 | 2013-08-15 | Center Laboratories, Inc. | Method and composition for treating a disease or condition related to orexin receptor 1, orexin receptor 2, somatostatin receptor 2 or dopamine d2l receptor |
JP2013510872A (ja) * | 2009-11-13 | 2013-03-28 | ブリストル−マイヤーズ スクイブ カンパニー | 低質量のメトホルミン製剤 |
Non-Patent Citations (2)
Title |
---|
DIABETES RESEARCH AND CLINICAL PRACTICE, vol. 115, JPN6019037378, 15 January 2016 (2016-01-15), pages 115 - 121, ISSN: 0004123601 * |
THE AMERICAN JOURNAL OF CARDIOLOGY, vol. 57, JPN6019014540, 1986, pages 39 - 43, ISSN: 0004123600 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022231357A1 (en) * | 2021-04-29 | 2022-11-03 | Ildong Pharmaceutical Co., Ltd. | Pharmaceutical composition comprising gpr40 agonist and sglt-2 inhibitor |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7266327B2 (ja) | 高血糖症を処置する方法 | |
AU2010237748B2 (en) | Pharmaceutical compositions | |
KR20120094908A (ko) | Bi―1356 및 메트포르민을 포함하는 약제학적 조성물 | |
US10813918B2 (en) | Use of Gaboxadol in the treatment of diabetes and related conditions | |
US11020447B2 (en) | Compositions, kits and methods for treating type II diabetes mellitus | |
MX2012011517A (es) | El uso de diacereina como una terapia adyuvante para diabetes. | |
WO2019120162A1 (en) | Compositions, kits and methods for treating type ii diabetes mellitus | |
US10639292B2 (en) | Method of treating hyperglycemia | |
US20190183959A1 (en) | Compositions, kits and methods for treating type ii diabetes mellitus | |
US20190321327A1 (en) | Method of treating hyperglycemia | |
AU2014221222A1 (en) | Pharmaceutical compositions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180625 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180625 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190507 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190807 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20190808 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191001 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20191211 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200227 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20200228 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200331 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200415 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6692903 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |