CN1248170A - 含人体生长激素和皮质甾醇合成抑制剂的用于治疗代谢综合症的制剂 - Google Patents
含人体生长激素和皮质甾醇合成抑制剂的用于治疗代谢综合症的制剂 Download PDFInfo
- Publication number
- CN1248170A CN1248170A CN98802782A CN98802782A CN1248170A CN 1248170 A CN1248170 A CN 1248170A CN 98802782 A CN98802782 A CN 98802782A CN 98802782 A CN98802782 A CN 98802782A CN 1248170 A CN1248170 A CN 1248170A
- Authority
- CN
- China
- Prior art keywords
- growth hormone
- metabolic syndrome
- synthetic inhibitor
- product
- hydrocortisone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 208000001145 Metabolic Syndrome Diseases 0.000 title claims description 35
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 title claims description 35
- 238000002360 preparation method Methods 0.000 title claims description 15
- 108010000521 Human Growth Hormone Proteins 0.000 title abstract description 15
- 102000002265 Human Growth Hormone Human genes 0.000 title abstract description 14
- 239000000854 Human Growth Hormone Substances 0.000 title abstract description 13
- 229940126165 cortisol synthesis inhibitor Drugs 0.000 title abstract 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims abstract description 23
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims abstract description 14
- 229960004125 ketoconazole Drugs 0.000 claims abstract description 14
- 229960003604 testosterone Drugs 0.000 claims abstract description 11
- 229940011871 estrogen Drugs 0.000 claims abstract description 7
- 239000000262 estrogen Substances 0.000 claims abstract description 7
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 108
- 229960000890 hydrocortisone Drugs 0.000 claims description 54
- 239000012622 synthetic inhibitor Substances 0.000 claims description 42
- 102000018997 Growth Hormone Human genes 0.000 claims description 35
- 108010051696 Growth Hormone Proteins 0.000 claims description 35
- 239000000122 growth hormone Substances 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 23
- 241000124008 Mammalia Species 0.000 claims description 9
- 230000003203 everyday effect Effects 0.000 claims description 8
- 210000001596 intra-abdominal fat Anatomy 0.000 claims description 8
- 239000000745 gonadal hormone Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 208000024891 symptom Diseases 0.000 claims description 6
- 241001597008 Nomeidae Species 0.000 claims description 5
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 claims description 3
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 claims description 3
- 229960003913 econazole Drugs 0.000 claims description 3
- 229960002509 miconazole Drugs 0.000 claims description 3
- 239000003405 delayed action preparation Substances 0.000 claims 2
- 230000002265 prevention Effects 0.000 abstract description 7
- 208000011580 syndromic disease Diseases 0.000 abstract description 6
- 239000003163 gonadal steroid hormone Substances 0.000 abstract description 2
- 230000000955 neuroendocrine Effects 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 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 16
- 239000008103 glucose Substances 0.000 description 16
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 206010022489 Insulin Resistance Diseases 0.000 description 8
- 239000011505 plaster Substances 0.000 description 7
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 230000035487 diastolic blood pressure Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 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 6
- 230000035488 systolic blood pressure Effects 0.000 description 6
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 4
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 229960005309 estradiol Drugs 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 206010033307 Overweight Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 2
- 229960003248 mifepristone Drugs 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- AURFZBICLPNKBZ-YZRLXODZSA-N 3alpha-hydroxy-5beta-pregnan-20-one Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-YZRLXODZSA-N 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 102000009025 Endorphins Human genes 0.000 description 1
- 108010049140 Endorphins Proteins 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- AURFZBICLPNKBZ-UHFFFAOYSA-N Pregnanolone Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 AURFZBICLPNKBZ-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 239000002775 capsule 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
- 238000007385 chemical modification Methods 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229950007402 eltanolone Drugs 0.000 description 1
- 229940074117 estraderm Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000009578 growth hormone therapy Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940095970 imodium Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000037257 muscle growth Effects 0.000 description 1
- 229940063137 norditropin Drugs 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000009645 skeletal growth Effects 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 150000003515 testosterones Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
Abstract
人体生长激素与皮质甾醇合成抑制剂,特别是酮康唑合并使用,它们用来预防或治疗与代谢综合症(神经性内分泌综合症)相关的疾病。可补充给予选自睾丸酮和天然或合成雌激素的性激素。本发明也揭示了相应的药物组合物。
Description
本发明涉及预防和治疗代谢综合症。更具体的是,本发明涉及用于治疗包括代谢综合症疾病的包含皮质甾醇合成抑制剂和生长激素的药物、制剂和治疗方法。
在男性和女性中,内脏(腹部内)脂肪积聚与下列疾病的危险性增加有关:非胰岛素依赖性的糖尿病的发病、心肌梗塞、中风和其它动脉硬化疾病及其相关的危险因素(包括胰岛素抵抗、增高的血脂、血糖和高血压)。这些危险因素群被称为“代谢综合症”,也被称为“综合症X”,“耐胰岛素综合症”或“致命四重奏”。该综合症的特征也在于一种或多种内分泌紊乱,因此称为“神经-内分泌综合症”(Marin,P.Neuroendocrine News,21(3),1996,2)。这些紊乱包括低血清水平的性类固醇(男性的睾丸激素和女性的雌激素),降低生长激素作用的信号和皮质甾醇的过量分泌。后者已被临床上证明是发生代谢综合症的主要成因,因为用皮质甾醇合成抑制剂酮康唑能成功地治疗所述代谢综合症(WO96/04912)。
与代谢综合症有关的疾病包括糖尿病II型(IDDM),非胰岛素依赖性的糖尿病,心肌梗塞,中风和其它动脉硬化疾病以及这些疾病的危险因素,一般的耐胰岛素,由腹腔内脂肪积聚导致的腹部肥胖,血脂升高,舒张压和/或收缩压的升高。
虽然皮质甾醇合成抑制剂,如酮康唑是治疗前述疾病的有价值的手段,但总还有余地与机会对统称为代谢综合症的疾病或症状的预防和治疗有进一步的改进。某些已知的抑制剂在治疗有效剂量下出现了不良的副作用,研究者和医生的目的是改进治疗的效果和/或降低必须给予以达到特定效果的活性组分的用量。
本发明因此寻求提供一种预防和治疗通称为代谢综合症的方法。
现已发现,通过共同给予皮质甾醇合成抑制剂和生长激素可达到有效地治疗代谢综合症和/或与其有关的症状或疾病的目的。
这样,根据本发明的一个方面,本发明提供了与哺乳动物中代谢综合症作斗争的方法,该方法包括对所述哺乳动物给予有效量的皮质甾醇合成抑制剂和生长激素以便与代谢综合症的临床表现作斗争。
本文使用的术语“作斗争”包括治疗和预防,因此治疗和预防代谢综合症的方法包含于本发明。
本文使用的术语“代谢综合症”指内脏脂肪的积聚和与其有关的危险因素,以及特征在于综合症的上述列举的内分泌紊乱。该术语也指与如上所讨论的代谢综合症有关的疾病、IDDM、NIDDM等。类固醇糖皮质激素皮质甾醇在肾上腺里从孕甾烷醇酮经黄体酮合成,本身涉及蛋白质、碳水化合物和脂质在大多数组织里的代谢和抑制炎症反应。“皮质甾醇合成抑制剂”应当被理解为减少但不是彻底阻断人体皮质甾醇的合成。给予的目的是将增加的皮质甾醇水平降低到正常水平或稍低于正常水平。
已知许多约剂能抑制人体的糖皮质激素的产生或抑制它们的受体结合:丙戊酸钠(Aggernaes,H.等,Acta Psychiatr.Scand.(1988)77 170-174);内啡肽和它们的合成类似物(Stubbs,W.A.等,The Lancet(1978)1225-1227);类鸦片药,如氯苯哌酰胺,商品名为IMODIUM,Janssen Pharmaceutica N.V.出售;抗高血压药氯压定(Slowinska-Srzednicka,J.等,European Journal of ClinicalPharmacology(1988)35 115-121);催产素(Legros,J.J.等,Endocrinologica(1987)114 345-349)和米非司酮(Mifepristone),称为RU 486或RU 38486,Roussel-Uclaf出售。
上述药剂或该技术领域公知的许多皮质甾醇合成抑制剂可用作本发明的皮质甾醇合成抑制剂。但是,许多已知的皮质甾醇合成抑制剂被局部外用给药以抵抗真菌感染;一般说来,它们的不良反应和/或胃肠道的吸收差使之不能用于本发明。本发明能口服给予皮质甾醇合成抑制剂。本发明发现含有皮质甾醇合成抑制剂酮康唑的治疗与药物特别有效,特别由于其低毒性和没有其它不良作用。酮康唑作用的特定作用机理是导致合成称为“削弱的皮质甾醇”的物质,以替代正常的皮质甾醇,前者缺乏天然皮质甾醇的生物功能。也可使用酮康唑的衍生物。
其它有用的皮质甾醇合成抑制剂包括氯苯甲氧咪唑(Squibb,英国)和双氯苯咪唑(Janssen,比利时)和它们的衍生物。酮康唑、氯苯甲氧咪唑或双氯苯咪唑与生长激素配合使用代表了本发明优选的技术方案。
人体生长激素是有191个氨基酸的蛋白质,其分子量为22,000道尔顿,在垂体前叶或腺垂体前叶里产生。激素以前体形式合成,一旦成为活性形式即从细胞分泌。人体生长激素(hGH)作用模式尚且不很明了,但它刺激肝脏产生躯体生长素-1(somatomedin-1),它接着导致肌肉和骨骼的生长;刺激脂肪、肌肉和软骨细胞分化,并影响脂质和碳水化合物代谢。生长激素类似物在其它种属里也是已知的,也可使用任何哺乳动物生长激素(GH)或其衍生物。
本发明也可使用萃取和纯化的GH,但优选的是使用重组GH(rGH),特别优选的是重组人体生长激素(rhGH)。这类重组体技术是本技术领域已知的;例如,US 5,268,277揭示了从转换的Bacillus subtilis培养物中制备与天然人体生长激素相同的人体生长激素的方法。
术语“生长激素”,除了哺乳动物肽的天然序列外,也包括具有修饰序列和化学修饰变体,特别是191氨基酸hGH。对完整生长激素掺入了氨基酸取代物,加成物和删去的所有肽片断均为该术语所包含,只要它们还保留,优选的是全部保留或基本保留天然生长激素的生物活性即可。对生长激素活性的分析是本技术领域已知的,可基于从前-脂细胞到脂细胞的分化上作出[Green,H.等,Differentiation 1985;29:195-198]。任何重组生长激素肽优选地有至少65%与天然肽同源。
下列实施例给出了可根据本发明“作斗争”或“治疗”的临床观察到与代谢综合症有关的症状与疾病的指征,以及可预期的改进点。
更具体的是,本发明提供了减少与哺乳动物代谢综合症有关的内脏脂肪块的方法,该方法包括对所述哺乳动物给予有效量皮质甾醇合成抑制剂和生长激素以减少内脏脂肪块。
本发明的再一个方面提供了利用皮质甾醇合成抑制剂和生长激素在制备与代谢综合症作斗争的药物中的应用。
本文中“药物”表示最宽的含义,不限于实际上包含两种活性组分的物理混合物的组合物。确实,在本发明优选的技术方案中,两种活性组分不是混合的,皮质甾醇合成抑制剂被口服给药,生长激素被皮下给药。另外,“药物”不限于在时间意义上的同时给药制剂。
在本发明的再一个方面,本发明提供了含(a)皮质甾醇合成抑制剂和(b)生长激素的产品,它作为同时、分开或依次使用以与代谢综合症作斗争的合并制剂。
这样的活性组分或药剂不一定必需同时给药。事实上,分开或依次使用来预防或治疗代谢综合症是本发明优选的技术方案。
在本发明的再一个方面,本发明提供了包含皮质甾醇合成抑制剂与生长激素配合使用来与代谢综合症作斗争的药品。
从另一方面来看,本发明也提供了用于同代谢综合症作斗争的药盒,包括:
(a)含有皮质甾醇合成抑制剂的第一容器;和
(b)含有生长激素的第二容器。
药品可常规地包含至少一种药学上可接受的载体或赋形剂。
“药品”也是具有最宽的含义,它不限于包括两个活性组分混合物的单个实体。但是,本发明的技术方案包括含有两种药剂和至少一种药学上可接受的载体或赋形剂的药物组合物。
在本发明的优选技术方案中,用以补偿由皮质甾醇合成抑制剂导致的睾丸激素水平降低的药理上有效量睾丸激素或其类似物或衍生物也可给予病人。但组合物使用皮质甾醇合成抑制剂、人体生长激素和睾丸激素仅在治疗对象是男性时是有用的。
在本发明的再一个技术方案中,也可将用以补偿由皮质甾醇合成抑制剂导致的雌激素水平降低的有效量的天然或合成的雌激素。如雌二醇和它的类似物或衍生物给予病人。但组合物使用皮质甾醇合成抑制剂、人体生长激素和雌激素仅在治疗对象是女性时才认为是有用的。
“药用有效量”是指每个组分分开使用时的药用有效量,即,足以得到皮质甾醇合成抑制剂可测得的血药浓度,和将hGH和睾丸激素水平分别升高到平均水平以上的用量。
未患代谢综合症病人的皮质甾醇正常水平基本上呈现每天昼夜切律性改变,最高水平在早晨。现已发现,为得到最佳结果,在傍晚给予皮质甾醇合成抑制剂能优选地覆盖该最大值。健康成人的平均皮质甾醇血药水平为10微克/100毫升级别。通过测量病人一天里的尿样里的皮质甾醇得到皮质甾醇生物合成的相关数据,参照范围为每24小时约80-400毫摩尔。
本发明的活性组分优选的是时间相关方式给药。“时间相关方式”指间隔或延缓释放给予药用有效量活性试剂,以基本重叠的时间方式进行重复给药(或延缓释放)。换言之,虽然皮质甾醇合成抑制剂(或至少部分每天剂量)优选的是在晚上、睡觉时给药,但生长激素优选地在早晨给药。若也给予性激素,它应当优选地以膏药剂给予,以使激素在一天内基本恒定地释放。但是,其它“定时”给药方案也可采用,由医生或开处方者根据临床需要或按常规医学实践和本技术领域已知的技术要求来决定。
优选的是在给药期间的至少80%时间里,每天给予皮质甾醇合成抑制剂和生长激素。性激素优选地在给药期间的至少50%时间里每天给予。
这类给药方案优选地是保持至少一个月,更好的是6个月或更长。成功的疗程特征尤其在于,减少内脏里脂肪块,血压降低,胰岛素敏感性增加,禁食血糖水平降低,血清胆固醇和甘油三酯水平降低。
本发明的药物和组合物可以常规的方式配制,与药学上可接受惰性稀释剂、载体和/或赋形剂混合。合适的制剂在实施例里讨论。可以冻干hGH制剂,以得到干粉末或即刻可使用的液体形式。WO 9535116揭示了hGH制剂,它包括蔗糖,它对于配制含重组人体生长激素的制剂尤为有效。根据本发明,可使用上述的任何方法。制剂可包括1-99%活性组分。需要时,皮质甾醇合成抑制剂组合物可含有这类抑制剂的混合物。活性剂或组合物因此可配制成片剂、丸剂、胶囊、栓剂、子宫套等,或配制成溶液、悬浮液、霜剂、糊剂、凝胶剂、植入剂、透皮膏药片等,或其它方法。
如上所述,活性剂可一起配制,或更优选的是分开配制。可使用任何可得到的给药形式,活性剂可经,如肠给药(如口服或直肠给药),非胃肠道给药(如静注,肌注或皮下给药),局部外用给药(包括透粘膜给药和透皮给药)或任何其它手段给药。
虽然皮质甾醇合成抑制剂优选的是口服给药,但性激素优选的是透皮给药,如通过膏药片或通过肌注给药,优选的是微胶囊,或通过植入设备给药,生长激素优选的是通过皮下注射给药。
本发明在下列非限制性实施例中将作更详尽的阐述。
实施例1
A.给予酮康唑
酮康唑(顺-1-乙酰基-4-[4-[[2-2(2,4-二氯苯基)-2-(1H-咪唑基甲基)-1,3-二氧戊环-4-基]-甲氧基]苯基]哌嗪;美国专利4,144,346和4,223,036;Janssen(比利时)制备了含200毫克的片剂,商品名为Fungoral。成人给予1-4片/天(优选范围是约50毫克到约1克/天),优选的是至少50%的每天剂量在睡觉前给予。
B.给予生长激素
重组人体生长激素(促生长素somatropin)由Novo Nordisk(丹麦)制造,商品名为Norditropin。供注射的液体是12 IE(I+II)/毫升。经皮下注射或肌注给药;每天给予该溶液0.2-2毫升。
C.给予睾丸激素
在苯甲酸苄酯/蓖麻油中的睾丸庚酸酯250毫克/毫升;由Schering AG(德国)制备,商品名为Testoviron-Depot。以约3周间隔肌注给予。优选的单剂为0.2-1.0毫升。另外的给药方式是通过膏药片释放约2.5毫克/天,由AB Astra(瑞典)生产的商品名为Atmos的膏药片。优选地是给予1-3片/天(每24小时2-10毫克睾丸酮)。
D.给予雌二醇
将足以补偿雌激素水平下降的用量在24小时里释放24微克的17β-雌二醇(Estraderm,Ciba)的膏药片施加到人体。
实施例2
对三个病人的观察
病人(2例男性,年龄47和62;1例女性,年龄57岁)患有内脏脂肪过多,体重中等超重到极度超重。三人都显示出血压中等度升高,胰岛素敏感性下降。给药(药物如上所示):酮康唑,2-3片/天,其中的一片或两片在睡觉时给予;hGH 0.15-0.20 IU/千克体重,皮下每天给予一次(通常在早晨给药);睾丸酮2或3片膏药片/天。
在第一个6-8周的治疗中,内脏脂肪块慢慢减少;在该期间没有观察到其它临床症状。在下一个阶段,从开始直到9-12个月,开始看到内脏脂肪进一步减少,用计算机化的断层摄影术(CT)测量到总的减少约20%到30%(典型地是约8-5.5千克)。收缩压从180-减少到165mm Hg,舒张压从92减少到84mm Hg。通过夹持方法(clamp methou)测量的胰岛素敏感性增加到约45%,平均为(约2-4到3-8毫克葡萄糖/升)。禁食血葡萄糖水平减少约0.5-1.0毫摩尔/升,例如,没有糖尿病的病人从5.8到5.0毫摩尔/升,患有糖尿病的病人从9到6.5。总的血清胆固醇从7.8降低到5.9毫摩尔/升;血清甘油三酯从2.7减少到1.9毫摩尔/升。病人也显示出体力和心智的健康状态改善。
实施例3
用皮质甾醇抑制剂(酮康唑剂量为400毫克)和剂量为0.15#IU/kg体重的生长激素治疗两例女性和两例男性。所有病人膜部都异常肥胖,一名男性和一名女性也患有明显的糖尿病。总之,他们都有代谢综合症的症状。8月后,所有病人在下列参数方面都有改善:
病例1(男性,58岁)
前 后禁食葡萄糖 6.3毫摩尔/升 5.7毫摩尔/升收缩压 187mm Hg 176mm Hg舒张压 102mm Hg 97mm Hg胰岛素敏感性(通过所述的夹持方法测量) 5.4mg葡萄糖 6.4mg葡萄糖
/kg/ml /kg/ml禁食胆固醇/S* 8.3毫摩尔/升 7.5毫摩尔/升
病例2(男性,62岁)
前 后禁食葡萄糖 5.3毫摩尔/升 5.0毫摩尔/升收缩压 173mm Hg 169mm Hg舒张压 97mmHg 92mm Hg胰岛素敏感性(通过所述的夹持方法测量) 6.5mg葡萄糖 7.5mg葡萄糖
/kg/ml /kg/ml禁食胆固醇/S* 7.9毫摩尔/升 7.5毫摩尔/升
病例3(女性,64岁)
前 后禁食葡萄糖 5.9毫摩尔/升 5.2毫摩尔/升收缩压 164mm Hg 159mm Hg舒张压 90mmHg 86mm Hg胰岛素敏感性(通过所述的夹持方法测量) 4.8mg葡萄糖 5.9mg葡萄糖
/kg/ml /kg/ml禁食胆固醇/S* 6.9毫摩尔/升 6.2毫摩尔/升
病例4(女性,67岁)
前 后禁食葡萄糖 5.2毫摩尔/升 4.9毫摩尔/升收缩压 171mm Hg 162mm Hg舒张压 89mmHg 85mm Hg胰岛素敏感性(通过所述的夹持方法测量) 6.8mg葡萄糖 7.9mg葡萄糖
/kg/ml /kg/ml禁食胆固醇/S* 6.5毫摩尔/升 6.0毫摩尔/升
另外,也报道了病例1、2和4的体力和心理健康状况得以改善。
8个月后,在治疗方案中加入睾丸酮治疗,其目的是将男性的睾丸酮水平修复到正常值,它们进一步改进了上述参数,其它治疗未变。对于女性加入了雌激素治疗,它们也合适地进一步改进了上述参数。
最后,还观察到所有病人的肝脏转胺酶减少约35-40%,这表明肝脏脂肪变性减轻。
Claims (16)
1.一种抵抗哺乳动物代谢综合症的方法,该方法包括对所述哺乳动物给予治疗代谢综合症临床症状有效量的皮质甾醇合成抑制剂和生长激素。
2.一种减少哺乳动物中与代谢综合症有关的内脏脂肪块的方法。该方法包括对所述的哺乳动物给予能有效地减少所述内脏脂肪块的皮质甾醇合成抑制剂和生长激素。
3.皮质甾醇合成抑制剂和生长激素用于制备抵抗代谢综合症的药物或用于减少与代谢综合症有关的内脏脂肪块的药物中的应用。
4.一种产品,含(a)皮质甾醇合成抑制剂,和(b)生长激素,它可作为同时、分开或连续用于抵抗代谢综合症的合并制剂或用于减少与代谢综合症有关的内脏脂肪块的合并制剂。
5.一种药品,包括皮质甾醇合成抑制剂与生长激素,它用于抵抗代谢综合症或用于减少与代谢综合症相关的内脏脂肪块。
6.根据前述权利要求的任一所述方法,用途或产品,其中皮质甾醇合成抑制剂选自酮康唑、氯苯甲氧咪唑和双氯苯咪唑及它们的衍生物。
7.根据权利要求6所述的方法,用途或产品,其中皮质甾醇合成抑制剂是酮康唑。
8.根据前述权利要求的任一所述方法、用途或产品,其中给药、药物或产品另外包括性激素,所述的性激素选自睾丸酮和天然或合成雌激素。
9.根据前述权利要求的任一所述方法、用途或产品,其中治疗延续1个月或更长的时间。
10.根据前述权利要求的任一所述方法、用途或产品,其中皮质甾醇合成抑制剂和生长激素每天给予,持续给药期的至少80%。
11.根据权利要求8-10任一所述的方法、用途或产品,其中性激素或者通过控释制剂给予,所述的控释制剂在治疗期间的至少50%里释放药理上有效量的性激素。
12.根据前述权利要求的任一所述方法、用途或产品,其中皮质甾醇合成抑制剂和生长激素以时间相关方式给药。
13.根据权利要求12所述的方法、用途或产品,其中皮质甾醇合成抑制剂在早晨给予病人,生长激素在傍晚给予病人。
14.根据权利要求12所述的方法、用途或产品,其中皮质甾醇合成抑制剂在任何一天生长激素给予后至少7小时之后给予。
15.根据权利要求14所述的方法、用途或产品,其中皮质甾醇合成抑制剂在生长激素给予之后至少10小时给予。
16.一种用于抵抗代谢综合症的药盒,包括:
(a)含皮质甾醇合成抑制剂的第一容器;和
(b)含生长激素的第二容器。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9700642A SE9700642D0 (sv) | 1997-02-24 | 1997-02-24 | Medel och sätt för förebyggande och behandling av det metabola syndromet |
SE97006423 | 1997-02-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1248170A true CN1248170A (zh) | 2000-03-22 |
CN1178696C CN1178696C (zh) | 2004-12-08 |
Family
ID=20405901
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB988027828A Expired - Fee Related CN1178696C (zh) | 1997-02-24 | 1998-02-24 | 含人体生长激素和皮质甾醇合成抑制剂的用于治疗代谢综合症的制剂 |
Country Status (12)
Country | Link |
---|---|
US (1) | US6274582B1 (zh) |
EP (1) | EP1030682A1 (zh) |
JP (1) | JP2001513082A (zh) |
KR (1) | KR20000075626A (zh) |
CN (1) | CN1178696C (zh) |
AU (1) | AU743277B2 (zh) |
CA (1) | CA2282467A1 (zh) |
NO (1) | NO994053L (zh) |
NZ (1) | NZ337123A (zh) |
RU (1) | RU2198679C2 (zh) |
SE (1) | SE9700642D0 (zh) |
WO (1) | WO1998036770A1 (zh) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6642236B1 (en) * | 1998-12-14 | 2003-11-04 | Cortendo Ab | Methods for prophylactic treatment of cardiovascular disease with inhibitor of cortisol synthesis |
NZ514290A (en) * | 1999-04-01 | 2003-08-29 | Akzo Nobel Nv | Formulation comprising testosterone undecanoate and castor oil |
AU2004200545B2 (en) * | 1999-08-18 | 2007-05-17 | Microdose Therapeutx, Inc. | Metering and packaging of controlled release medication |
US6428809B1 (en) * | 1999-08-18 | 2002-08-06 | Microdose Technologies, Inc. | Metering and packaging of controlled release medication |
GB0001449D0 (en) * | 2000-01-21 | 2000-03-08 | Cortendo Ab | Compositions |
SE0001899D0 (sv) | 2000-05-22 | 2000-05-22 | Pharmacia & Upjohn Ab | New compounds |
US7094792B2 (en) | 2001-11-22 | 2006-08-22 | Biovitrum Ab | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 |
US6967194B1 (en) * | 2002-09-18 | 2005-11-22 | Susan Matsuo | Bio-identical hormones and method of use |
US7383084B2 (en) * | 2002-10-31 | 2008-06-03 | Transpharma Medical Ltd. | Transdermal delivery system for dried particulate or lyophilized medications |
US8133505B2 (en) * | 2002-10-31 | 2012-03-13 | Transpharma Medical Ltd. | Transdermal delivery system for dried particulate or lyophilized medications |
IL152574A (en) * | 2002-10-31 | 2009-09-22 | Transpharma Medical Ltd | A system for passing through the skin of dry items or dried medicines |
US7662404B2 (en) * | 2002-10-31 | 2010-02-16 | Transpharma Medical Ltd. | Transdermal delivery system for dried particulate or lyophilized peptides and polypeptides |
JO2505B1 (en) | 2003-03-14 | 2009-10-05 | باير شيرنغ فارما اكتنجيسيلشافت | Pharmacy methods and formulations for obtaining acceptable serum testosterone levels |
US20050031718A1 (en) * | 2003-04-10 | 2005-02-10 | Pharmanex, Llc | Sea Buckthorn compositions and associated methods |
US20050232911A1 (en) * | 2004-04-19 | 2005-10-20 | Schreiber Brian D | Prevention and treatment of metabolic abnormalities associated with excess intramyocellular lipid |
DE102004034640A1 (de) | 2004-07-16 | 2006-02-16 | Institut für Molekular- und Systemmedizin | Verfahren zur systemischen Biokorrektur eines Organismus |
ATE528005T1 (de) * | 2005-01-10 | 2011-10-15 | Cortendo Ab Publ | 2s,4r ketoconazol zur behandlung von diabetes, metabolischem syndrom und anderen erkrankungen |
KR100705981B1 (ko) * | 2005-10-12 | 2007-04-10 | 주식회사 리제론 | 인간 성장호르몬을 포함하는 탈모방지 또는 발모촉진용조성물 |
CA2664800A1 (en) | 2006-10-02 | 2008-04-10 | Timothy Andrew Stewart | Ketoconazole enantiomer in humans |
US8439033B2 (en) | 2007-10-09 | 2013-05-14 | Microdose Therapeutx, Inc. | Inhalation device |
CA2742964C (en) | 2008-11-07 | 2020-07-07 | University Of Sheffield | Medicament and method of diagnosis |
MY187036A (en) | 2010-01-05 | 2021-08-27 | Microdose Therapeutx Inc | Inhalation device and method |
US9200277B2 (en) * | 2010-01-11 | 2015-12-01 | Curna, Inc. | Treatment of sex hormone binding globulin (SHBG) related diseases by inhibition of natural antisense transcript to SHBG |
KR20170020779A (ko) | 2014-06-17 | 2017-02-24 | 머크 샤프 앤 도메 비.브이. | 테스토스테론 운데카노에이트의 안정한 제제 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1360960A1 (en) * | 1994-08-09 | 2003-11-12 | Cortendo AB | Use of ketoconazole and related substances in medicaments for treatment of type II diabetes |
-
1997
- 1997-02-24 SE SE9700642A patent/SE9700642D0/xx unknown
-
1998
- 1998-02-24 CA CA002282467A patent/CA2282467A1/en not_active Abandoned
- 1998-02-24 AU AU63023/98A patent/AU743277B2/en not_active Ceased
- 1998-02-24 WO PCT/GB1998/000574 patent/WO1998036770A1/en not_active Application Discontinuation
- 1998-02-24 KR KR1019997007690A patent/KR20000075626A/ko not_active Application Discontinuation
- 1998-02-24 RU RU99120189/14A patent/RU2198679C2/ru not_active IP Right Cessation
- 1998-02-24 JP JP53641898A patent/JP2001513082A/ja active Pending
- 1998-02-24 NZ NZ337123A patent/NZ337123A/en unknown
- 1998-02-24 CN CNB988027828A patent/CN1178696C/zh not_active Expired - Fee Related
- 1998-02-24 EP EP98907037A patent/EP1030682A1/en not_active Withdrawn
-
1999
- 1999-08-23 NO NO994053A patent/NO994053L/no not_active Application Discontinuation
- 1999-08-24 US US09/379,832 patent/US6274582B1/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
NO994053D0 (no) | 1999-08-23 |
CN1178696C (zh) | 2004-12-08 |
SE9700642D0 (sv) | 1997-02-24 |
KR20000075626A (ko) | 2000-12-26 |
US6274582B1 (en) | 2001-08-14 |
WO1998036770A1 (en) | 1998-08-27 |
EP1030682A1 (en) | 2000-08-30 |
NZ337123A (en) | 2005-05-27 |
JP2001513082A (ja) | 2001-08-28 |
NO994053L (no) | 1999-09-24 |
CA2282467A1 (en) | 1998-08-27 |
RU2198679C2 (ru) | 2003-02-20 |
AU6302398A (en) | 1998-09-09 |
AU743277B2 (en) | 2002-01-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1178696C (zh) | 含人体生长激素和皮质甾醇合成抑制剂的用于治疗代谢综合症的制剂 | |
JP5042312B2 (ja) | Hghを含む経口送達用医薬組成物 | |
AU718500B2 (en) | Remedies for diabetes | |
EP0612531A1 (en) | Therapeutic agent for digestive tract diseases | |
CN112055592A (zh) | 用于治疗代谢疾病的组合物和方法 | |
Youngs | Hormonal control of pancreatic endocrine and exocrine secretion. | |
CN103702668A (zh) | 治疗糖尿病的组合物和方法 | |
CA2044511A1 (en) | Pharmaceutical resorption-improved somatostatin compositions, their preparation and use | |
CA3091729A1 (en) | Glp-1 composition for treating obesity and weight management | |
Ebert et al. | Gastric inhibitory polypeptide | |
EP1229927B1 (en) | Use of a growth hormone or a growth hormone secretagogue for appetite-suppression or induction of satiety | |
WO2023231730A2 (zh) | 使用mazdutide的治疗方法 | |
PT98764B (pt) | Processo para a preparacao de composicoes contendo factor de desenvolvimento de insulina 1 completo para o tratamento terapeutico ou profilactico de estado catabolicos | |
US7229965B2 (en) | Use of growth hormone in low dose | |
CZ298999A3 (cs) | Výroba léčiva, kombinovaný therapeutický prostředek a směs a kit obsahující inhibitor syntézy kortisolu a růstový hormon | |
TWI228992B (en) | Treatment of subnormal bone mineral density | |
Haller et al. | Incretin therapy in feline diabetes mellitus–a review of the current state of research | |
AU2006200127B2 (en) | Use of growth hormone in low dose | |
CN118267476A (zh) | 一种药物组合、药物组合物及其应用 | |
WO2021113233A1 (en) | Combination therapy using glucagon and glp-1 co-agonists for the treatment of obesity | |
EP4087596A1 (en) | Glucagon and glp-1 co-agonists for the treatment of chronic kidney disease and diabetic kidney disease in type 2 diabetes | |
WO2023228155A1 (en) | Compositions and methods for treatment of neurological disorders | |
Tormey et al. | Nocturnal ulcer pain associated with slow-wave sleep |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |