CN1135177A - 用氧化氮合酶底物和/或供体治疗更年期疾病的方法 - Google Patents
用氧化氮合酶底物和/或供体治疗更年期疾病的方法 Download PDFInfo
- Publication number
- CN1135177A CN1135177A CN94194167A CN94194167A CN1135177A CN 1135177 A CN1135177 A CN 1135177A CN 94194167 A CN94194167 A CN 94194167A CN 94194167 A CN94194167 A CN 94194167A CN 1135177 A CN1135177 A CN 1135177A
- Authority
- CN
- China
- Prior art keywords
- purposes
- nitric oxide
- progestogen
- estrogen
- mammal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000758 substrate Substances 0.000 title claims abstract description 39
- 102000008299 Nitric Oxide Synthase Human genes 0.000 title claims description 17
- 108010021487 Nitric Oxide Synthase Proteins 0.000 title claims description 17
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 141
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class 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 claims abstract description 53
- 239000000583 progesterone congener Substances 0.000 claims abstract description 47
- 239000000262 estrogen Substances 0.000 claims abstract description 43
- 229940011871 estrogen Drugs 0.000 claims abstract description 42
- 241000124008 Mammalia Species 0.000 claims description 29
- 230000009245 menopause Effects 0.000 claims description 29
- 239000002840 nitric oxide donor Substances 0.000 claims description 27
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 26
- 229930064664 L-arginine Natural products 0.000 claims description 26
- 235000014852 L-arginine Nutrition 0.000 claims description 26
- 229960003387 progesterone Drugs 0.000 claims description 25
- 239000000186 progesterone Substances 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 20
- 208000011580 syndromic disease Diseases 0.000 claims description 18
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims description 16
- 238000002657 hormone replacement therapy Methods 0.000 claims description 16
- 229960003711 glyceryl trinitrate Drugs 0.000 claims description 15
- 230000035935 pregnancy Effects 0.000 claims description 14
- 239000000006 Nitroglycerin Substances 0.000 claims description 13
- 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 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 229960005309 estradiol Drugs 0.000 claims description 10
- 229930182833 estradiol Natural products 0.000 claims description 10
- -1 methylnorethindron Chemical compound 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 claims description 8
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 claims description 8
- 229960004766 estradiol valerate Drugs 0.000 claims description 8
- 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 claims description 6
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical group [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 claims description 6
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 claims description 6
- 229940083618 sodium nitroprusside Drugs 0.000 claims description 6
- 230000017531 blood circulation Effects 0.000 claims description 5
- 230000001076 estrogenic effect Effects 0.000 claims description 5
- 229940088597 hormone Drugs 0.000 claims description 5
- 239000005556 hormone Substances 0.000 claims description 5
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229940063238 premarin Drugs 0.000 claims description 5
- NCGICGYLBXGBGN-UHFFFAOYSA-N 3-morpholin-4-yl-1-oxa-3-azonia-2-azanidacyclopent-3-en-5-imine;hydrochloride Chemical compound Cl.[N-]1OC(=N)C=[N+]1N1CCOCC1 NCGICGYLBXGBGN-UHFFFAOYSA-N 0.000 claims description 4
- 229960004976 desogestrel Drugs 0.000 claims description 4
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 229960002667 norelgestromin Drugs 0.000 claims description 4
- ISHXLNHNDMZNMC-XUDSTZEESA-N norelgestromin Chemical compound ON=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 ISHXLNHNDMZNMC-XUDSTZEESA-N 0.000 claims description 4
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001348 estriol Drugs 0.000 claims description 3
- 229960003399 estrone Drugs 0.000 claims description 3
- 238000009448 modified atmosphere packaging Methods 0.000 claims description 3
- 229940053934 norethindrone Drugs 0.000 claims description 3
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 claims description 3
- 150000000307 17β-estradiols Chemical class 0.000 claims description 2
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 2
- SIGSPDASOTUPFS-XUDSTZEESA-N gestodene Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](C=C4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 SIGSPDASOTUPFS-XUDSTZEESA-N 0.000 claims description 2
- 229960005352 gestodene Drugs 0.000 claims description 2
- 235000019837 monoammonium phosphate Nutrition 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims 1
- 208000024891 symptom Diseases 0.000 abstract description 15
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 abstract 1
- 230000001668 ameliorated effect Effects 0.000 abstract 1
- 229910017604 nitric acid Inorganic materials 0.000 abstract 1
- 230000003203 everyday effect Effects 0.000 description 42
- 230000000694 effects Effects 0.000 description 20
- 241000700159 Rattus Species 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- KCWZGJVSDFYRIX-YFKPBYRVSA-N N(gamma)-nitro-L-arginine methyl ester Chemical compound COC(=O)[C@@H](N)CCCN=C(N)N[N+]([O-])=O KCWZGJVSDFYRIX-YFKPBYRVSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 206010020772 Hypertension Diseases 0.000 description 10
- 230000003213 activating effect Effects 0.000 description 9
- 230000036772 blood pressure Effects 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- QFFCYTLOTYIJMR-XMGTWHOFSA-N promegestone Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@@](C(=O)CC)(C)[C@@]1(C)CC2 QFFCYTLOTYIJMR-XMGTWHOFSA-N 0.000 description 7
- 210000004291 uterus Anatomy 0.000 description 7
- 206010060800 Hot flush Diseases 0.000 description 6
- 201000011461 pre-eclampsia Diseases 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003270 steroid hormone Substances 0.000 description 6
- 206010027304 Menopausal symptoms Diseases 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000002354 daily effect Effects 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000008298 dragée Substances 0.000 description 5
- 230000001605 fetal effect Effects 0.000 description 5
- 210000003754 fetus Anatomy 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 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 description 4
- 201000010099 disease Diseases 0.000 description 4
- 210000003038 endothelium Anatomy 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229940060626 estradiol valerate 2 mg Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000002464 muscle smooth vascular Anatomy 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229940123134 Nitric oxide inhibitor Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 238000009795 derivation Methods 0.000 description 2
- RPLCPCMSCLEKRS-BPIQYHPVSA-N desogestrel Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RPLCPCMSCLEKRS-BPIQYHPVSA-N 0.000 description 2
- 201000003914 endometrial carcinoma Diseases 0.000 description 2
- 229940083543 estradiol 1 mg Drugs 0.000 description 2
- 229940020394 estriol 0.5 mg Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940063877 norethindrone acetate 1 mg Drugs 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 229960001584 promegestone Drugs 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- CTULHRFLFQFJDU-UHFFFAOYSA-N siderone Natural products C1CC2C3(C)CCCC(C)(CO)C3CC(=O)C22C=C(C)C1C2 CTULHRFLFQFJDU-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- GYIQPJWVMMGMBL-WCCKRBBISA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid;guanidine Chemical compound NC(N)=N.OC(=O)[C@@H](N)CCCNC(N)=N GYIQPJWVMMGMBL-WCCKRBBISA-N 0.000 description 1
- WFHDOIKSUKQTLH-IBXXTFBESA-N (8r,9s,10r,13s,14s,17r)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one;[(8r,9s,13s,14s,17s)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] pentanoate Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1.C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 WFHDOIKSUKQTLH-IBXXTFBESA-N 0.000 description 1
- PGHBYDVOOPRPQW-UHFFFAOYSA-N 1,3-dinitrooxypropan-2-yl nitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O.[O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O PGHBYDVOOPRPQW-UHFFFAOYSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- 102100032381 Alpha-hemoglobin-stabilizing protein Human genes 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 206010014756 Endometrial hypertrophy Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101000797984 Homo sapiens Alpha-hemoglobin-stabilizing protein Proteins 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- UYZFAUAYFLEHRC-LURJTMIESA-N L-NIO Chemical compound CC(N)=NCCC[C@H](N)C(O)=O UYZFAUAYFLEHRC-LURJTMIESA-N 0.000 description 1
