WO1997026005A9 - Traitement anti-diabetique par une combinaison d'igf-1 avec des hypoglycemiants - Google Patents
Traitement anti-diabetique par une combinaison d'igf-1 avec des hypoglycemiantsInfo
- Publication number
- WO1997026005A9 WO1997026005A9 PCT/US1997/000085 US9700085W WO9726005A9 WO 1997026005 A9 WO1997026005 A9 WO 1997026005A9 US 9700085 W US9700085 W US 9700085W WO 9726005 A9 WO9726005 A9 WO 9726005A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- igf
- insulin
- glucose
- sulfonylurea
- rats
- Prior art date
Links
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 42
- 239000003472 antidiabetic agent Substances 0.000 title claims abstract description 23
- 229940126904 hypoglycaemic agent Drugs 0.000 title claims abstract description 22
- 238000011282 treatment Methods 0.000 title description 33
- 230000002218 hypoglycaemic effect Effects 0.000 title description 10
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims abstract description 65
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims abstract description 64
- 229940100389 Sulfonylurea Drugs 0.000 claims abstract description 64
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 17
- 241000124008 Mammalia Species 0.000 claims abstract description 12
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 claims abstract description 11
- 101150088952 IGF1 gene Proteins 0.000 claims description 71
- 102100037852 Insulin-like growth factor I Human genes 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 229940122199 Insulin secretagogue Drugs 0.000 abstract description 21
- 230000002641 glycemic effect Effects 0.000 abstract description 15
- 239000003795 chemical substances by application Substances 0.000 abstract description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 4
- 102000044162 human IGF1 Human genes 0.000 abstract description 3
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 130
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 122
- 239000008103 glucose Substances 0.000 description 121
- 241000700159 Rattus Species 0.000 description 71
- 102000004877 Insulin Human genes 0.000 description 65
- 229940125396 insulin Drugs 0.000 description 65
- 108090001061 Insulin Proteins 0.000 description 64
- 210000004369 blood Anatomy 0.000 description 50
- 239000008280 blood Substances 0.000 description 50
- 230000003914 insulin secretion Effects 0.000 description 50
- 230000000694 effects Effects 0.000 description 48
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 43
- 229960005371 tolbutamide Drugs 0.000 description 43
- 238000007446 glucose tolerance test Methods 0.000 description 42
- 229960001381 glipizide Drugs 0.000 description 26
- 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 description 26
- 235000013305 food Nutrition 0.000 description 22
- 241001465754 Metazoa Species 0.000 description 18
- 229960004580 glibenclamide Drugs 0.000 description 18
- 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 description 18
- 230000008859 change Effects 0.000 description 14
- 238000002560 therapeutic procedure Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 230000009471 action Effects 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 230000006872 improvement Effects 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- 229940068196 placebo Drugs 0.000 description 10
- 239000000902 placebo Substances 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 238000000338 in vitro Methods 0.000 description 9
- 230000037396 body weight Effects 0.000 description 8
- 241000282412 Homo Species 0.000 description 7
- 235000005911 diet Nutrition 0.000 description 7
- 230000037406 food intake Effects 0.000 description 7
- 235000012631 food intake Nutrition 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000012453 sprague-dawley rat model Methods 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 6
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 6
- 230000037213 diet Effects 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 210000004153 islets of langerhan Anatomy 0.000 description 6
- 229960003299 ketamine Drugs 0.000 description 6
- 238000003305 oral gavage Methods 0.000 description 6
- 210000000496 pancreas Anatomy 0.000 description 6
- -1 ascorbic acid Chemical class 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 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 5
- 230000002354 daily effect Effects 0.000 description 5
- 108700001680 des-(1-3)- insulin-like growth factor 1 Proteins 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000003304 gavage Methods 0.000 description 5
- 201000001421 hyperglycemia Diseases 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 230000036515 potency Effects 0.000 description 5
- 230000000580 secretagogue effect Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 5
- 229960001600 xylazine Drugs 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 102000007513 Hemoglobin A Human genes 0.000 description 4
- 108010085682 Hemoglobin A Proteins 0.000 description 4
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 4
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000003538 oral antidiabetic agent Substances 0.000 description 4
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 3
- 208000013016 Hypoglycemia Diseases 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 238000010241 blood sampling Methods 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 3
- 238000011284 combination treatment Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000000081 effect on glucose Effects 0.000 description 3
- 230000014101 glucose homeostasis Effects 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 239000005022 packaging material Substances 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 2
- 108010075254 C-Peptide Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 206010066901 Treatment failure Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 238000011260 co-administration Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012931 lyophilized formulation Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000002297 mitogenic effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000022001 negative regulation of insulin secretion Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000004923 pancreatic tissue Anatomy 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960002277 tolazamide Drugs 0.000 description 2
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XMQUEQJCYRFIQS-YFKPBYRVSA-N (2s)-2-amino-5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CC[C@H](N)C(O)=O XMQUEQJCYRFIQS-YFKPBYRVSA-N 0.000 description 1
- 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 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102000005548 Hexokinase Human genes 0.000 description 1
- 108700040460 Hexokinases Proteins 0.000 description 1
- 102000038455 IGF Type 1 Receptor Human genes 0.000 description 1
- 108010031794 IGF Type 1 Receptor Chemical group 0.000 description 1
- 101150002416 Igf2 gene Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 206010054805 Macroangiopathy Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102000018692 Sulfonylurea Receptors Human genes 0.000 description 1
- 108010091821 Sulfonylurea Receptors Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000569 acute exposure Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 230000002098 anti-diabetogenic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960003362 carbutamide Drugs 0.000 description 1
- VDTNNGKXZGSZIP-UHFFFAOYSA-N carbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 VDTNNGKXZGSZIP-UHFFFAOYSA-N 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000006362 insulin response pathway Effects 0.000 description 1
- 102000028416 insulin-like growth factor binding Human genes 0.000 description 1
- 108091022911 insulin-like growth factor binding Proteins 0.000 description 1
- 230000002608 insulinlike Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000002363 skeletal muscle cell Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Definitions
- Type II, non- ⁇ nsul ⁇ n-dependentd ⁇ abetesmell ⁇ tus(NIDDM) which constitutesabout 80-90% of the total incidence of diabetes (Type I insulin- dependent diabetes mellitus ( IDDM ) makes up the rest) continues to grow rapidly, with respect to its incidence, prevalence, and cost
- Diabetic therapy has a numberof goals, includingrelievingsymptoms of hyperglycemiaand preventing long-term complications of diabetes such as microvascular and macrovascular disease
- the incidence and severity of these complications in IDDM are related at least in part to the degree of glycemic control, as confirmed by the results of the Diabetes Control and ComplicationsT ⁇ al (DCCT)
- DCCT Diabetes Control and ComplicationsT ⁇ al
- the medical managementof NIDDM is a progressive process F ⁇ rstly,d ⁇ et control (hypocalonc/eucaloric) and exercise is attempted to achieve weight loss especially in obese subjects, secondly oral hypoglycemic drugs are used and finally, treatment with
- the sulfonylurea are oral hypoglycemics that are used to stimulate pancreatic insulin release Sulfonylureaare the most widely prescribed of the oral hypoglycemic agents currently approved for use in the United States Approximately 30 percent of patients initially treated with sulfonylureahave a poor response, and in the remaining 70 percent the subsequent failure rate is approximately 4 to 5 percent per year (Defronzo et al , NEJM 333.541 -549,[ 1995]) and has been reported as high as 10 percent (Gerich. NEJM 321.1231 - 1245,[ 1989]) This indicates that there is a clear need to improve sulfonylurea therapy
- Sulfonylurea are divided into two classes loosely based on their chemistry and potency All sulfonylureaare substituted arylsulfonylureas which differ by substitutions at the para position on the benzene ring and at one nitrogen residue of the urea moiety
- the first generation sulfonylurea include acetohexamide, chloropropamide, tolazamide and tolbutamide
- the second generation drugs include glybu ⁇ de (gl ⁇ benclam ⁇ de),gl ⁇ p ⁇ z ⁇ de and gl ⁇ claz ⁇ de
- Second generation sulfonylurea show increased potency partly because they are larger and non - polar compared to the smaller, polar, first generation molecules Therefore, improved lipid solubility may account for the greater potency of the second generation sulphonylureas
- the sulfonylurea have similar qualitative activities, their pharmacokinetics may also define their potency After absorption from the gut sulfonylureaare all present in plasma bound greater than 90% to protein, especially to albumin
- the first generation sulfonylurea vary greatly in their serum half- lives with that of chloropropamidebemg long at 24-48 hours, and that of tolbutamide being 4-7 hours Despite this variation in half- life their duration of action is uniformly short, so that they need to be given in divided daily doses
- the second generation molecules are 100 times as potent and even though their half-lives are short (1-5 hours) they have a long duration of hypoglycemic action and thus may be administered only once daily
- the exact mechanisms, causing the large discrepancy between half- life and duration of action of the sulphonylureas, are not known Therefore, despite this class of drug being widely used, simple concepts, such as the relationship between persistence in the body and duration of action, remain to be explained
- pancreatic beta cells exhibit a maintained drug effect or because peripheral target tissues become more sensitive to insulin in response to the sulfonylurea (Kolterman.DiabetesMetab Rev 3.399-414f l9871)
- IGF-1 and IGF-2 are growth factors with molecular weights of approximately 7500 daltons Both IGF- 1 and IGF-2 have insulin - like activities as indicated by the chosen name of the peptide, and are mitogenic for the cells in reproductive tissue, muscle, skeletal tissue and a wide variety of other tissues
- the IGF- 1 and -2 peptides were originally named somatomedins indicative of their growth promoting or mitogenic effect
- IGF's are present m high concentrations in the circulation, but only a small fraction of IGF is not protein bound
- the overwhelmingmajo ⁇ ty of IGF circulatesas part of a non- covalently associated ternary complex composed of IGF- 1 or IGF-2, and insulin like growth factor binding prote ⁇ n-3 (IGFBP-3), and a large protein termed the acid labile subunit (ALS)
- IGFBP-3 insulin like growth factor binding prote ⁇ n-3
- ALS acid labile subunit
- This complex is composed of equimolar amounts of each ofthe three components
- the ternary complex of IGF plus IGFBP-3 plus ALS has a molecular weight of approximately 150,000 daltons, and it has been suggested that the function of this complex in the circulation may be to serve as a reservoir and buffer for IGF- 1 and IGF-2 preventing rapid changes of free IGF-1
- IGF-1 is produced in many tissues, most circulating IGF-1 is believed to be synthesized in the liver
- IGF- 1 may be purified from natural sources or produced from recombinant sources
- IGF- 1 can be purified from human serum (Rmderknecht and Humbel J Biol Chem 251,2769-2773 [1978])
- Recombinant IGF- 1 processes are exhibited in Patent EPO 128,733, published in December 1984
- a suppression of blood insulin levels was observed (Guler et al.NEJM 317.137- 140[ 1987])
- the most pertinent data was demonstrated in the studies carried out in Type II diabetics by Schlach et al fJ Clin.Metab 77.1563- 1568f 1993]) which demonstrated a fall in both serum insulin as well as a paralleled decrease in C peptide levels which indicated a fall in pancreatic insulin secretion after five days of IGF- 1 treatment This effect has been independently confirmed by Froesch et al (Horm Res 42.66-71 f 1994]) In vivo
- This invention provides a method for treating diabetes in a mammal comprising administering to the mammal an effective amount of a hypoglycemic agent, preferably an insulin secretagogue of the sulfonylurea class, with an effective amount of IGF-1 so as to improve glycemic control and limit the progression of the disease.
- a hypoglycemic agent preferably an insulin secretagogue of the sulfonylurea class
- the literature describes a complex role for insulin secretagogues in controlling blood glucose in diabetes.
- IGF-1 is being investigated as a treatment for diabetes as it has direct hypoglycemicactivity.
- IGF-1 has been reported to have the opposite effect to sulfonylurea on insulin secretion. Sulfonylurea stimulate insulin secretion whereas IGF- 1 inhibits insulin secretion.
- IGF-1 inhibits insulin secretion.
- IGF-1 inhibits insulin secretion.
- This confusion provides no clear basis to predict the effect of the co-administration of insulin secretagogues and IGF- 1 on insulin secretion or glucose control. in many patients the insulin secretagogues either fail initially (primary failure), or fail subsequently
- IGF- 1 did not oppose the insulin release caused by an insulin secretagogue such as a sulfonylurea. Even more surprisingly, when islets were cultured in the setting of long- term high glucose exposure in the presence of a sulfonylurea, IGF-1 had the opposite effect in that it actually stimulated rather than inhibited insulin secretion. Further, IGF- 1 was tested during secretagogue failure in animals and in human diabetics. In animals, in a situation where glucose tolerance was worsened by sulfonylurea,the co-administrationof IGF- 1 was found to prevent the failure and maintain glucose tolerance.
- IGF- 1 therapy can be combined with insulin secretagogue therapy to improve the ongoing regulation of blood glucose during the progression of diabetes. Additionally, when the insulin secretagogue exhibits a failure to adequately regulate glucose, IGF-1 can be used either to prevent this failure from occurring or to restore glycemic control if failure has already occurred.
- FIG.1. shows a bar graph of the effect of glucose and tolbutamide on insulin secretion over a 24 hour period by isolated rat pancreatic islets (means +/-SE).
- FIG.2. showsa bar graph of the effect of glucose and IGF- 1 on insulin secretion over a 24 hour period by isolated rat pancreatic islets (means+/-SE).
- FIG .3. shows a bar graph of the effect of the combination of IGF- 1 and tolbutamideon insulin secretion, over a 24 hour period (means +/-SE).
- FIG.4. representsthe % change in blood glucose over 90 minutes following a bolus administration of glucose after a fast (a glucose tolerance test) in one group of normal rats pretreated with alcohol as placebo (control), or in a group of rats pretreated with tolbutamide at either 25 or 125 mg/kg (means+/-SE).
- FIG.5. represents the % change in blood glucose over 90 minutes in normal rats, following a glucose tolerance test, either pretreated with alcohol as placebo (control),or pretreated with tolbutamide at 25 mg kg (means +/-SE).
- FIG 6 represents the % change in blood glucose over 90 minutes in normal rats, following a glucose tolerance test either pretreated with alcohol as placebo (control) or pretreated with tolbutamide at 50 mg/kg (means+/-SE)
- FIG 7 represents the % change in blood glucose over 90 minutes in normal rats, following a glucose tolerance test in a group pretreated with normal rat chow (control) or a group that were pretreated with glybunde mixed in their food for 6 days (means+/-SE , * represents statistical significance, p ⁇ 0 05)
- FIG 8 representsthe serum insulin concentrationstaken during the glucose tolerance test performed in the control and glybunde treated rats depicted in FIG 7 (means +/SE)
- FIG 9 shows a bar graph representing basal serum blood glucose (mg%) and insulin concentration (ng/m l) in four groups of rats, control group (placebo continuously administered-no oral glybunde), IGF-1 treated group no glybunde,a glybunde treated group with no IGF-1 treatment and a group treated with both glybunde and IGF- I (means+/-SE)
- FIG 10 representsthe %change in blood glucose over 120 minutes, following a glucose tolerance test, in the four groups of rats depicted in FIG 9 (means+/-SE) after 3 days of the study
- FIG 1 1 represents the serum insulin concentration over the same 120 minutes following the glucose tolerance test given to the four groups of rats depicted in FIG 9 (means+/-SE) after 3 days of study
- FIG 12 representsthe %change in blood glucose over 120 minutes, following a glucose tolerance test given to four groups of normal rats, a control group (placebo continuously administered for 14 days-no oral glipizide), a des(l -3)IGF- l treated group with no glipizide, a glipizide treated group with no des( l -3)IGF- l treatment and a group treated with both des(l-3)IGF- l and glipizide after 3 days of treatment (means+/-SE)
- FIG 13 represents the serum insulin concentration over the same 120 minutes following the glucose tolerance test given to the four groups of rats depicted in FIG 12 (means+/-SE) after 3 days of study
- FIG 14 represents the blood glucose over 120 minutes, following a glucose tolerance test, in all four groups of rats depicted in FIG 12 (means+/-SE) after 7 days of study
- FIG 15 representsthe change in Hemoglobin A l c(%) over 12 weeks in Typell Diabetic patients being treated with IGF- 1 subsequent to a period of treatment with an oral hypoglycemic agent (HA),group p is the placebo treated group, groups 1 , 2, 4 and 8 are the IGF- 1 treated groups, (being 10,20,40,80 ⁇ g/kg,respect ⁇ vely) (means+/-SE)
- HA oral hypoglycemic agent
- FIG 16 represents the change in Hemoglobin A lc(%) over 12 weeks in Typell diabetic patients being treated with IGF- 1 subsequentto a period of treatment with insulin (mean+/-SE) Groupdesignationsare the same as those depicted in FIG 15
- mammal signifies humans as well as other mammals, and includes animals of economic importance such as bovine, ovme, and porcine animals
- the preferred mammal herein is a human
- IGF-1 refers to insulin-like growth factor- 1 from any species, including bovine, ovine, porcine, equine and preferably human, in native-sequence or in variant form, and from any source, whether natural, synthetic, or recombinant
- Preferred herein for animal use is IGF-I from the particular species being treated, such as porcine IGF-I to treat pigs, ovine IGF-I to treat sheep, bovine IGF-1 to treat cattle, etc
- Preferred herein for human use is human native-sequence, mature IGF-I, more preferably without a N-terminal methionine, prepared, e g , by the process described in EP 230,869 published Aug 5, 1987, EP 128,733 published Dec 19, 1984 or EP 288,451 published Oct 26,
- IGF-I variants are those described in PCT WO 87/01038 published Feb 26, 1987 and m PCT WO 89/05822 published June 29, 1989, l e , those wherein at least the glutamic acid residue is absent at position 3 from the N-terminusof the mature molecule or those that have a deletion of up to five amino acids at the N-terminus
- the most preferred variant has the first three ammo acids from the N-terminus deleted
- brain IGF (variously designated as brain IGF, tIGF-I, des(l -3)-IGF-I or des-IGF-I)
- treatment refers to therapeutic and prophylactictreatment Those in need of treatment include those already with the disorder as well as those in which treatment of the disorder has failed As used herein, "diabetic'Vefers to a progressive disease of carbohydrate metabolism involving inadequate production or utilization of insulin and is characterized by hyperglycemia and glycosu ⁇ a
- hypoglycemic agent is a secretagogue, preferably an oral agent, excluding insulin, which causes the secretion of insulin by the pancreas More preferred herein for human use are the sulfonylurea class of oral hypoglycemic agents Examples include glybunde, glipizide and gliclazide B Modes for carrying out the invention
- the IGF-I is directly administered to the mammal by any suitable technique, including parenterally, intranasal ly, orally, or by any other effective route
- parenteral administration include subcutaneous, intramuscular, intravenous, lntraartal, and intraperitonealadministration
- the administration is by continuous infusion (using, e g , minipumps such as osmotic pumps), or by injection (using e g , intravenous or subcutaneous means)
- the administration is subcutaneous and by injection for IGI--1
- the administration may also be as a single bolus or by slow-release or depot formulation
- the IGF-1 is suitably administered together with one of its binding proteins, for example, IGFBP-3, which is described in WO 89/09268 published Oct 5, 1989 and by Martin and Baxter, J Biol Chem 261 8754-8760 ( 1986)
- IGFBP-3 which is described in WO 89/09268 published Oct 5, 1989 and by Martin and Baxter, J Biol Chem 261 8754-8760 ( 1986)
- the IGF-I may also be suitably coupled to a receptor or antibody or antibody fragment for administration
- the treatment regimen or pattern of administration of the agents may be one of simultaneous administration with the hypoglycemic agent and the IGF-1
- the treatment regimen may be phasic with an alternating pattern of administration of one agent followed at a later time by the administration of the second agent
- Phasic administration includes multiple administrations of one agent followed by multiple administrationsof the second agent
- the total pharmaceutically effective amount of IGT-I administered parenterally per dose will be in the range of about 10 ⁇ g/kg/day to 200 ⁇ g/kg/day of patient body weight, although this will be subject to therapeutic discretion
- the IGF-I is typically administeredat a dose rate of about 0 5 g/kg/hour to about 10 ⁇ g/kg/hour, either by 1-2 injections per day or by continuous subcutaneous release, for example, using a minipump, patch, implant, or a depot formulation
- the IGF-1 is also suitably administered by sustained- release systems Suitable examples of sustained- release compositions include semi-permeable polymer matrices in the form of shaped articles, e g films, or microcapsules Sustained-release matrices include polylactides (U S Pat No 3,773,919), copolymers of L- glutamic acid and gamma-ethyl-L-glutamate (Sid an et al , Biopolvmers 22
- IGF- 1 compositions also include liposomally entrapped IGF- 1 Liposomes are prepared by methods known per se DE3,218, 121 ,U S Pat Nos 4,485,045 and 4,545,545 Ordinarily, the liposomes are of small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol % cholesterol, the selected proportion being adjusted for the optimal IGF- 1 therapy
- the IGF-1 is formulated by mixing it at the desired degree of purity, a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, i e ,one that is non toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation
- a pharmaceutically acceptable carrier i e ,one that is non toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation
- the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides
- the formulations are prepared by contactingthe IGF-1 uniformly and intimately with liquid carriers or finely divided solid carriers or both Then, if, necessary, the product is shaped into the desired formulation
- the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient Examples include water, saline, Ringers solution, and dextrose solution
- Non- aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes
- the carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability
- additives such as substances that enhance isotonicity and chemical stability
- Such materials are non- toxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) polypeptides, e g , polyarginine or t ⁇ peptides, proteins, such as serum albumin, gelatin, or ⁇ mmunoglobul ⁇ ns,hydrophil ⁇ cpolymers such as poly-vmyl -pyrrolidone, ammo acids, such as glycine, glutamic acid, aspartic acid, or arginine, monosaccha ⁇ des, disacchandes, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dext ⁇ ns, chelating agents such as EDTA,
- the IGF- 1, preferably the full- length IGF- 1 is suitably formulated in an acceptable carrier vehicle to form a pharmaceutical composition, preferably one that does not contain cells
- the buffer used for formulation will depend on whether the composition will be employed immediately upon mixing or stored for later use If employed immediately, the full length IGF- I can be formulated in mannitol, glycine, and phosphate at pH 7 4 If this mixture is to be stored, it is formulated in a buffer at a pH of about 6, such as surfactantthat increases the solubility of the IGF-1 at this pH, such as 0 1% polysorbate20 or poloxamer 188
- the final preparation may be a stable liquid or a lyophilized solid
- IGF- 1 to be used for therapeutic use must be sterile Sterility is readily accomplished by filtration through sterile filtration membranes (e g 0 2 micron membranes)
- Therapeutic IGF- 1 compositions generally are placed into a container having a sterile access port, for example, a vial having a stopper pierceable by a hypodermic injection needle
- IGF-1 ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution, or as a lyophilized formulation for reconstitution
- 10-ml vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous IGF-1 solution, and the resulting mixture is lyophilized
- the infusion solution is prepared by reconstituting the lyophilized IGF-1 in bacte ⁇ ostatic Water-for-lnjection
- the insulin secretagogue or hypoglycemic agent is administered to the mammal by any suitable
- rhIGF-I at both 13nM and 65nM enhanced 5 mM and 16 mM glucose stimulated insulin secretion, reaching significance for high dose rhIGF-I (3.6 ⁇ 0.8 and 10.1 ⁇ 1.34 for 5 and 16mM glucose respectively; vs. 6.1 ⁇ 0.96 and 15.3 ⁇ 1.75 ng /islet, for 5 and 16mM glucose plus rhIGF-I; respectively). Therefore acute exposure to rhlGF- 1 did not affect glucose- stimulated insulin secretion. Unexpectedly, chronic exposure to rhIGF-I, even when islets were desensitized by high glucose, resulted in an increased release of insulin.
- IGF- 1 suppresses insulin secretion by acting directly on the pancreas.
- concentrations 100-500 ng/ml
- rhIGF-I does not affect acute glucose-stimulatedinsulin secretion.
- rhIGF-I does not antagonize tolbutamide-stimulated insulin secretion at either 5mM or l6mM glucose.
- Study 3 This experiment used a higher dose of tolbutamide (50 mg/kg) than the 25 mg/kg dose used in Study 2
- the object was to study the short-term effects of tolbutamideadministrationon blood glucose and the effects on the glucose concentrations after a glucose tolerance test
- mice Twenty-eight SD rats (250 g) were housed in individual cages and their intake of powdered food (diet 5001 ) was measured Glybu ⁇ dewas incorporated into the food to give a dose of 2 5 mg/kg/d of glybunde, or the rats were fed the 5001 diet without glybunde Osmotic minipumps (Alzet 2001 TMpumps, Alza Palo Alto, CA) were implanted sub-cutaneously into the rats to deliver IGF-1 at a dose of 670 ⁇ g/rat d or 2 5 mg/kg/d, while other pumps were filled with the IGF-1 excipient There were 4 groups of rats,
- Figure 10 shows the GTT data
- Figure 1 1 the insulin concentrations after the GTT given 3 days following the beginning of drug dosing.
- Glucose tolerance was worsened by glyburide 30 and 60 minutes after the GTT.
- the insulin concentrations in the glyburide treated rats did not rise with a glucose challenge.
- IGF- 1 had little effect on glucose tolerance.
- IGF-1 and glyburide were given in combination, IGF- 1 reversed the deterioration in glucose tolerance caused by glyburide. Therefore, although IGF- 1 caused a reduction in basal insulin levels, it restored insulin secretion in responseto a glucose load in glyburide- treated rats.
- the GTT was then repeated after 7 days of treatment.
- This experiment produced su ⁇ rising results. Insulin secretion was stimulated by glyburide after a 6- hour food withdrawal and blood glucose concentrations were reduced. IGF- 1 suppressed basal insulin concentrations in the presence of glyburide, but by itself had no effect on basal blood glucose. Despite the rise in basal insulin concentrations, indicating that glyburide was stimulating insulin secretion, glyburide suppressed the insulin secretory response to a simulated meal (the GTT) and compared to control animals worsened glucose tolerance. IGF-1 plus glyburide, despite suppressing basal insulin levels, allowed an insulin response to the GTT and improved glucose tolerance compared to treatment with glyburide alone.
- IGF- 1 which is generally thought to inhibit insulin secretion and did so in the fasted state, equally su ⁇ risingly allowed insulin secretion to be recovered in response to the GTT both in the presence and the absence of the sulfonylurea.
- Osmotic minipumps (Alzet 2002TMpumps, Alza Palo Alto, CA) were implanted sub-cutaneously into the rats to deliver des(l -3)IGF-l at a dose of 270 ⁇ g/rat/d or 1 1 mg/kg/d while other pumps were filled with the IGF- 1 excipient
- the analog of IGF- 1 , des( l -3)IGF-l was used at a lower dose than was used for IGF- 1 m Study 5, as des( l-3)IGF-l is more potent than IGF- 1
- the blood glucose concentrationsbefore the GTT were lower in the glipizide- treated rats ( 1 l ⁇ 7 mg/dl in control vs 133 ⁇ 4 mg/dl, p ⁇ 0 05), were not affected by des( l-3)IGF- l , and were not reduced in the group treated with both drugs ( 167 ⁇ 12 mg/dl)
- the low blood glucose before the GTT m the glipizide rats was not associated with a change blood insulin concentration (control, 1 4 ⁇ 0 14 vs glipizide, 1 3 ⁇ 0 14 ng/ml), but des( l-3)IGF-l reduced basal insulin levels
- Figure 12 shows the GTT data
- Figure 13 the insulin concentrations after the GTT given 3 days following the beginning of drug dosing Glucose tolerance was worsened by glipizide at 30 and 60 minutes
- IGF-1 and glipizide caused a reduction in insulin levels, only glipizide reduced glucose clearance glipizide and des( 1 -3)IGF- 1 plus glipizide (control 154 ⁇ 7 mg%, des( 1 -3)IGF- 1 , 148 ⁇ 6 mg%, glipizide, 127 ⁇ 6 mg%, IGF- 1 + glipizide, 131 ⁇ 7 mg%)
- glucose tolerance was dramatically impaired
- the treatment period was twelve weeks Patients had either previously been treated with insulin or with a hypoglycemic agent, in most cases glybunde
- Example 1 using cultured pancreatic islets of Langerhans, IGF-1 did not oppose the insulin release caused by an insulin secretagogue sulfonylurea In fact, when the islets were cultured in the setting of high glucose exposure and in the presence of a sulfonylurea, to mimic the diabetic state, IGF- I had the opposite effect to that predicted in that it stimulated rather than inhibited insulin secretion The in vitro data would therefore predict that the combination treatment of IGF-1 and an insulin secretagogue would improve glycemic control in diabetic patients In Examples 2 and 3 IGF-1 was tested during secretagogue failure in animals and in humans.
- Example 3 a study in Type II diabetic humans produced very compelling evidence supporting the use of the combination of IGF- I and oral hypoglycemics.
- diabetics who were being treated with either sulfonylurea or insulin and were poorly controlled, and therefore were considered treatment failures, were then treated with IGF-I .
- IGF- I therapy can be combined with insulin secretagogue therapy to improve the regulation of blood glucose in diabetes.
- IGF- 1 can be used either to prevent this failure from occurring or to restore glucose regulation if failure has already occurred.
- IGF- 1 can be used either to prevent this failure from occurring or to restore glucose regulation if failure has already occurred.
Abstract
La présente invention concerne un traitement permettant de mieux gérer, chez les mammifères, l'évolution du diabète, et notamment du diabète de type II, et consistant en une administration d'IGF-1 en combinaison avec une administration d'hypoglycémiants. L'IGF-1 est de préférence un IGF-1 mature en séquence native et d'origine humaine, les hypoglycémiants étant des sécrétagogues tels que la sulfonylurée. Cette combinaison d'agents améliore la régulation glycémique dans des cas de diabète.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU15709/97A AU1570997A (en) | 1996-01-16 | 1997-01-10 | Igf-i in combination with hypoglycemics for treatment of diabetes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3128996P | 1996-01-16 | 1996-01-16 | |
US60/031,289 | 1996-01-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1997026005A1 WO1997026005A1 (fr) | 1997-07-24 |
WO1997026005A9 true WO1997026005A9 (fr) | 1997-09-18 |
Family
ID=21858618
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/000085 WO1997026005A1 (fr) | 1996-01-16 | 1997-01-10 | Traitement anti-diabetique par une combinaison d'igf-1 avec des hypoglycemiants |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU1570997A (fr) |
WO (1) | WO1997026005A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999049894A1 (fr) * | 1998-04-01 | 1999-10-07 | Genentech, Inc. | Antagonistes du gene 6 specifique de l'arret de croissance, et leur utilisation contre des troubles insulinoresistants |
WO2002060473A2 (fr) * | 2001-01-31 | 2002-08-08 | Colorado State University Research Foundation | Methode de traitement de la retinopathie diabetique a l'aide de facteurs de croissance semblables a l'insuline (igfs) naturels et d'analogues d'igfs |
-
1997
- 1997-01-10 WO PCT/US1997/000085 patent/WO1997026005A1/fr active Application Filing
- 1997-01-10 AU AU15709/97A patent/AU1570997A/en not_active Withdrawn
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2083159C (fr) | Combinaison d'une hormone de croissance et du facteur de croissance insulinoide i accelerant la croissance | |
KR0131087B1 (ko) | 인슐린 유사성 성장인자 i을 함유하는 약제학적 제제 | |
US5374620A (en) | Growth-promoting composition and its use | |
KR100429966B1 (ko) | 위장 운동성 조절을 위한 제약 조성물 | |
US5597802A (en) | Method of formulating IGF-I with growth hormone | |
EP1114644B1 (fr) | Composition comportant NPH insuline (insuline protamine neutre de Hagedorn) | |
US7312196B2 (en) | Formulations for amylin agonist peptides | |
US9867864B2 (en) | Use of somatostatin analogs in control of hypoglycemia | |
US5466670A (en) | Use of IGF-1 | |
Sakurai et al. | The role of glucagon in the pathogenesis of the endogenous hyperglycemia of diabetes mellitus | |
EP0766966A2 (fr) | Méthode de traitement de la résistance à l'insuline | |
JPH11505265A (ja) | Igf−iの投与法 | |
Russell-Jones et al. | Protein anabolic action of insulin, growth hormone and insulin-like growth factor I | |
AU663094B2 (en) | New medicinal use of IGF-II | |
AU755897B2 (en) | Methods of Increasing Sex Hormone Binding Globulin (SHBG) in a Subject | |
Ljunhgall et al. | Effects of epinephrine and norepinephrine on serum parathyroid hormone and calcium in normal subjects | |
WO1997026005A9 (fr) | Traitement anti-diabetique par une combinaison d'igf-1 avec des hypoglycemiants | |
WO1997026005A1 (fr) | Traitement anti-diabetique par une combinaison d'igf-1 avec des hypoglycemiants | |
AU752411B2 (en) | Formulation | |
Hoich et al. | Insulin-potentiating action of gliclazide (dianicron) | |
Sherwin et al. | Metabolic Effects of IGF-I: Implications for the Therapy of Diabetes Mellitus | |
Rosenfeld et al. | Use of Recombinant IGF-I in Syndromes of GH Insensitivity | |
Thomas et al. | Insulin and Oral Hypoglycemic Agents | |
SHERWIN et al. | Implications for the Therapy of | |
NZ241617A (en) | Treating and preventing secondary effects of hyperinsulinemia using insulin-like growth factor i (igf i) and lower than normal amounts of insulin |