JP2007291139A - 脂質及びグルコースの代謝疾患治療剤及び組成物 - Google Patents
脂質及びグルコースの代謝疾患治療剤及び組成物 Download PDFInfo
- Publication number
- JP2007291139A JP2007291139A JP2007211789A JP2007211789A JP2007291139A JP 2007291139 A JP2007291139 A JP 2007291139A JP 2007211789 A JP2007211789 A JP 2007211789A JP 2007211789 A JP2007211789 A JP 2007211789A JP 2007291139 A JP2007291139 A JP 2007291139A
- Authority
- JP
- Japan
- Prior art keywords
- agonist
- dopamine
- plasma
- glucose
- ergot alkaloid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000002632 lipids Chemical class 0.000 title claims abstract description 16
- 238000011282 treatment Methods 0.000 title abstract description 25
- 239000003795 chemical substances by application Substances 0.000 title abstract description 11
- 239000000203 mixture Substances 0.000 title abstract description 7
- 208000018914 glucose metabolism disease Diseases 0.000 title abstract description 5
- 208000017170 Lipid metabolism disease Diseases 0.000 title description 4
- 239000003814 drug Substances 0.000 claims abstract description 35
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 17
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 16
- 208000008589 Obesity Diseases 0.000 claims abstract description 15
- 235000020824 obesity Nutrition 0.000 claims abstract description 15
- 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 13
- 201000008980 hyperinsulinism Diseases 0.000 claims abstract description 13
- 239000003136 dopamine receptor stimulating agent Substances 0.000 claims abstract description 12
- 229960003133 ergot alkaloid Drugs 0.000 claims abstract description 12
- 201000001421 hyperglycemia Diseases 0.000 claims abstract description 9
- 208000002705 Glucose Intolerance Diseases 0.000 claims abstract description 7
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims abstract description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 5
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 5
- 208000034189 Sclerosis Diseases 0.000 claims abstract 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 claims description 44
- 229940079593 drug Drugs 0.000 claims description 31
- 102000004877 Insulin Human genes 0.000 claims description 22
- 108090001061 Insulin Proteins 0.000 claims description 22
- 229940125396 insulin Drugs 0.000 claims description 22
- 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 18
- 229960002802 bromocriptine Drugs 0.000 claims description 18
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 claims description 18
- 239000008103 glucose Substances 0.000 claims description 18
- 210000004369 blood Anatomy 0.000 claims description 14
- 239000008280 blood Substances 0.000 claims description 14
- 239000002288 dopamine 2 receptor stimulating agent Substances 0.000 claims description 14
- 201000001320 Atherosclerosis Diseases 0.000 claims description 12
- 230000037396 body weight Effects 0.000 claims description 11
- 230000004153 glucose metabolism Effects 0.000 claims description 9
- 210000000577 adipose tissue Anatomy 0.000 claims description 8
- 230000037356 lipid metabolism Effects 0.000 claims description 8
- JUDKOGFHZYMDMF-UHFFFAOYSA-N 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol Chemical group C1=2C=C(O)C(O)=CC=2CCNCC1C1=CC=CC=C1 JUDKOGFHZYMDMF-UHFFFAOYSA-N 0.000 claims description 7
- 102000004895 Lipoproteins Human genes 0.000 claims description 5
- 108090001030 Lipoproteins Proteins 0.000 claims description 5
- 235000021588 free fatty acids Nutrition 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 3
- SUHGRZPINGKYNV-GJZGRUSLSA-N (1R,3S)-1-(aminomethyl)-3-phenyl-3,4-dihydro-1H-2-benzopyran-5,6-diol Chemical compound C1([C@H]2O[C@H](C3=CC=C(O)C(O)=C3C2)CN)=CC=CC=C1 SUHGRZPINGKYNV-GJZGRUSLSA-N 0.000 claims description 2
- BWHPNJVKFAPVOG-QYFJGNGUSA-N (1R,3S)-3-(adamantan-1-yl)-1-(aminomethyl)-3,4-dihydroisochromene-5,6-diol hydrochloride Chemical compound Cl.C1C(C2)CC(C3)CC2CC13[C@H]1O[C@@H](CN)C2=CC=C(O)C(O)=C2C1 BWHPNJVKFAPVOG-QYFJGNGUSA-N 0.000 claims description 2
- BGOQGUHWXBGXJW-YOEHRIQHSA-N (6as,12br)-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound N1CC2=CC=CC=C2[C@@H]2[C@@H]1CCC1=C2C=C(O)C(O)=C1 BGOQGUHWXBGXJW-YOEHRIQHSA-N 0.000 claims description 2
- KWTPHNVUAVFKGB-UHFFFAOYSA-N 3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepine-7,8-diol;hydrobromide Chemical compound Br.C1N(C)CCC2=CC(O)=C(O)C=C2C1C1=CC=CC=C1 KWTPHNVUAVFKGB-UHFFFAOYSA-N 0.000 claims description 2
- OZWXDWVFTIFZHS-UHFFFAOYSA-N 9-chloro-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepine-7,8-diol Chemical compound C1N(C)CCC2=C(Cl)C(O)=C(O)C=C2C1C1=CC=CC=C1 OZWXDWVFTIFZHS-UHFFFAOYSA-N 0.000 claims description 2
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229960002724 fenoldopam Drugs 0.000 claims description 2
- TVURRHSHRRELCG-UHFFFAOYSA-N fenoldopam Chemical compound C1=CC(O)=CC=C1C1C2=CC(O)=C(O)C(Cl)=C2CCNC1 TVURRHSHRRELCG-UHFFFAOYSA-N 0.000 claims description 2
- 229960003587 lisuride Drugs 0.000 claims description 2
- 229960004851 pergolide Drugs 0.000 claims description 2
- YEHCICAEULNIGD-MZMPZRCHSA-N pergolide Chemical compound C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 YEHCICAEULNIGD-MZMPZRCHSA-N 0.000 claims description 2
- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 claims 1
- 208000034656 Contusions Diseases 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 230000009519 contusion Effects 0.000 claims 1
- 239000000556 agonist Substances 0.000 abstract description 47
- KYTDBKDWDOVRLJ-FQBRJNOBSA-N 1,2-dihydro-2,11-epoxycephalotaxine Chemical compound O1C(OC)([C@H]([C@H]2C3=C4)O)C[C@]52CCCN5CC1C3=CC1=C4OCO1 KYTDBKDWDOVRLJ-FQBRJNOBSA-N 0.000 abstract 1
- 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 22
- 230000000694 effects Effects 0.000 description 21
- 102000003946 Prolactin Human genes 0.000 description 18
- 108010057464 Prolactin Proteins 0.000 description 18
- 229940097325 prolactin Drugs 0.000 description 18
- 241000282412 Homo Species 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 239000003925 fat Substances 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 230000000862 serotonergic effect Effects 0.000 description 12
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 11
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 9
- 108010010234 HDL Lipoproteins Proteins 0.000 description 8
- 102000015779 HDL Lipoproteins Human genes 0.000 description 8
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 8
- 229940000425 combination drug Drugs 0.000 description 7
- 230000003247 decreasing effect Effects 0.000 description 7
- 150000003626 triacylglycerols Chemical class 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 6
- 235000012631 food intake Nutrition 0.000 description 6
- 230000033764 rhythmic process Effects 0.000 description 6
- 108010007622 LDL Lipoproteins Proteins 0.000 description 5
- 102000007330 LDL Lipoproteins Human genes 0.000 description 5
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 5
- 229960003638 dopamine Drugs 0.000 description 5
- 230000003291 dopaminomimetic effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000002354 daily effect Effects 0.000 description 4
- 239000000510 dopamine 1 receptor stimulating agent Substances 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 241000894007 species Species 0.000 description 4
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 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 3
- 230000002060 circadian Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 108060003345 Adrenergic Receptor Proteins 0.000 description 2
- 102000017910 Adrenergic receptor Human genes 0.000 description 2
- 102000015554 Dopamine receptor Human genes 0.000 description 2
- 108050004812 Dopamine receptor Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- HLXRWTJXGMHOFN-XJSNKYLASA-N Verbenalin Chemical compound O([C@@H]1OC=C([C@H]2C(=O)C[C@H](C)[C@H]21)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HLXRWTJXGMHOFN-XJSNKYLASA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000533 adrenergic alpha-1 receptor agonist Substances 0.000 description 2
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 2
- 229960001214 clofibrate Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- UJYGDMFEEDNVBF-UHFFFAOYSA-N ergocornin Chemical compound C1=CC(C=2C(N(C)CC(C=2)C(=O)NC2(C(=O)N3C(C(N4CCCC4C3(O)O2)=O)C(C)C)C(C)C)C2)=C3C2=CNC3=C1 UJYGDMFEEDNVBF-UHFFFAOYSA-N 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- HJHVRVJTYPKTHX-HTMVYDOJSA-N (4ar,8ar)-5-propyl-1,4,4a,6,7,8,8a,9-octahydropyrazolo[3,4-g]quinoline;hydrochloride Chemical compound Cl.C([C@H]1CCCN([C@@H]1C1)CCC)C2=C1C=NN2 HJHVRVJTYPKTHX-HTMVYDOJSA-N 0.000 description 1
- HLRBSTGXOFUEHW-UHFFFAOYSA-N 2-oh-npa Chemical compound C1CN(CCC)C2CC3=CC=C(O)C(O)=C3C3=C2C1=CC(O)=C3 HLRBSTGXOFUEHW-UHFFFAOYSA-N 0.000 description 1
- PTAYFGHRDOMJGC-UHFFFAOYSA-N 4-aminobutyl(diaminomethylidene)azanium;hydrogen sulfate Chemical compound OS(O)(=O)=O.NCCCCN=C(N)N PTAYFGHRDOMJGC-UHFFFAOYSA-N 0.000 description 1
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- 229940000681 5-hydroxytryptophan Drugs 0.000 description 1
- HIHZDNKKIUQQSC-UHFFFAOYSA-N 6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino]-1,3,5-trimethylpyrimidine-2,4-dione Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2C)C)CC1 HIHZDNKKIUQQSC-UHFFFAOYSA-N 0.000 description 1
- QNBCPLWFVGLFHO-UHFFFAOYSA-N 6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-2,10,11-triol Chemical compound C1CN(C)C2CC3=CC=C(O)C(O)=C3C3=C2C1=CC(O)=C3 QNBCPLWFVGLFHO-UHFFFAOYSA-N 0.000 description 1
