CN101636166B - Progesterone for the prevention of spontaneous preterm birth - Google Patents
Progesterone for the prevention of spontaneous preterm birth Download PDFInfo
- Publication number
- CN101636166B CN101636166B CN200880008665.XA CN200880008665A CN101636166B CN 101636166 B CN101636166 B CN 101636166B CN 200880008665 A CN200880008665 A CN 200880008665A CN 101636166 B CN101636166 B CN 101636166B
- Authority
- CN
- China
- Prior art keywords
- progesterone
- purposes
- medicine
- administration
- week
- 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.)
- Expired - Fee Related
Links
- 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 title claims abstract description 370
- 229960003387 progesterone Drugs 0.000 title claims abstract description 178
- 239000000186 progesterone Substances 0.000 title claims abstract description 178
- 208000005107 Premature Birth Diseases 0.000 title claims abstract description 40
- 230000002265 prevention Effects 0.000 title claims description 30
- 230000002269 spontaneous effect Effects 0.000 title abstract description 19
- 230000035935 pregnancy Effects 0.000 claims abstract description 69
- 238000011282 treatment Methods 0.000 claims abstract description 69
- 210000003679 cervix uteri Anatomy 0.000 claims abstract description 48
- 208000006399 Premature Obstetric Labor Diseases 0.000 claims description 68
- 206010036600 Premature labour Diseases 0.000 claims description 67
- 208000026440 premature labor Diseases 0.000 claims description 67
- 230000035606 childbirth Effects 0.000 claims description 49
- 208000007502 anemia Diseases 0.000 claims description 48
- 239000003814 drug Substances 0.000 claims description 46
- 210000001215 vagina Anatomy 0.000 claims description 28
- 230000003203 everyday effect Effects 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 10
- 238000012377 drug delivery Methods 0.000 claims description 8
- 210000004291 uterus Anatomy 0.000 claims description 8
- 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 claims description 7
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 claims description 7
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 claims description 6
- 229960004976 desogestrel Drugs 0.000 claims description 6
- 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 claims description 6
- 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 6
- 229960005352 gestodene Drugs 0.000 claims description 6
- 229960004400 levonorgestrel Drugs 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229920000642 polymer Polymers 0.000 claims description 5
- DBPWSSGDRRHUNT-UHFFFAOYSA-N 17alpha-hydroxy progesterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)(O)C1(C)CC2 DBPWSSGDRRHUNT-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- YNVGQYHLRCDXFQ-XGXHKTLJSA-N Lynestrenol Chemical compound C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 YNVGQYHLRCDXFQ-XGXHKTLJSA-N 0.000 claims description 3
- IMONTRJLAWHYGT-ZCPXKWAGSA-N Norethindrone Acetate Chemical compound 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 IMONTRJLAWHYGT-ZCPXKWAGSA-N 0.000 claims description 3
- APTGJECXMIKIET-WOSSHHRXSA-N Norethindrone enanthate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)CCCCCC)[C@@]1(C)CC2 APTGJECXMIKIET-WOSSHHRXSA-N 0.000 claims description 3
- ICTXHFFSOAJUMG-SLHNCBLASA-N Norethynodrel Chemical compound C1CC(=O)CC2=C1[C@H]1CC[C@](C)([C@](CC3)(O)C#C)[C@@H]3[C@@H]1CC2 ICTXHFFSOAJUMG-SLHNCBLASA-N 0.000 claims description 3
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- METQSPRSQINEEU-UHFFFAOYSA-N dihydrospirorenone Natural products CC12CCC(C3(CCC(=O)C=C3C3CC33)C)C3C1C1CC1C21CCC(=O)O1 METQSPRSQINEEU-UHFFFAOYSA-N 0.000 claims description 3
- 229960004845 drospirenone Drugs 0.000 claims description 3
- METQSPRSQINEEU-HXCATZOESA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 claims description 3
- 229940012028 ethynodiol diacetate Drugs 0.000 claims description 3
- ONKUMRGIYFNPJW-KIEAKMPYSA-N ethynodiol diacetate Chemical compound C1C[C@]2(C)[C@@](C#C)(OC(C)=O)CC[C@H]2[C@@H]2CCC3=C[C@@H](OC(=O)C)CC[C@@H]3[C@H]21 ONKUMRGIYFNPJW-KIEAKMPYSA-N 0.000 claims description 3
- GCKFUYQCUCGESZ-BPIQYHPVSA-N etonogestrel Chemical compound O=C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 GCKFUYQCUCGESZ-BPIQYHPVSA-N 0.000 claims description 3
- 229960002941 etonogestrel Drugs 0.000 claims description 3
- 238000007918 intramuscular administration Methods 0.000 claims description 3
- 238000007912 intraperitoneal administration Methods 0.000 claims description 3
- 229960001910 lynestrenol Drugs 0.000 claims description 3
- 229960002985 medroxyprogesterone acetate Drugs 0.000 claims description 3
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 claims description 3
- 229940053934 norethindrone Drugs 0.000 claims description 3
- 229960001652 norethindrone acetate Drugs 0.000 claims description 3
- 229960002082 norethindrone enanthate 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
- 229960001858 norethynodrel Drugs 0.000 claims description 3
- 229960000417 norgestimate Drugs 0.000 claims description 3
- KIQQMECNKUGGKA-NMYWJIRASA-N norgestimate Chemical compound O/N=C/1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(OC(C)=O)C#C)[C@@H]4[C@@H]3CCC2=C\1 KIQQMECNKUGGKA-NMYWJIRASA-N 0.000 claims description 3
- 238000009597 pregnancy test Methods 0.000 claims description 3
- 239000007909 solid dosage form Substances 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- JUNDJWOLDSCTFK-MTZCLOFQSA-N trimegestone Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@@](C(=O)[C@@H](O)C)(C)[C@@]1(C)CC2 JUNDJWOLDSCTFK-MTZCLOFQSA-N 0.000 claims description 3
- 229950008546 trimegestone Drugs 0.000 claims description 3
- 229940044959 vaginal cream Drugs 0.000 claims description 3
- 239000000522 vaginal cream Substances 0.000 claims description 3
- 229940120293 vaginal suppository Drugs 0.000 claims description 3
- 239000006216 vaginal suppository Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 210000000664 rectum Anatomy 0.000 claims 1
- 239000000286 vaginal jelly Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 25
- 230000036541 health Effects 0.000 abstract description 14
- 208000024891 symptom Diseases 0.000 abstract description 9
- 238000011321 prophylaxis Methods 0.000 abstract description 4
- 238000004904 shortening Methods 0.000 abstract 1
- 239000000902 placebo Substances 0.000 description 65
- 229940068196 placebo Drugs 0.000 description 65
- 238000011160 research Methods 0.000 description 45
- 239000000583 progesterone congener Substances 0.000 description 21
- 238000004393 prognosis Methods 0.000 description 21
- 238000012360 testing method Methods 0.000 description 20
- 201000010099 disease Diseases 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 238000012545 processing Methods 0.000 description 12
- 208000003107 Premature Rupture Fetal Membranes Diseases 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 241001597008 Nomeidae Species 0.000 description 8
- 206010036595 Premature delivery Diseases 0.000 description 7
- 238000000227 grinding Methods 0.000 description 7
- 208000032170 Congenital Abnormalities Diseases 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 239000000227 bioadhesive Substances 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 230000032696 parturition Effects 0.000 description 4
- 230000009984 peri-natal effect Effects 0.000 description 4
- 230000003449 preventive effect Effects 0.000 description 4
- 150000003146 progesterones Chemical class 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 230000036266 weeks of gestation Effects 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 208000000203 Hyaline Membrane Disease Diseases 0.000 description 3
- 208000032571 Infant acute respiratory distress syndrome Diseases 0.000 description 3
- 208000034702 Multiple pregnancies Diseases 0.000 description 3
- 206010051606 Necrotising colitis Diseases 0.000 description 3
- 206010028974 Neonatal respiratory distress syndrome Diseases 0.000 description 3
- 229920000148 Polycarbophil calcium Polymers 0.000 description 3
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000002146 bilateral effect Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 210000003754 fetus Anatomy 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 206010025482 malaise Diseases 0.000 description 3
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 3
- 201000002652 newborn respiratory distress syndrome Diseases 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 description 3
- 229950005134 polycarbophil Drugs 0.000 description 3
- 230000002028 premature Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000012502 risk assessment Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 206010060937 Amniotic cavity infection Diseases 0.000 description 2
- 206010007556 Cardiac failure acute Diseases 0.000 description 2
- 206010007558 Cardiac failure chronic Diseases 0.000 description 2
- 208000008158 Chorioamnionitis Diseases 0.000 description 2
- 208000011359 Chromosome disease Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 208000001300 Perinatal Death Diseases 0.000 description 2
- 208000036216 Placenta Previa Diseases 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 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 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 206010046910 Vaginal haemorrhage Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 208000019812 amnionitis Diseases 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000008821 health effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- 208000019423 liver disease Diseases 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
- 230000003821 menstrual periods Effects 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- 238000010197 meta-analysis Methods 0.000 description 2
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 description 2
- 229960004719 nandrolone Drugs 0.000 description 2
- 230000000474 nursing effect Effects 0.000 description 2
- 230000000505 pernicious effect Effects 0.000 description 2
- 210000002826 placenta Anatomy 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 210000005000 reproductive tract Anatomy 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000023281 Fallot tetralogy Diseases 0.000 description 1
- 208000001951 Fetal Death Diseases 0.000 description 1
- 206010055690 Foetal death Diseases 0.000 description 1
- 208000032754 Infant Death Diseases 0.000 description 1
- 206010056254 Intrauterine infection Diseases 0.000 description 1
- 206010023204 Joint dislocation Diseases 0.000 description 1
- 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 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 206010035669 Pneumonia aspiration Diseases 0.000 description 1
- 208000002787 Pregnancy Complications Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000034972 Sudden Infant Death Diseases 0.000 description 1
- 206010042440 Sudden infant death syndrome Diseases 0.000 description 1
- 201000003005 Tetralogy of Fallot Diseases 0.000 description 1
- 208000037063 Thinness Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 238000009246 art therapy Methods 0.000 description 1
- 201000009408 aspiration pneumonitis Diseases 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000007698 birth defect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 206010008129 cerebral palsy Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000024971 chromosomal disease Diseases 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 208000010515 dystocia Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 231100000479 fetal death Toxicity 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000005153 frontal cortex Anatomy 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 206010021093 hypospadias Diseases 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 201000003723 learning disability Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- -1 progesterone chemical compound Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 208000002254 stillbirth Diseases 0.000 description 1
- 231100000537 stillbirth Toxicity 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 150000003515 testosterones Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 206010048828 underweight Diseases 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
A method for treating or preventing spontaneous preterm birth in pregnant women and improving neonatal morbidity and mortality. The method includes administering to a pregnant woman in need thereof an effective amount of a progesterone sufficient to prolong gestation by minimizing the shortening or effacing of her cervix. Treatment and prophylaxis with progesterone in pregnant women having symptoms of short cervix has been clinically shown to increase neonatal health.
Description
Cross reference in first to file
The application requires the priority of the U.S. Provisional Application 60/973,667 that the U.S. Provisional Application 60/888,480 submitted on February 6th, 2007 and JIUYUE in 2007 submitted on the 19th, and these two pieces of documents are incorporated this paper into as a reference in full.
Technical field
The present invention relates to a kind ofly be used for the treatment of or prevent anemia of pregnant woman's spontaneous preterm birth and improve simultaneously the method for neonatal health.More particularly, the present invention relates to a kind ofly by the anemia of pregnant woman being given the outbreak that the preterm delivery of premature labor was treated or prevented to cause to a certain amount of progesterone, described a certain amount of progesterone enough shortens or disappears and prolong trimester of pregnancy by postponing cervix uteri.In addition, the present invention relates to a kind of by giving a certain amount of progesterone to postpone childbirth and to reduce neonatal mortality and/or morbidity is treated or the outbreak of prevention of preterm birth childbirth and reduce simultaneously the method for neonatal mortality and/or morbidity to having the shorten anemia of pregnant woman of symptom of cervix uteri.
Background technology
Usually known, preterm delivery (also being called as interchangeably in this article " in advance childbirth ") appearred in the anemia of pregnant woman of experience spontaneous preterm birth (PTB) before it reaches about 37 weeks of gestation, it begins the well-regulated uterine contraction of tool, causes cervix uteri open or attenuation (being called as expansion and effacement) and deliquescing.If the anemia of pregnant woman produced before 37 weeks, it typically and traditionally is known as premature labor and the baby is called as the premature infant.
Because premature labor causes tremendous influence to anemia of pregnant woman, its family and society, so premature labor remains one of problem the most serious in the obstetrics.According to studies show that United States Medicine institute (the Instituteof Medicine) is announced recently, since 1981, the incidence rate of premature labor increases by 33%, and only have about 500 every year in the U.S., 000 anemia of pregnant woman gives a birth in advance, brings 26,000,000,000 dollars premature labor expense every year for the health care system of the U.S..Report recently, in developed country, anemia of pregnant woman's 15% Preterm Delivery, and in the U.S., premature labor in 2006 account for whole childbirths 12.7% and account for 12.4% of whole childbirths premature labor in 2004.For example, referring to Use ofprogesterone to reduce preterm birth, American College ofObstetricians and Gynecologists Committee Opinion No.291, Vol.102, No.5, November 2003, the 1115-1116 pages or leaves; Hamilton, B.E., Annal Summary of Vital Statistics:2005, Pediatrics, Vol.119, No.2, February 2007, the 345-360 pages or leaves.
Believe that the premature labor early than pregnant 32 weeks brings high morbidity and the risk of mortality rate.In addition, the premature labor that occurs between pregnant 32 weeks to 36 weeks is uneasy especially, because give birth to many babies that are in danger.In advance childbirth accounts for the 60-70% of infant mortality, and is the main cause of the health cost aspect two between the whole vital stage in perinatal stage and survival baby.The new development of modern obstetrics and newborn care has caused the baby to be survived being improved, yet, have 55% to show the sign that clinical significant cognition, education and behavior damage in the utmost point under-weight of surviving extremely young mid-term (＜1000 gram) neonate or early premature labor (＜28 week) of the utmost point neonate.
About 20%-30% is that the doctor makes the result that childbirth determines according to mother or fetus indication in the premature labor.Remaining is given a birth in advance is spontaneous, is usually occuring after laboronset or the premature rupture of fetal membrane in advance.Some risk factors of the preterm delivery that has been identified comprise: multiple pregnancy, mother stress, system and intrauterine infection, race and socioeconomics.Prediction of Preterm Labor research (Preterm Prediction Study) finds that previous spontaneous preterm birth history is indicating that consumingly the later risk in that in advance childbirth occurs in 23-27 week increases by 11 times.Yet, regrettably, only use the methods of risk assessment of premature labor history risks and assumptions to have unacceptable muting sensitivity and poor predictive value.Operation technique, particularly cervix uteri ultrasound investigation technology are replenished the risk assessment based on the premature labor history, have increased the sensitivity and the specificity that improve.The ultrasonic evaluation that cervix uteri shortens increases relevant with the logarithm of the risk of giving a birth in advance.Referring to the people's such as lams The length ofthe cervix and the risk of spontaneous premature delivery, N.Engl.J.Med.1996; 334:567-572.
In the premature infant of survival, many being subject to all the life such as following torment: cerebral palsy, mental retardation, chronic lung disease, audition and visual impairment and learning disabilities.Child is born more as scheduled, and then he or she just more may survive and he or she just unlikely has relevant health problem.Premature infant in 34-37 week birth is generally relatively healthy.Yet if the anemia of pregnant woman gave a birth before the 34th week, the risk of disadvantageous health effect and/or medical complication increases.
Generally known, women's LCU has indicated well whether the anemia of pregnant woman will experience preterm delivery and premature labor.Antenatal examining when visiting for the first time, the doctor checks the length of woman cervix uteri routinely, thereby makes it can monitor LCU along with the variation of gestation progress.If woman cervix uteri shortened in mid trimester of pregnancy, it means that cervix uteri begins to disappear (attenuation), and it indicates that well this women is under the risk of higher in advance childbirth at least.
Cervix uteri shortens and to a certain extent such as following feature: previous premature labor history, age, race, Body Mass Index (BMI) and cervix uteri operation are the known risk factor relevant with premature labor of routine.Data support is at LCU and have inverse relationship between the childbirth in advance.In the perspective study of the relation between an investigation of being participated in by 2915 women is being lacked LCU and given a birth in advance, research worker is found, between gestation the 24th week to 28 weeks, even LCU has and very little shortens that also relevant with the premature delivery risk that increases (RR 2.03; 95%CI, 1.28-3.22).Referring to the people's such as lams The length of the cervix and the riskof spontaneous premature delivery, N.Engl.J.Med.1996; 334:567-572.In 24 weeks, when comparing greater than the women of the 75th percentile of standard with LCU, (＜3.0cm) women has 3.79 the in advance relative risk (95%CI, 2.32-6.19) of childbirth to LCU at the 25th percentile; (＜2.6cm) women has 6.19 relative risk (95%CI, 3.84-9.97) at the 10th percentile; (＜2.2cm) women has 9.49 relative risk (95%CI, 5.95-15.15) at the 5th percentile; With (＜1.3cm) women has 13.99 relative risk (95%CI, 7.89-24.78) at the 1st percentile.Ibid.Other research is definite, and the monitoring LCU can help to identify the women under the repeatedly premature delivery risk that is in increase.Referring to Spong, C, Prediction andprevention of recurrent preterm birth, American College ofObstetricians and Gynecologists, Vol.110, No.2, Part 1, August2007,407-408 page or leaf.
Be not approved at present the treatment of prevention of preterm birth in the U.S..Referring to the report (Institute of Medicine Report on PretermBirth, 2006) of United States Medicine institute about premature labor.Short Cervical preventative-therapeutic existing medical practice comprises mechanotherapy/operative treatment about First Trimester.For example, shirodkar-Baster operation is a kind of operation process of wherein cervix uteri being sewed up or being sewed up, thereby physical property prevention cervix uteri shortens or attenuation too early.Then, generally remove stitching thread in about the 37th week, thereby make cervix uteri in the farrowing interval normal expansion.Unfortunately, the typical side effect relevant with shirodkar-Baster operation comprises the usually risk relevant with operation of early-age shrinkage risk, cervical dystocia risk (can not normal expansion in the farrowing interval cervix uteri), cervical infection risk and other.In addition, cerclage there is being dispute aspect the short Cervical effectiveness for the treatment of.Several these operative treatments of research proposal recently are good unlike placebo.Although known LCU, particularly cervix uteri shorten relevant with premature labor, not having at present known is effective non-surgical intervention measure.Referring to Spong, C, 407-408 page or leaf.That is to say do not have received medical service law for the in advance childbirth that is called as " short cervix uteri " and the risk factor of premature labor at present.
In some considered to be in women under the excessive risk, advocated the administration progesterone and be used for prevention of preterm birth, although principal focal point concentrates on the patient who before has the premature labor history.Among the women under being in the extra high risk of giving a birth in advance, particularly in the women that shortens of experience cervix uteri, the vagina administration progesterone not yet is shaped with the effectiveness of prevention of preterm birth and is unknown to a great extent.For example, the people such as O ' Brien determine that the prophylactic treatment that adopts vagina progesterone gel to carry out can not reduce the frequency of repeatedly premature labor effectively in according to the selecteed excessive risk women of spontaneous preterm birth history.Yet, obstetrics as AAOG (American College ofObstetricians and Gynecologists) put into practice committee (Committee onObstetric Practice) at its publication Use of Progesterone to ReducePreterm Birth, American College of Obstetricians andGynecologists Committee Opinion No.291, Vol.102, No.5, November 2003, provide in the 1115-1116 page or leaf, desirable progesterone preparation is unknown.
At present, treat all women who is under the premature delivery risk with progesterone and can not get absolute support.Some authors have expressed carrying out the needs through the random experiment of abundant design in larger crowd, identifying desirable progesterone preparation and dosage, and are used for being presented at that premature labors before 37 weeks descend and perinatal morbidity and mortality rate reduce.For example, referring to the people's such as Dodd Prenatal administration of progesterone for preventing preterm birth, Cochrane Database Syst Rev 2006.
Although about progesterone and the relevant use of childbirth, particularly relevant use has many arguements with trimester of pregnancy,, based on the treatment to prevention of preterm birth, also only have if any the conventional art analytical effect for the neonate crowd seldom.The analysis-by-synthesis (Meta-analysis) of the random experiment of being participated in by the women has disclosed that premature delivery risk reduces between less than 37 weeks and 34 weeks.Dodd, the people such as J.M., Prenatal administration of progesterone forpreventing preterm birth (Review), The Cochrane collaboration, John Wiley Sons, Ltd, 2006, the 1-36 pages or leaves.Yet, importantly, the women who is given progesterone be given and do not have statistically significant difference aspect the generation of the perinatal death between the women of placebo.Dodd, the people such as J.M., 4-5 page or leaf.In fact, prognosis it is reported there is not difference about neonate between placebo group and progesterone group.Dodd, the people such as J.M., the 4-5; Mackenzie, R. wait the people, Progesterone for the prevention ofpreterm birth among women at increased risk:A systematic reviewand meta-analysis of randomized controlled trials, Journal ofObstetrics and Gynecology, 194,2006, the 1234-42 pages or leaves.
Research provides about gestation and has prolonged and the information of children's morbidity.The people such as Lam F., Evaluation of the pregnancy prolongation index (PPI) as a measureof success of obstetric interventions in the prevention ofptrterm birth and associated morbidities, Journal of Obstetricsand Gynecology, 192,2005,2047-54.Yet this research is not provided at the comparative experiments data between treatment group and the matched group.In addition, this research does not relate to that progesterone is used for the treatment of or the application of prevention of preterm birth.At last, the function in this study limitation pregnant age when having investigated simply Neonatal Health as childbirth but not because due to therapeutic agent/preventive.
Therefore, need a kind for the treatment of or prevention anemia of pregnant woman's the outbreak of preterm delivery and the method for the premature labor that occurs thus, particularly for having short Cervical women, and do not have the typical disadvantageous health effect relevant with present known method.In addition, not only pay attention to mother's of childbirth health, also need pay attention to consumingly and intervene and improve the neonate prognosis.That is to say that premature labor is relevant with high perinatal stage morbidity and mortality rate; And the in advance inhibition of childbirth is irrelevant with the baby's prognosis that improves routinely.The routine techniques present situation does not show has any direct health advantages to neonate.Therefore, need in the art therapy and/or prophylaxis to improve preterm delivery, particularly neonatal health.
Summary of the invention
The present invention relates to a kind ofly be used for the treatment of or prevent anemia of pregnant woman's the outbreak of preterm delivery and the method for the premature labor that occurs subsequently.In preferred version, the method comprises the progesterone that the anemia of pregnant woman that needs are arranged is given effective dose, and enough cervix uteri shortens the progesterone of this effective dose or cervical effacement prolongs gestation by postponing.Preferably, progesterone as vagina gel, vaginal suppository, vaginal cream or vagina solid dosage forms (such as tablet) or the mechanism by being inserted into intravaginal delivery apparatus such as uterus neck ring or this area, this area usually known other device by administration.
The invention provides a kind of have in mid trimester of pregnancy (mid-pregnancy) improve the method that Neonatal Health is morbidity and/or mortality rate in the women's of short LCU the childbirth.The described method of improving neonate morbidity and mortality rate comprises the progesterone that the Cervical anemia of pregnant woman that the short cervix uteri of having of needs or disappearance are arranged is given enough to prolong the effective dose of gestation.In some embodiments, the neonatal feature of being given birth to by the women who accepts progesterone treatment and/or prevention is, compare with the baby by the Mothers of the progesterone that is not provided effective amount at pregnancy duration, the former neonate morbidity and mortality rate reduce, neonatal intensive care unit (NICU) natural law reduces, the probability of being admitted to hospital NICU reduces, or its combination.In preferred version, by administration, progesterone is natural progesterone or synthetic progesterone or derivatives thereof to about 45 milligrams to 800 milligrams progesterone as vagina gel.In other embodiments, beginning gives progesterone until about the 37th week of gestation preferably continues about 14-19 week every day in 22 week of about the 18th week to the of gestation.
In other embodiments of the present invention, progesterone be given to its LCU greater than about 1.0 centimetres, more preferably greater than 1.5 centimetres anemia of pregnant woman, wherein progesterone be given to its LCU be about 1.0 centimetres to 8.0 centimetres anemia of pregnant woman.In the embodiment variant, the LCU that has been given the women of progesterone is less than or equal to about 3.0 centimetres, preferably less than 2.8 centimetres, is more preferably less than 2.5 centimetres.
In embodiments of the invention, the progesterone that is given can be progesterone molecule (from any source, comprising natural or synthetic source) or progesterone metabolite (from any source, comprising natural or synthetic source), or any other progestogen.Progesterone self is preferred, although can use other progestogen.When using synthetic progestogen, synthetic progesterone is preferably selected from the derivant that derivatives of progesterone or testosterone derivative or other have the molecule of progesterone activity.These progestogen include but not limited to 17-Alpha-hydroxy progesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethisterone enanthate, desogestrel, levonorgestrel, lynestrenol, ethynodiol diacetate, norgestrel, norgestimate, Norethynodrel, gestodene, drospirenone, trimegestone, left desogestrel, gestodene, Nai Situo ketone, etonogestrel, and derive from the derivant of 19-nortestosterone.In preferred version, progesterone comprises any in natural progestogen, progesterone or the 17-Alpha-hydroxy progesterone.But some progestogen transvaginal are sent, and some are sent by intramuscular injection, and some are sent by oral administration, and some are sent by rectally, although the route of administration that can use like that other as known in the art.In preferred version, progesterone is given by means of drug delivery system, and this drug delivery system comprises crosslinked polycarboxylic acid polymer and at least a auxiliary agent of progesterone, water miscible and water-swellable.
In preferred version, progesterone carries out administration every day by vaginal approach.Yet this administration frequency may be as few as and is administered once weekly or as many as is administered four times every day, different and different according to the feature of progestogen and progestin preparation.Preferably, 22 weeks of about the 18th week to the of gestation beginning to give progesterone until about the 37th week of gestation perhaps continues about 14-19 week different and different according to the pregnant age when the treatment beginning and childbirth day.In another embodiment, about the 16th week of gestation beginning to give progesterone until about the 37th week of gestation perhaps continues about 21 weeks.In other embodiment, when approximately pregnancy tests are positive, begin to give progesterone until about the 37th week of gestation perhaps begins to give progesterone in 4 weeks of about the 2nd week to the of gestation, continue about 33-35 week.
The amount of the progesterone that is given is preferably about 45 milligrams to 800 milligrams, more preferably about 90 milligrams to 250 milligrams, based on the difference of the progestogen effect of the natural progesterone of intravaginal administration and different, but in varying degrees can be according to the effectiveness of progestogen and route of administration different and different.Progesterone preferably when gestation begins, be given to its LCU greater than about 1.0 centimetres anemia of pregnant woman.Progesterone more preferably is given when gestation begins to its LCU and is at least about 1.0 centimetres and maximum about 8.0 centimetres anemia of pregnant woman, progesterone even more preferably be given the anemia of pregnant woman who is less than or equal to 2.5 centimetres or 3.0 centimetres to its LCU.
Another embodiment of the invention provides by the anemia of pregnant woman being given a certain amount of progesterone is treated or the improving one's methods of the outbreak of prevention of preterm birth childbirth and premature labor, this a certain amount of progesterone enough make its Cervical shorten or disappear minimize or postpone, and Cervical deliquescing and expansion are minimized or postpone.
Description of drawings
From the following description also by reference to the accompanying drawings, other features and advantages of the present invention will be apparent, and non-limiting way illustrates possible embodiment of the present invention to described accompanying drawing with way of example.
Fig. 1 is a form, and it comprises the base-line data according to the participant in the research of the effectiveness of the progesterone treatment premature labor between one embodiment of the invention comparison placebo group and the treatment group;
Fig. 2 is one the form according to one embodiment of the invention participant's test model has been described;
Fig. 3 is about have the data form less than 2.8 centimetres the Cervical participant of weak point according to one embodiment of the invention;
Fig. 4 comprises the form in the LCU data in 28 weeks according to the participant of one embodiment of the invention in placebo group and treatment group;
Fig. 5 a and Fig. 5 b have described the delivery time curve according to one embodiment of the invention participant in placebo group and progesterone treatment group;
Fig. 6 is the delivery time curve that has the participant of the baseline LCU that is less than or equal to 3.2 centimetres according to one embodiment of the invention;
Fig. 7 has delivery time curve greater than the participant of 3.2 centimetres baseline LCU according to one embodiment of the invention;
Fig. 8 is the delivery time curve that has the participant of the baseline LCU that is less than or equal to 3.0 centimetres according to one embodiment of the invention;
Fig. 8 is survival curve, and it has estimated the in advance childbirth up to 37 weeks that has the participant of the LCU that is less than or equal to 3.0 centimetres according to one embodiment of the invention;
Figure 10 has delivery time curve less than the participant of 2.8 centimetres LCU according to one embodiment of the invention;
Figure 11 is a form, and it has summed up the premature labor prognosis less than the research participant of 2.8 centimetres LCU of having according to one embodiment of the invention registrations;
Figure 12 is a form, and it has been summed up according to one embodiment of the invention has neonate prognosis less than the research participant of 2.8 centimetres baseline LCU;
Figure 13 a-e represents a curve, and it has been described according to one embodiment of the invention has≤placebo patients of 3.0 centimetres baseline LCU and the baby's prognosis among the treatment patient; With
Figure 14 a-e represents a curve, and it has been described according to one embodiment of the invention has≤placebo patients of 2.8 centimetres baseline LCU and the baby's prognosis among the treatment patient.
Preferred version describes in detail
At obstetrics, give progesterone to the Cervical anemia of pregnant woman with short cervix uteri or disappearance, purpose is to affect cervical dilatation and effacement so that outbreak and this method of premature labor for the treatment of or prevention of preterm birth childbirth generally are unknown.Especially, known to the inventor, do not have the instruction of document or other publication or hinted progesterone can be given to have short Cervical anemia of pregnant woman with by make Cervical shorten or disappear minimize and may prolong gestation by Cervical deliquescing and expansion are minimized.
The present invention relates to improve Neonatal Health by the progesterone or derivatives thereof that the Cervical anemia of pregnant woman with short cervix uteri or disappearance is given effective dose.In preferred version, the use of progesterone has reduced by having LCU neonatal morbidity and/or the mortality rate that the anemia of pregnant woman of symptom gives birth to that shorten.In some embodiment variants, the neonate that its mother treats with progesterone show following characteristics one of at least: 1) neonatal intensive care unit (" NICU ") natural law reduces, and 2) the NICU percent of being admitted to hospital reduces (be NICU be admitted to hospital baby's percent reduce).Being given the neonate that the women of progesterone gives birth to by pregnancy duration also shows, compare at the neonate that pregnancy duration is not given progesterone with its mother, the former newborn child's illness and disease such as respiratory distress syndrome (RDS), ventricle internal hemorrhage, necrotizing enterocolitis, sepsis and dead incidence rate reduce.This evidence prove sickness rate reduces and shows by treat and/or prevent the anemia of pregnant woman with short cervix uteri symptom with progesterone falls ill baby still less.According to the present invention, mother's of the short cervix uteri symptom of performance treatment and prevention increased 37 weeks of gestation or before the neonatal clinical health of giving birth to and be reduced in 37 weeks of gestation or before parturition rate.
Embodiment of the present invention have hinted uses progesterone to cause being less than or equal to the remarkable minimizing of premature labor (PTB) in pregnant 32 weeks and/or the remarkable improvement of selected baby's prognosis in short cervix uteri patient.In addition, embodiment of the present invention have hinted the women with short LCU, LCU preferably less than 3.0 centimetres, be more preferably less than 2.8 centimetres, benefit from the progesterone treatment as the PTB Intervention Strategy.
Term used herein " premature labor " generally refers to cause the human pregnancy of childbirth before 37 weeks.Therefore, " premature labor " contained and be lower than After Gravidity 35 Weeks or be less than or equal to the childbirths that 32 weeks of gestation occur.In addition, another definition of preterm delivery is included in Cervical expansion and/or the effacement relevant with the persistence uterine contraction that gestation was detected by touch before 37 weeks.In embodiments more discussed in this article, preterm delivery is defined as following (documented) cervix uteri that is recorded to change the per hour uterine contraction more than 6 times of generation, cervical dilatation is greater than 2 centimetres, cervical effacement is greater than 80%, and perhaps being recorded of cervical effacement changes greater than 50%.
Short cervix uteri used herein refers to LCU from greater than 1.0 centimetres to 3.5 centimetres, preferably from greater than 1.0 centimetres to 3.0 centimetres, and more preferably from greater than 1.0 centimetres to 2.5 centimetres, even more preferably from greater than 1.0 centimetres to 2.0 centimetres.Cervix uteri less than 1.0 centimetres is commonly called " extremely short cervix uteri " and is distinguishing with " short cervix uteri " clinically.How to identify that having short Cervical anemia of pregnant woman with clinical diagnosis can be understood and can be comprised method such as for example sonography and clinical examination by those skilled in the art.
" neonate " used herein contained about 6 months or less child, preferred about 3 months or less child, more preferably from about 2 months or less child, even preferred about 1 month or less child.In certain embodiments, neonate is used for containing perinatal stage, preferably divides the period in puerperium.
Neonate prognosis used herein (being called as convertibly in this article " Neonatal Health ") is measured by generation, universality and the clinical state of mortality rate and morbidity.For example, health can be directly relevant with infant weight.Health also can with the following inverse relationship: the be admitted to hospital incidence rate of (being NICU) of connatae special care, neonate hospital time of staying during birth, the incidence rate of RSD, the incidence rate of ventricle internal hemorrhage, the incidence rate of necrotizing enterocolitis, the incidence rate of sepsis and the incidence rate of neonatal death.Other measuring method of morbidity can be used by those skilled in the art.
Term " pharmacy effective dose " (or be called as convertibly in this article " effective dose ") has the common implication in this area, that is, can induce and reply in the body that helps reply, prevention or treatment and/or the amount of the medicine of clinical response.This term can be contained the treatment effective dose or prevent effective dose or the two.Term used herein " suitable " refers to be applicable to the preferred people's purposes of mammal purposes and is used for pharmacy purpose disclosed herein.
Term " treatment " or " processing " refer to any treatment of mammiferous disease or disease, comprising: prevent or prevent disease or disease, cause that namely clinical symptoms does not develop; Suppress disease or disease, namely stop or the development of containment clinical symptoms; And/or palliate a disease or disease, that is, cause that clinical symptoms disappears.In some embodiments, term " treatment " or " processing " comprise recovery from illness or the healing of the improvement of the symptom of given disease, given disease and prevent given advancing of disease.
A member of term " prevention " conduct " treatment " is intended to contain " prevention " defined herein and " containment ".Those skilled in the art can understand, can the two distinguish with " prevention " and " containment " in human medicine, because one or more events of finally inducing may be unknown, potential or until for a long time just be determined by the patient after these one or more events occur.
Be not bound by any theory, believe in all premature labors, have short Cervical women and account for about 20-30%.The present invention surprisingly and be surprised to find that, suffer from short Cervical female population, to premature labor event susceptible, have among tendentiousness in advance or the women relevant with the premature labor event, at pregnancy duration treatment, prevention and/or other treatment of progesterone are replied, thus the generation of prevention or minimizing premature labor.Be enjoyably, in the art about reduce the many arguements of having of premature labor with progesterone.Fig. 5 a of the application and Fig. 5 b have hinted to treat the crowd and accept the anemia of pregnant woman who accepts progesterone does not have difference aspect trimester of pregnancy between the contrast crowd of placebo, and wherein the women in two groups has the average baselining LCU greater than 3.2 centimetres.Fig. 6 and Fig. 7 show that short cervix uteri patient's the crowd that replys (referring to Fig. 6) is hidden among total crowd of result (referring to Fig. 5 a and Fig. 5 b) and does not show similarly the progesterone effect than eldest son's cervix uteri crowd patient (referring to Fig. 7) and whole crowds (referring to Fig. 5 a and Fig. 5 b).That is to say that the probability in early stage childbirth of trimester of pregnancy generally is not similar between two groups, in fact, statistically, the result is covered like this, and the result that the instruction of prior art and the present invention obtain runs counter to.
Yet, this weak point cervix uteri crowd's (for example LCU is less than or equal to 3.0 centimetres) investigation is shown (as shown in Figure 8), the women who accepts progesterone increases at the probability of the slower childbirth of pregnancy duration than the women who accepts placebo.In Fig. 9, the baby who is given birth to by the women who is given progesterone has larger chance of surviving due to being reduced by premature labor than the baby who is given birth to by the women who accepts placebo.Referring to Figure 10,11 and 12.Similarly the result is found in less than 2.8 centimetres women at LCU.
The progesterone that is given according to the present invention can be that the progesterone molecule (derives from any source, comprise natural or synthetic source) or the progesterone metabolite (derive from any source, comprise natural or synthetic source), such as for example 17-Alpha-hydroxy progesterone, perhaps it can be any other progestogen.Also can use these any combination.In certain embodiments, term " natural progesterone " comprises progesterone and/or natural progesterone metabolite.Progesterone self is preferred, although also can use other progestogen.When using synthetic progestogen, preferably, synthetic progesterone is selected from derivant or the derivant of testosterone or the derivant of other molecule and/or chemical compound with progesterone activity of progesterone.Term " derivant " refers to be prepared or to be obtained by one or more chemical reactions from parent compound by one or more chemical reactions the chemical compound of parent compound.Natural or synthetic derivant or its combination of natural progesterone, synthetic progesterone, progesterone and/or other progesterone chemical compound contained in term used herein " progestogen ".
Therefore, progestogen include but not limited to: 17-Alpha-hydroxy progesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethisterone enanthate, desogestrel, levonorgestrel, lynestrenol, ethynodiol diacetate, norgestrel, norgestimate, Norethynodrel, gestodene, drospirenone, trimegestone, left desogestrel, gestodene, Nai Situo ketone, etonogestrel, and derive from the derivant of 19-nortestosterone.In preferred version, progesterone comprises any in natural progestogen, progesterone or the 17-Alpha-hydroxy progesterone.But some progestogen transvaginal are sent, and some are sent by intramuscular injection, and some are sent by oral administration, and some send by rectally, although can use other route of administration as known in the art.In preferred version, progesterone is given by means of drug delivery system, and this drug delivery system comprises crosslinked polycarboxylic acid polymer and at least a auxiliary agent of progesterone, water miscible, water-swellable.
In preferred version, progesterone carries out administration every day by vaginal approach.Yet this administration frequency can lack to being administered once weekly or as many as is administered four times every day, different and different according to the feature (comprising concentration and route of administration) of progestogen and progestin preparation.Preferably, 22 weeks of about the 18th week to the of gestation beginning to give progesterone until about the 37th week of gestation perhaps continues about 14-19 week different and different according to the pregnant age when the treatment beginning and childbirth day.In another embodiment, about the 16th week of gestation beginning to give progesterone until about the 37th week of gestation, or continuing about 21 weeks.In other embodiment, when approximately pregnancy tests are positive, begin to give progesterone until about the 37th week of gestation perhaps in about the 2nd week to the 4 week beginning of gestation, continues about 33-35 week.
Progesterone preferably when gestation begins, be given to its LCU greater than about 1.0 centimetres or more preferably greater than 1.5 anemia of pregnant woman.Progesterone more preferably is given when gestation begins to its LCU and is at least about 1.0 centimetres and maximum about 8.0 centimetres anemia of pregnant woman, in a more preferred embodiment, progesterone even more preferably be given to its LCU and be less than or equal to 3.0 centimetres or be less than or equal to 2.5 centimetres anemia of pregnant woman.
The amount of the progesterone that is given is preferably about 45 milligrams to 800 milligrams, more preferably about 90 milligrams to 250 milligrams, based on the difference of the progestogen effect of the natural progesterone of intravaginal administration and different, but in varying degrees can be different and different with route of administration according to effectiveness, the delivery system of progestogen.The concentration of progesterone is about 0.01% to about 50%, and is preferred about 1% to 40%, and more preferably from about 2.5% to about 30%, and more preferably from about 5% to about 20%, more preferably from about 6% to about 15%.In most preferred scheme, the concentration of progesterone is about 7% to about 9%.
For some embodiments, the amount of progesterone and concentration need to be enough to rest among the experimenter so that prevention or treatment to be provided, about more than 1 hour such as stopping, be preferably greater than about 2 hours, more preferably greater than 6 hours, more preferably greater than about 12 hours, also more preferably greater than about 24 hours, and most preferably greater than about 36 hours.
For some embodiments, medication can comprise administration in parenterai administration, drug administration by injection, oral administration, topical, intravenous administration, intraperitoneal administration, subcutaneous administration, transdermal administration, intradermal administration, subcutaneous administration, intra-articular administration, the ventricle, intrathecal drug delivery, intravaginal administration or intramuscular administration.The other preparation that is suitable for other administering mode comprise suppository and sometimes by in cheek, Sublingual, intraperitoneal, sheath, anus or intracranial approach.In preferred version, medication is vagina administration.
In certain embodiments, progesterone in solution such as in oil or intelligible other the suitable carrier of those skilled in the art, being provided.Other sends mode, such as oil base capsule and suppository, also is available in certain embodiments.For suppository, can use any traditional binding agent and/or carrier, for example one or more poly alkylene glycol or triglyceride; These suppositorys can be made by the mixture that comprises preferred about active component of 0.5% to 10%, more preferably from about 1 to 2%.Oral formulations can comprise normally used excipient, such as the acceptable mannitol of for example pharmacy, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate, etc., or its any combination.
Embodiment of the present invention according to effectively be used for preventing and/or treating premature labor namely postpone to give a birth and prolong gestation preferred surpass or equal the needs in 37 weeks repeatedly give progesterone every day, in some variant of these embodiments, the administration frequency of progesterone every day is 1-4 time.Those skilled in the art can understand, and the administration frequency of every day changes according to concentration and the different of amount of the progesterone of being sent.For example, 90 milligrams 8% progesterone delivery system gives once preferred every day.In other embodiments, 200 milligrams progesterone gives 2-4 time every day.
Embodiments more of the present invention are sent and compositions progesterone together or in compositions, and described compositions has the acceptable bioadhesive carrier of pharmacy, and this carrier comprises crosslinked carboxylic acid polyalcohol.Some variant of these embodiments comprises the polycarboxylic acid polymer of water-swellable, and it provides local target tissue level and effectiveness and without harmful haemodialysis agent level when administration.
In preferred version of the present invention, compositions of the present invention can be used for vagina administration.For example, because the vagina administration approach compares with intramuscular administration and may have larger patient satisfaction, and have the effectiveness of improvement by the drug delivery to the enhancing of target tissue, therefore can select the vagina administration approach.Bioadhesive preparation of the present invention has been found to provide the local vagina administration of the progesterone that can be used for topical remedy's level and has avoided simultaneously causing the level of unwelcome side effect.Vagina administration has also been avoided the first pass metabolism problem, for example, the effect through the uterus is provided at first, and directly has been delivered to the uterus, allows reduction system drug level.
In preferred version, progesterone is given at the progesterone bioadhesive preparation that comprises the basic gel of polycarbophil (polycarbophil) that is used for vaginal application, and it comprises the progesterone of 8% (wt/wt).In scheme most preferably, progesterone is sent as 8% progesterone gel and placebo, usually conduct
Or
Obtained, it is by ColumbiaLaboratories, Inc., and NJ. makes.In some embodiments, progesterone is sent in prefill, that single uses, disposable plastics giver, and described giver is sent the gram gel of the 1.125 gram dosage that comprise 90 milligrams of progesterone.Embodiment of the present invention are sent progesterone according to the United States Patent (USP) 5,543,150 that obtains from U.S. Patent application 08/122,371, and it incorporates this paper in full into.
Method disclosed by the invention can with other be used for prevent and/or treat premature labor and/or the short Cervical method of anemia of pregnant woman such as operation cerclage, to give supplementary/complementarity compositions and unite use such as for example antibiotic, indomethacin and polymer composition.Therefore, the present invention is applicable to therapeutic alliance.
Embodiment
The present invention further describes by following examples, and described embodiment only is used for illustrative purpose, is not considered to limit scope of the present invention or its mode that can put into practice.Although result of study shows, progesterone can be given to the baseline LCU effectively, and to be about 1.0 centimetres to 8.0 centimetres anemia of pregnant woman shorten with the LCU for the treatment of or prevention pregnancy duration, therefore and outbreak and the premature labor for the treatment of or prevention of preterm birth childbirth, following examples have shown the effectiveness that prolongs in specific group.
Embodiment 1a. progesterone on premature labor impact at random, double blinding, placebo-controlled trial
According to the present state of the art, study the impact that is intended to examine or check among the women that progesterone formerly has the premature labor history preterm delivery and premature labor.The base-line data of research as shown in Figure 1.The participant of this research comprises 611 valuable anemia of pregnant woman, 308 selected treatment groups that enter wherein, 302 selected placebo group that enter.Two groups selection, classify and be subdivided in the flow chart of Fig. 2 and summarize.This research is expection, at random, placebo, double blinding, the multiple center trial that carries out among the pregnant experimenter under being in high spontaneous preterm birth risk.The research participant goes out from 16 0/7 and 22 6/7 gestation are screened weeks.Give medicine or placebo with experimenter's from 18 0/7 to 22 6/7 pregnant periderm randomized groupings.
The experimenter who satisfies research standard between weeks in 18 0/7 to 22 6/7 gestation is registered by the investigator and accepts same packing, sequentially numbered progesterone or placebo vagina gel with 1: 1 ratio.Use SAS (SAS Institute Inc., Cary, NC, the USA) rules that are used for variable region group size to produce randomizing scheme, it is by testing site and the standard that is comprised (previous premature labor or short cervix uteri) layering.Quintiles, Inc. (Kansas City, MO, USA) produces random sequence, and it is offered packaging company in confidence.By by Aptuit, the hidden processing of the same Packaging and Labeling method that Inc. (Mount Laurel, NJ, USA) carries out distributes.Do not know grinding patient's exposed state (progesterone or placebo) for all grinding patient, obstetrical nursing person, research person, research coordination person and research surveillant.
Behind randomized grouping, the experimenter brings into use the drugs of being assigned to process also administration every day until 37 all pregnant ages, generation premature rupture of fetal membrane or childbirth.With 1: 1 ratio the experimenter is accepted at random
8% (vagina gives the natural progesterone gel of 90mg) or placebo vagina gel.All women carry out the drugs that it is assigned with every day
The automedication of (ketone) or placebo.
Embodiment 1b. about progesterone on premature labor impact at random, the following up a case by regular visits to of double blinding, placebo-controlled trial
The data that exist in the present embodiment provide the further analysis to the data that exist among the embodiment 1a.The purpose of this test is whether the preventive administration of determining the vagina progesterone reduces the premature delivery risk of the women with spontaneous preterm birth history.
This test is that 659 anemia of pregnant woman that only have the spontaneous preterm birth history are registered multinational test with at random, double blinding, the placebo of randomized grouping.
Between 180/7 to 226/7 gestation week, divide the processing of the use 8% progesterone vagina gel tasked once a day or placebo until childbirth, 37 all pregnant ages or premature rupture of fetal membrane (PROM) occurs to patient's randomization.Main prognosis is the premature labor in≤32 gestation weeks.Statistical analysis is based on Intentionality treatment (intent-to-treat) principle.
If anemia of pregnant woman's age, then this anemia of pregnant woman met the condition of testing between 18 to 45 years old and estimate that be that 16 0/7 to 226/7 gestation weeks and the medical record by qualified premature labor are proved in last multiparity before and have from bill tire premature labor history pregnant age between 20 0/7 to 35 0/7 gestation weeks.Also require the patient to understand English or local language commonly used, the informed consent form of voluntary signature is provided, expressed research purpose is had gained some understanding and agreed to observe the research agreement.
If the registration patient has history of adverse reaction to any composition that exists in progesterone or the processing medicine; Accepted progesterone treatment in 4 weeks before registration; Or just carrying out the treatment of epilepsy, mental sickness or chronic hypertension at present, then this patient is excluded from test.If the patient suffers from acute or chronic heart failure, renal failure or uncontrolled diabetes; The activeness hepatopathy; CD4 counts＜350 cell/mm
3And need the HIV of multiple antiviral agents to infect; The placenta previa or the low-lying placenta that need the vagina preventive measure; The pernicious medical history of breast or reproductive tract is arranged or this suspection is arranged; The thrombotic disease history is arranged or this suspection is arranged; Or have Miller pipe abnormal development, then this patient is excluded from test.In one month before carrying out this research screening, the patient who is participating in or participating at present another research is not included in this test.If this gestation of patient is accompanied with great fetal anomaly or known chromosomal disorders or multiple pregnancy, then this patient can not participate in this test.Carry out in this gestation that uterus, original place neck ring is pricked or the registration patient that plans to carry out the registration patient of cervical cerclage and have premature rupture of fetal membrane, vaginal hemorrhage, amnionitis or a preterm delivery sign can not participate in this research.At last, the qualified in advance patient of childbirth who can not or be reluctant to observe the patient of research rules or have a not Preterm Delivery childbirth is not included in this test.
According to by Quintiles, 1: 1 the randomizing scheme that Inc (Kansas City, MO, USA) provides is to carrying out Packaging and Labeling grinding medicine.Use SAS (SAS Institute Inc., Cary, NC, the USA) rules that are used for variable region group size to produce by the randomizing scheme of testing site layering.At least 1 randomization district group of 92% that accounts for the registration patient is finished at 32 centers at 53 centers.Grind medicine (
8% progesterone gel) and placebo (
) by Columbia Laboratories, Inc. (Livingston, NJ, USA) provides.The patient is instructed every day in about identical time, and preferably in the morning, the oneself gives whole vagina gel giver.The patient when randomized grouping and after each accept when 2 weeks, research was followed up a case by regular visits to the processing medicine that is assigned with 2 week amount supply with.In all research centers, all medicines are supplied with and will be brought when following up a case by regular visits at every turn, and from the empty package that reclaims with do not determine grinding the compliance of medicine with packing.The total compliance of processing the persistent period of compliance percent conduct: (total giver number of use/total administration natural law) * 100 are estimated.Total administration natural law be defined as be play the premature rupture of fetal membrane day of too early generation during from registration, not with the interval between premature rupture of fetal membrane day or 370/7 gestation week.
At all centers, when 2 each all researchs are followed up a case by regular visits to, if the patient has any complaint or problem, the generation of the harmful event of inquiry.When processing beginning, just in case the experimenter can not carry out the next time good approximately timing of periodic plan, the experimenter accepts the medicine in extra 1 week and supplies with.Be the progesterone bioadhesive preparation that comprises polycarbophil base gel for vaginal application grinding pharmaceutical preparation, it comprises the progesterone of 8% (wt/wt).The gel that comprises 90 milligrams of progesterone pre-filled, that single uses, that disposable plastics giver is sent 1.125 gram dosage.Placebo is
The bioadhesive delivery system that does not namely contain progesterone.
Experimenter with the record of spontaneous preterm birth history was screened by investigator or research coordination person between 16 0/7 to 22 6/7 gestation weeks.Pregnant age is based on last menstrual period of patient and related with ultrasonic biometrics method.Every patient accepts at least one times ultrasonic examination with definite pregnant age and gets rid of great fetal anomaly when randomized grouping, and the experience transvaginal scans to determine Cervical length.The experimenter who satisfies research standard between 18 0/7 to 22 6/7 gestation weeks is registered to accept the drugs processing of double blinding by the investigator.Behind randomized grouping, begin to carry out processing every day and lasting until 37 0/7 all pregnant ages, generation premature rupture of fetal membrane or in advance childbirth by the patient.Every patient is to estimate as the interval in 2 weeks.In pregnant 28 weeks, all experimenters experience another time Transvaginal Ultrasound to determine LCU.
Baseline characteristic is similar in two processed group.Progesterone does not reduce incidence of preterm birth when≤32 week.AGA, baby's morbidity or mortality rate when childbirth or other mother or neonate prognosis do not have difference in measuring.The harmful event that occurs during processing is similar in two groups.
Based on these results, the prophylactic treatment that uses vagina progesterone gel to carry out can not reduce the frequency of repeatedly premature labor effectively in according to the selecteed excessive risk anemia of pregnant woman of spontaneous preterm birth history.Need to study other methods of risk assessment.
Determine that in whole 53 testing sites (the consulting office that comprises these testing sites) patient's of sieve accurate number is not thought feasible in advance.1500 estimative figures by the experimenter of pre-sieve have been obtained by the inquiry testing site.711 women are determined through formal screening (obtain Informed Consent Form and still do not carry out randomized grouping) altogether, have subsequently 42 women to be excluded.In that to obtain the modal reason that is excluded behind the letter of consent be plan ring bundle, complication and spontaneous preterm birth occurs can't record before in qualified pregnant age the time.669 patients are considered to be suitable for registration and study altogether, and 659 are randomized and are divided into two processed group that are instructed to only be used for mother's family history.Nine patients be registered enter only be used for short Cervical plan assist investigation and one qualified but the patient that before randomized grouping, loses visit from then on analyze and be excluded.To obtain the drugs of at least one dosage and provide the patient of administration day to be included into Intentionality treatment (ITT) crowd.Do not provide the patient of administration day to be considered to lose the visit crowd.
ITT crowd with patient of previous premature labor history comprises 309 patients and comprise 302 patients in placebo group in the progesterone group.It is being the processed group of optimum matching aspect age, race and the Body Mass Index (BMI) that randomized grouping provides.Parity, formerly premature labor number of times and spontaneous abortion also are similar.When randomized grouping about the AGA of progesterone group and placebo group (± SD) be respectively 19.9 (± 2.1) and 20.1 (± 3.3) weeks.About previous pregnant history, 74.5% of progesterone patient's 76.4% and placebo patients has once previous spontaneous preterm birth history, and in each group, and experimenter's 23.6% and 25.5% has respectively twice or previous premature labor history more frequently.
In premature labor (main prognosis) rate in≤pregnant 320/7 week without significant difference: being 10.0% (n=31) in the progesterone group, is 11.3% (n=34) in placebo group.In the main prognostic analysis that carries out according to country /region, do not observe and between the country, have significant difference.For the two, the AGA during childbirth all was 36.6 weeks for progesterone group and placebo group.The rate of complying with of use research medicine also is similar: 96.2% women is arranged in the progesterone group, and 96.4% women is arranged in placebo group.
Other result of study between progesterone group and placebo group is zero difference also.Productive rate early: be respectively 41.7% (n=129)＜370/7 week to 40.7% (n=123); Be respectively 22.7% (n=70)≤350/7 week to 26.5% (n=80), be respectively 3.2% (n=10)≤280/7 week to 3.0% (n=9).About the survival curve of delivery time shown in Fig. 5 a.Between two groups, preterm delivery is admitted to hospital (progesterone is that 25.6% pair of placebo is 24.8%), and suppressing the childbirth medicine is similar with the frontal cortex steroid therapy of giving a birth.In the patient who treats that is admitted to hospital because of preterm delivery, the natural law of giving a birth from being admitted to hospital to is: progesterone is 30 days, placebo be 19.6 days (95%CI ,-23-2.3).In addition, between progesterone group and placebo group, all there is not respectively difference in premature rupture of fetal membrane rate (12.0% pair 12.6%) or stillbirth/intra-uterine fetal death (1.6% pair 1.3%) rate.
In progesterone group and placebo group, neonatal average birth weight similar (being respectively 2680 ± 710 grams to 2661 ± 738 grams), head circumference is similar (being respectively 32.3 ± 3.34 centimetres to 32.5 ± 3.75 centimetres) also.Between treatment group and placebo group, about 1 minute (the meta mark=8 of each group) and 5 minutes (each the meta mark of organizing=9) APGAR zero difference of marking, perhaps about admission rate (the 17.5% pair 21.5%) zero difference of neonatal intensive care unit.For progesterone group and placebo, the incidence rate of hyaline membrane disease of newborn (11.0% pair 11.9%), 3 grades or 4 grades of ventricle internal hemorrhages (0.3% pair 0.3%) and necrotizing enterocolitis (1.0% pair 1.7%) also is similar.In two neonates, observe second three months or the 3rd three middle of the month potential birth defect is arranged: an example is arranged in every group, for hip joint subluxation and lung narrow.Do not comprise with the organ of first trimester form relevant developmental character unusually such as hypospadias, refer to toe and tetralogy of Fallot more.Still collect 6,12 and baby's follow up data of 24 months and at report these not yet obtain described data as a result the time.
This research further is included in when registration without the premature labor history but has short Cervical women.Comprise 9 patients although only have short Cervical crowd, the result has hinted the possible impact of progesterone: the parturition rate in≤32 weeks when giving placebo is 40% (2/5), and the parturition rate in≤32 weeks when giving progesterone is 0 (0/4).Because some participants with previous premature labor history also have short cervix uteri, therefore, the premature labor study population is divided into quartile based on LCU.Minimum quartile (≤3.2cm) with only to have a short Cervical patient merged and segment according to the order of sequence, to LCU≤3.0cm when the registration and＜women's of 2.8cm main prognosis and less important prognosis analyze.Can not obtain enough numbers have in addition the patient of shorter LCU is used for further analyzing.For the purpose of studying, short Cervical standard is set as less than 2.8 centimetres.46 participants belong to such altogether, and their demographic factor and feature are as shown in Figure 3.
Usually, determined LCU＜2.8 centimetre in 46 anemia of pregnant woman that are randomized: accepting has 19 among 313 of progesterone, and has 27 in accepting 307 of placebo.Two groups baseline characteristic is similar.When giving progesterone≤productive rate morning in 32 weeks significantly is lower than when giving placebo≤and productive rate morning in 32 weeks (0% pair 29.6%, P=0.014).Give progesterone, have still less NICU be admitted to hospital (15.8% pair 51.9%, P=0.016) and (1.1 days to 16.5 days, P=0.013) the shorter NI CU time of staying.Also have the tendency that the hyaline membrane disease of newborn incidence rate reduces (5.3% pair 29.6%, P=0.060).Determined that vagina administration progesterone gel reduces in advance early productive rate and improves the neonate prognosis in having the anemia of pregnant woman that three months mid-terms, cervix uteri shortened.
This research be included in have spontaneous preterm birth record history (＜35 week) in the singleton pregnancy of previous last multiparity and with the irrelevant women of LCU, and do not have the premature labor history but three months this mid trimester of pregnancy the shorten women of (≤2.5 centimetres) of cervix uteri occur to be invited to register research for 180/7-226/7 gestation week.Raise in April, 2004 begin and the whipper-in patient submitted on January 8th, 2007.
If the anemia of pregnant woman suffers from the patient's condition or pregnancy complication before screening, it has increased harmful prognostic risk of mother or fetus, significantly increased the risk of medically (non-spontaneity) premature labor of indication or may cause lacking the compliance of research or give up the study of in advance, these anemia of pregnant woman are excluded from this research.Therefore, if there is following situation, then the women is excluded: the age is less than 18 years old or greater than 45 years old; Multiple pregnancy; Any composition that exists in progesterone or the processing medicine had history of adverse reaction; Before registration, treat with progesterone in 4 weeks; Or carry out at present the treatment of epilepsy, mental sickness or chronic hypertension.If the patient has acute or chronic heart failure, renal failure or uncontrolled diabetes; The activeness hepatopathy; CD4 counts＜350 cell/mm
3And need the HIV of multiple antiviral agents to infect; Placenta previa or low-lying placenta also give the vagina preventive measure; The pernicious medical history of breast or reproductive tract is arranged; The thrombotic disease history is arranged; Or have Miller pipe abnormal development, then this patient is excluded from test.The patient who is participating in or participating in another research in one month before randomized grouping is not included in this test.
If this gestation is accompanied with great fetal anomaly or known chromosome disease, then this patient also is under an embargo and participates in this test.Carry out in this gestation that uterus, original place neck ring is pricked or the registration patient that plans to carry out the patient of shirodkar-Baster operation and have premature rupture of fetal membrane, vaginal hemorrhage, amnionitis or a preterm delivery sign can not participate in this research.
Have the spontaneous preterm birth history in the gestation formerly and and the irrelevant women of LCU or do not have the premature labor history but three months this mid trimester of pregnancy the women that cervix uteri shortens occuring is screened by investigator or research coordination person between 160/7 and 226/7 gestation week.Confirm the previous history of spontaneous preterm birth by the appraisal to the medical record of patient before registration.Pregnant age is based on last menstrual period of patient and related with ultrasonic biometrics method.Every patient accepted at least one times ultrasonic examination and has determined Cervical length to determine pregnant age and the great fetal anomaly of eliminating and the scanning of experience transvaginal before randomized grouping.The experimenter who satisfies research standard between week in 180/7 to 226/7 gestation is registered by the investigator and accepts same packing, sequentially numbered progesterone or placebo vagina gel with 1: 1 ratio.Use SAS (SASInstitute Inc., Cary, NC, the USA) rules that are used for variable region group size to produce randomizing scheme, it is by testing site and the standard that is comprised (previous premature labor or short cervix uteri) institute's layering.Quintiles, Inc. (Kansas City, MO, USA) produces random sequence, and it is offered packaging company in confidence.By by Aptuit, the hidden treatment of the same Packaging and Labeling method that Inc. (Mount Laurel, NJ, USA) carries out distributes.Do not know grinding patient's exposed state (progesterone or placebo) for all grinding patient, obstetrical nursing person, research person, research coordination person and research surveillant.
Behind randomized grouping, begun to carry out that process every day and continue until 37 0/7 all pregnant ages, premature rupture of fetal membrane or childbirth occur by the patient.Every patient is to estimate as the interval in 2 weeks.In pregnant 28 weeks, all experimenters experience another time Transvaginal Ultrasound to determine LCU.
Before beginning one's study, obtain every participant LCU baseline measures and be summarised among Fig. 1.During studying, by ultrasonic measurement baseline LCU with at the LCU in rear the 28th week in administration 6-10 week.For treatment group and placebo group, average LCU is identical, all be 3.7 centimetres, and the scope of LCU is 1.1 centimetres to 7.9 centimetres for all participants.In the 28th week of gestation, again measure every participant's cervix uteri and data and base-line data are compared, and obtained beyond thought and surprising discovery.As shown in Figure 4, for the participant in the placebo group, 0.61 centimetre of LCU shorten in average after 28 weeks, and for the participant in the treatment group (namely giving the progesterone treatment scheme), the shorten in average of LCU only is 0.44 centimetre within the identical period.Because the p value of full check is 0.038, the result shows, the women who uses the progesterone treatment scheme than the women who uses placebo LCU shorten or the amount that disappears aspect the reduction of generation statistical significance.
Result of study is used the Kaplan-Meier curve description shown in Fig. 5 b-10, has investigated the premature labor terminal point in the research.Fig. 5 b is the curve about the delivery time of all randomized patients.Although as if overlapping substantially about the curve of each group shown in Fig. 5 b, when described result is decomposed when further analyzing according to patient's baseline LCU, the prognosis difference between treatment group and placebo group is apparent.Be less than or equal to 3.2 centimetres patient (Fig. 6) for the baseline LCU, the baseline LCU is less than or equal to 3.0 centimetres patient (Fig. 8 and Fig. 9), with the patient (Figure 10) of baseline LCU less than 2.8 centimetres, the participant in treatment group clearly shows not childbirth probability within longer trimester of pregnancy than the patient in the placebo group.As shown in Figure 7, the baseline LCU greater than 3.2 centimetres patient in, do not reflect that between treatment group and placebo group prognosis has statistically significant difference.
Referring to Figure 10, it has shown the baseline LCU less than 2.8 centimetres but has kept the not patient's of childbirth probability that LCU is organized the remarkable minimizing of having experienced incidence of preterm birth less than 2.8 centimetres participant.As shown in figure 10, (19 with progesterone for example 46 experimenters
The progesterone of trade mark is processed, and uses placebo treatment for 27) in, the incidence of preterm birth in treatment group is 0%, is 29.6% (P=0.014) with respect to the incidence of preterm birth in placebo group.For the purpose of this research, the premature labor parameter setting is for being less than or equal to for 32 weeks.Figure 11 comprises in more detail the childbirths termination of namely being less than or equal to 37 weeks, 35 weeks, 32 weeks and 28 weeks about progesterone group and placebo group at different pregnant time points.At each time point, the prognosis for the treatment of group is significantly improved with respect to placebo group.Specifically, about being less than or equal to for 37 weeks and being lower than for 35 weeks, treatment makes the number of giving a birth in advance reduce half, about being less than or equal to for 32 weeks and being less than or equal to for 28 weeks, in treatment group, occur without in advance childbirth, 8 examples and 3 examples occur respectively in placebo group give a birth in advance.
Result of study also shows: the neonatal prognosis of being given birth to by the participant in the progesterone group makes moderate progress, and this as shown in figure 12.When progesterone is given to LCU during less than 2.8 centimetres anemia of pregnant woman, progesterone treatment reduced NICU be admitted to hospital number (15.8% pair 51.9%, P=0.016) and reduced the NICU time of staying that (1.1 days to 16.5 days, P=0.013).Use progesterone treatment also have total neonate be admitted to hospital natural law reduce (5.8 days to 18.2 days, P=0.055) and the hyaline membrane disease of newborn incidence rate reduce (5.3% pair 29.6%, P=0.060).
In the group of LCU less than 2.8 centimetres registration women, 2 routine fetus/infant death occur in placebo group, and (SIDS is survived by 11 months in [1] childbirth; [2] After Gravidity 35 Weeks, aspiration pneumonitis), in vagina progesterone group without death.
Based on the result of this research, clearly, give progesterone to the anemia of pregnant woman and particularly in short cervix uteri anemia of pregnant woman, effectively reduce the amount that its cervix uteri shortens or disappears.
The data of the group of the participant with the baseline LCU that is less than or equal to 2.8 centimetres are provided in following table 1.The result shows, has 8 early than the childbirth of 32 weeks among the participant that 27 are accepted the placebo treatment scheme, and unmanned early than the childbirth of 32 weeks among 19 participants that accept progesterone placebo treatment scheme.As bilateral p value be 0.014 and 95%CI be-0.469, shown in-0.124, the result shows, in the Pregnant women that has less than 2.8 centimetres baseline LCU, by giving progesterone than having the statistically significant impact by giving placebo reducing aspect the childbirth in 32 weeks.Also referring to Figure 12 and Figure 14 a-e, it provides the patient who uses placebo treatment with respect to use
Between the patient that progesterone is processed about the comparison of baby's prognosis.
Table 1
| ＞32 weeks of birth | ≤ 32 weeks of birth | Add up to | |||
| | Number | 19 | 8 | 27 | |
| | Number | 19 | 0 | 19 | |
| Add up to | 38 | 8 | 46 | ||
| Fisher Precision Test p-value | 0.014 | ||||
| 95％CI | -0.469，-0.124 |
The data of the group of the participant with the baseline LCU that is less than or equal to 3.0 centimetres are provided in following table 2.The result shows, has 11 in 32 weeks or early than the childbirth of 32 weeks among the participant that 58 are accepted the placebo treatment scheme, and only has 5 in 32 weeks or early than the childbirth of 32 weeks among 58 participants that accept progesterone placebo treatment scheme.According to 95%CI and bilateral p value, these results show, have≤Pregnant women of 3.0 centimetres baseline LCU in, by giving progesterone than giving placebo in reduction early than the influential trend of tool aspect the childbirth in 32 weeks.Also referring to Figure 13 a-e, it provides the patient who uses placebo treatment with respect to use
Between the patient that progesterone is processed about the comparison of baby's prognosis.
Table 2
| ＞32 weeks of birth | ≤ 32 weeks of birth | Add up to | ||
| Placebo group | Number | 47 | 11 | 58 |
| Treatment group | Number | 54 | 4 | 58 |
| Add up to | 101 | 15 | 116 | |
| Bilateral Pr≤P | 0.094 | |||
| 95％CI | -0.214，-0.001 |
Term " about " used herein should be made broad understanding and refer to corresponding numerical value and numerical range.In addition, all numerical rangies of this paper should be understood to include each integral body in this scope.
Although herein disclosed is exemplary embodiment of the present invention, will be understood that, can be by those of ordinary skills the various variants of design and other embodiment.The feature of embodiment described herein can be combined, separates, exchanges and/or rearrange to obtain other embodiment.Therefore, can understand, claims are intended to cover all these variants and the embodiment that is in the spirit and scope of the present invention.
Claims (26)
1. progesterone is for the preparation of the outbreak with treatment among the short Cervical anemia of pregnant woman of 1.0-3.5cm or in advance childbirth of prevention and the purposes of the medicine of the premature labor of generation subsequently, and wherein progesterone is enough to make cervix uteri shorten or the minimized amount that disappears exists.
2. the purposes of claim 1, wherein said medicine is the form of vagina gel, vaginal suppository, vaginal cream or vagina solid dosage forms.
3. the purposes of claim 1, wherein said medicine be formulated for by in intramuscular, per os, per rectum, subcutaneous, vagina, Intradermal, part, intranasal, intraperitoneal, intraarticular, the ventricle, in the sheath, intravaginal or intravenous route administration.
4. the purposes of claim 1, wherein progesterone comprises natural progesterone.
5. the purposes of claim 1, wherein progesterone comprises and is selected from following synthetic progesterone: 17-Alpha-hydroxy progesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethisterone enanthate, desogestrel, levonorgestrel, lynestrenol, ethynodiol diacetate, norgestrel, norgestimate, Norethynodrel, the gestodene, drospirenone, trimegestone, left desogestrel, gestodene, Nai Situo ketone and etonogestrel.
6. the purposes of claim 1, wherein said medicine is used for administration every day.
7. the purposes of claim 1, wherein said medicine were used for from gestation the 18th weeks to the 22 week beginning administration until the 37th week of gestation.
8. the purposes of claim 6, wherein said medicine are used for administration and continue 14-19 week.
9. the purposes of claim 6, wherein said medicine were used for from gestation the 16th week beginning administration until the 37th week of gestation.
10. the purposes of claim 6, wherein said medicine are used for administration and continued for 21 weeks.
11. the purposes of claim 6, wherein said medicine are used for beginning administration when pregnancy tests are positive until the 37th week of gestation.
12. the purposes of claim 6, wherein said medicine are used for from the 4 week beginning administration of the 2nd week to the of gestation.
13. being used for administration, the purposes of claim 6, wherein said medicine continue 33-35 week.
14. the purposes of claim 6, wherein said medicine are used for according to the pregnant age when treatment begins and childbirth day carrying out administration.
15. being formulated for, the purposes of claim 1, wherein said medicine send 45 milligrams to the progesterone of 800 milligrams of dosage.
16. the purposes of claim 1, wherein said medicine are following form or are comprised in the following form: comprise progesterone, water miscible and the crosslinked polycarboxylic acid polymer of water-swellable and the drug delivery system of at least a auxiliary agent.
17. the purposes of claim 1, wherein pregnant woman uterus neck length degree is 1.0 centimetres to 3.0 centimetres.
18. the purposes of claim 1, wherein progesterone comprises natural progesterone and 17-Alpha-hydroxy progesterone.
19. the purposes of claim 1, wherein said medicine be formulated for the progesterone of sending 90 milligrams of dosage and wherein progesterone be natural progesterone.
20. the purposes of claim 1, wherein said medicine be used for to improve be expected by or subsequently by neonate morbidity and mortality rate with PN that short Cervical anemia of pregnant woman gives birth to.
21. each purposes among the claim 1-20, wherein said medicine are used for being used for the treatment of with one or more or the chemical compound of prevention of preterm birth is united and given.
22. each purposes among the claim 1-20, wherein said medicine gives for uniting with the clinical manipulation for the treatment of or prevention of preterm birth.
23. the purposes of claim 1, wherein said drug use are built as be used to inserting intravaginal drug delivery device administration.
24. the purposes of claim 23, wherein this device is the uterus neck ring or comprises the uterus neck ring.
25. progesterone has the purposes of the medicine of the outbreak of giving a birth in advance that is less than or equal to the Cervical anemia of pregnant woman of 3.5cm and the premature labor that occurs subsequently for the preparation for the treatment of or prevention, wherein said medicine is the form of vaginal jellies, vaginal suppository, vaginal cream or vagina solid dosage forms, and described medicine comprises the progesterone of 45-800mg.
26. the purposes of claim 25, wherein said anemia of pregnant woman's cervix uteri has the length that is less than or equal to 3.0cm.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US88848007P | 2007-02-06 | 2007-02-06 | |
| US60/888,480 | 2007-02-06 | ||
| US97366707P | 2007-09-19 | 2007-09-19 | |
| US60/973,667 | 2007-09-19 | ||
| PCT/GB2008/000397 WO2008096122A2 (en) | 2007-02-06 | 2008-02-05 | Progesterone for the prevention of preterm birth |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101636166A CN101636166A (en) | 2010-01-27 |
| CN101636166B true CN101636166B (en) | 2013-04-10 |
Family
ID=41595066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200880008665.XA Expired - Fee Related CN101636166B (en) | 2007-02-06 | 2008-02-05 | Progesterone for the prevention of spontaneous preterm birth |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101636166B (en) |
| UA (1) | UA101474C2 (en) |
| ZA (1) | ZA200905726B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102012009057A1 (en) * | 2012-05-09 | 2013-11-14 | Dr. Arabin GmbH & Co. KG | Rotational pessary made from a polymer comprises an active substance against premature births |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006042021A2 (en) * | 2004-10-07 | 2006-04-20 | Duramed Pharmaceuticals, Inc. | Methods of hormonal treatment utilizing ascending-dose extended cycle regimens |
-
2008
- 2008-02-05 CN CN200880008665.XA patent/CN101636166B/en not_active Expired - Fee Related
- 2008-02-05 UA UAA200908995A patent/UA101474C2/en unknown
-
2009
- 2009-08-18 ZA ZA200905726A patent/ZA200905726B/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006042021A2 (en) * | 2004-10-07 | 2006-04-20 | Duramed Pharmaceuticals, Inc. | Methods of hormonal treatment utilizing ascending-dose extended cycle regimens |
Non-Patent Citations (2)
| Title |
|---|
| ORION RUST等.A randomized trial of cerclage versus 17-hydroxyprogesterone(17P) for the treatment of short cervix.《American journal of obstetrics and gynecology》.2006,第195卷(第6期),s112. * |
| Pasquale等.对预先给与雌激素治疗的妇女阴道给与同剂量孕酮后外周血孕酮水平与子宫内膜的反应.《国外医学计划生育分册》.1998,第17卷(第4期),第240页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| UA101474C2 (en) | 2013-04-10 |
| ZA200905726B (en) | 2010-05-26 |
| CN101636166A (en) | 2010-01-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7884093B2 (en) | Progesterone for the treatment or prevention of spontaneous preterm birth | |
| Griebel et al. | Management of spontaneous abortion | |
| Conde-Agudelo et al. | Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis | |
| Edlund et al. | Antipsychotic drug use and birth defects: an epidemiologic reassessment | |
| JP5555631B2 (en) | Compositions and means for treating uterine leiomyoma, leiomyoma, myoma, uterine fibroid, endometriosis, or adenomyosis with mifepristone | |
| Henshaw et al. | Pre‐operative cervical preparation before first trimester vacuum aspiration: a randomized controlled comparison between gemeprost and mifepristone (RU 486) | |
| Hoffmann et al. | Oral misoprostol vs. placebo in the management of prelabor rupture of membranes at term | |
| Walles et al. | Maternal health care program and markers for late fetal death | |
| Safi et al. | Effect of intramuscular hyoscine-n-butyl bromide on fallopian tube spasm and pain perception during and after hysterosalpingography in infertile women: A randomized single-blind controlled clinical trial | |
| Casikar et al. | Methotrexate vs placebo in early tubal ectopic pregnancy: a multi-centre double-blind randomised trial | |
| CN101636166B (en) | Progesterone for the prevention of spontaneous preterm birth | |
| Oppegaard et al. | The use of oral misoprostol for pre‐abortion cervical priming: a randomised controlled trial of 400 versus 200 μg in first trimester pregnancies | |
| Ali et al. | Retracted: Misoprostol versus expectant management in women with incomplete first‐trimester miscarriage after failed primary misoprostol treatment: A randomized clinical trial | |
| Schaff et al. | Methotrexate and misoprostol when surgical abortion fails | |
| De Berti et al. | Oxytocin versus prostaglandins for labour Induction of women with an unfavourable cervix after 24 hours of cervical ripening (OPIC): protocol for an open multicentre randomised non-inferiority trial | |
| Barick et al. | Vaginal delivery in case of isolated longitudinal vaginal septum: an uncommon situation: a case report | |
| Kukielka | An Analysis of Patient Safety Events Submitted by Abortion Facilities in Pennsylvania 2017–2019 | |
| AU2014202051C1 (en) | Progesterone for the treatment of preterm birth | |
| Mohapatra et al. | Role of Hystero-Laparoscopy (DHL) in Management of Infertility Cases | |
| BAKO et al. | Results of hysterosalpingography in the exploration of female infertility in Niamey | |
| Soliman | Single dose Methotrexate injection, could be a safe and effective treatment for early cases of tubal ectopic pregnancy, with minimal maternal health hazards | |
| Qadir | Comparison of Vaginal Versus Sublingual Misoprostol in the Treatment of First-Trimester Missed Miscarriages | |
| Pourali et al. | Comparison of Outpatient and Inpatient Vaginal Misoprostol Administration for First-Trimester Abortion: A Randomized Clinical Trial | |
| Spirina et al. | CASE OF SUCCESSFUL CONSERVATIVE TREATMENT OF MOLAR PREGNANCY DURING MEDICINAL INTERRUPTION OF NON-DEVELOPING PREGNANCY | |
| Ashnaf | Maternal and fetal outcomes of women referred to Charlotte Maxeke Johannesburg Academic Hospital with prolonged labour |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130410 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |