審議結果報告書 平成 19 年 12 月 4 日医薬食品局審査管理課 [ 販売名 ] リコモジュリン点滴静注用 12800 [ 一 般 名 ] トロンボモデュリンアルファ ( 遺伝子組換え ) [ 申 請 者 ] 旭化成ファーマ株式会社 [ 申請年月日 ] 平成 18 年 8 月 29 日 [ 審議結果 ] 平成 19 年 11 月 22 日に開催された医薬品第一部会において 本品目を承認して 差し支えないとされ 薬事 食品衛生審議会薬事分科会に上程することとされた なお 本品目は生物由来製品に該当し 再審査期間は 8 年とし 原体及び製剤 ともに毒薬又は劇薬に該当しないとされた
19 11 14 12,800 12800 18 8 29 1 12,800U 1 1-498cDNA 498 C 2230 H 3357 N 633 O 718 S 50 52,124.58 64,000 Glycoprotein (molecular weightca.64,000) consists of 498 amino acid residues (C 2230 H 3357 N 633 O 718 S 50 molecular weight52,124.58) produced in Chinese hamster ovary cells by expression of cdna encoding amino acid residues at position 1-498 of human thrombomodulin Thrombomodulin Alfa (Genetical Recombination) 1
β-hydroxyl Asn(Asn 324 ) 2
(a) (b) (c) O 3
19 11 14 12,800 12800 18 8 29 Disseminated Intravascular CoagulationDIC DIC DIC DIC DIC DIC DIC DIC 7 DIC 1 1 380U/kg 30 4
19 10 25 12,800 12800 18 8 29 1 12,800U DICDIC 1 1 380U/kg 30 1. Disseminated Intravascular CoagulationDIC DIC DIC 20079 2002Biologicals; 30, 69-76. 2002 12,800 2. 5
rhtmαhtm 1-498 cdna CHO 498 C 2230 H 3357 N 633 O 718 S 50 52,124.58 64,000 5 Asn 29 Asn 97 Asn 98 Asn 364 Asn 391 N 7 Ser 287 Ser 474 Ser 480 Ser 482 Ser 485 Thr 486 Thr 488 O 46 Cys 23 1 1 rhtmα cdna cdna TMJ2 TMD123TMD123 cdna SV40 psv2tmd123 psv2tmd123 psv2dhfr DHFR DHFR CHO MTX MTX rhtmα MCBMCB WCB 2 MCBWCB in vitro CAL 2-1 2-2 2-1 MCB WCB CAL MTX MTX NT MTX NT NT rhtmα NT 1 rhtmα rhtmα µg/10 6 cells/day µg/10 6 cells/day µg/10 6 cells/day DNA NT DNA kb NT kb 6
mrna RT-PCR cdna MCB WCB CAL kb kb NT NT NT cdna rhtmα 2-2 MCB WCB CAL NT S L NT 1 NT NT NT In vitro VeroMRC-5CHO-K1 NT In vivo NT NT NT NT NT 2 NT NT MCB CAL WCB WCB MCB 1 MCB MCB WCB MCB MCB WCB WCB in vitro in vivo 1 BT Bovine viral diarrhea virusbovine adenovirus type 3Bovine parvovirusinfectious bovine rhinotracheitis virusbovine parainfluenza virus type 3 2 PT1 Porcine parvovirus 7
3 WCB 2-3 cells/ml L 2-3 ± L/ cells/ml µm in vitro MRC5VeroCHO-K1 U/mL EU/mL 2-3 *) 1L ml 1L ml * Medium 4 rhtmα 1 1 ph ± 2 ph 2 mg/ml 2 2 rhtmα 3 3 mg/ml 3 3 nm 0.22µm 20±5 AEXC AFCCEXC SEC 1 2-4 1 8
2-4 APC IgG ELISA IgG ELISA ELISA DNA IgG AEXC AFC CEXC SEC AFC rhtmα 2-5 2-5 S L XC In vitro MRC-5VeroNIH-3T3 In vivo MAP 3 4 Bovine testiclebovine turbinatevero 3 12 2 22 329 3 Rodent ParvovirusMouse parvovirusprospect Hill virus 4 Bovine respiratory syncytial virus BRSVBovine viral diarrhea virus BVDVRabies virusbluetongue virus type17reo 3Bovine parvovirus BPVBovine adenovirus BAV 9
rhtmα in vivo passage A rhtmα SDS-PAGESDS-PAGEpH AFC AFC 5 MCBWCB / MCBWCB / MCBWCB CAL CHO 2.12 in vitro MRC5VeroCHO-K1 ICH Q5A 12 2 22 329 CHO XMuLVXenotropic murine leukemia virus PRVPseudorabies virus 3 Reo 3 MVMMinute virus of mice 3 2-6 2-6 PRV XMuLV Reo 3 MVM / DNA/ env RNA/ env RNA/ env DNA/ env AEXC AFC CEXC ph nm 11.92 17.16 11.89 8.38 10
rhtmα 2-5 in vivo passage rhtmα in vitro MRC-5VeroNIH-3T3 MAP 6/ L CEXC A rhtmα 2 B C AC C D D L L E nm CEXC F E F mmol/l mmol/l G G G L L L H H G H G H G H 11
2 1 N C MALDI-TOF/MS MALDI-TOF/MS SDS-PAGEMALDI-TOF/MS SDS-PAGE RP-HPLCSECAEXC C cdna SDS-PAGE 1 SDS-PAGE MALDI-TOF/MS 64,000 N Ala Ala LC/MS Ala ± ±C 2 Gly 498 Gly LC/MS 46 Cys 23 Cys 12 -Cys 17 Cys 34 -Cys 149 Cys 78 -Cys 115 Cys 119 -Cys 140 Cys 157 -Cys 206 Cys 227 -Cys 238 Cys 234 -Cys 247 Cys 249 -Cys 262 Cys 270 -Cys 278 Cys 274 -Cys 290 Cys 292 -Cys 305 Cys 311 -Cys 322 Cys 318 -Cys 331 Cys 333 -Cys 344 Cys 351 -Cys 360 Cys 356 -Cys 370 Cys 372 -Cys 386 Cys 390 -Cys 395 Cys 399 -Cys 407 Cys 409 -Cys 421 Cys 427 -Cys 437 Cys 433 -Cys 446 Cys 448 -Cys 462 280nm SDS-PAGE pi pi rhtmα 1 rhtmα 12
rhtmα 1 U C S-2366L-Pyroglutamyl-L-prolyl-L-arginine-p-nitroaniline hydrochloride p-rhtmα 1 U 1 0.1µmol p-biologicals 2002; 30, 69-76rhTMα 1mg U rhtmα C C rhtmα K d 4.0nmol/LrhTMα C K m 5.1µmol/Lk cat 48min 1 N 5 O 7 N 2 O 1-1 SEC AEXC rhtmα AEXC rhtmα SDS-PAGE rhtmα SEC AEXC rhtmα SEC rhtmα Native-PAGE -2 2. 21-1 SEC AEXC 2.3 13
-3 DNA IgG 2 SDS-PAGE IEFpH SECAEXCDNA IgG 3 G L2 Lot No H L1 Lot No 20±5 36 5±3 6 25±2 3 20±2 2,500lx 120 lxhr ml ml ml µl 36 5±36 25±23 SECAEXC SDS-PAGE 20±536 3 1 mmol/l ph mmol/l rhtmα rhtmα L- 6,400U mg 14
2-7 G mmol/l C 2-7 A B C D 0.1mg640U 1mg6,400U 1mg6,400U 2mg12,800U 12,800U rhtmα 0.1 mg 1 mg 1 mg 2 mg 12,800 U mg mg L- 20 mg 20 mg 40 mg 40 mg D D G G G H 2 L- ph 0.22µm PVDF g± rhtmα 100 3 ph SEC 4 10 / 3 Lot No. 25±260RH5RH36 15
40±275RH5RH6 60±23 20±22,500lx 120 lxhr SDS-PAGE 36 SEC SDS-PAGE 36 36 1,000lx 24 24 4 2 SDS-PAGEIEF SECAEXC 1 U mg mg ml Lot No.TS6 406070 80 20 97 100 Biologocals; 30:69-76, 2002 2 mg/ml ml/ RP-HPLCN MALDI-TOF/MS 16
SECAEXC Lot No. Lot No. 1AFC rhtmα rhtmα 1mL 4.1 10 5 1.6 10 6 A C XuMLV rhtmα AFC 2-8 2-8 rhtmα XMuLV / RNA/ env A AFC CEXC ph nm 12.99 2 AEXC AFC AEXC PRVReo3MVMXMuLV AFC Reo3MVM XMuLV 17
3 rhtmα rhtmα rhtmα rhtmα rhtmα rhtmα 2. 21 AEXC SEC rhtmα 4 N N pi 18
36 3. 1 1C C 4.2.1.1-10 1100nmol/L 2nmol/L C 10µmol/L K d 4.0nmol/L 0.5µmol/L C C n=3 C 4.2.1.1-14 310µg/mL C C n=2 2 FVa4.2.1.1-9 0.010.3µg/mL tissue factortf FVa 50%IC 50 0.052µg/mL FVa4.2.1.1-14 FVa 0.1µg/mL FVa 50% 2.6µg/mL FVa 4.2.1.1-34.2.1.1-9-10 TF CaCl 2 0.0021µg/mL IC 50 0.023µg/mL C 5.410 27% S 01020 100% AT 861 99% C S C 27% 19
S 20% C S 10% 1µg/mL AT TF 4.2.1.1-1 TF CaCl 2 0.0053µg/mL0.0110µg/mL 0.160µg/mL IC 50 0.0900.36 8.0µg/mL IC 50 0.072 0.12 0.14U/mL 20% 80%IC 80 /IC 20 110 7.0 n=3 TF4.2.1.1-9-15 TF CaCl 2 5 CAPCAT AT ATAT 0.010.3µg/mLAPC TF 5 IC 50 0.034µg/mL0.030µg/mL0.15µg/mL 0.58µg/mL0.037U/mL 0.065IU/mL APC IC 80 /IC 20 24204.3 2.6 APC C 3 TCT4.2.1.1-2 2 2 TCT 2 9.812 5.4µg/mL 0.170.15 0.21U/mL TCT4.2.1.1-9 20
APC TCT 2 8.2µg/mL6.7µg/mL 0.4µg/mL0.15µg/mL0.25U/mL 0.74 IU/mL 4.2.1.1-10 IC 50 ±24±4.5nmol/L1.5±0.3µg/mL IC 50 4.0±0.7 nmol/l97±20 nmol/l0.08±0.02u/ml 0.15±0.03IU/mL n=3 5-500µg/mL 4DIC TFDIC1TF4.2.1.1-4 Sprague-Dawley 89 TF150mg/kg 1 DIC DIC TAT APTTPT FDP D- 6406,400U/kg0.1 1mg/kgTF 30300IU/kg 330mg/kg 0.33mg/kg TF 1 Control TF Normal DIC 1,900U/kg 0.3mg/kg PT 6,400U/kg1mg/kg TATFDP D- APTT 30IU/kg/hr 100IU/kg/hr TAT PT 100IU/kg/hr D-300IU/kg/hr APTT 0.3mg/kg/hr FDP D-n=56 TFDIC4TF4.2.1.1-12 Sprague-Dawley 180270g TF100mg/kg 4 DIC DIC 1,900U/kg0.3mg/kg 300U/kg n=781,900u/kg0.3mg/kg 21
300U/kg 0.25 4 30 60µg/mL 0.30.7U/mL TFDIC1TFAT 4.2.1.1-13 Sprague-Dawley 180240g TF150mg/kg 1 DIC DIC AT 6406,400U/kg0.11mg/kg 30100U/kg TF 6,400U/kg 1mg/kg 100U/kg DIC n=412 Sprague-Dawley 180240g AT 20mg/kg 1 6,400U/kg1mg/kg 100U/kg TF 90mg/kg 1 AT AT92 57% 6,400U/kg1mg/kgTF 100U/kg n=56 LPSDIC4LPS4.2.1.1-11 Wistar 67 LPS 055:B5 50mg/kg 4 DIC DIC APTT PT FDP GFD 1,90019,000U/kg0.3 3.0mg/kg 100400U/kg LPS 4 DIC FDP 6,400U/kg 1mg/kg1,900U/kg0.3mg/kg 1,900U/kg0.3mg/kg 200U/kg GFD 6,400U/kg 400U/kg n=617 TFDIC0.5TF4.2.1.1-7-8 36kgTF50mg/kg 0.5 DIC DIC TAT FDP C APTT PT 6.46,400U/kg0.0011.0mg/kg 540U/kg TF 0.250.50.75 1 TATFDP C APTTPT APTT TAT APTT 640U/kg0.1mg/kg 20U/kg TAT 64U/kg 0.01mg/kg 20% 70%ED 70 /ED 20 23 3.5 22
n=37 0.27µg/mL 5DIC TFDIC0.5TF4.2.1.1-5 Sprague-Dawley 89 TF50mg/kg 0.5 DIC TF 1901,900U/kg0.030.3mg/kg 30 300U/kg/hr 1.5 640U/kg0.1mg/kgTF 1 30300U/kg/hr 300U/kg/hr n=10 6DIC LPSDIC24LPS4.2.1.1-6 Sprague-Dawley 7 LPS 055:B5 30mg/kg 24 DIC LPS 19,000U/kg3mg/kgLPS 1,900U/kg/hr 0.3mg/kg/hr 56%14/2592%23/25 GPT GOT C APC FVa Fa 2 1TAFI TAFI4.2.1.2-2 Sprague-Dawley 56nmol/L2.9µg/mLCaCl 2 TAFI TFDIC0.5TFTAFI 4.2.1.2-1 Sprague-Dawley7TF1.9U/kg0.5 DIC6,400U/kg1mg/kg TFTAFI TATn=6 23
2 4.2.1.1-9-14 APTTPTXa2 1813016µg/mLC APTT 4.2.1.1-14 APTT2 100µg/mL1,000µg/mL2 3 4.2.1.2-3 Sprague-Dawley320420g13,000 51,000U/kg28mg/kg100400U/kg 1526,000U/kg4mg/kg200U/kg n=717 4DIC CLP-αTNF-α -6IL-64.2.1.2-4 C57BL/681020% CLP19,000U/kg3mg/kgCLP 117CLP612 TNF-αIL-6CLP744% TNF-αIL-6n=483%n=18 LPSDIC3LPS-1β IL-1β4.2.1.2-5 Sprague-Dawley7LPS055:B5 3.75mg/kg3DIC 19,000U/kg3mg/kgLPSLPS 1,900U/kg/hr0.3mg/kg/hrLPS IL-1β770pg/mL 482pg/mL 3 1 4.2.1.3-4 ddy5619,000u/kg3mg/kg 1Irwin510 153060open-field5 24
thiopental sodium 35mg/kg 5pentetrazol65125mg/kg 510153060 510153060 4.2.1.3-44.2.1.3-2 Wistar6719,000U/kg3mg/kg 1Irwin Sprague-Dawley81,900U/kg0.3mg/kg 19,000U/kg3mg/kg190,000U/kg30mg/kg0.25 0.2512424 2 herg4.2.1.3-1 herg2 20200µg/mL 4.2.1.3-3 4.2.1.3-4 23kg19,000U/kg 3mg/kg510153060 3.04.2kg19,000U/kg3mg/kg 0.5123624 4.2.1.3-3 3.04.2kg64,000U/kg10mg/kg 0.53pH 34.2.1.3-4 Hartley250g10100µg/mL 51.0 10-7 mol/l 1.0 10-6 mol/l2.5 10-5 mol/l1.0 10-3 mol/l 24ddY5 619,000U/kg3mg/kg520 44.2.1.3-4 25
Wistar6719,000U/kg3mg/kg 5 4 1APTT4.2.1.4-1-4 APTT13µg/mL0.168U/mL 0.11IU/mL0.1122µg/mL 0.130.29µg/mL 30 C Thromb Haemost; 70: 418-22. 1993J Biol Chem; 270: 4053-7. 1995 APC 15 Chest; 124(3 Suppl): 26S-32S. 2003 380U/kg 0.06mg/kg 1 1 6 30 IC 50 90ng/mL 0.1 241 TF DIC 270ng/mL 0.2 196.5 20 DIC 1 1 30 30 IC 50 90ng/mL 6 0.1 DIC 30 C DIC DIC DIC DIC 26
ELISAenzyme-linked immunosorbent assay 125 I- 1 4.2.2.2-156 320U/kg50µg/kg α β T 1/2α T 1/2β 0.35 7.1hr 64320 1,600U/kg1050 250µg/kg 2 31 38 41mL/kgCL 5.04.8 5.7mL/hr/kg AUC C 0 64320 1,600U/kg10 50 250µg/kg 3136 34mL/kgCL 6.35.2 5.2mL/hr/kg AUC C 0 320U/kg50µg/kg 2 C max AUC C max 320U/kg50µg/kg AUC C 0 T 1/2β CL 125 I- 320U/kg50µg/kg 1 1 7 24 3 1.4 320 U/kg50µg/kg 1 1 7 4 7 13,00038,000 120,000U/kg26 18mg/kg 1 1 28 1,3003,800 13,000U/kg0.2 0.6 2mg/kg 1 1 6 C 5min AUC 0-24hr 2 4.2.2.2-2 125 I- 320U/kg50µg/kg 24 94 65 21 8 72 6 24 72 12 27
125 I- 125 I 125 I - 125 I- 320U/kg50µg/kg 1 1 7 7 24 24 1.33.3 7 168 16 6 5.3 15.5 12 18 125 I- 320U/kg50µg/kg 125 I- 320U/kg50µg/kg 8 13 8 70 3 4.2.2.2-2 125 I- 320U/kg50µg/kg 1 1 7 5 24 95 125 I 5 8 20 4 4.2.2.2-25 125 I- 320U/kg50µg/kg 120 93 2 120 40 48 5.41 1 7 168 95 3 64320 1,600U/kg1050 250µg/kg 120 48.354.5 43.1 2 1 1 7 7 120 58.8 28
5 4.2.2.7-1 5/6 320U/kg 50µg/kgT 1/2α 0.20 0.18hrT 1/2β 7.4 9.2hr T 1/2α T 1/2β 0.1 5.0hr 2-1 2- Vd 1 125 I Vd 2 Vd 1 Vd 1 Vd 2 1 4.2.3.1-1-2 4.2.3.7.6-1 130,000380,000 1,200,000U/kg2060 180mg/kg 5 1,200,000U/kg 180mg/kg 1 1 5 1,200,000U/kg180mg/kg 1 2 1,200,000U/kg180mg/kg 2 1,200,000U/kg180mg/kg 2 4.2.3.2-1-5 29
1 13,00038,000 120,000U/kg26 18mg/kg 1 1 13,000U/kg 10 15 13,000U/kg 1 120,000U/kg18mg/kg 2 1 GOTGPT 1 38,000U/kg/6mg/kg/ 2 3 3801,300 3,800U/kg0.06 0.2 0.6mg/kg 1 1 3,800U/kg0.6mg/kg 2 3,800U/kg/0.6mg/kg/ 1 1,3003,80013,000 38,000U/kg0.20.6 2 6mg/kg 1 1 1,300U/kg 3 5 1,300U/kg 1 13,000U/kg2mg/kg 1 38,000U/kg6mg/kg 2 38,000U/kg6mg/kg 2 13,000U/kg 2mg/kg 1 13,000U/kg2mg/kg 1 38,000U/kg6mg/kg 1 3,800U/kg0.6mg/kg 13,000U/kg2mg/kg 3,800U/kg0.6mg/kg 2 1 13,000U/kg2mg/kg 2 3 38,000U/kg6mg/kg 3 3,800U/kg0.6mg/kg GOTGPT 38,000U/kg6mg/kg 2 13,000U/kg2mg/kg 3,800U/kg0.6 mg/kg 13,000U/kg2mg/kg 1 1,300U/kg/ 0.2mg/kg/ 6 4 1,3003,800 13,000U/kg0.20.6 2mg/kg 1 1 30
3,800U/kg 0.6mg/kg 1 13,000U/kg2mg/kg 2 3 13,000U/kg 2mg/kg 1 2 1 1 13,000U/kg2mg/kg 1 1 1 3,800U/kg 0.6mg/kg 1 13,000U/kg2mg/kg 2 Fe 3,800U/kg0.6mg/kg 1 13,000U/kg2mg/kg 2 3,800U/kg0.6mg/kg 3,800U/kg 0.6mg/kg 13,000U/kg2mg/kg 1 13,000U/kg2mg/kg 1 1,3000.2 3,800U/kg0.6mg/kg 27 13,000U/kg 2mg/kg 1 C 5min AUC 0-24hr 1,300U/kg/0.2mg/kg/ 3 4.2.3.3.1-1 Don D-6 in vitro 4 5 1 4.2.3.5.1-1 1 120,000U/kg18mg/kg 3.2 120,000U/kg18mg/kg 13,00038,000 120,000U/kg26 18mg/kg 63 14 711 25 2038,000U/kg 6mg/kg 1 1 120,000U/kg 31
18mg/kg 3 26 1 38,000U/kg6mg/kg 38,000U/kg6mg/kg 7 120,000U/kg18mg/kg 13,000U/kg/2mg/kg/ 38,000U/kg/6mg/kg/ 13,000U/kg/2mg/kg/ 13,000U/kg2mg/kg 2 4.2.3.5.2-1-3 13,00038,000 120,000U/kg26 18mg/kg 717 1 1 2325 20 38,000U/kg6mg/kg 2 120,000U/kg18mg/kg 22 38,000U/kg 6mg/kg 1 120,000U/kg18mg/kg 15 1517 120,000U/kg18mg/kg 38,000U/kg6 mg/kg 13,000 38,000U/kg2 6mg/kg 120,000U/kg18mg/kg120,000U/kg18mg/kg 120,000U/kg18mg/kg 13,000U/kg2mg/kg 3,800 13,000U/kg0.6 2mg/kg 717 1 1 25 20 13,000U/kg2mg/kg 2 38,000U/kg6mg/kg 3,80013,000 32
38,000U/kg0.62 6mg/kg 717 1 1 15 38,000U/kg6mg/kg 1 10 38,000U/kg6 mg/kg4/ 1 38,000U/kg(6mg/kg) 13,000U/kg/2mg/kg/ 3,800U/kg/0.6mg/kg/ 38,000U/kg/6mg/kg/ 3 4.2.3.5.2-4 4.2.3.5.2-44. 7,700 U/kg1.2mg/kg 1/3 7,700U/kg1.2 mg/kg 1,300 3,800 7,700U/kg0.20.6 1.2mg/kg 2050 5 7,700 U/kg 1.2mg/kg 3 2 7,700 U/kg1.2mg/kg 3 2540 3,800U/kg/0.6mg/kg/ 4 4.2.3.5.3-1 4.2.3.5.3-111. 3 38,000U/kg6mg/kg 3,80013,000U/kg 38,000U/kg0.62 6mg/kg 17 21 3.6 ml/kg 1 1 25 38,000 U/kg6mg/kg 22 1 13,000U/kg2mg/kg 1 24 38,000U/kg6mg/kg 1 12 13,000U/kg 2mg/kg 5 38,000 U/kg6 mg/kg 33
3,800U/kg/0.6mg/kg/ 3,800U/kg/0.6mg/kg/ 13,000U/kg/ 2mg/kg/ 6 4.2.3.6-1 1901,900 19,000U/mL0.030.3 3mg/mL 0.05mL/ 3 8 6 ()3mg/mL 7 4.2.3.7.1-1 6 ASA 8 4.2.3.7.6-2-4 37 19 ASA PCA ASA 6 0.01 0.1mg/14 1mg/ PCA 12 ASA 11 4 1mg/ ASA PCA PCA 3 0.001 0.01mg/ 24 1mg/ 64,000 DNA in vitro 34
8 4 2 1 DIC ELISA 1 1 5.3.3.1-1 12 190640 1,900U/0.030.1 0.3mg/ 2 C max 190U/ 24 640 1,900U/ 48 C max ± 10.15±2.6739.70±6.84 121.75±5.16ng/mL AUC AUC inf ± 256.55±31.731,074.72±162.00 3,030.89±291.62 nghr/ml T 1/2α 2.803.97 hrt 1/2β 18.3420.75 hr CL1.471.91 ml/hr/kg 24 48 33.344.9 54.359.8 5.3.3.1-2 4 1,900U/0.3mg/ 1 C 0 140.99±5.43 ng /ml±auc inf 3321.34±394.60 35
nghr/mlt 1/2α 3.37±2.27 hrt 1/2β 19.82±2.10 hrcl 1.49±0.24 ml/hr/kg 24 48 43.7±8.4 60.3±10.3% C 100 45.324 53.248 62.0 48 2 5.3.3.1-1 4 1,300U/0.2mg/ 2 1 1 3 C max AUC inf 93.29±4.62ng/mL 2,143.09±204.43nghr/mL T 1/2α 3.94±1.83hrT 1/2β 18.73±4.25hrCL 1.40±0.31mL/hr/kg 3 48 73.6 2 1 5.3.5.1-1 DIC 38130 380U/kg0.0060.02 0.06mg/kg 30 1 1 6 2836 2740 3439 1 97.8±46.1289.1±97.5 915.9±237.9ng/mL6 172.6±69.3627.0±226.8 1,730.7±445.1ng/mL6 24 100.8±45.5349.9±143.5 902.2±313.7ng/L 10.6±14.86.9±4.6 6.3±6.8ng/mL 4 7 DIC DIC 2 7 4048 1.2 1533.5ng/mL 3 834 100ng/mL 500ng/mL 300900ng/mL 70% 380U/kg0.06mg/kg6 36
3 5.3.3.5 PPK 20 116 136 653 58 65 80 65 75 29 75 80 16 80 11 55kg3190kg 1.14 mg/dl 0.311.5 mg/dl 29.211.453.3 1- NONMEM 79 / 57 65 56 80 GOT 75 59 GPT 77 57 98 25 31 105 50 86 49 87 39 97 CV Vd 34.4%CL 31.3% Vd0.0508 WT 1.43 HT CL0.00180 WT 0.839 AGE HT1 or 0 AGE1 or 0 WTkg PPK CL 16% 43% 1 DIC 30 I 20 1 1 DIC 30 37
I 2 2 C max 30 C max 30 2 30 2 C max 24 30 2PPK PPK PPK 1 I 2 PPK 1-2- 1-2- 2-6 6 24 1- AUC CL 2-1- 4 2- AUC 3509 nghr/ml α AUC 436 nghr/ml 12β AUC 3,073 nghr/ml 88% 1- PPK 1- PPK 38
2- α 1-2 PPK PPK 0.25 Tukey P-value 0.05 / 1.2 mg/dl 25 21 Cockcroft and Gault 40mL/min 20mL/min 1 11 15 CL PPK 25 380U/kg 0.06mg/kg 4mg/dL 1mg/dL C max 1.2 PK 9 25 39
kg 25 38 82 65 19 10 55kg15 48kg 4mg/dL 5 1 1 1 2.1mg/dL PPK PPK CL 15% 1 130U/kg 130U/kg DIC PPK 25 4mg/dL PPK PPK 40
3 7 100ng/mL 1,000ng/mL 100ng/mL 1000ng/mL 100ng/mL APC IC 50 90ng/mL IC 50 2 2 1 5 I I DIC * 16 0.030.10 3mg/0.2mg/ 1 1 3 2 4 0.3mg/1 DIC DIC 45 0.30.6mg0.61.2mg1.22.0mg 2.03.0mg/1 1 6 30 : 0; 75.0 1; 40.0 2; 55.6 3; 83.3 DIC DIC DIC 120 0.006mg0.02mg0.06mg/kg1 1 6 30 232 0.06 mg/kg 1 1 6 30 8 U/kg/hr 6 24 DIC * 50kg 1,90019,000U/0.33.0mg/38380U/kg0.0060.06mg/kg : 0.006mg/kg 39.30.02mg/kg 60.7 0.06mg/kg 67.6% DIC Woolson-Bean 66 1 vs. 49.9 1 5.3.3.1-1 19 19 19 1906401,900U/0.030.10.3mg/ 2431,300U/0.2mg/2 41 41
30.1mg10.3mg22 30.03mg 20.3mg120.2mg 16 4. 114.12 2 5.3.3.1-219 4 1,900U/0.3mg/ 1 4 1 40 24 10024 48 ±45.3±11.953.2±10.7 62.0±14.6% 48 4. 11 100 (%) 75 50 25 0 0 24 48 (hr) 42
3 5.3.5.2-119 19 DIC DICDIC 32 50 02 11 0 0.3mg// 0.6mg// 1 3 1015 6 3 3 01,900U/0.3mg/ 3,800U/0.6mg/ 13,800U/ 0.6mg/ 7,700U/1.2mg/ 27,700 U/1.2 mg/ 13,000U/2.0mg/ 313,000U/2.0mg/ 19,000U/3.0mg/ 4 1 1 30 7 46 1 45 7 38 012 3 4139 12 DIC 2 36 4119 12 4 7 2 7 2 3 5 34 4 10 8 12 7 7 34 7 1 5 35 4109 12 36 21 15 DIC 0 1 2 3 100%1/1 16.7%1/6 0%0/2 100%5/5 43
100%3/3 16.7%1/6 60.0%3/5 66.7%2/3 100%3/3 11.1%1/9 42.9%3/7 66.7%2/3 75.0%3/4 50.0%5/10 55.6%5/9 83.3%10/12 DIC 50.0%2/4 30.0%3/10 33.3%3/9 75.0%9/12 75.0%3/4 40.0%4/10 55.6%5/9 83.3%10/12 25.0%1/4 30.0%3/10 33.3%3/9 50.0%6/12 38 0123 1/4 0/13 1/9 1/12 1 44 6 28 11 17 6 1 5 4 5.3.5.1-119 19 DIC DICDIC 92 38U/kg0.006mg/kg 1,900U/0.3mg/130U/kg 0.02mg/kg 6,400U/ 1.0mg/380U/kg0.06mg/kg19,000U/3.0mg/ 3 1 1 6 30 7 FDP 4 FDP 3 123 FDP 3 0.02mg/kg 120 6 0.006mg/kg 33/39 84.6%0.02mg/kg 31/40 77.5%0.06mg/kg 39/41 95.1% 0.006mg/kg 2 0.02mg/kg 5 0.06mg/kg 0 44
125 2 3 120 0.0060.02 0.06mg/kg 3940 41 3 20 100 3431 35 90 28 28 34 0.006mg/kg 39.3%11/28 0.02mg/kg 60.7%17/28 0.06mg/kg 67.6%23/34 Cochran-Armitage p=0.0188 90 48 20 15 7 0.006 mg/kg 0.02 mg/kg 0.06 mg/kg 7 4 8 6 3 25.00% 14.30% 28.60% 21.40% 10.70% 39.30% 12 5 6 3 2 42.90% 17.90% 21.40% 10.70% 7.10% 60.70% 16 7 3 3 5 47.10% 20.60% 8.80% 8.80% 14.70% 67.60% 35 16 17 12 10 38.90% 17.80% 18.90% 13.30% 11.10% 56.70% 28 28 34 90 DIC 0.006 mg/kg 0.02 mg/kg 0.06 mg/kg 60.015/25 52.013/25 59.316/27 57.144/77 25.03/12 54 56/11 62.55/8 45.214/31 35.710/28 60.717/28 67.623/34 55.650/90 DIC 34.411/32 50.014/28 55.919/34 46.844/94 DIC 5 2 DIC DIC DIC DIC 100 3 117 0.0060.02 0.06mg/kg 3739 41 3 0.006mg/kg 2 0.02 mg/kg 1 1 1 45
234 5. 5 0.006 mg/kg 3597.2 12.8 00 00 00 36 1 0.02 mg/kg 3694.7 25.3 00 00 00 38 1 0.06 mg/kg 3895.0 25.0 00 00 00 40 1 10995.6 54.4 00 00 00 114 3 8 0.0060.02 0.06mg/kg 14/39 35.9%20/40 50.0 18/41 43.9 4 5 1 1 2 2 1 2 3 5 1 2 ALP 1 1 1 2 GOT GPT 28 0.0060.02 0.06mg/kg 15/39 38.513/40 32.512/41 29.3 0.0060.02 0.06 mg/kg 1 2 1 0.02mg/kg 1 0.0060.02 0.06mg/kg 0 1 0 DIC 0.06mg/kg/ 5 5.3.5.1-220 20 DIC DICDIC DIC DICDIC 101 113 0.06mg/kg/ 30 1 46
8U/kg/hr 24 6 241 234 DIC 2 1 1 232 116 116 DIC 126 64 62 103 50 53 3 2 1 5 227 114 113 Full Analysis SetFAS FAS 17 210 104 106 Per Protocol SetPPS 232 2 2 1 231 116 115 241 48 19.9%PPS 28 28 PPS 23 17.6% 22 20.6% 17 10 7 DIC FAS DIC 224 DIC DIC DIC FAS DIC 95 64 42 65.6 22 34.4 52.777.1 DIC DIC 95 61 28 45.9 33 54.1 33.159.2 19.7 2.636.8 48 32 66.7 16 33.3 51.679.6 51 28 54.9 23 45.1 40.368.9 11.8-7.330.9 DIC 5 2 DIC DIC DIC FAS DIC 100 DIC Woolson-Bean DIC FAS -%- 95% 95% 112 66.1 57.075.2 112 49.9 40.759.0 16.2 3.329.1 47
7 7 FAS 62 2 64 96.9 3 1 59 61 96.7 50 52 45 90.0 45 86.5 95% 95% 89.299.6 2 3 3 88.799.6 0.2-6.06.3 5 10.0 78.296.7 7 13.5 74.294.4 3.5-9.015.9 Mantel-Haenszel χ 2 0.2373 1 P 0.6262 28 28 FAS 95% 95% 53 11 64 82.8 17.2 71.391.1 50 11 61 82.0 18.0 70.090.6 0.8-12.514.2 36 14 50 72.0 28.0 57.583.8 34 18 52 65.4 34.6 50.978.0 6.6-11.324.6 Mantel-Haenszel χ 2 0.3763 :1 P 0.5396 7 FAS 95% 95% FDPµg/mL -8.5-18.70.0 PICµg/mL -7.1-19.04.8 10^4/µL -0.6-1.70.4 D-µg/mL -14.6-28.4-4.2 10^4/µL α2pi% 2.5-1.16.2 4.0-1.09.0 mg/dl -1.05-37.035.0 C% 11.0 4.017.0 PT 0.01-0.040.05 PAI-1ng/mL -29.2-47.9-11 3 APTT -6.0-8.8-3.4 µg/ml -9.55-27.80.0 TATng/mL AT% -15.9-27.1-5.5 16.0 11.021.0 11 21 5 1 231 116 115 14 50% 70.7%82/116 57.867/116 48
53.462/116 72.2%83/115 60.0% 69/115 52.260/115 14 27/116 23.3 29/115 25.2 3 GOT 6.07/116 6.0 7/116 GPT 5.26/116 4.35/116 3.4 4/116 3.44/116 3.44/116 6.17/116 5.26/115 5.26/115 4.35/115 LDH 3.54/115 GOT 3.54/115 GPT 3.54/115 3.54/115 3.54/115 28 26/116 29/115 7 7/116 9/115 0.9%1/112 vs. 5.5%6/110 0.9%1/112 vs. 5.5%6/110 0.9%1/112 vs. 5.5%6/110 AL-P 1.0%1/103 vs. 4.9%5/102 LDH 0 0/109 vs. 3.8%4/106 GOT 6.5%7/107 vs. 3.8%4/106 5.6%5/89 vs. 1.2%1/84 4.3%4/92 vs. 1.1%1/90 3.2%3/93 vs. 0.0%0/90 28 37/116 31.960 41/115 35.762 14 28/116 24.145 33/115 28.751 14 5.2%6/116 5.2%6/115 28 4 11 7 7 4 15 8 6 4 4 1 28 7/116 6.08 8/115 7.0 9 1 1 3 4 3/116 2.65 6/115 5.212 10/116 8.613 18/115 15.725 2/116 49
1.74 7/115 6.18 1 DIC DIC DIC DIC DIC DIC DIC DIC DIC 1983;38:1279-1283 DIC 1520% 5% 4.11 DIC 4.13 4.14 DIC DIC DIC DIC Principles of Internal Medicine 16 th ed.mcgraw Hill DIC DIC DIC 4.11 50
4.12DIC DIC 4. 13 DIC 1 DIC 300500U/Levi M, et al. N Engl J Med 1999; 341: 586-592 DIC 200300U/kg/ 21 pp509-512 DIC 20 1 10,000U J.Pediatr; 91: 695-700. 1977JAMA; 286: 1869-1879. 2001 C PROWESS 15,000U/N. Engl. J. Med; 344: 699-709. 2001 DIC 7 10U/kg/hr; 23: 2815-2834. 1995 C DIC 8U/kg/hrInt. J. Hematol; 75: 540-547. 2002 DIC 10U/kg/hrThromb. Res; 72: 475-500. 1993 DIC 8U/kg/hr 8,64012,480 U// DIC 10,000U// DIC. 1. : ; p. 91-107.1997 DIC Blood; 75: 2112-2117. 1990 8U/kg/hr DIC AT AT AT 50 2DIC DIC DIC 1980 51
, 54 : 5-12. 19801988, 62 : 37-41. 19882004 DIC Clin Appl Thromb Hemost; 11: 71-6. 20052005 DIC Crit Care Med; 34: 625-31 2006 2001 ISTH DIC overt-dic DICCrit Care Med; 32: 2416-21. 2004ISTH overt-dic DIC 1988 overt-dic DIC ISTH overt-dic DIC DIC ; 31: 1659-1663. 2005 DIC 1 DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC FDP 3 PT 2 DIC DIC DIC DIC DIC DIC 52
DIC DIC FDP 3 FDP DIC DIC FDP ; 18: 127-139. 2007FDP ;pp1985-1994. 2006 DIC DIC FDP DIC FDP CT DIC DIC DIC DIC DIC DIC DIC ISTH overt-dic Am. J. Hematol; 4: 17-22. 2003 DIC DIC DIC 7 DIC DIC DIC DIC 15 14 1 DIC 53
3 DIC DIC 28 1 DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC 7 DIC 28 DIC DIC 10.0%6/60 59.0%23/39 DIC DIC 8.6%6/70 29.1%16/55 7 DIC 28 DIC 3.1%1/32 68.8%11/16 DIC 7.1%3/42 36.4%8/22 DIC DIC DIC DIC 7 DIC DIC DIC DIC DIC DIC 7 3 FDP515.5µg/mLD-6.4722.84µg/mL ATTAT8.126.2ng/mLα2 54
PIC 0.52.9µg/mLSFMC9.848.6µg/mL DIC DIC DIC TAT DIC DIC TAT 4 DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC Woolson-Bean 66.1 49.9DIC 95% 16.23.329.1% 95 5% DIC DIC 9519.72.636.8 DIC 11.87.330.9 DIC N Engl J Med; 341: 586-592.1999 DIC DIC DIC 55
DIC FAS DIC DIC FAS 60/82 73.2 9/35 25.7 1/7 14.3 37/46 80.4% 5/15 33.3% 0/2 0.0 23/36 63.9 4/20 20.0 1/5 20.0 38/46 82.6 14/29 48.3 8/24 33.3% 23/25 92.0 6/13 46.2 3/10 30.0 15/21 71.4 8/16 50.0 5/14 35.7 DIC DIC DIC -1 FAS 227 8 6 1 0 DIC DIC FAS DIC 95 DIC 95 55 3869.1 55.2-80.9 55 2647.3 33.7-61.2 21.83.839.8-2 FDP 7 7 DIC LOCF FDP DIC FAS DIC DIC 95()() 64 4265.6 18.20.935.4 59 2847.5 41 3073.2 18.81.038.6 46 2554.3 56
-3 DIC DIC 273 93 106 DIC ; 16: 188-202. 2005 DIC DIC DIC FAS 102 14 88 D- FDP D-/FDP FDP DIC DIC 7 DIC 2 3 DIC DIC 87 7 86 43 43 DIC DIC DIC DIC DIC DIC DIC DIC 2 DIC DIC DIC 95()()) 43 2558.1 9.3 43 2148.8 11.730.3 380U/kg0.06mg/kg 6 1 5 DIC DIC 60%3/5 DIC 4 DIC DIC 2 SIRS DIC DIC 85 SIRS 3 1 ; 16: 188-202. 2005 SIRS 3 DIC 2 DIC DIC 7 DIC 3 4 DIC DIC 2 3 DIC DIC 3 DIC DIC 57
42 2764.3 41 2253.7 95 10.6 10.431.7 380U/kg0.06mg/kg DIC 60.0%3/5 DIC -4 overt-dic ISTH overt-dic Crit Care Med; 32: 2416-21. 2004DIC FAS 227 overt-dic DIC 7 DIC 4 5 overt-dic overt-dic 157 136 96 70.6 91 61 67.07 147 DIC overt-dic Fibrin-related marker overt-dic Fibrin-related markerd- 0 1µg/mL1µg/mL 2 10µg/mL10µg/mL 3 PT 0 1.251.25 1 1.671.67 2 overt-dic DIC Overt-DIC DIC DIC Overt-DIC 95% 42 2969.0 42 1126.2 42.923.662.2 33 2472.7 30 1963.3 9.413.632.4 380U/kg0.06mg/kg 35 overt-dic 29 19 16 6 4 7 7 3 2 DIC 68.8% 11/16 100.0%4/4 42.9%3/7 50.0%1/2 ) -5 LOCFlast observation carried forward DIC 1 3 7 58
8 LOCF DIC 38U/kg0.006mg/kg 35.3%12/34 130U/kg 0.02mg/kg 45.2%14/31 380U/kg0.06mg/kg 54.3%19/35-6 FFP DIC FFP C S 17 9 DIC FFP FFP FFP DIC FFP DIC FAS FFP 10U 10U 95 DIC 37/53 69.8 26/49 16.8 53.1 1.935.4 1/2 50.0 0/8 50.0 0 19.3100 4/9 44.4 2/4 5.6 50.0 (64.353.2) DIC 26/36 72.2 21/34 61.8 4/5 80.0 3/8 37.5 2/7 28.6 4/9 44.4 95 10.5 11.532.4 42.5 6.091.0 15.9 62.5 30.8 PPS FDP FDPµg/mL 38 48.15 95.4 210 51 46.2 97.5 319.3 10 4 /µl 21 0.1 25.5 6.0 26 0.05 6.5 17.2 19 10.3 4.6 38.3 25 4.3 5.7 24.7 mg/dl 39 24 393 338 50 1.25 436 475 PT 39 0 0.89 0.71 51 0.04 0.89 0.27 TATng/mL 35 58.8 98.4 347.5 46 29.9 92.7 45983.8 59
PICµg/mL 35 39 89.6 480 46 24.8 90.6 310 D-µg/mL 35 60.3 97.3 253 46 46.65 99.5 722.5 α2pi% 35 5 26 36 46 1 38 67 C% 35 8 11 74 46 2 22 36 PAI1ng/mL 35 26.1 91 377.7 46 9.3 83.5 1477.8 SFMCµg/mL 34 59.45 97.4 395.9 44 36.75 96.9 1520 AT% 35 6 34 34 46 9.5 87 25 TAT 4 13 TAT TAT FAS 5 ART-123 ART-123 DIC 186 ART-123 1 ART-123 DIC 28 542 4 ART-123 1 60
ART-123 1 2 DIC 4.55 6 60 55.0% vs.60 73.3%65 43.8% vs.65 78.9% 60 73.3%vs. 60 40.0%65 63.2%vs. 65 43.8% 60 9 81.8 2 18.2 11 0 0 2 100 2 1 100 0 0 1 1 100 1 15 60 4 50.0 4 50.0 8 4 50.0 4 50.0 8 2 66.7 1 33.3 3 1 100 1 20 65 10 83 3 2 16.7 12 2 50.0 2 50.0 4 1 100 0 0 1 2 100 2 19 65 3 42 9 4 57.1 7 2 33.3 4 66.7 6 2 66.7 1 33.3 3 0 0 0 16 DIC DIC DIC DIC DIC 2 1 7 43.1%50/116 56.5%65/115 61
p=0.0487fisher 14 55.2%64/116 65.2%75/115 p=0.1397 1.7%2/116 6.1%7/115 1 4 DIC 3 3.6 10/280 4 1 2 1 1 1 1 20 N=116 N=115 1 0.9 3 2.6 3 2.6 2 1.7 19 16.4 30 26.1 10 8.6 7 6.1 3 2.6 1 0.9 5 4.3 7 6.1 19 16.4 22 19.1 1 0.9 3 2.6 1 0.9 2 1.7 2 1.7 3 2.6 17 14.7 7 6.1 4 3.4 6 5.2 1 0.9 2 1.7.. 2 1.7 2 1.7 4 3.5 2 1.7.. 1 0.9 2 1.7 5 4.3 7 6.1 2 1.7 1 0.9 15 12.9 21 18.3 4 3.4 9 7.8 2 1.7 2 1.7 AMLM3 62
α 2 PI DIC α 2 PI 2 38 1 120 2 116 1 1 1 125 1 1 436 2 3 ART-123 28 ART-123 19 28 ART-123 79 21 ART-123 63
88 1 CBS GmIgGHCP 79 CBS0 migg1 HCP1 88 CBS1 migg1 HCP2 85 CBS1 migg1 HCP0 HCP 4.55 4 FFP DIC DIC 3 DIC DIC ; 23: 2815-2834. 19956 16.9 vs. 12.1 DIC Thromb Res; 72: 475-500. 1993 64
6 6.6 vs. 20.3 ATJAMA; 286: 1869-1878. 200128 AT38.9 vs. 38.7 CAPC DIC Int. J. Hematol; 75: 540-547. 200228 APC20.4 vs. 40.0 APC N. Engl. J. Med; 344: 699-709. 200128 APC24.7 vs. 30.8 DIC DIC 7 6.2 7.928 22.0 25.5 ATJAMA; 286: 1869-1878. 2001 28 90 AT44.9 vs. 52.528 28 DIC DIC DIC 2001 ISTH SSCDIC DIC Thromb. Haemost; 86: 1327-1330. 2001DIC DIC DIC DIC 2 Harrison s Principles of Internal Medicine 16 th ed.mcgraw Hill DIC DIC DIC DIC DIC DIC DIC 2007 9 DIC AT Blood; 75: 2112-2117. 1990; 8: 423-452. 1992; 23: 2815-2834. 1995 ; 124: 144-54. 1983; 65: 229-248. 1988DIC 65
AT 4 1 DIC DIC DIC DICDIC DIC 4 DIC DIC DIC DIC DIC DIC DIC TF Levi M, et al. N Engl J Med; 341: 586-592. 1999 DIC DIC DIC DIC ; 8: 423-452. 1992 ; 65: 229-248. 1988 DIC DIC DIC DIC DIC DIC DIC DIC DIC TAT DIC DIC DIC 28 DIC DIC 25.01/4 vs. 66
DIC 53.8%7/13 DIC DIC DIC 28 1997 DIC 11, pp57-64. 199923.2 31.1 DIC 54 DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC 67
DIC DIC DIC 3 2 C C C C 10% 4 DIC In vitro C C 30% C 10% ; 34(4): 347-53. 2006 C C 10% DIC C 10% C DIC DIC In vitro C 10 C 10% 4 In vitro C 10% C 10% K C C 23 DIC C 68
C C 10% DIC C DIC C Wintrobe s Clinical Hematology 11 th edt.lippinvott Williams&Wilkins C 3 DIC DIC DIC DIC DIC ; 47: 471-478. 2006 DIC DIC ; 47: 471-478. 2006 DIC DIC DIC DICAML M3 4 DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC DIC 69
DIC DIC DIC DIC DIC DIC DIC DIC DIC 5 DIC DIC DIC15 15 9 4 25 607 15 DIC 6 DIC 5 1 70
0.06mg/kg 380U/kg 0.06mg/kg 67.6% 38U/kg 0.006mg/kg130U/kg0.02mg/kg380U/kg0.06mg/kg 3 130U/kg0.02mg/kg 380U/kg0.06mg/kg DIC DIC 380U/kg0.06mg/kg in vitro in vivo 380U/kg0.06g/kg 0.02 0.006mg/kg 0.02 0.06mg/kg DIC DIC 38130U/kg0.006 0.02mg/kg 130 380U/kg0.02 0.06mg/kg 012 3 0%0/4 15.4%2/13 0%0/8 20.0%2/10 0.0060.02 0.06mg/kg 15.4%4/26 13.6%3/22 31.3%10/32 0.06mg/kg 380U/kg0.06mg/kg 2 71
DIC Thromb Haemost; 74: 848-52. 1995 329/352 DIC pre-dic DIC DIC DIC DIC pre-dic non-overt-dic 80 8 Thromb. Haemost; 78: 1463-1467. 1997pre-DIC 3 6 7 DIC 6 7 DIC 6 6 6 73.344/60 71.1%32/45 DIC 7 6 6 DIC DIC 7 7 4 7 7 32 11 21 72
1 DIC DIC DIC DIC 6 DIC DIC 7 DIC TAT DIC 4.11 2TAT 7 4 DIC 130U/kg 0.02mg/kg1 1 30 5 1 77 2 27,700 U/1.2 mg/ 13,000U/2.0mg/ 28 DIC DIC 1 DIC 1 ART-123 1 1 73
1 DIC DIC ART-123 186 1 ART-123 ART-123 6 3 6 1 3,000 DIC 6 1 74
C 10% DIC ART-123 DIC 1. 2GCP DIC DIC DIC DIC DIC DIC DIC DIC 75
2 19 11 14 12,800 12800 18 8 29 1 19 5 8 1 21 1 DIC DICDICDIC DICDIC DIC 1 4.12DICDIC DICDICDIC DICDIC DIC DICDICDIC 2 DIC DIC 14.14 3 DIC 76
4 DIC DIC DIC 1 DIC DIC DIC DIC DIC 14.414 DIC DIC DIC 7 5 380U/kg0.06mg/kg 130U/kg0.02mg/kg 130U/kg 130U/kg 77
DIC 130U/kg DIC 130U/kg 7 DICDIC 7 6 7 DIC 6 7 DIC1 1 DIC DIC 78
DIC DIC DIC 6 3 in vitro DIC 7 DIC DIC DIC DIC DIC DIC DIC DIC 100 3 79
3,000 1 C 10% DIC DIC DIC DIC DIC DIC DIC DIC DIC 80
DIC 2 MR DIC 1,000 3,000 2 1,000 1 2,000 1 6 6 MR DIC DIC DIC DIC MR DIC DIC 81 1 6 6 Ser 482 Thr 482 8 35 cells/ml cells/ml 10 38 11 11 16 19 17 16 XuMLV XMuLV 81
17 17 2-8 2-8 18 31 18 37 pi 18 40 19 2 pi 19 3 20 26 21 40 1,900U/kg0.3mg/kg 19, 000U/kg3mg/kg 40 21 130U/kg 43 6 51 16 15,000U/ 15,000U/ 53 25 DIC ISTH ISTH 65 1 6.6 vs. 20.3 9.8 vs. 23.4 1. 2GCP 5.3.3.1-15.3.3.1-25.3.5.2-15.3.5.1-1 5.3.5.1-2 GCP 1 GCP GCP 1 82
GCP 1 14. 3 5.3.5.2-1 46 1 44 7 37 012 3 3 139 12 DIC 2 35 3119 12 4 7 2 7 2 3 5 33 3 10 8 12 7 7 33 7 1 5 34 3109 12 35 21 14 DIC 0 1 2 3 100%1/1 16.7%1/6 0%0/2 100%5/5 100%2/2 16.7%1/6 60.0%3/5 66.7%2/3 100%2/2 11.1%1/9 42.9%3/7 66.7%2/3 66.7%2/3 50.0%5/10 55.6%5/9 83.3%10/12 DIC 33.3%1/3 30.0%3/10 33.3%3/9 75.0%9/12 66.7%2/3 40.0%4/10 55.6%5/9 83.3%10/12 0%0/3 30.0%3/10 33.3%3/9 50.0%6/12 37 0123 0/3 0/13 1/9 1/12 1 43 6 28 11 17 6 1 83
8 DIC 1 1 380U/kg 30 84