- DHSSDEDRBUKTQY-UHFFFAOYSA-N 6-prop-2-enyl-4,5,7,8-tetrahydrothiazolo[4,5-d]azepin-2-amine Chemical compound C1CN(CC=C)CCC2=C1N=C(N)S2 DHSSDEDRBUKTQY-UHFFFAOYSA-N 0.000 description 1
- QUIKMLCZZMOBLH-UHFFFAOYSA-N 8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;hydrochloride Chemical compound Cl.C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 QUIKMLCZZMOBLH-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 208000032841 Bulimia Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 230000010654 Dopamine Receptor Interactions Effects 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- WDZVGELJXXEGPV-YIXHJXPBSA-N Guanabenz Chemical compound NC(N)=N\N=C\C1=C(Cl)C=CC=C1Cl WDZVGELJXXEGPV-YIXHJXPBSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020710 Hyperphagia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 description 1
- HLXRWTJXGMHOFN-UHFFFAOYSA-N Verbenalin Natural products C12C(C)CC(=O)C2C(C(=O)OC)=COC1OC1OC(CO)C(O)C(O)C1O HLXRWTJXGMHOFN-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- IEJXVRYNEISIKR-UHFFFAOYSA-N apraclonidine Chemical compound ClC1=CC(N)=CC(Cl)=C1NC1=NCCN1 IEJXVRYNEISIKR-UHFFFAOYSA-N 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- NOJMTMIRQRDZMT-GSPXQYRGSA-N bromocriptine methanesulfonate Chemical compound CS(O)(=O)=O.C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 NOJMTMIRQRDZMT-GSPXQYRGSA-N 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 229960001389 doxazosin Drugs 0.000 description 1
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 235000005686 eating Nutrition 0.000 description 1
- 230000000678 effect on lipid Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- RHGUXDUPXYFCTE-ZWNOBZJWSA-N ergoline Chemical class C1=CC([C@@H]2[C@H](NCCC2)C2)=C3C2=CNC3=C1 RHGUXDUPXYFCTE-ZWNOBZJWSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000004634 feeding behavior Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 229960003050 guanabenz acetate Drugs 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 235000006486 human diet Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 210000001596 intra-abdominal fat Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000004904 long-term response Effects 0.000 description 1
- 235000015263 low fat diet Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- YSONYEIWWIFWEV-MRXNPFEDSA-N mdo-npa Chemical compound C([C@H]1N(CCC)CC2)C3=CC=C4OCOC4=C3C3=C1C2=CC=C3 YSONYEIWWIFWEV-MRXNPFEDSA-N 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 208000009928 nephrosis Diseases 0.000 description 1
- 231100001027 nephrosis Toxicity 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 235000020830 overeating Nutrition 0.000 description 1
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 229960001130 urapidil Drugs 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- QYEFBJRXKKSABU-UHFFFAOYSA-N xylazine hydrochloride Chemical compound Cl.CC1=CC=CC(C)=C1NC1=NCCCS1 QYEFBJRXKKSABU-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
【解決手段】本発明の特定の脂質及びグルコースの代謝疾患治療のための薬剤及びその組合わせは、第1の量のD1ドパミンアゴニスト、及び第2の量の麦角アルカロイドドパミンD2アゴニストを含む。
【選択図】なし
Description
ヒトにおいて肥満とは、同じ性、身長及び体格の個体の望ましい体重より20%を越える体重の過剰と定義することができる(Salans, L.B., Endocrinology& Metabolism、第2版、McGraw-Hill、New York、1987、第1203〜1244頁;また、R. H. Williams、Textbook of Endocrinology、1974、第904〜916頁参照)。他の動物において(又はヒトにおいて)、若くやせていて「健康的」な(即ち、代謝疾患だけでなくいかなる疾患をも有していない)種の構成員が、種に特徴的なパターンに従う一日の血漿プロラクチン水準プロフィールを有するとすると、肥満はプロラクチンプロフィールと相関する体重のパターンにより決定することができる。このパターンは再現性が高く、わずかな標準的な逸脱を伴う。しかしながら少なくとも一つの脂質及び代謝の疾患を有する種の構成員は、正常な(又は健康な被検者の)パターンから、少なくとも2つの間隔をおいて離れた時間点において少なくとも1SEM、又は少なくとも1つの時間点において少なくとも2SEM(Standard error of the mean、標準誤差)離れた異常なプロラクチンプロフィールを有する。
肥満即ち過剰な脂肪の蓄積は、様々な脂質及び/又はグルコース代謝疾患例えば高血圧、タイプII糖尿病、じゅく状硬化等と相関し、かつこれらの発症の引き金となりうる。
主な病気の中で最も潜行的なものである糖尿病は、突然発症するか、又は血管及び神経に打撃を与えながら診断されずに何年も放置される。群としての糖尿病患者は、非常に高い頻度で失明、心臓病、発作、腎臓病、難聴、壊疽及びインポテンスに苦しめられる。医師への来診の3分の1はこの病気及びその合併症がきっかけとなっており、糖尿病及びその合併症は米国及び欧州の早死の主な原因となっている。
本発明者らによる研究は、野生の脊椎動物に広くみられる、自然に発生する一年の体脂肪貯蔵水準のサイクルは、視床下部の概日神経部分(circadian hypothalamic neural components)に含まれる調節可能な中枢の代謝体(metabolistat)の活動性を反映していることを示している。ドパミン作動性及びセロトニン作動性の概日活動性の相関係の変更は、代謝における季節的な変更を誘発し、これらの概日活動性は、ホルモン又は神経伝達物質に作用する薬物による適切なタイミングの処置により調整することができる。これに関して、α2アゴニスト的活性及びα1アンタゴニスト的活性並びにセロトニン阻害活性を備える交換神経遮断性ドパミンD2アゴニストであるブロモクリプチンは、ヒトを含む様々な動物において、食物の消費を減少させることなく体脂肪貯蔵水準を減少させ、また高インスリン症、高脂血症、及びグルコース不耐を低下させることが示されている。
(ii)アドレナリン作動性α1アンタゴニスト、アドレナリン作動性α1アゴニスト及びセロトニン作動性阻害剤のうち少なくとも1つ;
(iii)ドパミンD2アゴニストであって、さらにアドレナリン作動性α1アンタゴニスト、アドレナリン作動性α2アゴニスト及びセロトニン作動性阻害剤のうち少なくとも1つと組み合わされたドパミンD2アゴニスト。
本発明は、高血糖症、高インスリン症、インスリン耐性、グルコース不耐性、糖尿病、高コレステロール血症、じゅく状硬化、肥満、及び心臓血管疾患のうち少なくとも1つを改善するための、同時に、別個に、又は連続して使用する、薬剤又は薬剤の組合わせを製造するための、D1ドパミンアゴニスト及び麦角アルカロイドドパミンD2アゴニストの使用に関する。
また本発明は、第1の量のD1ドパミンアゴニスト、及び第2の量の麦角アルカロイドドパミンD2アゴニストを含む、高血糖症、高インスリン症、インスリン耐性、グルコース不耐性、糖尿病、高コレステロール血症、じゅく状硬化、肥満、及び心臓血管疾患のうち少なくとも1つを改善するための治療学的薬剤の組合せに関する。
6週令のC57BL/6 ob/obマウス(機能的レプチン蛋白(functional leptin protein)を欠如している)の異なる群を、ブロモクリプチン(「BC」)(10mg/kg体重)、SKF38393(「SKF」) (10mg/kg体重)、両方の薬剤、又は賦形剤で2週間、1HALO(hour after lightonset、光照射開始後時間)において処置した。動物は一日12時間の光周期で照射され、自由摂食を許容された。食物消費は治療開始3日前から14日間の処置期間中毎日モニターされた。動物を最後の処置の次の日の1〜3HALOの間(即ち最後の注射後24〜26時間)に屠殺し、血漿を回収しインスリン、グルコース及び脂質を分析し、一方死体をエタノール性KOHに溶解し、蛋白及び脂質含有量を分析した。ブロモクリプチン及びSKF38393単独では、体重増加を減少させる効果がなかった。SKFは食物消費を減少させた(19%、P<0.01)が、BCではその効果はなかった。しかしながら、14日間の処置において、ブロモクリプチンとSKF38393とを組み合わせた処置(BC/SKF)では、食物消費が46%(4.8±0.2から2.6±g/日;P<0.001)、体重が15%(対照において3.2g増から4.3減;P<0.005)減少した(図1)。対照と比較して、絶対的に、BC/SKF処置動物の脂質含有量は40%(4.2±0.2から2.5±0.3gグリセロール/動物;P<0.0003)減少し、一方蛋白含有量は8%(3.7±0.08から4.0±0.08g/動物;P<0.05)増加した。従って、対照マウスに比べて、BC/SKF処置動物はより少ない食物を消費したが、実際蛋白量は増加する一方、同時に体重及び脂肪を失った。この体の組成に対する効果はSKF(P<0.003)又はBC(P<0.04)単独処置においても観察されたが、その程度はBC/SKFの組合せに比べて少なかった(P<0.05)。BC単独及びSKF単独では血漿グルコース濃度が有意に(それぞれ31%;P<0.02及び43%;P<0.004)減少したが、BC/SKFの組合せは血漿グルコースを(60%;P<0.0004)実質的にそれぞれの薬剤単独より多く(P<0.03)減少させ、ユーグリセミックC57BL/6マウス(+/+)(1)で報告された値と同等の値まで減少させた。血漿インスリン水準は、BC及びBC/SKF処置において同量減少した(50%;P<0.04)が、SKF単独には影響されなかった。BC/SKFは血漿トリグリセリド及び遊離脂肪酸水準を減少させた(36%;P<0.05及び44%;P<0.007)が、BC又はSKF単独では減少させなかった(表1)。これらのデータは、BC及びSKFの相互作用的効果によりob/obマウスにおいて効果的に過食、肥満、インスリン耐性、高血糖症、高インスリン症及び高脂血症が減少することを示す。
Claims (9)
- 高血糖症、高インスリン症、インスリン耐性、グルコース不耐性、糖尿病、高コレステロール血症、じゅく状硬化、肥満、及び心臓血管疾患のうち少なくとも1つを改善するための、同時に、別個に、又は連続して使用する、薬剤又は薬剤の組合わせを製造するための、D1ドパミンアゴニスト及び麦角アルカロイドドパミンD2アゴニストの使用。
- 前記薬剤又は薬剤の組合わせが、以下の脂質及びグルコース代謝指標のうち少なくとも1つを改善するのに効果的である、請求項1記載の使用:体重、体脂肪、血漿インスリン、血中又は血漿グルコース、血漿脂質、血漿遊離脂肪酸水準、血中HbA1c水準、血中トリグリセリド水準、並びに血漿リポ蛋白。
- 前記麦角アルカロイドドパミンD2アゴニストが、2−ブロモ−α−エルゴクリプチン、6−メチル−8−β−カルボベンジルオキシアミノエチル−10−α−エルゴリン、8−アシルアミノエルゴリン、ペルゴリド、リスリド、6−メチル−8−α−(N−アシル)アミノ−9−エルゴリン、6−メチル−8−α−(N−フェニル−アセチル)アミノ−9−エルゴリン、エルゴコミン、9,10−ジヒドロエルゴコミン、D−2−ハロゲン化−6−アルキル−8−置換エルゴリン、及びD−2−ブロモ−6−メチル−8−シアノメチルエルゴリンからなる群より選択される、請求項1記載の使用。
- 前記D1ドパミンアゴニストが、SKF38393、ジヒドレキシジン、SKF75670、SKF82957、A77636、A68930、SKF82526(フェノルドパム(fenoldopam))、及びトランス−10,11−ジヒドロキシ−5,6,6a,7,8,12b−ヘキサヒドロ葡萄酸からなる群より選択される、請求項1記載の使用。
- 前記D1ドパミンアゴニストがSKF38393を含む、請求項1記載の使用。
- 前記麦角アルカロイドドパミンD2アゴニストがブロモクリプチンを含む、請求項3記載の使用。
- 前記麦角アルカロイドドパミンD2アゴニストを一日の所定の時間に投与する、請求項1記載の使用。
- 前記D1ドパミンアゴニストを前記麦角アルカロイドドパミンD2アゴニストと略同時に投与する請求項6記載の使用。
- 第1の量のD1ドパミンアゴニスト、及び第2の量の麦角アルカロイドドパミンD2アゴニストを含む、高血糖症、高インスリン症、インスリン耐性、グルコース不耐性、糖尿病、高コレステロール血症、じゅく状硬化、肥満、及び心臓血管疾患のうち少なくとも1つを改善するための治療学的薬剤の組合せ。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1737796P | 1996-05-07 | 1996-05-07 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP16355596A Division JP4530433B2 (ja) | 1996-05-07 | 1996-05-22 | 脂質及びグルコースの代謝疾患治療のための方法及び組成物 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2007291139A true JP2007291139A (ja) | 2007-11-08 |
Family
ID=21782248
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP16355596A Expired - Fee Related JP4530433B2 (ja) | 1996-05-07 | 1996-05-22 | 脂質及びグルコースの代謝疾患治療のための方法及び組成物 |
JP2007211789A Pending JP2007291139A (ja) | 1996-05-07 | 2007-08-15 | 脂質及びグルコースの代謝疾患治療剤及び組成物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP16355596A Expired - Fee Related JP4530433B2 (ja) | 1996-05-07 | 1996-05-22 | 脂質及びグルコースの代謝疾患治療のための方法及び組成物 |
Country Status (1)
Country | Link |
---|---|
JP (2) | JP4530433B2 (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9655865B2 (en) * | 2002-07-29 | 2017-05-23 | Veroscience, Llc | Therapeutic treatment for metabolic syndrome, type 2 diabetes, obesity, or prediabetes |
US8821915B2 (en) | 2002-08-09 | 2014-09-02 | Veroscience, Llc | Therapeutic process for the treatment of the metabolic syndrome and associated metabolic disorders |
AU2003213328A1 (en) * | 2003-03-12 | 2004-09-30 | Bml, Inc. | Method of selecting adipocyte differentiation controller |
US8741918B2 (en) * | 2007-06-21 | 2014-06-03 | Veroscience Llc | Parenteral formulations of dopamine agonists |
US20100035886A1 (en) | 2007-06-21 | 2010-02-11 | Veroscience, Llc | Parenteral formulations of dopamine agonists |
US9352025B2 (en) | 2009-06-05 | 2016-05-31 | Veroscience Llc | Combination of dopamine agonists plus first phase insulin secretagogues for the treatment of metabolic disorders |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996011701A1 (en) * | 1994-10-14 | 1996-04-25 | Glaxo Wellcome Inc. | Enteric coated compositions of 1,5-benzodiazepine derivatives having cck antagonistic or agonistic activity |
WO2009013294A1 (fr) * | 2007-07-24 | 2009-01-29 | Thales | Laser bi-frequence fibre par melange d'ondes dans des fibres optiques amplificatrices |
-
1996
- 1996-05-22 JP JP16355596A patent/JP4530433B2/ja not_active Expired - Fee Related
-
2007
- 2007-08-15 JP JP2007211789A patent/JP2007291139A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996011701A1 (en) * | 1994-10-14 | 1996-04-25 | Glaxo Wellcome Inc. | Enteric coated compositions of 1,5-benzodiazepine derivatives having cck antagonistic or agonistic activity |
JPH10511930A (ja) * | 1994-10-14 | 1998-11-17 | グラクソ、ウェルカム、インコーポレーテッド | Cckアンタゴニスト活性またはアゴニスト活性を有する1,5−ベンゾジアゼピン誘導体を含んでなる腸溶性コーティング組成物 |
WO2009013294A1 (fr) * | 2007-07-24 | 2009-01-29 | Thales | Laser bi-frequence fibre par melange d'ondes dans des fibres optiques amplificatrices |
Also Published As
Publication number | Publication date |
---|---|
JPH09301892A (ja) | 1997-11-25 |
JP4530433B2 (ja) | 2010-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5877183A (en) | Treatment of lipid and glucose metabolism disorders with dopamine and serotonin agonists | |
US6855707B2 (en) | Method for the treatment of lipid and glucose metabolism disorders | |
US5716962A (en) | Process for therapeutically modifying and resetting prolactin rhythm with a dopamine agonist | |
US5866584A (en) | Therapeutic process for the treatment of the pathologies of type II diabetes | |
US5668155A (en) | Administration of pirenzepine, methyl scopolamine and other muscarinic receptor antagonists for treatment of lipid metabolism disorders | |
EP1776955B1 (en) | Medical use and composition for the treatment of lipid and glucose metabolism disorders | |
US5741503A (en) | Method for regulating metabolism with dopamine beta hydroxylase inhibitors | |
US5585347A (en) | Methods for the determination and adjustment of prolactin daily rhythms | |
WO1997041873A9 (en) | Method and composition for the treatment of lipid and glucose metabolism disorders | |
Weltzin et al. | Serotonin and bulimia nervosa | |
JP2007291139A (ja) | 脂質及びグルコースの代謝疾患治療剤及び組成物 | |
US5830895A (en) | Methods for the determination and adjustment of prolactin daily rhythms | |
US6004972A (en) | Therapeutic process for the treatment of the pathologies of type II diabetes | |
WO1997046239A1 (en) | Treatment of lipid and glucose metabolism disorders with dopamine and serotonin agonists | |
RU2104698C1 (ru) | Способ лечения патологических отклонений при диабете типа ii | |
CZ378796A3 (en) | Method of determining abnormal states and adjustment of prolactin daily rhythms | |
De Pergola et al. | D-(—)-β-hydroxybutyrate inhibits catecholamine-stimulated lipolysis and decreases β-adrenoceptors' affinity in human fat cells but not in lymphomonocytes | |
WO1997017083A1 (en) | Method for treating obesity and type ii diabetes by adjusting the circadian rhythm of human growth hormone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20070911 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100907 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20101203 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20101208 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20110107 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20110113 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20110203 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20110208 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110307 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20110802 |