- 150000008535 L-arginines Chemical class 0.000 description 1
- MRAUNPAHJZDYCK-BYPYZUCNSA-N L-nitroarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O MRAUNPAHJZDYCK-BYPYZUCNSA-N 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 206010027514 Metrorrhagia Diseases 0.000 description 1
- NTNWOCRCBQPEKQ-YFKPBYRVSA-N N(omega)-methyl-L-arginine Chemical compound CN=C(N)NCCC[C@H](N)C(O)=O NTNWOCRCBQPEKQ-YFKPBYRVSA-N 0.000 description 1
- UYZFAUAYFLEHRC-UHFFFAOYSA-N NG-iminoethyl-L-ornithine Natural products CC(N)=NCCCC(N)C(O)=O UYZFAUAYFLEHRC-UHFFFAOYSA-N 0.000 description 1
- NTNWOCRCBQPEKQ-UHFFFAOYSA-N NG-mono-methyl-L-arginine Natural products CN=C(N)NCCCC(N)C(O)=O NTNWOCRCBQPEKQ-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical group C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 1
- MPSOHXLZDRQABN-KOAPPJMKSA-N [(8r,9s,10r,13s,14s,17r)-17-ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate;(8r,9s,13s,14s,17s)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol;(8r,9s,13s,14s,16r,17 Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1.OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1.C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 MPSOHXLZDRQABN-KOAPPJMKSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940124572 antihypotensive agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000010692 aromatic oil Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000006828 endometrial hyperplasia Diseases 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940083544 estradiol 2 mg Drugs 0.000 description 1
- 229940008214 estradiol 4 mg Drugs 0.000 description 1
- 229940071887 estradiol 50 mg Drugs 0.000 description 1
- 229940060591 estradiol valerate 1 mg Drugs 0.000 description 1
- 229940063169 estriol 1 mg Drugs 0.000 description 1
- 229940020395 estriol 2 mg Drugs 0.000 description 1
- 229950008385 estrone sulphate Drugs 0.000 description 1
- HZEQBCVBILBTEP-ZFINNJDLSA-N estropipate Chemical compound C1CNCCN1.OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 HZEQBCVBILBTEP-ZFINNJDLSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000008175 fetal development Effects 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000011010 flushing procedure 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
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000000745 gonadal hormone Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002395 mineralocorticoid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229960002460 nitroprusside Drugs 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000007833 oxidative deamination reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 208000025934 placenta disease Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000021395 porridge Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000003191 uterotonic effect Effects 0.000 description 1
- 230000009441 vascular protection Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/04—Nitro compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/295—Iron group metal compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Pregnancy & Childbirth (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
通过对患者使用单一的或任意地与孕激素,或者,对于非妊娠雌性患者与孕激素或雌激素或二者的组合,结合的氧化氮合酶和/或氧化氮供体或二者的组合,改善更年期症状。
Description
发明背景
本发明涉及使用单一的或(对于雌性患者)与雌激素和/或用来进行孕激素的激素替补疗法(HRT)的物质结合的氧化氮合酶底物的(L-精氨酸),氧化氮供体或二者的组合,治疗及预防与中年妇女卵巢功能退化有关的绝经期更年期疾病如热潮红,异常凝块模式,泌尿生殖器官不适,心血管疾病发生率增加,等的方法,或者,对于男性更年期疾病患者,使用与孕激素结合的上述药物治疗的方法。
众所周知,HRT,如雌激素治疗,可改善或扭转绝经期卵巢的性甾类化合物分泌的多方面影响。已知雌激素可改善绝经后妇女的情绪和心理健康并可预防生殖泌尿道萎缩。已知雌激素可影响动脉紧张程度,这有助于解释用雌激素治疗可缓减绝经期后妇女热潮红的原因。另一方面,不能排斥雌激素治疗与子宫内膜增生和子宫内膜癌有关。
很多研究已显示在雌激素HRT中加入孕激素可减小子宫内膜癌的危险率,并且甚至可扭转子宫内膜的增生。然而,孕激素不是没有它们自己的不利的副作用。
孕激素可通过诱导浆液中致动脉粥样化因素的全视而排斥雌激素对心血管系统的有益影响。另外,当进行持续或相继的雌激素-孕激素联合治疗时,常见持续的无规律的或者停药后的出血。
无论如何,正如通常在避孕药中所使用的那样。现代HRT使用雌激素和孕激素的结合。
生物学和医学最令人兴奋的最新进展之一是氧化氮由内皮细胞产生而它涉及血管紧张程度的调节,血小板的聚集,神经传递和免疫激活(Furchgott and Zawadzki,1980;Moncada,Palmer and Higgs,1991;Ignarro,1991)。氧化氮是舒张平滑肌的重要介质(Montada,Palmer and Higgs,1991)为已知的EDRF(内皮衍生的舒张因子)(Furrchgott and Zawadzki,1980;Moncada,Palmer and Higgs,1991)。氧化氮由L-精氨酸胍基氮在含黄素的酶,氧化氮合酶的至少一种的异构体的作用下的氧化脱氨而合成(Montada,Palmar and Higgs,1991)。已知氧化氮的合成可被L-精氨酸类似物;NG-硝基-L-精氨酸甲酯(L-NAME),NG-单甲基-L-精氨酸(LMMA),N-亚氨基乙基-L-山金车花素(arnithine)(L-NIO),L-单甲基-L-精氨酸(L-NNMA)和L-NG-甲基精氨酸(LNMA)以及Nw-硝基-L-精氨酸(L-NA)完全抑制。
氧化氮升高血管平滑肌中的cGMP(1,3,5-环鸟苷单磷酸)水平,产生舒张作用,降低血管紧张程度(Moncada,Palmer and Higgs,1991)。氧化氮与血红素结合,因而激活可溶性鸟苷酸环化酶(Ig-narro,1991),增加细胞的cGMP含量。很久以来已经认识到硝基血管扩张剂,如硝普盐和硝酸甘油,抑制血管平滑肌收缩,产生舒张作用或降低血管紧张程度。从十九世纪晚期起,这些药剂已被用作血管扩张剂。但是,直到最近,这些化合物的作用机理才被认识。由硝基血管扩张剂被代谢时可释放氧化氮,因此它们现在被归入氧化氮供体之类(Moncada,Palmer and Higgs,1991)。长期使用硝基血管扩张剂可被认为是缺乏生理机能的替代治疗。氧化氮也可由巨噬细胞及其他免疫细胞产生。
从动物实验何得到一个实体的证据,证明氧化氮缺乏可导致某些疾病,包括高血压,动脉粥样硬化和糖尿病(Moncada,Palmer 15and Higgs,1991)。很多的最新研究显示抑制氧化氮合酶可显著地升高血压。用L-NNMA,L-NA或L-NAME抑制氧化氮合成将导致血压的长期升高,暗示其原因与高血压的发病机理有关(Mon-cada and Palmer,1992)。进一步,用L-NAME处理可增强压力器对血管紧张肽II,加压素和去甲肾上腺素的响应。而且,对于妊娠诱发的高血压患者,其脐部血管氧化氮的释放减弱(Pinto et al.1991),患妊娠期自发性高血压的大鼠的生理性降压依赖于内皮氧化氮(A-hokas,Merces and Sibai,1991)。另外,注入L-NA将增加妊娠大鼠的血压,增强对血管加压药的响应(Molnar and lderte lendy,1992)。这些研究揭示减少氧化氮的合成可能是心血管疾病的重要的病因学机理。
氧化氮合成和氧化氮效应系统(cGMP-决定的舒张机理)被认为是由甾类激素调节的,绝经后妇女心血管疾病增多,这可能与性甾类激素减少及氧化氮改变有关。已显示雌性甾类激素可通过氧化氮调节依赖于内皮的血管平滑肌舒张作用。用雌二醇处理大鼠导致血管组织周围产生的氧化氮的增加,而孕酮对抗这种现象(Miller andVan Houtte,1991)。众所周知孕激素与心脏输出量的增加与实际上体内所有的血管床的抵抗力的降低有关。尽管这个现象的机理尚不清楚,但它可能与氧化氮的产生的变化有关,或者为升高甾类激素水平产生的结果。与上述机理有关的一个重要观察是抗孕激素(RU486)可调节动物的血压(Kalimi,1989)并且使人,男性(Grunberg etal.,1993)及女性(Kettel et al.,1991)产生热潮红。这种潮红可由氧化氮的释放的甾类作用而调解。热潮红是绝经期,绝经后妇女的主要症状,它们可由雌激素(estrogep)和孕酮缓减(Avis et al.,1993)。
以下所述的研究显示氧化氮及随后的子宫舒张作用由孕酮控制。在调节妊娠大鼠孕酮水平时,氧化氮底物,L-精氨酸,的舒张效果在妊娠晚期增强。而且,用孕酮处理来自非妊娠的,切除卵巢的大鼠的子宫条时,L-精氨酸的子宫舒张作用增强。另外,用氧化氮抑制剂处理妊娠大鼠会产生子痛前期的征兆及症状(例如,高血压,胎儿发育迟缓及蛋白尿-典型的子痫前期三联症)。这些症状与血管抵抗和胎盘灌注的疾病有关。正如胎盘减小伴随胎内纤维蛋白沉积增加和血栓形成增加一样,子痫前期是众所周知的动脉粥样硬化的模型(Robert et al.,1989)。单一的或与雌激素和孕酮结合的氧化氮底物和/或供体将作为激素替代治疗的时别有效的药物、预防更年期疾病(climacterium)如动脉粥化硬化,高血压,热潮红,等。
EP 0441 119 A2公开了L-精氨酸在治疗高血压和其他血管疾病中的用途。它揭示L-精氨酸对该疾病有效的机理为它可能是“最有效的内皮衍生的释放因子,氧化氮“的生理学前体。该公开申请中未讨论L-精氨酸与其他药学活性剂结合的用途。
本发明的目的
本发明的目的是提供一种使用氧化氮底物和/或供体预防和治疗雄性及非妊娠雌性哺乳动物更年期症状(Climacteric symptoms)的方法。
本发明的另一个目的是提供一种使用与氧化氮底物和/或供体结合的促孕制剂预防和治疗雄性及非妊娠雌哺乳动物更年期症状(climacteric symptoms)的方法。
本发明另外的目的是提供一种使用与氧化氮底物和/或供体结合的雌激素制剂对绝经前后非妊娠雌性哺乳动物进行激素替代治疗(HRT)的方法。
本发明另外的目的是提供一种使用与氧化氮底物和/或供体结合的雌激素制剂和促孕制剂对绝经前后非妊娠雌性哺乳动物进行激素替代治疗(HRT)的方法。
本发明另外的目的是提供用于实施本发明方法的药物组合物。
在对说明书及所附权利要求书作进一步研究的基础上,本领域技术人员将明白本发明的其他目的和优点。发明的概要
在方法方面,本发明涉及治疗非妊娠雌性或雄性哺乳动物更年期症状的方法,其中包括,以及善症状有效量对表现该症状的患者使用单一的或与孕激素结合的,或者,对于雌性哺乳动物,进一步与孕激素和雌素之一或二者结合的,对于雄性哺乳动物,进一步与雄激素结合的氧化氮(底物和/或)供体之一或二者的组合,雌激素的量为每天使用约2mg雌二醇(Progynovas R,Schering)的生物当量,而所使用的促孕制剂的量为注射50-300mg孕酮的生物当量,氧化氮合酶底物,氧化氮供体或二者的组合的量分别为可将使用药物组合物的妊娠雌性哺乳动物血液循环中L-精氨酸的水平在正常的50-100nmole循环水平之上至少升高约10-50nmole,或将氧化氮供体的水平升至约1-100nmolar(纳摩尔)的量。
在产品方面,本发明涉及包括至少一种单一的或进一步与一种或多种雌激素和/或孕激素结合的氧化氮合酶底物和氧化氮供体的药物组合物,其中雌激素的量为相当于每天使用约2mg雌二醇(例如,Progynora R,Schering)的生物当量,雌激素的量为相当于注射50-300mg孕酮醇的生物当量,各单剂量药物中使用的氧化氮合酶底物,氧化氮供体或二者的组合的量分别为可将血液循环中L-精氨酸的水平在正常的50-100nmolar循环水平之上至少升高约10-50nmole,或将氧化氮供体的水平升至约1到1000nmolar的量。
本发明的另一方面涉及使用a)氧化氮合酶底物,b)氧化氮供体,或二者的组合,以及,任意地,与d)孕激素或者,当哺乳动物是雌性的时,c)雌激素和d)孕激的组合,制备治疗非妊娠雌性或雄性哺乳动物更年期症状(dimacteric symptoms)的药物的用途。
本发明一个优选的具体方面中,a)和/或b)的用量为可使血液循环中L-精氨酸的水平在正常的50-100nmolar循环水平上至少升高约10-50nmolar的量。
本发明另一个具体方面中,哺乳动物为患有绝经期的更年期症状的非妊娠妇女。
本发明另外的具体方面中,哺乳动物为已进行或将进行激素替补治疗的非妊娠妇女。
根据本发明另外的方面,哺乳动物是非妊娠妇女而a)为氧化氮合酶底物。
在本发明优选的具体方面中,氧化氮底物为L-精氨酸。
根据本发明另外的具体方面,哺乳动物是非妊娠妇女而b)为氧化氮供体。
在本发明优选的具体方面中,氧化氮供体为硝普钠,硝酸甘油(nitroglycerin),硝酸甘油(glyceryl-trinitrate)。SIN-1,异山梨醇单硝酸酯或异山梨醇二硝酸酯。
在本发明优选的具体方面中,氧化氮供体可被口服使用。
在另外的具体方面中,哺乳动物为非妊娠妇女,氧化氮底物或供体与雌激素结合口服使用。
雌激素优选使用雌二醇戊酸酯,结合的与雌激素,17β-雌二醇,雌酮或雌三醇。
在本发明另外的具体方面中,哺乳动物是非妊娠妇女,氧化氧底物或供体与孕激素结合口服使用。
孕激素优选使用孕酮,脱氢孕酮,6α-甲-17-羟孕酮,炔诺酮,左旋18-甲基炔诺酮,甲基炔诺酮,甲地妊娠素,甲烯甲炔诺或3-酮基甲烯甲炔诺。
在本发明进一步优选的具体方面,哺乳动物为用雌激素或孕激素进行同时的和持续的激素替代或用雌激素或孕激素进行同时的和相继的激素替代治疗的非妊娠妇女。
在本发明最后的具体方面中,哺乳动物为用雌性激素或孕激素进行同时的和相继的激素替治疗的非妊娠妇女。
本发明在HRT(激素替代治疗)中所述的用途在脉管末梢(血管保护)和就骨质疏松症预防而言的骨骼两方面都具有有利的效果。越来越多的证据证明氧化氮传递甾类激素(雌激素和/或孕激)对骨骼的影响[C.W.G.M.Lowik et al.,J.Clin.Invest.,Vol.93,1994,1465-1472;T.P.Kasten et al.,Proc.Natl.Acad-Sci.USA,Vol.91,1994,3569-3573;L.MacIntyre et al.,Proc.Natl.Acad.Sci.USA,Vol.88,1991,2936-2940;M.Zaidi et al.,Bone,14,1993,97-102;A.S.M.Towhidul Alam et al.,Bioscience Reports,Vol.12,No.5,1992,369.]。详细的讨论
本发明的方法治疗出现更年期症状(dimacteric symptoms)或患该症状危险率高,例如,取决于骨质损失率的绝经期/绝经后哺乳动物,例如非妊娠妇女或男子的更年期症状。
因为这些绝经期/绝经后的非正常状态由不正常的氧化氮合成产生或累积所致,因此,氧化氮合酶底物,例如,L-精氨酸,和氧化氮供体,例如,硝普钠,硝酸甘油(nitroglyeerin),硝酸甘油(glycerin-trinitrate),SIN-1,异山梨醇单硝酸酯和异山梨醇二硝酸酯,都可用于改善上述症状,并且作为本发明方法的一个方面,二者可结合使用。
当促孕制剂与氧化氮底物和/或氧化氮供体同时使用时,可达到添加的效果。对于雌性哺乳动物,雌激素可与孕激素同时使用或代替孕激素。对于雄性哺乳动物,如果孕激素导致睾酮水平向不调节,可以将血清总睾酮水平升至约100到约600mg/dl之间的有效量,将雄性激素与孕激素同时使用。
因此,本发明的方法和本发明的药物组合物使用单一的氧化氮供体和氧化氮合酶底物或二者的组合以及,任意地,一种或一种以上的孕激素(例如,孕酮或甲基炔诺酮),或者,对于雌性哺乳动物,孕激素和雌激素(例如,Prygynova R,Schering)。
典型的NO-底物和NO-供体的剂量范围的例子为:
总剂量:L-精氨酸 500mg-10g p.o.硝普钠 500-2000μg/kg/天硝酸甘油(Nitroglycerin) 0.5-10mg异山梨醇单硝酸酯 10-100mg异山梨醇二硝酸酯 10-100mg
可与氧化氮底物和/或氧化氮供体同时使用的活性剂的组合物例子是下列雌激素和孕激素的组合物,与氧化氮底物或供体结合物雌激素和孕激素活性剂的典型的口服剂量为:
雌激素:日剂量为相当于每天约1到2mg的生物当量的量,例如,Premarin R,Wyeth-Ayerst,0.625mg/天,雌二醇戊酸酯,50μg/天经皮使用,阴道雌二醇乳膏,1.25mg/天和阴道雌二醇环,0.2mg/天以及通常在UK中用于激素替代治疗的天然存在的雌激素。
孕激素:日剂量为相当于50-300mg孕酮/天的生物当量的量,例如,周剂量为100-1000mg的6α-甲-17-羟孕酮乙酸酯的注射用悬浮液或口服日剂量为5-10mg/天的该药的片剂或糖锭剂,周剂量为250-500mg的己酸羟孕酮的注射溶液;日剂量为5-20mg的northindron acetate的片剂,胶囊或糖锭剂。
雌激素与孕激素结合的例子如下:产物 结合 剂量(mg每天)Climaval R(Sandoz) 雌二醇戊酸酯 1或2Progynova R(Scher- 雌二醇戊酸酯 1或2ing)Harmogen R(Abbott) 硫酸雌酮哌嗪盐 1.5或2.5
Hormonin R(Shire) 雌二醇+雌酮+雌三醇 0.6Premarin R(Wyeth- 结合的马雌激素 0.625或1.25或Ayerst) 2.5mg
商业上可得到的用于激素替代治疗的可列出的结合单体包括“Estrapak”,“Prempak-C”,“Tvisequens”,“Trisequens forte’”和“Cycloprogynova”。以下列举这些产物的组合物:
雌二醇每天50mg(28天,8patch)
结合的马雌激素每天0.625mg(28天)
雌二醇戊酸酯每天2mg(11天)
雌二醇戊酸酯每天2mg
甲基炔诺酮每天0.5mg(10天)
甲基炔诺酮每天0.15mg(12天)
结合的马雌激素每天1.25mg(28天)
甲基炔诺酮每天0.15mg(12天)
雌二醇每天2mg+雌三醇每天1mg(22天)
醋炔诺酮每天1mg(10天)
雌二醇每天1mg+雌三醇每天0.5mg(6天)
雌二醇每天4mg+雌三醇每天2mg(21天)
醋炔诺酮每天1mg(10天)
雌二醇每天1mg+雌三醇每天0.5mg(6天)
戊酸雌二醇每天1mg(21天)
左旋18-甲基炔诺酮每天0.25mg(10天)
戊酸雌二醇每天2mg(21天)
左旋18-甲基炔诺酮每天0.5mg(10天)
对口服或经皮使用雌激素的病人每月使用12天的孕激素组合物,其日剂量为:炔诺酮 0.7-2.5mg每天 甲孕酮
本发明使用的药理学活性剂可以与常规赋形剂,即,适当的药学上可接受的液态,半液态或固态有机或无机载体,例如,用于肠胃外或经肠给药的并且不与混合物中活性化合物发生有害反应的载体混合使用。适当的药学上可接受的载体包括但不限于水,盐溶液,醇,植物油,聚乙二醇,明胶,乳糖,直链淀粉,硬脂酸镁,滑石,硅酸,粗石蜡(vicious paraffin),芳香油,脂肪酸单甘油酯和二甘油酯,季戊四醇脂肪酸酯,羟甲基纤维素,聚乙烯吡咯烷酮,等。
药物制剂可被消毒灭菌,如果需要可与辅助剂,例如,润滑剂,防腐剂,增溶剂,润湿剂,乳化剂,调节渗透压的盐,缓冲剂,加色剂,芳香剂等混合,条件是它们不与活性化合物发生有害反应。
对于肠胃外用药,特别合适的是溶液,优选油或水溶液,以及悬浮液,乳液,或植入剂,包括栓剂和经皮制剂。安瓿是便利的单剂量形式。
优选地,本发明组合物适于食入。
对于经肠给药,特别合适的单剂量形式是,例如,含有滑石和/或碳水化合物载体或粘合剂等的片剂,糖锭剂或胶囊,载体优选地为乳糖和/或玉米淀粉和/或土豆淀粉;特别的固体,例如,颗粒剂;以及液体和半液体,例如,糖浆和酏剂,其中使用了甜味介质。可配制的缓释组合物包括被不同的降解性质的涂层,例如,被微囊包封,多层涂层,等保护的活性化合物。
合适的口服制剂为片剂,糖锭剂,胶囊,丸剂,颗粒剂,悬浮液和溶液。每个单剂量形式,例如,每汤匙液体或每个片剂,或糖锭剂含,例如,5-5000mg活性剂。
肠胃外使用在水或醇溶液中的溶液含,例如0.01-1%的活性剂。
氧化氮底物和/或供体可以与雌激素和/或促孕制剂及其他任意的活性剂混合的形式使用,也可以分离的单剂量形式使用,既可同时使用,也可在每天的不同时间使用。
活性剂的结合优选地每天至少使用一次(除非以连续地释放活性剂的形式使用),更优选每天使用数次,例如,以2到6次的分剂量。尽管需要很少的活性剂,典型的剂量为约0.5到1000mg各种活性剂,例如,L-精氨酸需要较高的口服剂量,例如,500到10,000mg,而另一些,例如,硝普钠,需要较低的剂量,例如,500-2,000μg/kg/天。典型的硝酸甘油剂量为每天口服2.5mg 2X;舌下,每天0.8mg 1-4X;经皮给药,0.2-0.4mg/hr。由于大多数上述活性剂的LD50剂量为现有技术,所以既可由低剂量开始,增加剂量直到达到确定的剂量,也可开始时使用较高的剂量,例如,当病情严重时,当症状缓减时将剂量调小。活性剂既可连续地也可相继地结合使用。
对于人,L-精氨酸和孕酮(或等生物当量的另一种孕激素)应该以使L-精氨酸的血浆水平为约50-200nmoler,孕酮为30-100nmolar而雌二醇为50到1000nmolar的速率给药。附图的简要说明
当结合附图考虑时,本发明的各种其他目的,特征和随之产生的优点将会被更充分地认识,同时,将会更好地理解它们,其中,通过不同的图解指出相似的参考特征中的相同或相似的部分,其中:
图1与剂量相关的L-精氨酸(0.1mM到10mM)对取自妊娠,分娩和产后的不同阶段的大鼠的自发收缩的子宫条的舒张效果;
图2:与剂量相关的L-精氨酸(0.1mM到10mM)对取自切除卵巢的非妊娠成年大鼠的子宫条的自发性收缩的舒张效果;
图3:为显示在使用50mg单一的或与L-精氨酸和孕激素丙甲雌烯酮,R5020之一或二者结合的氧化氮抑制剂L-NAME后,对试验动物大鼠血压的影响的条形图。
图4:为显示在相同的实验中上述化合物对实验动物胎儿体重的影响的条形图。详细的讨论
在具结果由图1的曲线显示的实验中:组织取自妊娠第17-22天(d17,d18,d19和d22),自然分娩的第22天(d 22del)(生出1-3个幼崽(,或产后第1(d1pp)和(d2pp)天。自发性子宫收缩的完全抑制期取决于剂量。与其他时间比,浓度为1mm的L-精氨酸在自然分娩期和产后期的效果很低(P<0.01)。通过在七组中重复测量ANO VA而做数据分析。各数据点表示+S.E.M.用于每个时间周期的研究的总条数为来自每组4-6只动物中的8-16条。
在其结果由图2的曲线表示的实验中,在3天内向非妊娠的,切除卵巢的非妊娠的大鼠s.c.注射1μg雌二醇17-β(OVX+E),2mg孕酮(OVX+P),雌二醇和孕酮(OVX+E+P)的芝麻油溶液或单一的芝麻油(OVX和Oil)以测量其收缩。测量值由每组4只大鼠每只动物取4条的+SEM表示。
*P<0.05 OVX+prs OVX+E。
图3的数据显示L-NAME导致高血压(“子痫前期”)。用单一的L-精氨酸处理动物不完全地降低了L-NAME诱导的血压。相似地,用L-NAME和R5020(丙甲雌烯酮),一种无抗盐皮质素作用或其他对抗的或紧张性的促孕剂,处理动物,也可不完全地降低L-NAME诱发的高血压。而且如图3所示,当同时使用相同剂量的L-精氨酸和R5020时,其联合作用的降血压效果要强于一般水平。
另外,按上述处理相同的动物,测量其胎儿的体重,显示子宫内胎儿发育迟缓(胎儿体重降低),为典型的子痫前期胎儿(图4)。
用单一的L-精氨酸或单一的R5020处理“子痫前期”组的动物可轻微地,在统计学上不显著地,提高胎儿体重。而且如图4所示,使用两种化合物的联合作用可在单独使用它们时更显著地提高胎儿的体重,在这些情况下,非常有利于胎儿的存活。
从这些研究中可以推断,L-精氨酸舒张妊娠子宫的效果依赖于孕酮。另外,由于孕酮的作用需要雌激素诱导孕酮受体,因此可以推断雌激素对舒张作用是重要的。-精氨酸是氧化氮合成的底物。因而,可以断定氧化氮的作用由甾类激素传递。另外,对未受损务的妊娠大鼠的研究显示,用L-NAME抑制氧化氮合成可显著地升高血压,降低胎儿体重。对L-NAME处理的大鼠使用单一的或与孕酮(R-5020)结合的氧化氮底物(L-精氨酸)有利于血压和胎儿体重。由于已知氧化氮可控制动脉粥样硬化,L-NAME处理可产生子痫前期,而该状态与其他硬化症有关,而动脉粥样硬化高血压在更年期发生增多,因而,用单一的或与雌激素和孕酮结合的氧化氮底物和/或氧化氮供体处理将非常有利于更年期疾病的治疗。
本发明使用的治疗方法也可按本申请所述的剂量制度,用于治疗高血压(对雌性及雄性哺乳动物),用作避孕的辅药,用于治疗血栓疾病,月红疾病(痛经,非功能性子宫出血),和出血,等。
可以确信,本领域技术人员无需进一步精心研究,使可根据前述而最大范围地利用本发明。因此,优选的特例仅是为了说明,而不以任何方式限制本发明。
在上面及下面引用的所有申请,专利和出版物的全部公开特此按参考结合。
实施例
实施例1:更年期症状(Climacteric Symptoms)的治疗
对出现绝经期或绝经后症状,包括经闭,热潮红,等的非妊娠妇女(Ca 45岁:50-80kg),每月分三次口服使用0.5到20g L-精氨酸,直到症状改善。然后,每日使用0.5到5g L-精氨酸。
实施例2:更年期症状(Climacteric Symeptoms)的治疗
对与实施例1相似并出现相同症状的妇女每天使用2×2.5mg硝酸甘油。
实施例3:更年期症状(Climacteric Symptoms)的治疗
对与实施例1相似并出现同样症状的妇女,每天使用2×2.5mg硝酸甘油与每天150mg孕激素(例如,甲基炔诺酮)。相似地,对出现更年期症状的男子(100kg)使用两次上述制剂。
实施例4:激素替代治疗
对与实施例1相似并出现同样症状的妇女,每日使用与每日1-2mg的雌激素(例如,雌二醇戊酸酯)结合的0.5到20g L-精氨酸。
实施例5:激素替代治疗
对与实施例1相似并出现同样症状的妇女,使用每天0.5到20g的L-精氨酸和/或一种氧化氮供体(例如,硝酸甘油,2×2.5mg每日),以及使用或不使用下列,每日1-2mg的雌激素(例如,雌二醇戊酸酯),或孕激素(例如,每天150mg甲基炔诺酮)。后面的甾类性激素可与L-精氨酸和/或氧化氮供体连续地使用,也可仅在每月中的6-12天相继地使用孕激素。
将用于前述实施例的一般地或特别地描述的本发明的试剂和/或操作条件替找,而重变上述实施例,可得同样好的效果。
从上述中,本领域技术人员可容易地弄清本发明的必要技术特征,并且可在不超出本发明的精神和范围情况下,改变及修饰本发明,以适应各种用途和条件。
Claims (26)
1.使用a)氧化氮合酶底物,b)氧化氮供体,或者二者的组合,以及,任意地,与d)孕激素或者,当哺乳动物是雌性的时,c)雌激素与d)孕激素的组合,制备治疗非妊娠雌性或雄性哺乳动物更年期症状的药物的用途。
2.权利要求1的用途,其中a)以有效地使血液循环中L-精氨酸的水平在正常的50-100nmolar循环水平之上至少升高约10-50nmolar的量被使用。
3.权利要求1或2的用途,其中哺乳动物为患有绝经期的更年期症状的非妊娠妇女。
4.权利要求1或2的用途,其中哺乳动物为已进行或将进行激素替补治疗的非妊娠妇女。
5.权利要求1或2的用途,其中哺乳动物为非妊娠妇女而a)为氧化氮合酶底物。
6.权利要求5的用途,其中氧化氮底物为L-精氨酸。
7.权利要求1或2的用途,其中哺乳动物是非妊娠妇女而b)是氧化氮供体。
8.权利要求7的用途,其中氧化氮供体为硝普钠,硝酸甘油(ni-troglycerin),(glyceryltrinitrate),SIN-1,异山梨醇单硝酸酯或异山梨醇二硝酸酯。
9.权利要求7的用途,其中氧化氮供体用于口服制剂。
10.权利要求1或2的用途,其中哺乳动物为非妊娠妇女,氧化氮底物或供体与雌激素结合用于口服制剂。
11.权利要求10的用途,其中雌激素为雌二醇戊酸酯,结合的马雌激素,17β-雌二醇,雌酮或雌三醇。
12.权利要求1或2的用途,其中哺乳动物为非妊娠妇女,氧化氮底物或供体与孕激素结合用于口服制剂。
13.权利要求12的用途,其中孕激素为孕酮,脱氢孕酮,6α-甲-17-羟孕酮,炔诺酮,左旋18-甲基炔诺酮,甲基炔诺酮,甲地妊娠素,甲烯甲炔诺酮或3-酮基甲烯甲炔诺酮。
14.权利要求1或2的用途,其中浦乳动物为用雌激素或孕激素进行同时的和持续的激素替代治疗的非妊娠妇女。
15.权利要求1或2的用途,其中哺乳动物是用雌激素和孕激素进行同时的和相继的激素替代治疗的非妊娠妇女。
16.权利要求1或2的用途,其中哺乳动物是用激素和孕激素进行同时的和相继的激素替代治疗的男子。
17.权利要求1或2的用途,其中哺乳动物是男人而氧化氮底物或供体与孕激素结合使用。
18.一种药物组合物,其中包括改善绝经期/绝经后雌性哺乳动物更年期症状有效量的(a)氧化氮合酶底物,(b)氧化氮供体,或二者的组合,以及,任意地,(c)雌激素,或者,与雌激素结合的(d)孕激素,其中雌激素的有效量为相当于使用给1-2mg雌二醇的生物当量,孕激素的量为相当于注射30-300mg孕酮的生物当量,而氧化氮合酶底物,氧化氮供或二者的组合的量为可有效地将血液循环中L-精氨酸的水平在正常的50-100nmole循环水平之上至少升高约10-50nmolar,或氧化氮供体的水平升至约1-1000nmolar的量。
19.权利要求18的组合物,其中(a)为氧化氮合酶底物。
20.权利要求18的组合物,其中氧化氮合酶底物(a)为L-精氨酸。
21.权利要求18的组合物,其中(b)为氧化氮供体。
22.权利要求21的组合物,其中氧化氮供体(b)为硝普钠,硝酸甘油(nitroglycerin,glyceryltrinitride),SIN-1,异山梨醇单硝酸酯或异山梨醇二硝酸酯。
23.权利要求18的组合物,其中雌激素(c)为雌二醇戊酸酯。
24.权利要求18的组合物,其中雌激素(c)为雌二醇。
25.权利要求18的组合物,其中孕激素(d)为甲基炔诺酮。
26.权利要求18的组合物,其中孕激素(d)为孕酮。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/153,345 US5595970A (en) | 1993-07-16 | 1993-11-16 | Treatment of climacteric disorders with nitric oxide synthase substrates and/or donors |
US153,345 | 1993-11-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1135177A true CN1135177A (zh) | 1996-11-06 |
Family
ID=22546812
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94194167A Pending CN1135177A (zh) | 1993-11-16 | 1994-11-17 | 用氧化氮合酶底物和/或供体治疗更年期疾病的方法 |
Country Status (16)
Country | Link |
---|---|
US (2) | US5595970A (zh) |
EP (1) | EP0730445A1 (zh) |
JP (1) | JPH09505069A (zh) |
KR (1) | KR960705554A (zh) |
CN (1) | CN1135177A (zh) |
AU (1) | AU8144694A (zh) |
BR (1) | BR9408062A (zh) |
CA (1) | CA2176727A1 (zh) |
CZ (1) | CZ140096A3 (zh) |
FI (1) | FI962110A (zh) |
HU (1) | HUT74459A (zh) |
NO (1) | NO961994L (zh) |
NZ (1) | NZ276106A (zh) |
PL (1) | PL178130B1 (zh) |
SK (1) | SK63496A3 (zh) |
WO (1) | WO1995013800A1 (zh) |
Families Citing this family (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6407082B1 (en) * | 1996-09-13 | 2002-06-18 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of a vitamin D compound |
DE69518729T2 (de) * | 1994-05-27 | 2001-05-31 | Cellegy Pharmaceuticals, Inc. | Stickstoffoxyd abgebendes präparat zur behandlung von analen erkrankungen |
US6425881B1 (en) | 1994-10-05 | 2002-07-30 | Nitrosystems, Inc. | Therapeutic mixture useful in inhibiting lesion formation after vascular injury |
US6239172B1 (en) * | 1997-04-10 | 2001-05-29 | Nitrosystems, Inc. | Formulations for treating disease and methods of using same |
US20110196039A9 (en) * | 1994-10-05 | 2011-08-11 | Kaesemeyer Wayne H | Controlled release arginine formulations |
US5968983A (en) | 1994-10-05 | 1999-10-19 | Nitrosystems, Inc | Method and formulation for treating vascular disease |
US5789442A (en) * | 1996-01-18 | 1998-08-04 | Schering Aktiengesellschaft | Treatment of urinary incontinence with nitric oxide synthase substrates and/or nitric oxide donors alone or in combination with estrogen or progesterone and/or other agents |
US5910482A (en) * | 1996-03-19 | 1999-06-08 | Board Of Regents, The University Of Texas System | Treatment or prevention of preeclampsia, eclampsia with calcitonin gene related peptide, CGRP analog, progestational agent, nitric oxide source, and cyclooxygenase inhibitor |
US5898038A (en) * | 1996-03-19 | 1999-04-27 | Board Of Regents, The University Of Texas System | Treatment of osteoporosis and metabolic bone disorders with nitric oxide substrate and/or donors |
US6040340A (en) * | 1996-05-07 | 2000-03-21 | Schering Aktiengesellschaft | Implantation rates after in vitro fertilization, treatment of infertility and early pregnancy loss with a nitric oxide donor alone or in combination with progesterone, and a method for contraception with nitric oxide inhibitors |
AU771012B2 (en) * | 1996-05-07 | 2004-03-11 | Board Of Regents, The University Of Texas System | Improvement of implantation rates after in vitro fertilization |
US6232434B1 (en) | 1996-08-02 | 2001-05-15 | Duke University Medical Center | Polymers for delivering nitric oxide in vivo |
AUPO203996A0 (en) * | 1996-08-30 | 1996-09-26 | Novogen Research Pty Ltd | Therapeutic uses |
US6034074A (en) | 1996-09-13 | 2000-03-07 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of a Vitamin D compound |
US6511970B1 (en) | 1996-09-13 | 2003-01-28 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of products that induce transforming growth factor-beta and/or apoptosis in the ovarian epithelium |
US6028064A (en) | 1996-09-13 | 2000-02-22 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of progestin products |
US6765002B2 (en) | 2000-03-21 | 2004-07-20 | Gustavo Rodriguez | Prevention of ovarian cancer by administration of products that induce transforming growth factor-β and/or apoptosis in the ovarian epithelium |
DE19701949A1 (de) * | 1997-01-13 | 1998-07-16 | Jenapharm Gmbh | Transdermales therapeutisches System |
WO1998040076A1 (en) * | 1997-03-10 | 1998-09-17 | Schering Aktiengesellschaft | Compositions for the treatment of climacteric disorders with nitric oxide synthase substrates and/or donors, in combination with partial estrogen antagonists |
US5906987A (en) * | 1997-03-10 | 1999-05-25 | Schering Aktiengesellschaft And Board Of Regents | Treatment of male climacteric disorders with nitric oxide synthase substrates and/or donors, in combination with androgens and/or aromatase inhibitors |
US20030114515A1 (en) * | 1997-04-10 | 2003-06-19 | Kaesemeyer Wayne H. | Therapeutic mixture of HMG-COA reductase inhibitors |
EP0998274B1 (en) * | 1997-06-23 | 2006-01-18 | Cellegy Pharmaceuticals, Inc | Microdose therapy of vascular conditions by no donors |
US20040044080A1 (en) * | 1997-10-28 | 2004-03-04 | Place Virgil A. | Treatment of dyspareunia with topically administered nitroglycerin formulations |
GB9807809D0 (en) * | 1998-04-09 | 1998-06-10 | Multimed Ltd | Compositions comprising ethisterone or its derivatives |
US6645954B2 (en) | 1998-04-09 | 2003-11-11 | Multimed Limited | Compositions comprising ethisterone or its derivatives |
JP2002539257A (ja) * | 1999-03-19 | 2002-11-19 | イーノス・ファーマシューティカルス・インコーポレーテッド | 薬剤の脳内生物学的利用率の増加 |
US20050113351A1 (en) * | 2000-03-21 | 2005-05-26 | Rodriguez Gustavo C. | Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium |
US20040176336A1 (en) * | 2000-03-21 | 2004-09-09 | Rodriguez Gustavo C. | Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium |
US20010044431A1 (en) * | 2000-03-21 | 2001-11-22 | Rodriguez Gustavo C. | Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium |
MXPA03007960A (es) | 2001-03-06 | 2003-12-04 | Cellegy Pharma Inc | Compuestos y metodos para el tratamiento de desordenes urogenitales. |
FR2842108B1 (fr) | 2002-07-09 | 2008-05-02 | Effik | Composes a base d'hormone et de monoxyde d'azote et leur utilisation en obstetrique et en gynecologie |
WO2005035001A1 (en) * | 2003-09-29 | 2005-04-21 | Enos Pharmaceuticals, Inc. | Sustained release l-arginine formulations and methods of manufacture and use |
US20080145424A1 (en) * | 2002-10-24 | 2008-06-19 | Enos Phramaceuticals, Inc. | Sustained release L-arginine formulations and methods of manufacture and use |
NZ539672A (en) * | 2002-10-24 | 2006-09-29 | Enos Pharmaceuticals Inc | Sustained release L-arginine-formulations and methods of manufacture and use |
US20040253326A1 (en) * | 2003-02-25 | 2004-12-16 | Mesko Charles A. | Composition for increasing levels of hormones and a method for preparation of said composition |
US20060067962A1 (en) * | 2004-09-30 | 2006-03-30 | Kimberly-Clark Worldwide, Inc. | Skin cooling compositions |
US20060067961A1 (en) * | 2004-09-30 | 2006-03-30 | Kimberly-Clark Worldwide,Inc. | Skin cooling compositions |
DE102008040479A1 (de) | 2007-07-23 | 2009-02-05 | Denso Corp., Kariya-shi | Kraftstoffzufuhrvorrichtung |
US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
LT2782584T (lt) | 2011-11-23 | 2021-09-10 | Therapeuticsmd, Inc. | Natūralios kombinuotos pakaitinės hormonų terapijos kompozicijos ir gydymas |
US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US20150313956A1 (en) * | 2014-05-05 | 2015-11-05 | Napier Consulting Llc | Compositions and methods for hair growth |
AU2015264003A1 (en) | 2014-05-22 | 2016-11-17 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
KR20170040209A (ko) | 2014-07-29 | 2017-04-12 | 쎄러퓨틱스엠디, 인코퍼레이티드 | 경피 크림 |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
US9931349B2 (en) | 2016-04-01 | 2018-04-03 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical composition |
US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
JP2021187789A (ja) * | 2020-06-01 | 2021-12-13 | 株式会社リアルメイト | ヒートショックプロテイン誘導剤、一酸化窒素産生促進剤、抗更年期障害剤、抗加齢剤、化粧品および食品または飲料 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5508045A (en) * | 1992-10-09 | 1996-04-16 | The Regents Of The University Of California | Method and agents for control and management of labor during pregnancy |
-
1993
- 1993-11-16 US US08/153,345 patent/US5595970A/en not_active Expired - Lifetime
-
1994
- 1994-11-17 EP EP95900760A patent/EP0730445A1/en not_active Withdrawn
- 1994-11-17 CA CA002176727A patent/CA2176727A1/en not_active Abandoned
- 1994-11-17 BR BR9408062A patent/BR9408062A/pt not_active Application Discontinuation
- 1994-11-17 PL PL94314466A patent/PL178130B1/pl unknown
- 1994-11-17 CZ CZ961400A patent/CZ140096A3/cs unknown
- 1994-11-17 SK SK634-96A patent/SK63496A3/sk unknown
- 1994-11-17 AU AU81446/94A patent/AU8144694A/en not_active Abandoned
- 1994-11-17 JP JP7514225A patent/JPH09505069A/ja active Pending
- 1994-11-17 CN CN94194167A patent/CN1135177A/zh active Pending
- 1994-11-17 HU HU9601301A patent/HUT74459A/hu unknown
- 1994-11-17 NZ NZ276106A patent/NZ276106A/en unknown
- 1994-11-17 WO PCT/EP1994/003818 patent/WO1995013800A1/en not_active Application Discontinuation
- 1994-11-17 KR KR1019960702551A patent/KR960705554A/ko not_active Application Discontinuation
-
1995
- 1995-06-06 US US08/466,538 patent/US5958878A/en not_active Expired - Fee Related
-
1996
- 1996-05-15 NO NO961994A patent/NO961994L/no not_active Application Discontinuation
- 1996-05-17 FI FI962110A patent/FI962110A/fi unknown
Also Published As
Publication number | Publication date |
---|---|
HU9601301D0 (en) | 1996-07-29 |
JPH09505069A (ja) | 1997-05-20 |
NZ276106A (en) | 1998-05-27 |
NO961994D0 (no) | 1996-05-15 |
WO1995013800A1 (en) | 1995-05-26 |
KR960705554A (ko) | 1996-11-08 |
NO961994L (no) | 1996-07-16 |
PL178130B1 (pl) | 2000-03-31 |
US5595970A (en) | 1997-01-21 |
AU8144694A (en) | 1995-06-06 |
US5958878A (en) | 1999-09-28 |
CZ140096A3 (en) | 1996-09-11 |
FI962110A (fi) | 1996-07-15 |
EP0730445A1 (en) | 1996-09-11 |
SK63496A3 (en) | 1997-03-05 |
HUT74459A (en) | 1996-12-30 |
CA2176727A1 (en) | 1995-05-26 |
FI962110A0 (fi) | 1996-05-17 |
PL314466A1 (en) | 1996-09-16 |
BR9408062A (pt) | 1996-11-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1135177A (zh) | 用氧化氮合酶底物和/或供体治疗更年期疾病的方法 | |
US5585370A (en) | Hormone preparation and method | |
CN1208346A (zh) | 使用氧化氮合酶底物和/或氧化氮供体治疗尿失禁 | |
JP2965160B2 (ja) | 避妊を達成する組成物 | |
US5108995A (en) | Hormone preparation and method | |
CN1128613C (zh) | 用于绝经前后妇女激素代替疗法中的孕甾醇拮抗剂与具有部分紧张作用的抗雌激素的结合体 | |
AU630334B2 (en) | Hormone preparations for hormone replacement therapy and contraceptive method | |
AU2010265180B2 (en) | Pharmaceutical composition for emergency contraception | |
US5256421A (en) | Hormone preparation and method | |
CN1142185A (zh) | 避孕组合物 | |
CN1108795C (zh) | 用氧化氮合酶底物和/或供体,或者氧化氮抑制剂治疗子宫收缩疾病 | |
CN1270521A (zh) | 第一阶段包含孕激素/雌激素并且第二阶段包含孕激素的口服避孕制剂 | |
KR20000029536A (ko) | 2상피임방법및프로제스틴과에스트로젠과의배합물을포함하는킷 | |
CN1672685A (zh) | 一种新的避孕药物 | |
NZ517470A (en) | Mesoprogestins (progesterone receptor modulators) as a component of female contraceptives | |
AU781836B2 (en) | Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (HRT) | |
EP0472628A1 (en) | Use of melatonin derivatives for effecting contraception | |
US7629334B1 (en) | Mesoprogrestins (progesterone receptor modulations) as a component of compositions for hormone replacement therapy (HRT) | |
CA1332228C (en) | Formulation and method for estrogen replacement therapy | |
AU644367B2 (en) | Use of melatonin derivatives for effecting contraception | |
Schneider | Estrogen/Progestogen | |
CN107875388A (zh) | 对延长的激素避孕方案中突破性出血的控制 | |
JP2007197459A (ja) | 月経の出血を少なくし維持された効力を持つ超低投与量避妊薬 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |