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2 mg 0.035mg 2 1

4 NET 1.0mg EE 0.035mg *NET *NET *NET *NET 88 NSAIDs GnRH GnRH NSAIDs

5 2 1 2 PVC PTP PET PE *NET *NET *NET 1 PTP PVC / 4075 RH 6 PVC PTP 4075 RH 6 4

6 PTP PVC PTP PET PE 1 2TLC RH / 4075 RH 6 / 50 / RH/ 3 D lx lx hr W hr/m 2 / 8 TLC

7 / ~

8 *NET *NET NET P 2.45 EE17β- E NET EE in vivo P E NET EE 1000 NET 20mg/kg EE 1mg/kg NET EE ALT AST 4 *NET E2P 1 MMP 7

9 in vitro E2 P MMP-3 MMP-7 J Clin Endocrinol Metab 87(10): , athymic ncr/nude E E2 P Fertil Steril 83:529-37, EE LPSLPS EE ALT AST Alcohol Clin Exp Res 26(8):70S-74S,2002 *NET *NET *NET C NET 14 C-NET 3mg/kg0.15mg/kg 1 Cmax C EE 14 C-EE 0.15mg/kg+NET 3mg/kg 0.5 Cmax BA NET 16 54EE 4 14 C-NET 3mg/kg 0.15mg/kg 14 C-EE 0.15mg/kg+NET 3mg/kg

10 14 C-NET 3mg/kg 0.15mg/kg 14 C-EE 0.15mg/kg+NET 3mg/kg NET EE C-NET 3mg/kg 0.15mg/kg 14 C-EE 0.15mg/kg+NET 3mg/kg 30 NET 96EE NET EE C-NET 3mg/kg 0.15mg/kg 30 8 NET NET 14 C-EE 0.15mg/kg+NET 3mg/kg EE 8 EE 5 in vitro C-NET 3mg/kg EE 0.15mg/kg C-EE 0.15mg/kg+NET 3mg/kg NET EE H-EE NET EE 2 *NET 9

11 1 EE mg/kg EE Cmax 6 J Chromatogr 793:309-15, α NET EE EE Drug Metab Disp 29:76-71&976-82, EE 1mg/kg EE AUC Cmax Contraception 62:253-57,2000., Contraception 70:423-27,2004 *NET 4 1 *NET NET LC/MS/MSRIA100 30pg/mLEE LC/MS/MS RIA ELISA pg/mL IKH-01-3 *NET BE *NET 1 10

12 mL 1 Cmax AUCt AUC *NET 90 NET log 0.856log log 0.925log 1.030EE log 0.898log log log log 0.80log IKH * 三相性 * 三相性 * 三相性 * 三相性 mg /0.750mg/1.000mg 0.035mg E2 pg/ml 41.9± ± ±* 三相性 U/mL 36.5± ±0.2 * 三相性 83.6± ±0.2 CA ± ± IKH CA125 U/mL 26.62± ± ± IKH CA125 U/mL 21.57± ± ± ±0.30 ± 5 in vitro NET A 3α 3β-hydroxy EE 2 2-hydroxy 2 3-metylether EE UGT1A1 1A4 1A8 UGT Ann Rev Pharmacol Toxicol 40: , *NET NET 7 *NET NET NET NET NET NET NET T max 1.1±0.2 Cmax 10.8±2.6ng/mL AUC ±14.0ng h/ml 11

13 t 1/2 6.3±1.0 EE 1.1± ±35.4pg/mL 1266±324pg h/ml 12.0±4.7 9 *NET NET T max 2.6±3.7 Cmax 22.4±11.1ng/mL AUC ±51.3ng h/ml t 1/2 9.7±2.2 EE 1.3± ±52pg/mL 1999±455pg h/ml 12.5±2.7 RIA NET 0.5mg 0.035mg 21 FSH LH NET EE DSG 0.15mg 0.030mg 21 DSG 0.050mg 0.125mg 15 FSH LH DSG 0.150mg 0.030mg 21 EE 0.050mg 7 DSG 0.150mg 0.050mg 15 E2 E2 E PG 0.150mg 0.030mg PGF 2α NET PG r-afs in vitro E mol/l 10-6 mol/l TNF α IL -8 12

14 5 EE E2 E2 EE NET 1 *NET *NET BE 1 NET 1.0mg EE 0.035mg BE BE *NET *NET BE EE NET ph1.2 ph ph1.2 ph ph1.2 ph *NET 1 NET LC/MS/MS EE ELISA LC/MS/MS EE ELISA LC/MS/MS RIA ELISA 17β

15 0.2NET ELISA NET 2 3 NET EE T max 1.5 t 1/2 7 9 NET NET ELISA ELISA NET 3α-hydroxy-5α-steroid NET BE BE BA *NET BE ph1.2 ph NET *NET BE BE BE BE *NET 2 NSAIDs GnRH NSAIDs 5 NSAIDs 14

16 *NET *NET NET EE GnRH 3 EE EE NET NET EE EE 15

17 IKH Andersch Fertil Steril. 60(1):75-9,1993 Biberoglu Fertil Steril. 77(1):52-61, * 三相性 NET mg/0.750mg/1.000mg 0.035mg * 三相性 17 Full Analysis Set FAS NET NET * 三相性 17 Per Protocol Set PPS 16

18 ± 4.5± ±1.6 * 三相性 NET 4.5± ±1.7 p< t -2.3±1.4 * 三相性 NET -2.5±1.5 p= t * 三相性 NET * 三相性 * 三相性 NET NET n n n n / * 三相性 NET 14/ * 三相性 NET 17

19 IKH ± FAS CA125 IL-6-2.0± ±1.42 p< t

20 3 FAS -1 ) t 1) p< t 1) P= FAS t 1) p< ) 5 5 FAS N ± VAS 1, ± ±1.46 1, ± ± ± ±22.87 VAS 1, ± ± N ,3 mm CA125 2, U/mL p< ) p= ) p= ) p= ) p= ) 19

21 IL-6 2, ) pg/ml t 62 Wilcoxon p= ) 5 p= p= Wilcoxon 49/ / n n n n n 40/ / / INR IKH

22 FAS PPS FAS 1 t 1) p= p< p< p< p< p< p< p< p< p< p= p< p< t /

23 114/ / PT B B () 10 B03-07 ( ) 13 () 13 B06-03 ( ) 89 () 180 B10-01 ()( ) 5 B B () 1 B16-04 () 1 ( ) 1 B16-08 () 5 B17-01 () 86 B17-05 AST ALT γ-gtp () 172 B18-07 ALT AST γ-gtp Al-P () 88 B20-08 () 89 B B21-06 () n n n 22

24 IKH *NET *NET *NET 10 9 *NET 31 13/ *NET *NET 17/ *NET *NET 1 1 NSAIDs NSAIDs NSAIDs GnRH NSAIDs 23

25 GnRH GnRH GnRH 24

26 2 1 Verbal Rating Scale VRS Andersch Am J Obstet Gynecol. 144(6):655-60,1982Biberoglu Am J Obstet Gynecol. 139(6):645-54,1981 Am J Obstet Gynecol. 175: ,1996 Andersch 3 Biberoglu Dysmenorrhea Nonmenstrual pain Deep dyspareunia 4 10 Andersch Dysmenorrhea and nonmenstrual pelvic pain Symptom and score Sum of the three groups Limitation of ability to work Coexistence of systemic Need for analgesics Mild : : Unaffected symptoms 0 : No Moderate : 4 and 5 1 : Rarely affected 0 : Absent 1 : Rarely Severe : 6 and 7 2 : Moderately affected 1 : Present 2 : Regularly 3 : Clearly inhibited 3 : Inefficacious Symptom and score Dysmenorrhea Nonmenstrual pain Deep dyspareunia 11 Biberoglu Severity 0 : Absence of pain 1 : Some loss of work efficiency Mild 2 : In bed part of 1 day, Occasional loss of work Moderate 3 : In bed for 1 or more days, Incapacitation Severe 0 : Absence of pain 1 : Occasional pelvic discomfort Mild 2 : Noticeable discomfort for most of the cycle Moderate 3 : Pain persisting during the cycle or requiring strong analgesics Severe 0 : No discomfort 1 : Tolerated discomfort Mild 2 : Intercourse painful to the point of interruption Moderate 3 : Intercourse avoided because of pain Severe 25

27 12 Biberoglu Category Score Description Dysmenorrhea 0 Absent No discomfort 1 Mild Some loss of work efficiency. Use of mild analgesics 2 Moderate Occasional loss of work efficiency. Use of moderate analgesics 3 Severe Incapacitation. Use of strong analgesics VAS VRS Andersch Biberoglu Andersch Andersch Biberoglu VRS VRS Andersch 26

28 13 VAS 13 FAS ) p= p= p< p= p= p= p< ) p= p= p= p= p= p= p=

29 2 1/2 1/2 2/3 2/3-1 ±49 7.0± ± ± ± /2 1/2 2/3 2/3 3/4 3/4 * 三相性 NET Fertil and Steril. 60(1):75-9, GnRH 4 28

30 ± ±1.42 p< t VAS CA125 CA

31 123 67/ / Beecham 30

32 American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Number 310, April Endometriosis in adolescents. Obstet Gynecol. 105(4):921-7,2005 NSAID GnRH OC 31

33 3 2 3 CA

34 Royal College of Obstetricians and Gynecologists, 2000ACOG Committee on Practice Bulletins-Gynecology, Clinical management guidelines for obstetrician-gynecologists.1999 Novak's Gynecology. 13th edition. p951-2,2002 Fertil Steril. 78:961-72,2002 N Engl J Med. 345:266-75,2001 *NET GnRH Fertil Steril. 60(1):75-9,1993 Fertil Steril. 77(1):52-61, *NET 1 NET1.0mgEE0.035mg * 三相性 NET

35 GnRH GnRH 34

36 CTD /

37 *NET *NET

38 OC WHO ± ± mm ± mm 3 p= t 37

39 ± mm ± mm 3 p= t 29.1% 48/ /30 p= Fisher % 11/ /30 p= Fisher

41 GnRH 2 40

42 3 4 1 *NET *NET 2 GnRH 4 41

43 5 18 GnRH

45 DSG 0.050mg 0.125mg EE0.05mg 7 EE0.05mg DSG0.125mg DSG 0.150mg DSG 0.125mg / B03-0 B

46 GCP GCP

2.7.6 MJR a MRI CT b 2 Beecham r-afs mg/ mg/ Gn-RH 742

2.7.6 MJR a MRI CT b 2 Beecham r-afs mg/ mg/ Gn-RH 742 MJR-35 34 1 1 a MRICT b 2Beecham r-afs 3 4 20 4 mg/ 20 40 5 6 2 1 2 3 44 mg/ 5 6 7 8 4 Gn-RH 742 9 10 11 12 1 20 60 1 1MJR-351 mg/ 0.25 2 Lot. No. 2MJR-352 mg/ 1 1 Lot. No. 3MJR-354 mg/ 1 2 Lot. No. 2