untitled
|
|
|
- さあしゃ もちやま
- 5 years ago
- Views:
Transcription
1 mg 50mg
2 mg 50mg mg 51.8mg 20mg 50mg 1 C 22 H 26 ClN 7 O 2 S H 2 O N-(2-Chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide monohydrate
3 mg 50mg mg mg mg mg mg 1 2 2
4 mg 50mg mg 51.8mg 20mg 50mg mg mg mg mg mg mg Bristol-Myers Squibb Bcr-Abl Philadelphia Philadelphia 9 bcr break point cluster region 22 abl abelson kinase bcr-abl CML Philadelphia Ph+ ALL Philadelphia bcr-abl Bcr-Abl CML Ph+ ALL Bcr-Abl Bcr-Abl 3
5 Abl CML Ph+ ALL CML Ph+ ALL CA CML Ph+ ALL 5 CA CA CA CA CA EU SPRYCEL dasatinib is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia CML with resistance or intolerance to prior therapy including imatinib. The effectiveness of SPRYCEL is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. SPRYCEL is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia Ph+ALL with resistance or intolerance to prior therapy. 11SPRYCEL is indicated for the treatment of adults with chronic, accelerated or blast phase chronic myeloid leukaemia CML with resistance or intolerance to prior therapy including imatinib mesilate. SPRYCEL is also indicated for the treatment of adults with Philadelphia chromosome positive Ph+ acute lymphoblastic leukaemia ALL and lymphoid blast CML with resistance or intolerance to prior therapy EU CML CML-CP 1 50mg mg BID mg100mg QD EU CML CML-AP CML CML-BC Ph+ ALL 1 70mg mg BID mg140mg QD /CA CML 1 90mg mg BID CML Ph+ ALL CA / 4
6 BMS BMS BMS Step 1 BMS BMS Step 2 Step1 BMS Step 3 Step X ph ph 4 ph pka pka pka 3 1- / ph ph ph H-NMR 13 C-NMR X
7 %RH %RH %RH %RH : 120 lx h : 200W h/m 2 % H-NMR mg 51.8mg 20mg 50mg mg 20mg 50mg 1) ) 6
8 2 BMS PTP 10 PTP mg 50mg %RH %RH
9 40 75%RH %RH %RH %RH mm lx hr 200W hr/m 2 20mg 50mg % % SCU SCU 20mg 50mg % % SCU SCU 20mg 50mg 20mg 50mg % % SCU SCU 20mg 50mg 20mg 50mg % % SCU SCU 20mg 50mg % % SCU SCU 20mg 50mg 20mg 50mg % % SCU SCU% % / EU 8
10 10CFU/g 1g 2 % GST Glutathione S-transferase 23 / Bcr-Abl Src c-kit PDGFβ EPHA2 IC 50 50nmol/L IC nmol/L IC 50 (nmol/l) c-src ,300 Src LCK YES 0.41 *1 31,000 FYN 0.2 *1 38,200 9
11 IC 50 (nmol/l) Bcr-Abl c-kit 22 *1 169 PDGFβ 28 *1 1,590 EPHA2 17 *1 ND *1: Abl X Abl X Abl Abl Abl Abl X Abl Abl 3 In vitro Bcr-Abl Bcr-Abl CML K562 KU-812 MEG-01 ALL SUP-B15 c-src c-kit c-src c-kit IC 50 (nmol/l) ( /) K562 CML KU-812 CML MEG-01 CML SUP-B15 ALL B *1 350 *1: 2 Bcr-Abl Ba/F3 Science 2004; 305: Cancer Res 2005; 65: Bcr-Abl 19 T315I 18 Bcr-Abl K562 MEG-01 SUP-B15 K562/STI-571/R MEG-01/IM SUP-B15/IM 10
12 IC 50 nmol/l CML K K562/STI-571/R ,288 CML MEG MEG-01/IM 1.1 1,110 ALL SUP-B B SUP-B15/IM 2.1 *1 2,500 *1 *1: CML K562/STI-571/R CML bcr-abl Bcr-Abl K562/STI-571/R Bcr-Abl K562/STI-571/R Src mrna K562/STI-571/R K562 mrna FYN 5 6 K562/STI-571/R FYN 900nmol/L 0.5nmol/L K562/STI-571/R FYN MEG-01/IM SUP-B15/IM Abl Q252H F359V CML P- P-gp P-gp MDR1 P-gp CML K562/ADM K562 K562/ADM 1/60 1/6 P-gp CML CML WDT-1 WDT-2 WDT-3 IC 50 nmol/l K562 K562-R WDT-1 WDT-2 WDT ~200 >10,000 >10,000 ~150 ~500 CML 11
13 BMS BMS BMS BMS BMS Bcr-Abl CML K562 Src msrc-a4 IC 50 BMS Abl Src IC 50 nmol/l IC 50 / IC 50 BMS BMS BMS BMS BMS msrc-a4 2.7( ) 25(9.2) 3.4(1.3) 341( 131) 49.4(18.2) 313( 122) K ( ) 8.6(12.7) 0.63(0.9) 150(221) 7.8(11.5) 46.7(68.8) in vitro EOL-1 FIP1L1-PDGFRA GRANTA-519 JEKO-1 P815 PC3 PC3/M MDA-PCa-2b DU145 WiDr LOVO SW-480 2C8 GEO MDA-MB-231 RD1 A549 In vivo CML CML K562 SCID mg 5 50mg/kg mg/kg Log cell kill Lck 10 1/2 CML K562 mg/kg/ Lck % % (g) QD 10, days on-and days off TID mg/kg mg/kg Lck % CML KU
14 50mg/kg CML K562/STI-571/R 5 50mg/kg CML (K562/STI-571/R) Lck (mg/kg/ % % (g) QD 10, days on-and days off TID MDR1 CML K562/ADM 30mg/kg 15mg/kg CML Ph+ ALL P-gp In vitro CML Ph+ ALL P-gp CML K K562 SCID mg/kg mg/kg MST %T/C MST MST % 5mg/kg 268% 15mg/kg 450% MST CML CML in vivo CML Ph+ ALL K mg/kg mg/kg 35mg 10 2/8 3/8 5mg/kg 6/6 8/8 K mg/kg/ mg/kg /
15 0/ HUVEC VEGF bfgf HUVEC VEGF HUVEC IC ,000nmol/L bfgf 248nmol/L 50,000nmol/L HUVEC 0.5nmol/L 5nmol/L 8.5% 73.5% Src PTH Ca PTH Ca 4 PTH IC 50 : 2nmol/L PTH 3 10mg/kg 3mg/kg 10mg/kg Ca Src Genechip 4 PD PK/PD K562 Bcr-Abl Crk mg/kg Bcr-Abl Crk1 Bcr-Abl Crk1 Bcr-Abl Crk1 c-src Bcr-Abl c-src 14
16 PBMC PC mg/kg PBMC c-src In vitro PBMC c-src ELISA IC 50 63nmol/L 48nmol/L PBMC c-src PK/PD PC3 c-src 50% µmol/L PBMC µmol/L GLP DS03098 GLP DT05071 GLP In vitro HEK293 herg IKr; µmol/L IKr 6.1±1.2% 36.5±6.3% 76.8±4.5% IC µmol/L GLP µmol/L 30µmol/L 50% 90%APD 50 APD 90 26±5% 11±0% GLP 10mg/kg 1 22 RR PR P QRS QT QT % 8 21% GLP BMS BMS BMS herg IKr in vitro GLP herg V max APD 50 APD 90 herg herg % 3µmol/L 10µmol/L 30µmol/L IC 50 BMS ±2.5% 10.6±2.8% BMS ±3.7% 72.3±3.1% 94.7±0.5% 5.8µmol/L BMS ±2.1% 11.5±2.7% BMS BMS µmol/L 15
17 V max :V/S(% ) APD 50 :ms(% ) APD 90 :ms(% ) BMS µmol/L µmol/L µmol/L BMS µmol/L µmol/L µmol/L BMS µmol/L µmol/L µmol/L % 100 herg nmol/l 2/ DS02147 GLP 15 25mg/kg 2 ECG GLP GLP In vitro 42 10µmol/L 4.9µg/mL 50% 10µmol/L 10% BMS BMS BMS BMS BMS µmol/L 50% BMS µmol/L β 2 α 2 5-HT 1 5-HT 1A 50 87% nmol/l 50% 16
18 CML Ph+ ALL QT/QTc in vitro torsade de pointes Bcr-Abl Src c-kit PDGF EPHA2 1 Bcr-Abl CML CML CML Bcr-Abl 1 Bcr-Abl bcr-abl 90 Abl T315I Bcr-Abl Bcr-Abl MEG-01/IM SUP-B15/IM 1 3 In vitro MEG-01/IM SUP-B15/IM Bcr-Abl Bcr-Abl Ba/F3 T315I 18 Science 2004; 305: Cancer Res 2005; 65: hoct1 hoct1 P-gp P-gp CML K562/ADM P-gp CML-AP Ph+ ALL P-gp 17
19 Blood 2008; 112: P-gp P-gp 3 Bcr-Abl Bcr-Abl Src LYN HCK FYN LYN FYN J Natl Cancer Inst 2008; 100: In vitro CML CML Ph Bcr-Abl Bcr-Abl CML Ph+ ALL Bcr-Abl in vitro in vivo Bcr-Abl in vitro IC nmol/L 1 3 In vitrobcr-abl 100mg C max 100nmol/L 2nmol/L in vivo CML 1.25mg/kg C max 70nmol/L 2nmol/L 18
20 C max C max In vivo CML CML Ph+ ALL 1 3 In vivo Src Src 3.2 PK 1 1 AUC 0-24 V ss 19
21 C max t max AUC 0-24 t 1/2 CL V ss BA µg/ml h µg h/ml h ml/min/kg L/kg % 10mg/kg, iv * 5mg/kg, po mg/kg, po mg/kg, ia mg/kg, po mg/kg, ipv mg/kg, iv mg/kg, po mg/kg, iv mg/kg, po n=3 * n=15 n=3/each point mg/kg2PK AUC mg/kg C max µg/ml 0.652, , , , , , AUC 0-24 µg h/ml 1.796, , , , , , t max h 1, 1 1, 1 1, 2 1, 2 1, 1 2, 2 P- P-gp10mg/kg 814.2% 15.0% P-gpC max AUC P-gp mg/kg AUCAUC 0-24 C max 1 15mg/kg 30mg/kg30mg/kg 14AUC 0-24 C max 1 15mg/kg 30mg/kg mg/kg mg/kg mg/kg 178mg/kg PK26 mg/kg * C max ng/ml AUC 0-t ** ng h/ml t max h
22 n=9 * ** 8 24AUC mg/kg AUC 0-t mg/kg10mg/kg7 1 3mg/kg mg/kg 6mg/kg mg/kg 181 3mg/kg 190 2mg/kg AUC 10mg/kg C max AUC 0-t C max AUC 0-t C max AUC 0-t 3 in vitro Caco-2 50µmol/L 24.4µg/mL P A B 102nm/sec 50% P B A 222nm/sec P A B 2 P-gp GF P A B 161nm/sec P B A 126nm/secP-gp C 10mg/kg C max 1 4 C max ng eq/g %t 1/ C 10mg/kg C 10mg/kg C max 8102ng eq/g ng eq/gc max
23 µmol/L 4880ng/mL N-M4 M4 10µmol/L 4880ng/mL 30 2 ng/ml ± ± ± ± ± ± ±5.4 M ± ± in vivo 14 C 15mg/kg % N- M5 M8 M8c M13 M6M20 42% 13% 8% 14 C 10mg/kg M5 M21 M8 M6 M4 M58% N- 14 C 10mg/kg 432% 19 M8aM6 M30 M6 M20 25% 14% 12% 14 C 2mg/kg M21 M6 M6 M7M30 3%M57% N- 2 in vitro 22
24 20µmol/L 9.8µg/mL 3 39% 22%11% 10M4 M7 M20 M21 M23a M23b M24 M306M4 M6 M20 M21 M24 13M3a M3b M4 M6 M9 M20 M24 M28a M28b M29a M29b M29c 7M3a M3b M4 M6 M20 M24 M20 M24 30% 39% M537% CYP1A1 1A2 1B1 2A6 2B6 2C8 2C9 2C19 2D6 2E1 3A4 3A5 4A11 FMO3 M4 M6 M20 M24 CYP1A1 1A2 1B1 3A5 3A4 FMO3 M4 M5 M20 M24 M4 M5 M20 M24 CYPFMO3 CYP3A4 M4 M20 M24 FMO3 M5 M4 M20 M24 CYP 1-aminobenzotriazole CYP3A4 troleandomycincyp3a4 FMO3 45 FMO3 CYP M5 M6 S9 M6 M4 M5 M20 M24 V max /K m µL/mg protein/min CYP3A4 M4 M24 M20 M20 31% M4 M244.2% in vivo UGT CYP3A4 FMO3 M4 M20 M24 in vitrocyp3a4 in vivo38%cyp3a4 FMO3 UGT C 15mg/kg %76.4% % 14 C 10mg/kg
25 3.0%76.8% % 2 14 C 10mg/kg 3.2% 12.0% 35.8% 67.4%53% 0.7% 12% 14 C 2mg/kg % 67.2% 13.7% C 10mg/kg 8C max 2070ng eq/g ng eq/gt 1/2 5.53AUC ng eq h/g HepG2/C3A µmol/L CYP3A4 CYP3A µmol/L CYP1A2 2B6 2C9 3A4 mrna 25µmol/L 12.2µg/mL70mg CML C max 100 CYP1A2 2B6 2C9 3A4 CYP µmol/L µg/mL CYP CYP1A2 2A6 2B6 2C8 2C9 2C19 2D6 2E1 3A4 CYP1A2 2B6 2C19 2D6 2E1 CYP2A6 2C8 2C9IC µmol/L CYP2C8 Ki3.6µmol/LCML70mg 1 2 C max 0.12µmol/L 57ng/mL65%C max /Ki 0.1CYP2C8 CYP3A4 IC µmol/L CYP3A4 K I 1/2 k inact 1.9µmol/L 0.022min -1 in vitro in vitro 24
26 CYP3A4 in vivo 3 Caco-2 3 H 5µmol/L P-gp 1 10µmol/L P-gp P-gp PK 1 PK 14 AUC 0-24 C max C max AUC PK C max AUC 0-24 C max AUC 0-24 C max AUC 0-24 PK C max AUC
27 20% 1 10% 1% 1 10% 1% 31% 10% 10% 3 P-gp P-gp Breast Cancer Resistance Protein BCRP in vitro P-gp PK mg/kg mg/kg 100mg/kg 25mg/kg 45mg/kg mg/kg/ /10/8*mg/kg/ 4 *: 8 10mg/kg/17 8mg/kg/ 1 25mg/kg 6 15/10/8mg/kg 1 15mg/kg/ 26
28 25mg/kg/15mg/kg/ 25mg/kg 25mg/kg AST ALT 0.9mg/kg/ 15mg/kg/ /10/8mg/kg 4mg/kg/ 1.5mg/kg/ 4mg/kg/ mg/kg/ /2* 10/6/4.5**mg/kg/ 4 *: 28 2mg/kg/**: 3 6mg/kg/ mg/kg/ /2mg/kg/ 1 5mg/kg/ 15mg/kg 5mg/kg/ 9 3/2mg/kg/ 1mg/kg/ / 3 S9 mix 2.5µg/mL C max
29 mg/kg/10mg/kg 20mg/kg 20mg/kg 2.5mg/kg 17.4% 5mg/kg 76.6% 10 20mg/kg 100% 5mg/kg/ 2.5mg/kg/ mg/kg/ 6mg/kg 6mg/kg/ 0.5mg/kg/ AUC 70mg 1 2 AUC T 2 in vitro in vivo ex vivo in vitro C max IC µg/mL C max 61ng/mL 3 BMS nm 328nm BALB/c 3T3 in vivo 28
30 1 30% 50,000/mm / 29
31 4 100mg CA BA 319kcal 20%68%12%985kcal52%34% 14%50mg 100mg C max AUC 0-90% mg % 120mg BID PK A B C B/A * C/A * C max ng/ml , , AUC 0- ng h/ml , , * 90% 2 CA mg 25mg 20 20mg 5 50mg 2 100mg A B C DBAA BC D A C max AUC 0- AUC 0-T 90% C max ng/ml A 90% 50mgA mgB , mgC , mgD ,
32 AUC 0- ng h/ml AUC 0-t ng h/ml A 90% 50mgA mgB , mgC , mgD , mgA mgB , mgC , mgD , T max t 1/2 3 CA mg 50mg 1 70mg 1 70mg 70mg A B C max AUC 0-t AUC 0- B A 90% mg BA BE PK PK 1 ph ph ph ph PK BA 1 PK 3 CYP3A4 Annu Rev Pharmacol Toxicol 1989; 29: Gastroenterol Clin North Am 1992; 21: PK CYP3A4 PK PK 31
33 Biol Pharm Bull 2001; 24: PK 4.2 PK H 2 CYP3A4 1 CA C 100mg AUC 29%BMS %9 4% 85% BMS % 19% 2 1/ CA CML-CP mg BMS PK C max 12 C max 6% CLo Vz/F t 1/2 50mg 70mg 28 90mg C max AUC 0-τ 30% 50%90mg 28 C max AUC 0-τ CLo Vz/F t 1/ Day n C max ng/ml AUC 0-τ ng h/ml T max * h t 1/2 ** h CL/F** L/h V/F** L 50mg , , mg , , *** 90mg , , *** *** n=6 BMS T max BMS BMS AUC 0-T BMS / % 32
34 2 CA CML Ph+ ALL 91 PK Q5D 15mg 180mg BID 52B5D 1 25mg 70mg 1 2 B7D 1 35mg 120mg B5D Q5D B7D BMS Crkl SrcSrc T max 1 t 1/2 t 1/ AUC AUC mg/ 90% AUC50mg 70mg BID 5 8CLo Vz/F L/h L 50mg 120mg B7D Q5D 8t 1/2 CLo CLo Vz/F t 1/2 C Day n max AUC 0-τ T max * t 1/2 ** CL/F** V/F** ng/ml ng h/ml h h L/h L , mg , Q5D , a , a 50mg , b B7D , b c , c 70mg , d B7D , e 90mg , , f B7D , g *** a n=7 b n=6 c n=20 d n 18 e n=14 f n=12 g n=9 BMS AUC 0-T BMS / 4 9% Src120mg BID % 55% 120mg BID 24 26/29Src 2480% 26/29 Src 20% Crkl35mg BID24 33
35 % 26/ % Src Crkl 3 CA CML-AP 45 PK 29 PK 70mg 1 2 B7D 8 C max AUC 0-T t 1/2 BMS AUC 0-T BMS / 4 6% C max Day n AUC 0-T T max * t 1/2 ** ng/ml ng h/ml h h , a , b *** a n=28 b n=26 4 CA CML-BC 45 PK 24 70mg 1 2 B7D 8 C max AUC 0-T t 1/2 C max Day n AUC 0-T T max * t 1/2 ** ng/ml ng h/ml h h , a , *** a n= CA pH BA 2 A B C 6 ABC ACB BAC BCA CAB CBA A50mg B50mg 122 A mg C50mg 122 A 30mL PK 102C max AUC 0-12 A 1 2 C max AUC
36 A 90% A B , C , A B , Day PK 1 C max ng/ml AUC 0-12 ng h/ml C , A C max B , ng/ml C , A AUC 0-12 B , ng h/ml C , H 2 PPI t 1/2 4 5 t 1/2 PK 2CA PK15 PK CYP3A mg mg C max AUC 0-τ BMS BMS PK 90% C max 14 ng/ml , 4.44 AUC 0-12 * 71 ng h/ml , 6.13 * n=14 CYP3A4 BMS BMS BMS FMO3 BMS BMS CYP3A4 BMS CYP3A4 BMS CYP3A4 3 CA PK CYP3A4 35
37 mg mg 1 1 BMS BMS PK 90% C max ng/ml , AUC 0-T ng h/ml , CYP3A4 BMS BMS BMS FMO3 FMO3 BMS CYP3A4 CYP3A4 BMS CA CYP3A4 PK 80mg 100mg PK PK 90% C max ng/ml , AUC 0-T ng h/ml , PK PK 90% C max 5.84 ng/ml , AUC 0-T ng h/ml , CYP3A4 PK C max AUC t 1/2 C max AUC 36
38 100mg PK n C max AUC 0-T T max * t 1/2 ** ng/ml ng h/ml h h a , , b *** a CA CA CA b n=47 4 PPK CML Ph+ ALL6 CA CA CA CA CA CA NONMEM PPK 2- CL/F = [ (HB-10)] EXP(η1) V2/F = 1250 EXP(η2) Q/F = 130 V3/F = 1320 KA = 314/1250 {1+1/[0.167 EXP(η3)]} F = EXP(ηiov) CL/F 32% F 51% CL/F F Hb Hb CL/F V2/F F Hb BMI BSA 50mg 70mg BID PPI CYP3A4 BA 3 5 PK 50 70mg BID T max t 1/ mg BID T max t 1/ T max t 1/2 CA CA C max AUC 0-τ 1AUCAUCCA CA PK PPK BA 50% 30% CA PK PK 37
39 AUC (ng h/ml) AUC = 4.66xDose 0.86 (Dose response curve based on Study CA ) Study CA Day Dose (mg) Study CA AUC (ng h/ml) Study CA Study CA AUC = 4.22xDose 0.88 (Dose response curve based on Study CA ) Day 26/28/ Dose (mg) 1 PK 1 2 C max AUC 5 PK AUC CA C max AUC CA C max AUC PPK 90% 10% CA CA CA PK PK PK C max AUC PK PK PK 2 CML-CP CA CML-CP 70mg BID 100mg QD CML-CP 100mg QD mg QD 38
40 PK PK CA CA CA PPK PPK CL/F 220L/h PPK 290L/h 26% CL/F 1 100mg C ss PPK PPK CL/F C ss C max AUC C min 100mg QD PPK /CA mg BID 1 100mg QD 100mg QD PK CA PK PK PK CA CML-CP majormcyr MCyR MCyR C ss Grade 1 Kaplane-Meier Cox 39
41 C min 2 C max 4 CA PK CA mg PK 70mg C max AUC 47% 8% 43% 28%t 1/2 ph BA PK t 1/2 CA PK PK BA ph PPI 3 PK CA CA PPI
42 / / 1 1 BID bis in die 1 2 CHR complete hematological response CI confidence interval CCyR complete cytogenetic response Ph+ 0% CML-AP chronic myelogenous leukemia in accelerated phase CML-BC chronic myelogenous leukemia in blast crisis CML-CP chronic myelogenous leukemia in chronic phase CyR cytogenetic response DLT dose limiting toxicity ELN European Leukemia Net HR hematological response HSCT allogeneic hematopoietic stem cell transplantation IFNα interferon alpha LBC lymphoid blastic crisis Major CyR major cytogenetic response Ph+ 0 35% Major HR major hematological response MBC myeloid blastic crisis Minimal CyR minimal cytogenetic response Ph % Minor CyR minor cytogenetic response Ph % Minor HR minor hematological response MTD maximum tolerated dose NCCN The National Comprehensive Cancer Network OS overall survival PCyR partial cytogenetic response Ph+ 1 35% PD progression disease Ph+ ALL philadelphia chromosome positive acute lymphoblastic leukemia QD quaque in die 1 1 TDD total daily dose 1 TKI tyrosine kinase inhibitor 41
43 CA / CA CML-CP CML-AP CML-BC Ph+ ALL CML-CP CML-AP CML-BC Ph+ ALL mg BID 70mg BID 58 CML-CP 18 CML-CP 12 CML-AP/BC 11 Ph+ ALL mg QD mg BID CML-CP 45 CML-AP CML-BC/Ph+ ALL mg BID * Major CyR CHR CML-CP 5.6 CML-AP/BC 2.8 Ph+ ALL CA CML-AP 70mg BID 197 Overall HR Major HR 14.8 CA CML-MBC 70mg BID 124 Overall HR Major HR 3.6 CA CML-CP 70mg BID 424 Major CyR 24.9 CA Ph+ ALL CML-LBC 70mg BID 103 Overall HR Major HR CML-LBC 48 Ph+ ALL CA CML-CP 70mg BID Major CyR 400mg BID CA CML-CP mg QD mg 70mg BID Major CyR 140mg QD mg BID 100mg 140mg QD mg BID 168 CA CA CA CML-CP CML-AP CML-BC Ph+ ALL CML-AP CML-BC Ph+ ALL * 50mg 70mg 90mg BID 70mg BID 140mg QD 44 CML-CP 29 CML-AP/BC 9 Ph+ ALL mg BID mg QD 304 CML-CP 16.1 CML-AP/BC 10.1 Ph+ ALL 2.7 Major HR / CA CML-CP CML-AP CML-BC Ph+ ALL / 26 I CML-CP 3 18 CML-CP CML-AP/BC Ph+ ALL 10 CML-CP 400mg/ Major CyR CCyR+PCyR Ph+ 30% CHR CHR 20,000/mm 3 nadir 2 50,000/mm 3 Major CyR CHR 20,000/mm 3 nadir 2 50,000/mm 3 3 CHR 6 CyR 42
44 12 Major CyR L248V G250E Q252H/R,Y253H/F E255K/V T315I/D F317L H369P/R CML-AP CML-CP 400mg/ CML-AP CML-AP 600mg/ 400mg/ Major HR Minor HR CML-AP CML-BC 600mg/ 400mg/ Major HR Minor HR CML-AP CML-BC CML-CP 400mg/ CML-BC CML-AP 600mg/ 400mg/ CML-BC CML-BC 600mg/ 400mg/ CML-CP Grade 3 7 Grade 4 CML-AP/BC 400mg/ Ph+ ALL CHR CHR CHR Ph+ ALL Grade 3 7 Grade 4 CML-CP 50mg 70mg 90mg BID mg 70mg BID CML-CP 24 CML-AP/BC Ph+ ALL CML-CP 18 50mg 7 70mg 7 90mg 4 CML-CP 12 CML-AP/BC 11 Ph+ ALL 13 MTD 28 DLT 50mg 1/6 Grade 4 70mg 1/6 Grade 4 90mg 0/3 MTD 70mg BID CHR Major HR CCyR Major CyR CML-CP Major CyR 7/12 Major CyR 58% 95% CI 27.7, 84.8% CML-AP/BC Ph+ ALL CHR 2/11 1/13 CHR 2/11 18% 95% CI 2.3, 51.8% 1/13 8% 95% CI 0.2, 36.0% 43
45 % CML-CP CML-AP/BC Ph+ ALL CHR Major HR CCyR Major CyR CML-CP 50mg BID Ph+ ALL 70mg BID 1 1 Ph+ ALL 70mg BID 2 CA N Engl J Med 2006; 354: CML Ph+ ALL DLTPK 2 4 mg/ CML-CP QD CML-CP BID CML-CP BID CML-AP BID CML-MBC BID CML-LBC Ph+ ALL BID CML-CP QD 22 CML-CP BID 23 CML-AP 12 CML-MBC 23 CML-LBC Ph+ ALL 11 DLT 3 DLT Grade 4 2 CML-CP 35mg 90mg BID 1 Grade 3 Grade 4 1 CML-MBC 120mg BID MTD CML-CP 3 30mg QD 50mg QD 35mg BID 25mg BID 25mg QD 90mg BID 70mg BID 1 CML-AP 1 70mg CML-MBC 7 50mg 1 70mg 3 90mg 2 120mg 1 CML-LBC Ph+ ALL 4 70mg 90mg CA CML-AP mg BID 100mg BID 50mg BID 40mg BID 2 44
46 174 Major HR Overall HR Major HR+Minor HR 112/ /174 Major HR Overall HR 64.4% 95% CI 56.8, 71.5% 79.9% 95% CI 73.2, 85.6% bcr-abl M244V L248V G250E Y253F/H E255K/V T315I F317L M351T/V E355G F359C/I/V V379I H396R S417Y E459K Major HR 73.3% 66/90 % Major HR Minor HR Overall HR Major CyR 40.2% 70/174 bcr-abl M244V L248V G250E Y253F/H E255K/V T315I F317L M351T/V E355G F359C/I/V V379I H396R S417Y E459K Major CyR 40.0% 36/90 % CCyR 0% PCyR >0-35% Minor CyR >35-65% Minimal CyR >65-95% No Response >95-100% CA CML-MBC CA Major HR 36/109 Major HR 33.0% 95% CI 24.3, 42.7%Overall HR 54/109 Overall HR 49.5% 95% CI 39.8, 59.3% bcr-abl M244V G250E Y253H E255K/V T315I M351T/V F359I/V H396R F486S Major HR 31.0% 13/42 45
47 % Major HR Minor HR Overall HR Major CyR 33.9% 37/109 bcr-abl M244V G250E Y253H E255K/V T315I M351T/V F359I/V H396R F486S Major CyR 28.6% 12/42 % CCyR 0% PCyR >0-35% Minor CyR >35-65% Minimal CyR >65-95% No Response >95-100% CA CML-CP CA mg BID Major CyR 240/387 Major CyR 62.0% 95% CI 57.0, 66.9% bcr-abl M244V K247R L248V del G250E/V Q252H Y253F/H/K E255K/V D276G E279K T315I F317L M351T F359C/I/V H396P/R E355G E450A/K/G E459K F486S Major CyR 62.6% 92/147 % CCyR 0% PCyR >0-35% Minor CyR >35-65% Minimal CyR >65-95% No Response >95-100%
48 CHR 91.0% 352/ % 93/ % 259/288 bcr-abl M244V K247R L248V del G250E/V Q252H Y253F/H/K E255K/V D276G E279K T315I F317L M351T F359C/I/V H396P/R E355G E450A/K/G E459K F486S Major HR 92.5% 136/ CA CML-LBC Ph+ ALL CA CML-LBC CML-LBC Major HR 17/48 Major HR 35.4% 95% CI 22.2, 50.5% Overall HR 19/48 Overall HR 39.6% 95% CI 25.8, 54.7% bcr-abl M244V G250E Y253H E255K D276G F311I T315I V379I E459K Major HR 31.0% 9/29 CML-LBC % CHR Major HR Overall HR Major CyR 52.1% 25/48 bcr-abl M244V G250E Y253H E255K D276G F311I T315I V379I E459K Major CyR 48.3% 14/29 CML-LBC % CCyR 0% PCyR >0-35% Minor CyR >35-65% Minimal CyR >65-95% No Response >95-100%
49 Ph+ ALL Ph+ ALL Major HR 19/46 Major HR 41.3% 95% CI 27.0, 56.8% Overall HR 22/46 Overall HR 47.8% 95% CI 32.9, 63.1% bcr-abl M244V G250E Y253H E255K/V D276G F311I/V T315I E355G F359I H396P F486S Major HR 45.2% 14/31 Ph+ ALL % CHR Major HR Overall HR Major CyR 56.5% 26/46 bcr-abl M244V G250E Y253H E255K/V D276G F311I/V T315I E355G F359I H396P F486S Major CyR 54.8% 17/31 Ph+ ALL % CCyR 0% PCyR >0-35% Minor CyR >35-65% Minimal CyR >65-95% No Response >95-100% CA Blood 2007; 109: mg/ CML-CP mg BID 40 90mg BID 400mg BID 600mg/ 600mg/ 2 1 CML-AP CML-BC CHR Major CyR 12 Major CyR 48
50 Major CyR 36/101 14/49 12 Major CyR 35.6% 95% CI 26.4, 45.8% 28.6% 95% CI 16.6, 43.3% CHR 93.1% 94/ % 40/49 % Major CyR % % CCyR % 4 8.2% PCyR % % Minor CyR 5 5.0% 3 6.1% Minimal CyR % % No Response % % 9 8.9% 4 8.2% Major CyR 95% CI 7% -9.8, 22.2% CCyR 95% CI 14% 0.6, 24.8% bcr-abl L248V G250E Q252H/R Y253F/H E255K/V T315I/D F317L H396P/R Major CyR 46.3% 19/ % 3/11 CHR 87.8% 36/ % 6/ CA CML-CP mg 70mg BID 100mg 140mg QD CML-CP QD BID Major CyR 15% 50mg BID 70mg BID 100mg QD 140mg QD 50mg BID 40 70mg BID 70mg BID 40 90mg BID 100mg QD mg QD 140mg QD mg QD mg QD mg QD mg BID mg BID CML-CP Major CyR QD BID 49
51 CML-CP Major CyR QD 247 BID mg TDD mg TDD 249 Major CyR % % % % Major CyR 95% CI 1.9% -6.8, 10.6% -0.2% -8.9, 8.5% CML-CP Major CyR CML-CP Major CyR QD 87 BID mg TDD mg TDD 86 Major CyR % % % % Major CyR 95% CI 1.4% -11.2, 14.1% 1.4% -11.2, 14.1% mg QD 3 140mg QD 2 50mg BID 6 70mg BID mg QD 1 140mg QD mg BID 1 70mg BID 100mg QD 24.1% 40/ mg QD 31.9% 52/163 50mg BID 32.5% 54/166 70mg BID 34.1% 57/ mg QD 4.2% 7/ mg QD 8.6% 14/163 50mg BID 4.2% 7/166 70mg BID 12.6% 21/167 1 CA /CA CA CA CML-CP 29 CML-AP/BC 9 Ph+ ALL 6 CML-CP 2 1 CML-AP/BC Ph+ ALL 5 4 CA CML-CP 1 CML-AP/BC 1 Ph+ ALL CA CML-AP CML-BC Ph+ ALL mg QD 70mg BID 50
52 mg QD 70mg BID Major HR 12% 140mg QD 70mg BID 140mg QD mg QD 70mg BID mg BID mg QD mg BID 305 SAE mg QD mg BID 305 Major HR QD BID Major HR QD BID Major HR % % Major HR 95% CI 0.8% -7.1, 8.7% 321/609 % QD BID ) 50mg 1 20mg 1 70mg 1 CA ) 14 C CA ) CA ) CA ) CA ) CA
53 7) CA ) CA CML Ph+ ALL 1 5 CA CA CA CA CA CA /CA CML-CP CyR CML-AP CML-BC Ph+ ALL HR CML CyR HR CyR HR Wintrobe s Clinical Hematology 11th edt Lippincott Williams & Wilkins, Philadelphia, USA NCCN Practice guidelines in Oncology v Ph bcr-abl Bcr-Abl CML Wintrobe s Clinical Hematology CML CyR CML 5 N Engl J Med 2006: 355; CML CyR HR CML CyR CyR CML HR time-to-event Ph+ ALL CyR HR Ph+ ALL CHR HSCT In: Hematology 2007 American Society of Hematology Education Program Book Ph+ ALL vol 6 HSCT HSCT Bone Marrow Transplant 2008; 41: Blood 2002; 100:
54 N. Engl. J. Med. 2000; 342: Ph+ ALL HSCT HSCT CHR HSCT Ph+ ALL CHR OS CHR CHR CHR HR Ph+ ALL CyR time-to-event 2 CML-CP CML-CP CA CA Major CyR n % CA CA mg BID QD BID mg mg mg mg 168 Major CyR CCyR PCyR CA mg mg 40mg BID CA mg QD mg 140mg QD mg 50mg BID mg 70mg BID mg CA CA mg QD 140mg QD 50mg BID 70mg BID Major CyR 600mg/ CML-CP Blood 2003; 101: mg BID 400mg BID CA Major CyR 36/ % 14/ %CCyR 22/ % 4/49 8.2% CyR CyR CML-CP CML-CP 53
55 CML-CP 6 CyR HSCT Cancer 2003: 97; Major CyR Blood 2004: 103; CCyR PCR 3log bcr-abl NIH Blood 2006: 108; International scale 0.1% N Engl J Med 2003: 349; N Engl J Med 2006: 355; NCCN CML ELN CML-CP In: Hematology 2007 American Society of Hematology Education Program Book 3 6 HR hematologic resistance 6 CyR Ph cytogenetic resistance 12 Major CyR 18 CCyR CML-CP CA n % CA n % HR CyR complete partial minor minimal Major CyR Major CyR CCyR MMR* 3log BCR/ABL * MMR: major molecular response CA MMR CA MMR CA mg QD 140mg QD 50mg BID 70mg BID MMR % 57(37.0) 55(38.2) 59(37.8) 56(38.4) CML-CP CyR HR CML-AP CML-AP CA Major HR 112/ % Overall HR 139/ % 54
56 Major CyR 5/ % 65/ % HR CyR CML-AP CML-BC CML-MBC CA CML-LBC CA Major HR 36/ % 17/ % Overall HR 54/ % 19/ % Major CyR 37/ % 25/ % HR CyR CML-MBC CML-LBC Ph+ ALL Ph+ ALL CA Major HR 19/ % Overall HR 22/ % Major CyR 26/ % HR CyR Ph+ ALL 3 CA CA CA CA CA CA HR CyR CML-CP CA CA CA CA n % n % n % n % 70mg BID 70mg BID 70mg BID 100mg QD 140mg QD 50mg BID 70mg BID CHR ) 94 93) ) ) ) ) CCyR 5 42) ) 22 22) 83 50) 84 50) 84 50) 90 54) Major CyR 7 58) ) 36 36) ) ) ) ) 55
57 CML-AP CML-BC CA CA CA CA CA CML-AP n % CML-AP n % CML-BC n % CML-MBC n % CML-LBC n % CHR Major HR CCyR Major CyR Ph+ ALL CA CA CHR Major HR CCyR Major CyR CML-CP Ph+ ALL CML-AP BC Ph CML 4 CML bcr-abl bcr-abl CML-CP CA bcr-abl bcr-abl Bcr-Abl bcr-abl bcr-abl IC 50 T315I bcr-abl bcr-abl HR CyR n % CHR Major CyR CCyR bcr-abl bcr-abl 56
58 n % CHR Major CyR CCyR M244V G250E Y253F/H/K E255K/V T315I F317L M351T E355G H396R/P bcr-abl Bcr-Abl CyR CML bcr-abl T315I bcr-abl 4.3 HR CyR CyR 1 Major CyR CML-CP CHR CA n/n (%) 100mg QD 50mg BID 140mg QD 70mg BID 65/75 (86.7) 83/88 (94.3) 66/78 (84.6) 72/81 (88.9) 44/49 (89.8) 31/36 (86.1) 39/45 (86.7) 40/45 (88.9) CML-CP Major CyR CA n/n (%) 100mg QD 50mg BID 140mg QD 70mg BID 37/75 (49.3) 40/88 (45.5) 37/78 (47.4) 38/81 (46.9) 35/49 (71.4) 23/36 (63.9) 31/45 (68.9) 29/45 (64.4) 57
59 5 CyR HR Time-to-event OS time-to-event CyR HR CyR HR OS time-to-event 2 QT/QTc ILD CML CML-CP CML-AP CML-MBC CML-LBC/ Ph+ ALL I CA * II CA CA CA CA CA III CA CA * BID 23 QD 22 58
60 CML-CP CML-CP CML-AP/BC Ph+ ALL CA Grade 3 Grade 3 /% CML-LBC/ CML-CP CML-AP CML-MBC Ph+ ALL / / / / / / / / / / / / / / / / / / / / Grade 3 /% CML-CP 18 CML-CP 12 CML-AP/BC 11 Ph+ ALL 13 5/ / / / / / / / / / / / / / / / Grade 3 2 Grade 3 Grade 3 n % CML-CP CML-AP CML-MBC CML-LBC Ph+ ALL Grade 3 CML-CP 1/18 5.6% Ph+ ALL 1/13 7.7% 1/13 7.7% 2/ % Grade 3 59
61 3.3 3 Grade 3 10% 223/2182 6% 141/2182 1% 25/ % CML-CP 1150 CML-AP 502 CML-MBC 280 CML-LBC Ph+ ALL 250 Grade Grade 3-5 Grade Grade Grad Grade Grade Grade Grade Grade 3-5 e < <1 3 < / < <1 <1 0 2 < <1 2 < n % CML-CP CML-CP CML-AP/BC 11 Ph+ ALL 13 Grade Grade 3-5 Grade Grade 3-5 Grade Grade 3-5 Grade Grade 3-5 Grade Grade QT/QTc QT/QTc 60
62 QT/QTc QT/QTc QT/QTc QTcF 3 6msec 95% CI 8msec I II n % N=911 2 <1 2 < <1 2 <1 / 5 1 QT 11 1 QT 4 <1 ECG 1 <1 ECG P 1 <1 ECG 1 <1 18 < <1 11 QT QTcF 500msec 5 1% torsade de pointes QT 2 CA QT 100mg QD 50mg BID 140mg QD 70mg BID 2msec 5msec 1msec 5msec 60msec 3 2% 2 1% 7 5% 3 2% 5 100mg QD 1 140mg QD 70mg BID 2 500msec QTcF torsade de pointes CML 1 QT QT 431msec msec 446msec msec QT/QTc QT/QTc 5 Grade 3 61
63 Grade 3 n % CML-CP CML-AP CML-MBC CML-LBC Ph+ ALL ) / CA Grade 3 6 ILD Am J Respir Crit Care Med 2007; 176: CA180- ILD Ph+ ALL 3 2 CT ILD 1/54 1.8% ILD ILD % ILD ILD Corporate Adverse Events Reporting and Evaluation System CARES % ILD ILD 62
64 CA180- ILD Grade 3 Grade 3 n % CML-CP CML-AP CML-MBC CML-LBC Ph+ ALL / / / / / ALT 9/ / / / / AST 10/ / / / / Grade 3 CML-CP AST 2/ % ALT 1/18 5.6% CML-CP ALT 1/12 8.3% Ph+ ALL AST 4/ % ALT 1/13 7.7% TKI 8 10% Grade 3 19/ % 2/ % Grade 3 CML-CP 1/13 7.7% CML-AP/BC 1/11 9.1% TKI 9 /CA CA CA CA CA CA CA CA
65 CML-CP 1150 n % 30 n % Grade Grade 3 Grade Grade < Grade 3 CML-CP / % 16 53% 466/ % 17 57% 212/ % 10 30% CML-AP CML-BC Ph+ ALL CML-AP Ph+ ALL CML-BC CML-AP n % CML-AP CML-BC Ph+ ALL CML-MBC n % CML-LBC/ Ph+ ALL n % CML-AP n % CML-BC n % Ph+ ALL n % Grade G1 G3 G1 G3 G1 G3 G1 G3 G1 G3 G1 G CMLAP CML-BC Ph+ ALL 3 2 CML-CP n % CA CA / CA CML-AP CML-BC Ph+ ALL n % CA CA CA / CA
66 n % CA CA CA / CA n % 271 Grade Grade 3-5 Grade Grade mg Grade 3 /CA CML Ph+ ALL 65
67 19 CML-CP 12 CML-AP/BC 3 Ph+ ALL Grade 3 AST Ph+ ALL 1 CML-CP CML-CP CA CA CA /73 1 CA Grade 3 2/ CA CA CA CA CA CA CA % CML-CP 1150 CML-AP 502 CML-MBC 280 CML-LBC
68 CML-CP 1150 Grade 3 % CML-AP CML-MBC CML-LBC/Ph+ ALL CML-CP 1150 Grade 3 CML-AP 502 % CML-MBC 280 CML-LBC / / / / / / / / / / / / / / / / / / / / ALT 8/ / / / / / / / / / / / AST 7/ / / / CML-CP CML-AP CML-BC 3 CML Ph+ ALL 1 CML CML-CP CML-CP 6 18 Major CyR CCyR 67
69 15 25% 4% In: Hematology 2007 American Society of Hematology Education Program Book ELN CML-CP HSCT IFNα Blood 2006: 108; CML-AP CML-BC HSCT In: Hematology 2007 American Society of Hematology Education Program Book, Blood 2006: 108; CML IFN HSCT IFN IRIS IFN Major CyR N Engl J Med 2003; 348: HSCT CML CA CML-CP 800mg Major CyR Major CyR CML Grade 3 CML CML CML CML-CP -AP -BC CML HSCT NCCN v pdf CML-CP TKI HSCT CML-AP TKI HSCT CML-BCHSCT CMLHSCT HSCT HSCT CML-CP -AP -BC 2 Ph+ ALL 68
70 Ph+ ALL Ph+ ALL HSCT Blood 2004; 103: J Clin Oncol 2006; 24: Ph+ ALL Ph+ ALL 600mg/ 600mg/ 800mg/ Blood 2002; 100: mg/ Ph+ ALL 800mg/ CA Ph+ ALL 52% 800mg/CHR 16/ % Major HR 19/ % Major CyR 26/ % Ph+ ALL 600 mg 800 mg/ CHR 8/ % Major CyR 15/ % 600mg/ Ph+ ALL Ph+ ALL Ph+ ALL Ph+ ALL Ph+ ALL Ph+ ALL ALL Ph+ ALL Ph+ ALL HSCT In: Hematology 2007 American Society of Hematology Education Program Book Ph+ ALL CA /CA CA Ph+ ALL 9/39 23% Ph+ ALL Ph+ ALL 69
71 Ph+ ALL CML Ph+ ALL CML Ph+ ALL 1 CML CML Ph CML Ph CML Ph CML Ph bcr-abl FISH RT-PCR bcr-abl RNA Ph CML Bcr-Abl CML 90 95% Ph In: Pathology & Genetics Tumours of Haematopoietic and Lymphoid Tissues 2000 IARC press, USA Wintrobe s Clinical Hematology 11 th edt Lippincott Williams & Wilkins, USA CML Ph Ph CML bcr-abl CML Ph CML
72 3 CML Ph+ ALL Ph+ ALL Ph+ ALL Ph+ ALL CA / CA Ph+ ALL 13 Ph+ ALL 9 4 Ph+ ALL Ph+ ALL Ph+ ALL mg mg mg
73 PK CML-CP CML-CP EU mg BID 90mg BID 70mg BID 90mg BID CA mg QD 140mg QD EU CML-CP EU EU 2006 EU SPRYCEL 1 70mg 1 2 CML-CP SPRYCEL 140 mg 1 100mg 1 1 QD CML-CP 1 90mg 1 2 CML-CP 1 140mg mg BID /CA mg BID 70mg BID CML-CP 70mg BID 1/3 27% 1 100mg CML-CP CA CML-CP QD Major CyR BID CA mg 100mg QD 50mg BID Major CyR 1 140mg 140mg QD 70mg BID CA CCyR CyR Major CyR CHR PFS OS Dose intensity 100mg QD 70mg BID 100mg QD 100mg QD 4 100mg QD 100mg QD CML-CP 72
74 CA QD n % BID n % 100mg mg mg mg Grade * * mg 165 CA QD n % BID n % 140mg 50mg mg 167 P * Grade 106/ / / / / / / / / / / / Grade / / / / / / / / / / / / *4 CA QD n % BID n % 100mg mg mg mg < < CML-CP 50mg BID CA BID 100mg QD CA CA
75 CML-CP mg QD 50mg BID 6 CyR mg QD 11 50mg BID mg QD 10 50mg BID mg QD 7/11 64% 11/11 100% 50mg BID 3/12 25% 10/12 83%100mg QD 50mg BID 1 100mg QD CCyR 3/11 27% Major CyR 5/11 45% CHR 10/11 91% 50mg BID CCyR 7/12 58% Major CyR 11/12 92% CHR 10/12 83% mg QD 2/ mg BID 3/12 ILD 1 CML-CP 100mg QD CA mg QD CA mg QD CML-CP 6 Major CyR 100mg QD CML-CP 100mg QD 2 CML-AP CML-BC Ph+ ALL CML-AP CML-BC Ph+ ALL CA CA CA CA DLT MTD CML-CP 35 70mg BID HR mg CCyR 1 140mg 140mg QD 70mg BID 1 50mg BID in vitro IC 50 Bcr-Abl Crk1 BID QD BID CML-CP Major CyR CHR QD 90mg 105mg BID 70mg 50mg CML-AP CML-BC Ph+ ALL Major HR 70mg BID Major CyR 70mg 90mg BID 70mg BID /CA CA CA CML-CP 74
76 70mg BID 1 CML-AP/BC 134mg/ Ph+ ALL 135mg/ CA mg BID CML-AP CML-BC Ph+ ALL CA CML-AP CML-BC Ph+ ALL 70mg BID 140mg QD EU CML-CP CML-AP CML-BC Ph+ ALL BID QD 140mg QD CML-AP CML-BC Ph+ ALL QD 3 CML-CP CA mg QD 140mg QD 140mg QD 180mg QD 50mg BID 70mg BID 70mg BID 90mg BID CML-CP 140mg QD BID /CA mg BID CA mg QD 140mg QD 1 100mg 140mg QD 140mg QD CML-AP CML-BC Ph+ ALL CML-AP CML-BC Ph+ ALL CA CA CA mg BID 100mg BID CML-AP 3/25 12% CML-MBC 6/40 15% CML-LBC Ph+ ALL 2/31 6% Major HR / CA Ph+ ALL 1 70mg BID 14 90mg BID T315I 90mg BID 100mg BID I CA CML-AP CML-BC 120mg BID 75
77 MTD CML-AP CML-BC Ph+ ALL 100mg BID CA I CML-CP I CML-CP 90mg BID 90mg BID CML-AP CML-BC Ph+ ALL CA mg BID 100mg BID CA mg BID 100mg BID CML-AP CML-BC Ph+ ALL CML-AP CML-BC Ph+ ALL 1 20mg CHR Major HR Minor HR 2 CML-BC 2 50% CML-AP CML-BC Ph+ ALL 1 HR CML-AP CML-BC 4 CHR Blood 2002; 99: Blood 2002; 99: CML-AP CML-BC Ph+ ALL CA CA CA CML-AP CML-MBC CML-LBC Ph+ ALL CML Ph+ ALL 4 CML-CP CML-AP CML-MBC CML-LBC/ Ph+ ALL
78 CML-CP CML-AP CML-MBC CML-LBC/ Ph+ ALL % % % % % / CA CML-CP CML-AP/BC Ph+ ALL % % % % 5 CML-BC Ph+ ALL M.D. Anderson Cancer Center CML-LBC Ph+ ALL Hyper CVAD 15/19 ASH meeting abstract 2007; 100: 2814 CML-AP CML-BC Ph+ ALL CML 2 2 Ph+ ALL % 95% QT/QTc 77
79 ILD CyR 7 secondary resistance PCR ELN Blood 2006: 108; CHR 2 CHR 3 CCyR 6 CCyR 12 Bcr-Abl mrna 3 Blood 2006: 108; failure abl NCCN v pdf TKI 8 CML Ph+ ALL 1 20 CML Ph+ ALL /CA Ph CA CML Ph+ ALL / CA
80 Grade 3/4 % Grade Grade 3 Grade 4 7 (39) 1 (6) 4 (22) 1 (6) % Grade Grade 3 Grade 4 6/18 33% 1 Grade 3/4 % Grade 3 Grade (22) 3 (17) 18 2 (11) 5 (28) 18 6 (33) 1 (6) 18 1 (6) 3 (17) 18 1 (6) 3 (17) 18 1 (6) 3 (17) 18 2 (11) 2 (11) 18 2 (11) 18 2 (11) 18 2 (11) 18 2 (11) 18 1 (6) CD (6) 18 1 (6) 18 1 (6) 18 1 (6) 18 1 (6) 18 1 (6) Grade 10% Grade 3/4 5% % CML-CP CML-AP CML-BC Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 7 (58) 3 (25) 1 (8) 3 (43) 2 (29) 2 (50) 2 (50) 3 (25) 4 (57) 1 (14) 2 (50) 2 (17) 3 (43) 4 (100) 6 (50) 1 (8) 2 (50) 3 (25) 3 (43) 1 (25) 4 (33) 1 (14) 1 (25) 2 (17) 1 (14) 3 (75) 3 (25) 1 (14) 1 (25) 3 (25) 2 (50) 79
81 % CML-CP CML-AP CML-BC Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 2 (17) 1 (8) 1 (14) 2 (50) 3 (25) 1 (14) 2 (17) 1 (14) 1 (25) 1 (8) 3 (43) 1 (8) 1 (14) 2 (50) 1 (8) 1 (14) 2 (50) 2 (17) 1 (25) 2 (17) 1 (14) 2 (17) 1 (14) 2 (17) 1 (25) 1 (25) 2 (17) 1 (14) 2 (17) 1 (8) 1 (14) 2 (17) 1 (14) 1 (8) 1 (14) 1 (25) 1 (8) 1 (14) 1 (25) 1 (8) 2 (50) 1 (8) 2 (50) 1 (8) 1 (14) 1 (25) 1 (8) 2 (50) 1 (25) 2 (29) 1 (25) 2 (17) 2 (17) 2 (17) 2 (17) 2 (17) 2 (17) 2 (17) 1 (8) 1 (25) 1 (8) 1 (14) 1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (25) 1 (25) 1 (8) 1 (25) 1 (8) 1 (14) 1 (8) 1 (14) 1 (8) 1 (25) 1 (14) 1 (14) 1 (25) 1 (25) 2 (50) 2 (50) 2 (50) 1 (14) 1 (25) 1 (14) 1 (25) 2 (29) 2 (29) 2 (29) 2 (50) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 80
82 % CML-CP CML-AP CML-BC Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 1 (14) 1 (25) 1 (25) 1 (14) 1 (14) 1 (14) 1 (25) 1 (25) 1 (14) 1 (14) 1 (14) 1 (14) 1 (25) 1 (14) 1 (14) 1 (14) 1 (25) 1 (25) 1 (14) 1 (25) 1 (25) 1 (14) 1 (14) 1 (25) 1 (25) 1 (25) 1 (14) 1 (14) 1 (14) 1 (25) 1 (25) 1 (14) 1 (14) 1 (25) 1 (14) Grade 10% Grade 3/4 5% % CML-CP CML-AP CML-BC Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 7 (58) 3 (25) 1 (8) 3 (43) 2 (29) 1 (25) 1 (25) 3 (25) 3 (43) 2 (50) 5 (42) 1 (8) 2 (50) 3 (25) 3 (43) 1 (25) 2 (17) 2 (29) 3 (75) 4 (33) 1 (14) 1 (25) 2 (17) 1 (14) 3 (75) 3 (25) 2 (50) 3 (25) 1 (14) 2 (17) 1 (14) 1 (25) 2 (17) 1 (8) 1 (14) 1 (25) 1 (8) 1 (14) 2 (50) 2 (17) 1 (25) 2 (17) 1 (14) 2 (17) 1 (25) 1 (25) 2 (17) 1 (14) 2 (17) 1 (14) 2 (17) 1 (8) 1 (14) 1 (8) 2 (29) 1 (8) 1 (14) 1 (25) 81
83 % CML-CP CML-AP CML-BC Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 1 (8) 2 (50) 1 (8) 2 (50) 1 (8) 1 (14) 1 (25) 1 (8) 2 (50) 1 (25) 2 (29) 1 (25) 2 (17) 2 (17) 2 (17) 2 (17) 1 (8) 1 (25) 1 (8) 1 (8) 1 (14) 1 (14) 1 (8) 1 (14) 1 (8) 1 (25) 1 (8) 1 (14) 1 (8) 1 (14) 1 (8) 1 (25) 1 (14) 1 (14) 1 (25) 1 (25) 2 (50) 2 (50) 1 (14) 1 (25) 1 (14) 1 (25) 2 (50) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 1 (8) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 1 (25) 1 (14) 1 (14) 1 (25) 1 (25) 1 (14) 1 (14) 1 (14) QT 1 (25) 1 (14) 1 (14) 1 (14) 1 (25) 1 (25) 1 (14) 1 (25) 1 (25) 1 (14) 1 (14) 1 (25) 1 (25) 1 (25) 1 (14) 1 (14) 1 (14) 1 (25) 1 (25) 1 (14) 82
84 % CML-CP CML-AP CML-BC Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 1 (14) 1 (14) 12 33% Grade 3/4 % CML-CP CML-AP CML-BC Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade (25) 5 (42) 7 2 (29) 2 (29) 4 4 (100) 12 4 (33) 3 (25) 7 2 (29) 3 (43) 4 4 (100) 12 4 (33) 7 1 (14) 1 (14) 4 1 (25) 3 (75) 12 2 (17) 7 1 (14) 4 1 (25) 1 (25) 12 1 (8) 7 1 (14) 4 1 (25) 12 1 (8) 7 1 (14) 4 1 (25) 12 1 (8) 7 1 (14) (14) 4 1 (25) (50) 12 1 (8) 7 4 γ 12 1 (8) (25) CD (14) (25) (25) (25) (14) (25) (14) 4 2 CA Grade 3/4 % CML-CP BID N=23 CML-CP QD N=22 CML-AP N=12 Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 23 (100) 9 (39) 2 (9) 22 (100) 7 (32) 5 (23) 12 (100) 4 (33) 0 17 (74) 3 (13) 0 17 (77) 2 (9) 0 10 (83) (61) (68) (67) (35) 3 (13) 0 5 (23) (25) (35) (32) 2 (9) 0 4 (33) (4) (17) (18) 2 (9) (4) (5) (8) (9) (18) (17) (4) (5) (8) (4) (5) (25) (61) 1 (4) 0 10 (45) 1 (5) 0 9 (75) (43) (59) 1 (5) 0 8 (67) (61) (68) 5 (23) 0 8 (67) (57) (55) 1 (5) 0 8 (67)
untitled
19 11 13 300 18 3 31 1300mg 4 6 C 15 H 22 FN 3 O 6 359.35 + -1-5--β-D--5--1,2--2- -4- 19 11 13 300 18 3 31 A B B A 30 1 2 21 7 1 1 1.31m 2 900mg 1.31m 2 1.64m 2 1,200mg 1.64m 2 1,500mg B 30 1 2 14 7 1
untitled
20 2 14 18 10 16 1 1.0mg 0.035mg 2 1 20 2 14 18 10 16 1 1 1 52 1 1 21 7 28 1 29 2 1 20 1 24 18 10 16 1 1 21 7 28 1 29 1 NET 1.0mg EE 0.035mg *NET *NET 1999 2007 *NET *NET 88 NSAIDs GnRH GnRH NSAIDs 20
03慢性骨髄性白血病CML.indd
慢* 59 病CML略語一覧 Ⅰ クリニカルクエスチョン一覧 Ⅱ 略語一覧 慢性骨髄性白血病 CML CQ 1 小児 CML の標準的治療は何か CQ 2 小児 CML 治療における造血幹細胞移植の役割は何か CML (Chronic Myelocytic Leukemia, 慢性骨髄性白血病 ) TKI (Tyrosine Kinase Inhibitor, チロシンキナーゼ阻害薬 ) CHR (Complete
E3200 BV FOLFOX4 FOLFOX4 PFS % 0.42, 0.65 p< log-rank % FOLFOX4 8.6% FOLFOX % FOLFOX4 259/ % FOL
E3200 BV FOLFOX4 FOLFOX4 PFS 4.5 7.5 0.518 95% 0.42, 0.65 p
untitled
Shinichiro Okamoto MD, PhD Keio University School of Medicine Tokyo Japan vincristine) Berberidaceae etoposide VP-16) MRD 10 12 PCR 10 10 10 8 10 6 10 4 10 2 ( CR) ( CR) AML Study n Ind Consol % 3
1.8.2 Page MIC () MIC 50 / MIC 90 µg/ml Candida albicans (54) / Candida glabrata (25) 0.25 / 0.5 Candida guilliermondii a) (2)
1.8.2 Page1 1.8.2 96% 2002 40 B 1 123 (1) in vitro 1) in vitro C. glabrata C. krusei 1 2 19951997 3 1999 2002 MIC MIC 2 1.8.2 Page2 1 19951997 MIC () MIC 50 / MIC 90 µg/ml Candida albicans (54) 0.016 /
Vol. 36, Special Issue, S 3 S 18 (2015) PK Phase I Introduction to Pharmacokinetic Analysis Focus on Phase I Study 1 2 Kazuro Ikawa 1 and Jun Tanaka 2
Vol. 36, Special Issue, S 3 S 18 (2015) PK Phase I Introduction to Pharmacokinetic Analysis Focus on Phase I Study 1 2 Kazuro Ikawa 1 and Jun Tanaka 2 1 2 1 Department of Clinical Pharmacotherapy, Hiroshima
200mg 2005 3 876179 2002 3 3 200mg VFEND for Intravenous Use (1) (2) [4.1 ] (3) [4.2 ] (1) [1] (2) (3) [1] 3
untitled
19 11 7 200mg 18 6 29 19 10 24 8 19 10 16 200mg 18 6 29 1 200mg 274mg 1 C 21 H 16 ClF 3 N 4 O 3 C 7 H 8 O 3 S 637.03 4-{4-[3-4--3- ] }-N 2 - -2-4- 18 8 210821002 19 10 16 200mg 18 6 29 1 200mg 274mg 1
50mg 75mg (1) H 3 C O OH HO H O O H OH SO H 3 Na H H N H 2 N NH OH H N O O H H O OH H 3 C H O O N H H H HO H NH CH 3 HN HO H OH O H OH H NH
3240 14 8 8 50mg 75mg 13 6 25 1-(1) H 3 C O OH HO H O O H OH SO H 3 Na H H N H 2 N NH OH H N O O H H O OH H 3 C H O O N H H H HO H NH CH 3 HN HO H OH O H OH H NH O N O C 56 H 70 N 9 NaO 23 S 1292.26 5-[(1S,2S)-2-
untitled
19 CSPOR CRC/2009.8.8-9 2009 8 8 ( ) - CSPOR CRC SEMINAR- twatanab@oncoloplan.com http://www.oncoloplan.com - Toru Watanabe MD - 2 Phase I: Dose Finding trial Phase II : Efficacy and Safety trial Phase
untitled
2303 16 2 9 1 14 5 31 (423) 1 (4), (6) C55H84ClN17O21S3 HCl (BLM-A2) 1487.47 11 2 1 4 104 2 14 5 31 [ ] ( ) ( ) 1. 15mg 30mg( ) 5 20mL 1 5mg( ) 2. 3 15mg 30mg( ) 5mL 1mg( ) 1mL 3. 5mg 15mg( ) 4. 1 2 1
エディロールカプセルインタビューフォーム
2012 4 5 873112 2008 () 1 0.5g 0.5g 0.75g 0.75g JAN EldecalcitolJAN 2011 1 21 2011 3 11 2011 4 11 TEL0120-591-818 03-3985-5599 8:3017:00 http://www.taishotoyama.co.jp/ 20124 http://www.info.pmda.go.jp/
Rinku General Medical Center
Rinku General Medical Center 4860 100 1620 Ann Intern Med. 1966; 64: 328 40 CHOP 63 1 83 J Clin Oncol. 1998; 16: 20065-69 Febrile Neutropenia IDSA(Infectious Diseases Society of America) 2002 Guidelines
山形PhALL座談会_MF.indd
Hematology Today 特別企画 VII 山形 Ph+ALL 座談会 Current Status and Future Perspectives in the Treatment for Ph+ALL 司 会 大本英次郎 出席者佐藤伸二 木村淳 加藤裕一 本間りこ コメンテーター太田秀一 213 7 チロシンキナーゼ阻害薬 (TKI) 登場以前の Philadelphia 染色体陽性急性リンパ性白血病
CML 旭川 CML 座談会 CML の治療戦略 :TKI free を目指して CMR 司会 出席者 コメンテーター 生田克哉先生 3 幸田久平先生 佐藤一也先生 柿木康孝先生 進藤基博先生 3 木村晋也先生 CML 生田 1 TKI CML 2 TKI 生田克哉先生 CML TKI CMR CM
Hematology Today 特別企画 VI 旭川 CML 座談会 CML の治療戦略 : TKI free を目指して ~CMR 未達成症例の今後を考える ~ 司会生田克哉 3 出席者幸田久平 佐藤一也 柿木康孝 進藤基博 3 コメンテーター木村晋也 慢性骨髄性白血病 (CML) の治療は, 第 1 世代チロシンキナーゼ阻害薬 (TKI) イマチニブの登場によって大きく進歩した さらに, 第
国試過去問集.PDF
I 89 16 3 130 ab c AMPcAMP a 1 --- b c --- 2 --- --- 3 --- --- 4 --- --- 5 --- --- camp camp Ca 2+ β1 camp A camp camp A β1 p.156 β p.146 b. p.157 p135 (ANP) p157 c PDE-III p.157 p.157, 183 PDE C Ca PDE-III
2009年133巻3号3月号.indb
Folia Pharmacol. Jpn.133 1 2 Chiroscience UCB S RR-..% AA C IC C/A A/ A R- II/ III II/III Chiroscience UCB S 1 - E-mail: koji_taya@maruishi-pharm.co.jp Author: Koji Taya, Satoshi Shimizu Title: Levobupivacaine
http://www.ike-dyn.ritsumei.ac.jp/ hyoo/wave.html 1 1, 5 3 1.1 1..................................... 3 1.2 5.1................................... 4 1.3.......................... 5 1.4 5.2, 5.3....................
( )
18 10 01 ( ) 1 2018 4 1.1 2018............................... 4 1.2 2018......................... 5 2 2017 7 2.1 2017............................... 7 2.2 2017......................... 8 3 2016 9 3.1 2016...............................
25 7 18 1 1 1.1 v.s............................. 1 1.1.1.................................. 1 1.1.2................................. 1 1.1.3.................................. 3 1.2................... 3
(1) ) ) (2) (3) (4) (5) (1) (2) b (3)..
... -1... -1... -2... -6.... -1 (1)... -1 1)... -1 2)... -14 (2)... -19 (3)... -52 (4)... -18 (5)... -136.... -196 (1)... -196 (2) b... -224 (3)... -233.... -251.... -286.... -289 (1)... -289 (2)... -32
1 1 H Li Be Na M g B A l C S i N P O S F He N Cl A e K Ca S c T i V C Mn Fe Co Ni Cu Zn Ga Ge As Se B K Rb S Y Z Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb T e
No. 1 1 1 H Li Be Na M g B A l C S i N P O S F He N Cl A e K Ca S c T i V C Mn Fe Co Ni Cu Zn Ga Ge As Se B K Rb S Y Z Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb T e I X e Cs Ba F Ra Hf Ta W Re Os I Rf Db Sg Bh
1) a) b) CRP c) d) e) a,b b,c c,d d,e a,e b,d 2) CKD a) ACE ARB b) 2mg/dL ACE ARB c) 2mg/dL d) e) ACE ARB a,b b,c c,d d,e a,e b,d 3) a) 130/85mmHg b)
2010.1.13 1) 4) 2 18 1) 1 2 3 4 2) 1 2 85 3 3) 1 metabolizer 2 metabolizer 3 metabolizer 4 metabolizer 4) CYP 1 2 metabolizer 3 metabolizer 4 5 6 4 7 2 5 (PPI) 1 2 PPI 2 3 2 3 3 3 3 PPI 3 1 ph 4 5 1) 5)
- 9 91, (2006)
Case study level Ma Management of testicular cancer - 9 91, 10 0.7 2.4 (2006) 20 30 20 20-40 AFP -hcg -hcg AFP TNM T ptx pt0 ptis pt1 / pt2 / pt3 / pt4 / N NX N0 N1 2cm 1 2cm N2 2cm 5cm 1 5cm N3 5cm TNM
untitled
twatanab@oncoloplan.com http://www.oncoloplan.com I II - III IV Fig 3. Survival curves overall and according to response Bruzzi, P. et al. J Clin Oncol; 23:5117-5125 25 Copyright merican Society of Clinical
03J_sources.key
Radiation Detection & Measurement (1) (2) (3) (4)1 MeV ( ) 10 9 m 10 7 m 10 10 m < 10 18 m X 10 15 m 10 15 m ......... (isotope)...... (isotone)......... (isobar) 1 1 1 0 1 2 1 2 3 99.985% 0.015% ~0% E
A(6, 13) B(1, 1) 65 y C 2 A(2, 1) B( 3, 2) C 66 x + 2y 1 = 0 2 A(1, 1) B(3, 0) P 67 3 A(3, 3) B(1, 2) C(4, 0) (1) ABC G (2) 3 A B C P 6
1 1 1.1 64 A6, 1) B1, 1) 65 C A, 1) B, ) C 66 + 1 = 0 A1, 1) B, 0) P 67 A, ) B1, ) C4, 0) 1) ABC G ) A B C P 64 A 1, 1) B, ) AB AB = 1) + 1) A 1, 1) 1 B, ) 1 65 66 65 C0, k) 66 1 p, p) 1 1 A B AB A 67
スライド 1
QOL 1 Goldberg, JCO 22:23-30, 2004 N9741: Oxaliplatin in First Line (US) IR 200 mg/m 2 OX 85 mg/m 2 every 3 weeks Efficacy IFL FOLFOX4 > IFL IROX FOLFOX4 IROX OS TTP RR 15.0 mo 6.9 mo 31 % P=0.0001 P=0.0014
20mg CTD 2.4 2.4 2.4... 5 2.4.1... 5 2.4.2... 7 2.4.3... 10 2.4.4... 13 2.4.5... 18 2.4.6... 20 3 2.4 2.4 2.4.1 JNS002 ( HSPC) N-(Carbonyl-methoxypolyethylene glycol 2000)-1,2- distearoyl-sn-glycero-3-phosphoethanolamine
cladribine 2-CdA ADA DCF HCL IFN- MTD LD50 LD90 DLT MDACC RWJPRI NHL ATL CLL 2-CdATP 5 -NT dckase (2-chloro-2 -deoxyadenosine) adenosine deaminase deoxycoformycin( ) hairy cell leukemia - (interferon alfa)
熊本県数学問題正解
00 y O x Typed by L A TEX ε ( ) (00 ) 5 4 4 ( ) http://www.ocn.ne.jp/ oboetene/plan/. ( ) (009 ) ( ).. http://www.ocn.ne.jp/ oboetene/plan/eng.html 8 i i..................................... ( )0... (
sick contact1l
Clinical Question 2017 年 5 月 15 日 分野 : 内分泌テーマ : 治療 19 14 15 18 sick contact1l 170cm/68.8kg, GCSE1V1M5, HR: 120/min, BP: 104/60mmHg, RR: 30/min, SpO 2 : 96%, BT: 38.0 WBC Hb PLT CRP Cr BUN 23400 15.0 35.5
36 th IChO : - 3 ( ) , G O O D L U C K final 1
36 th ICh - - 5 - - : - 3 ( ) - 169 - -, - - - - - - - G D L U C K final 1 1 1.01 2 e 4.00 3 Li 6.94 4 Be 9.01 5 B 10.81 6 C 12.01 7 N 14.01 8 16.00 9 F 19.00 10 Ne 20.18 11 Na 22.99 12 Mg 24.31 Periodic
PowerPoint プレゼンテーション
* ** 117,320 70,293 109,140 49,830 93,402 45,744 60,986 31,875 47,318 28,829 45,367 18,186 29,025 12,838 27,822 11,970 20,734 10,823 19,994 10,336 * 2007 ** 2011 65% 25% 9 DNA P53, ATM G1 S G2 G1 M 1
日本化学療法学会雑誌第54巻第S-1号
β β β Key words β β I HP- -CD CHR RHC R R R R CHR R R R R RHC R R R CHR R R R RHC CHR R H CH CH Fig.. Structuralformulaofhydroxypropyl-β -cyclodextrin(hp-β -CD). CH n H β β β β Table-. Dosageandadministration(Singleadministrationstudy)
fpj
Folia Pharmacol. Jpn. 145 C 天野 学 1), 石川博樹 2) 要約 : genotype C C IFN C HCV A NS A NS / A NS / AHCV in vitro HCV genotype genotype HCV HCV Genotype b C mg mg IL B IFN IFN 1. はじめに C HCV, HCV HCV HCV, C HCV.
IMUSERA 3 3 4 4 5 5 5 5 6 1 1 12 18 25 25 31 31 31 31 32 32 37 43 43 45 48 48 48 48 49 5 1 2 3 4 3 4 1.56mg.5mg D- 3 15.9mm 5.8mm.96g FTY.5mg FTY.5mg OH NH2 OH H3C HCI 5 6 7 BCG Torsades de pointes a 2
I II III IV V
I II III IV V N/m 2 640 980 50 200 290 440 2m 50 4m 100 100 150 200 290 390 590 150 340 4m 6m 8m 100 170 250 µ = E FRVβ β N/mm 2 N/mm 2 1.1 F c t.1 3 1 1.1 1.1 2 2 2 2 F F b F s F c F t F b F s 3 3 3
200 30 984 1 1854 1713 1000 1008 ED ADL/QOL The European Working Group on Sarcopenia in Older People EWGSOP Asian Working Group for Sarcopenia AWGS D C Zhang, 2006 C Imamura, 2008 ATP Imamura, 2009 Imamura,
(1.2) T D = 0 T = D = 30 kn 1.2 (1.4) 2F W = 0 F = W/2 = 300 kn/2 = 150 kn 1.3 (1.9) R = W 1 + W 2 = = 1100 N. (1.9) W 2 b W 1 a = 0
1 1 1.1 1.) T D = T = D = kn 1. 1.4) F W = F = W/ = kn/ = 15 kn 1. 1.9) R = W 1 + W = 6 + 5 = 11 N. 1.9) W b W 1 a = a = W /W 1 )b = 5/6) = 5 cm 1.4 AB AC P 1, P x, y x, y y x 1.4.) P sin 6 + P 1 sin 45
「産業上利用することができる発明」の審査の運用指針（案）
1 1.... 2 1.1... 2 2.... 4 2.1... 4 3.... 6 4.... 6 1 1 29 1 29 1 1 1. 2 1 1.1 (1) (2) (3) 1 (4) 2 4 1 2 2 3 4 31 12 5 7 2.2 (5) ( a ) ( b ) 1 3 2 ( c ) (6) 2. 2.1 2.1 (1) 4 ( i ) ( ii ) ( iii ) ( iv)
. ev=,604k m 3 Debye ɛ 0 kt e λ D = n e n e Ze 4 ln Λ ν ei = 5.6π / ɛ 0 m/ e kt e /3 ν ei v e H + +e H ev Saha x x = 3/ πme kt g i g e n
003...............................3 Debye................. 3.4................ 3 3 3 3. Larmor Cyclotron... 3 3................ 4 3.3.......... 4 3.3............ 4 3.3...... 4 3.3.3............ 5 3.4.........
Folia Pharmacol. Jpn mg/14 ml mg/ ml Genentech, Inc. Genentech HER human epidermal growth factor receptor type HER - HER HER HER HER
Folia Pharmacol. Jpn. 143 420 mg/14 ml 1 2 3 4 mg/ ml Genentech, Inc. Genentech HER human epidermal growth factor receptor type HER - HER HER HER HER HER KPL- HER BO HER CLEOPATRA HER HER 1. HER HER EGFR
CTD 2 2.6 5.3mg 0.4mg 0.6mg 0.8mg 1.0mg 1.2mg 1.4mg 1.6mg 1.8mg 2.0mg 12mg 2.6 Page 3 2.6.6...5 2.6.6.1...6 2.6.6.2...9 2.6.6.3...9 2.6.6.4... 11 2.6.6.5... 11 2.6.6.6... 11 2.6.6.7... 11 2.6.6.8... 11
n ξ n,i, i = 1,, n S n ξ n,i n 0 R 1,.. σ 1 σ i .10.14.15 0 1 0 1 1 3.14 3.18 3.19 3.14 3.14,. ii 1 1 1.1..................................... 1 1............................... 3 1.3.........................
I PD-I-3 VA ICD 2006 NYHA ~ LVEF 35% a ICD SCD-HeFT ICD MADIT- ICD a CABG-Patch ICD EF b MADITø MADIT- MUSTT EPS EPS 19 EPS 5/19 VA PD-I-4 Holter LP f
J Arrhythmia Vol 23 (Suppl) 2007 PD-I-1 OACIS 95% 6.4 (1.5 27.8 4.3 (1.0 18.5), 0.2 (0.05 0.93), respectively MADIT LVEF 30% 192 2.0 12.4% 24 3.1% MADIT 12.1% p=.001), ICD direct PCI OACIS (Osaka Acute
Understanding Stem Cell Transplant 2007
Understanding Stem Cell Transplant IMF International Myeloma Foundation 12650 Riverside Drive, Suite 206 North Hollywood, CA 91607 USA Telephone: 800-452-CURE (2873) (USA & Canada) 818-487-7455 Fax: 818-487-7454
RN201602_cs5_0122.indd
ISSN 1349-1229 No.416 February 2016 2 SPECIAL TOPIC113 SPECIAL TOPIC 113 FACE Mykinso 113 SPECIAL TOPIC IUPAC 11320151231 RI RIBFRILAC 20039Zn30 Bi83 20047113 20054201283 113 1133 Bh107 20082009 113 113
(1) (2) (1) (2) (1) Seg (2) Seg (3) Seg (4) Seg (1) (2) (3) ( ) (1) (PCA)...12
(1)...109 (2)...110 (1) 28...111 (2) 28...113 (1) Seg...115 (2) Seg...117 (3) Seg...119 (4) Seg...120 (1)...122 (2)...122 (3) ( )...126 (1) (PCA)...127 (2) Draize...128 (1) Ames...129 2 in vitro...132
PowerPoint プレゼンテーション
Institute of Accelerator Analysis Ltd. HPLC Drug Concentration (ng/ml) 7 6 5 4 3 2 1 B D F Drug Concentration (ng/ml) 450 400 350 300 250 200 150 100 50 CREAM (MD) T007 (MD) CREAM (TD) 0 0 2
2001 Mg-Zn-Y LPSO(Long Period Stacking Order) Mg,,,. LPSO ( ), Mg, Zn,Y. Mg Zn, Y fcc( ) L1 2. LPSO Mg,., Mg L1 2, Zn,Y,, Y.,, Zn, Y Mg. Zn,Y., 926, 1
Mg-LPSO 2566 2016 3 2001 Mg-Zn-Y LPSO(Long Period Stacking Order) Mg,,,. LPSO ( ), Mg, Zn,Y. Mg Zn, Y fcc( ) L1 2. LPSO Mg,., Mg L1 2, Zn,Y,, Y.,, Zn, Y Mg. Zn,Y., 926, 1 1,.,,., 1 C 8, 2 A 9.., Zn,Y,.
入試の軌跡
4 y O x 4 Typed by L A TEX ε ) ) ) 6 4 ) 4 75 ) http://kumamoto.s.xrea.com/plan/.. PDF) Ctrl +L) Ctrl +) Ctrl + Ctrl + ) ) Alt + ) Alt + ) ESC. http://kumamoto.s.xrea.com/nyusi/kumadai kiseki ri i.pdf
橡
TP T-13i AST ALT ALP Y CTP LOH CHE CRP 8.7 id 0.4 mg/d 21 AWL 131U/L 257 LU/L 12 111/L 234 11J/L 344 IU/L 0.30 mid No K a BUN ORE UA 142 meq/1 4.3 meqa 108 meqa 15.8 met! 0.71 mg/di 5.0 mg/d CEA 5_5 n8/m1
untitled
( ) - 1 - - 2 - 38% 26% A) Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma 124 (J Clin Oncol 7: 126-131, 1989) 124 95 29 II 1 2,000mg/m 2 x 4 8g/m
SBP hospitalist network.key
1 Treatment and Prophylaxis of Spontaneous Bacterial Peritonitis (1); (2), (3). (1) (2) (3) :, :, 2 Clinical Question 1 72...,.,,.,... 3. CT..,. 4? SBP? SBP. 5 Clinical Question SBP? SBP,? 6 SBP (Spontaneous
x, y x 3 y xy 3 x 2 y + xy 2 x 3 + y 3 = x 3 y xy 3 x 2 y + xy 2 x 3 + y 3 = 15 xy (x y) (x + y) xy (x y) (x y) ( x 2 + xy + y 2) = 15 (x y)
x, y x 3 y xy 3 x 2 y + xy 2 x 3 + y 3 = 15 1 1977 x 3 y xy 3 x 2 y + xy 2 x 3 + y 3 = 15 xy (x y) (x + y) xy (x y) (x y) ( x 2 + xy + y 2) = 15 (x y) ( x 2 y + xy 2 x 2 2xy y 2) = 15 (x y) (x + y) (xy
K E N Z U 2012 7 16 HP M. 1 1 4 1.1 3.......................... 4 1.2................................... 4 1.2.1..................................... 4 1.2.2.................................... 5................................
( ) 2002 1 1 1 1.1....................................... 1 1.1.1................................. 1 1.1.2................................. 1 1.1.3................... 3 1.1.4......................................
食道がん化学放射線療法後のsalvage手術
2006 2 17 52 Daly JM, et al. J Am Coll Surg 2000;190:562-573 Esophageal Cancer: Results of an American College of Surgeons Patient Care Evaluation Study Daly JM, et al. J Am Coll Surg 2000;190:562-573
1 見出し1，12ポ，日本語ゴシック，英語Arial，段落後は6ポの設定です
8. Page1 8. B 1 5) 6) 2099 2370 50 400 mg 19 (1) 1) (a) 78.9% 30/38 4 3 35.7% 5/14 71.4% 10/1485.7% 12/142 1 83.3% 5/63 2 1 1 1 8. Page2 (b) 2099 1897 82.4% 1562/1897 2 84.0% 1298/1545 3 2 80.4% 472/58779.0%
6 2 T γ T B (6.4) (6.1) [( d nm + 3 ] 2 nt B )a 3 + nt B da 3 = 0 (6.9) na 3 = T B V 3/2 = T B V γ 1 = const. or T B a 2 = const. (6.10) H 2 = 8π kc2
![6 2 T γ T B (6.4) (6.1) [( d nm + 3 ] 2 nt B )a 3 + nt B da 3 = 0 (6.9) na 3 = T B V 3/2 = T B V γ 1 = const. or T B a 2 = const. (6.10) H 2 = 8π kc2](/thumbs/92/109118076.jpg "6 2 T γ T B (6.4) (6.1) [( d nm + 3 ] 2 nt B )a 3 + nt B da 3 = 0 (6.9) na 3 = T B V 3/2 = T B V γ 1 = const. or T B a 2 = const. (6.10) H 2 = 8π kc2")
1 6 6.1 (??) (P = ρ rad /3) ρ rad T 4 d(ρv ) + PdV = 0 (6.1) dρ rad ρ rad + 4 da a = 0 (6.2) dt T + da a = 0 T 1 a (6.3) ( ) n ρ m = n (m + 12 ) m v2 = n (m + 32 ) T, P = nt (6.4) (6.1) d [(nm + 32 ] )a
Detection methods of minimal residual disease and their prognostic value in patients with malignant hematological diseases はじめに (m
92 124 3 92 96 2015 Detection methods of minimal residual disease and their prognostic value in patients with malignant hematological diseases はじめに (minimal residual disease: MRD) MRD MRD ( 1) MRD PCR
構造と連続体の力学基礎
II 37 Wabash Avenue Bridge, Illinois 州 Winnipeg にある歩道橋 Esplanade Riel 橋6 6 斜張橋である必要は多分無いと思われる すぐ横に道路用桁橋有り しかも塔基部のレストランは 8 年には営業していなかった 9 9. 9.. () 97 [3] [5] k 9. m w(t) f (t) = f (t) + mg k w(t) Newton
gtf Wnt5a-Ror2 IL-8 in vitro Ozony Tron P. gingivalis SOD ELISA Location of main occluding areas and masticatory ability in patients with reduced occlusal support 12-Methacryloyloxydodecylpyridinium bromide
125 2 P 1st washout 2 PB P mg/dL nd washout 2 P 5.5mg/dL< mg/dL <2.5mg/dL P P 2 D D 3 Ca 10
. (1) 125 1 125 Renagel PB-94 P intact-pth P 1 b c a b 1 18 2 3 3 3 1 P 4 D 1 5 6 7 2 1HIV 2 3 4 5Hb 8.0g/dL ALT 48IU/L 6 7 PB-94 440mg 403mg 1-196 125 2 P 1st washout 2 PB-94 1 2 4 4 P 2.5 5.5mg/dL 1
mg (1) (2) QT (3) 1 400mg 1 1 2
17 8 10 400mg 14 9 30 1 400mg 1 C21H24FN3O4 HCl 437.89 1 6 8 7 [(4aS, 7aS) [3,4 b] 6 ] 4 1,4 3 1-Cyclopropyl-6-fluoro-8-methoxy-7-[(4aS,7aS)-octahydropyrrolo[3,4-b]pyridine -6-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic
linearal1.dvi
19 4 30 I 1 1 11 1 12 2 13 3 131 3 132 4 133 5 134 6 14 7 2 9 21 9 211 9 212 10 213 13 214 14 22 15 221 15 222 16 223 17 224 20 3 21 31 21 32 21 33 22 34 23 341 23 342 24 343 27 344 29 35 31 351 31 352
CAR-T実施
Building a Clinical CAR-T Program - Jichi Medical University Experience l l l Anti-CD3/28 mabs & IL-2: 29% Anti-CD3/28 beads: 66% Retroviral: 41% Lentiviral: 54% T-Flasks: 22% Static Culture Bags: 35%
S I. dy fx x fx y fx + C 3 C vt dy fx 4 x, y dy yt gt + Ct + C dt v e kt xt v e kt + C k x v k + C C xt v k 3 r r + dr e kt S Sr πr dt d v } dt k e kt
S I. x yx y y, y,. F x, y, y, y,, y n http://ayapin.film.s.dendai.ac.jp/~matuda n /TeX/lecture.html PDF PS yx.................................... 3.3.................... 9.4................5..............
2 1 7 - TALK ABOUT 21 μ TALK ABOUT 21 Ag As Se 2. 2. 2. Ag As Se 1 2 3 4 5 6 7 8 9 1 1 2 3 4 5 6 7 8 9 1 1 2 3 4 5 6 7 8 9 1 Sb Ga Te 2. Sb 2. Ga 2. Te 1 2 3 4 5 6 7 8 9 1 1 2 3 4 5 6 7 8 9 1 1 2 3 4
untitled
PGF 17 6 1 11 1 12 1 2 21 2 22 2 23 3 1 3 1 3 2 3 3 3 4 3 5 4 6 4 2 4 1 4 2 4 3 4 4 4 5 5 3 5 1 5 2 5 5 5 5 4 5 1 5 2 5 3 6 5 6 1 6 2 6 6 6 24 7 1 7 1 7 2 7 3 7 4 8 2 8 1 8 2 8 3 9 4 9 5 9 6 9 3 9 1 9
untitled
1) American College of Surgeons:Advanced Trauma Life Support Course Manual. American College of Surgeons 1997;103-112 24 2) American Society of Anesthesiologists Task Force:Practice guideline for blood
総合_H1-H4_1810
4-6-1 SS30 24 4-261-1 7 1-2-2 8 1-1-10 20 17-1 5 3-17 5 4-9-24 980-6024 330-0843 141-0032 461-0005 564-0053 730-0036 812-0016 Tel 022-722-1710 Tel 048-600-3888 Tel 03-5434-8550 Tel 052-957-3821 Tel 06-6337-8300
dynamics-solution2.dvi
1 1. (1) a + b = i +3i + k () a b =5i 5j +3k (3) a b =1 (4) a b = 7i j +1k. a = 14 l =/ 14, m=1/ 14, n=3/ 14 3. 4. 5. df (t) d [a(t)e(t)] =ti +9t j +4k, = d a(t) d[a(t)e(t)] e(t)+ da(t) d f (t) =i +18tj
37, 9-14, 2017 : cefcapene piperacillin 3 CT Clostridium difficile CD vancomycin CD 7 Clostridium difficile CD CD associate
37, 9-14, 2017 : 36 2015 8 6 cefcapene piperacillin 3 CT Clostridium difficile CD vancomycin 20 1983 2016 3 CD 7 Clostridium difficile CD CD associated diarrhea : CDAD CD 1,2 PPI 3 1 36 33 2015 8 6 5 5
CRA3689A
AVIC-DRZ90 AVIC-DRZ80 2 3 4 5 66 7 88 9 10 10 10 11 12 13 14 15 1 1 0 OPEN ANGLE REMOTE WIDE SET UP AVIC-DRZ90 SOURCE OFF AV CONTROL MIC 2 16 17 1 2 0 0 1 AVIC-DRZ90 2 3 4 OPEN ANGLE REMOTE SOURCE OFF
V(x) m e V 0 cos x π x π V(x) = x < π, x > π V 0 (i) x = 0 (V(x) V 0 (1 x 2 /2)) n n d 2 f dξ 2ξ d f 2 dξ + 2n f = 0 H n (ξ) (ii) H
199 1 1 199 1 1. Vx) m e V cos x π x π Vx) = x < π, x > π V i) x = Vx) V 1 x /)) n n d f dξ ξ d f dξ + n f = H n ξ) ii) H n ξ) = 1) n expξ ) dn dξ n exp ξ )) H n ξ)h m ξ) exp ξ )dξ = π n n!δ n,m x = Vx)
まえがき
JAAS0012006 1 -------------------------------------------------------------------------------------------------------- 1 2 --------------------------------------------------------------------------------------------------------
P F ext 1: F ext P F ext (Count Rumford, ) H 2 O H 2 O 2 F ext F ext N 2 O 2 2
1 1 2 2 2 1 1 P F ext 1: F ext P F ext (Count Rumford, 1753 1814) 0 100 H 2 O H 2 O 2 F ext F ext N 2 O 2 2 P F S F = P S (1) ( 1 ) F ext x W ext W ext = F ext x (2) F ext P S W ext = P S x (3) S x V V
分子標的薬アプデート 2018
Primary imatinib, 2002-2008 (CML IV) 5-year survival 93% n = 2830 Survival probability IFN or SCT, 1997-2008 (CML IIIA) 5-year survival 71% IFN or SCT, 1995-2008 (CML III) 5-year survival 63% IFN, 1986-2003
橡DI月報200.PDF
2004.3.2 DI 22-2668 15 10 WHIWomen s Health Initiative 15 8 Million women study HRT :1.24 2 1 :1.45 14 :1.74 59 :2.17 10 :2.31 HRT 1 :1.81 HRT :1.31 HRT 65 :2.05 CKCPK http://www.pharmasys.gr.jp http://www.mhlw.go.jp
m dv = mg + kv2 dt m dv dt = mg k v v m dv dt = mg + kv2 α = mg k v = α 1 e rt 1 + e rt m dv dt = mg + kv2 dv mg + kv 2 = dt m dv α 2 + v 2 = k m dt d
m v = mg + kv m v = mg k v v m v = mg + kv α = mg k v = α e rt + e rt m v = mg + kv v mg + kv = m v α + v = k m v (v α (v + α = k m ˆ ( v α ˆ αk v = m v + α ln v α v + α = αk m t + C v α v + α = e αk m
18 5 10 1 1 1.1 1.1.1 P Q P Q, P, Q P Q P Q P Q, P, Q 2 1 1.1.2 P.Q T F Z R 0 1 x, y x + y x y x y = y x x (y z) = (x y) z x + y = y + x x + (y + z) = (x + y) + z P.Q V = {T, F } V P.Q P.Q T F T F 1.1.3
?
240-8501 79-2 Email: nakamoto@ynu.ac.jp 1 3 1.1...................................... 3 1.2?................................. 6 1.3..................................... 8 1.4.......................................
indd
Molecular Targeted Therapy for Lung Cancer from a Pharmaceutical Point of Viewe Naho SASAKI epidermal growth factor receptor tyrosine kinase inhibitor :EGFR-TKI vascular endothelial growth factor:vegf
1 I
1 I 3 1 1.1 R x, y R x + y R x y R x, y, z, a, b R (1.1) (x + y) + z = x + (y + z) (1.2) x + y = y + x (1.3) 0 R : 0 + x = x x R (1.4) x R, 1 ( x) R : x + ( x) = 0 (1.5) (x y) z = x (y z) (1.6) x y =
DE-resume
- 2011, http://c-faculty.chuo-u.ac.jp/ nishioka/ 2 11 21131 : 4 1 x y(x, y (x,y (x,,y (n, (1.1 F (x, y, y,y,,y (n =0. (1.1 n. (1.1 y(x. y(x (1.1. 1 1 1 1.1... 2 1.2... 9 1.3 1... 26 2 2 34 2.1,... 35 2.2
,, 2. Matlab Simulink 2018 PC Matlab Scilab 2
(2018 ) ( -1) TA Email : ohki@i.kyoto-u.ac.jp, ske.ta@bode.amp.i.kyoto-u.ac.jp : 411 : 10 308 1 1 2 2 2.1............................................ 2 2.2..................................................
untitled
1988 2000 2002 2004 2006 2008 IFN Lamivudine Adefovir Entecavir 1 Total number 560 Sex (male/female) 424/136 Age (years)* 38 (15-68) Duration of treatment (weeks)* 26 (1-592) Follow-up time (years) 75(05-21
untitled
CTCAE v3.0 JCOG/JSCO v1.0 Instructions and Guidelines for Japanese CTCAE v3.0 by JCOG and JSCO JCOG JCOG JCOG JCOG 2004 5 13 2004 7 1 2004 10 1 2004 10 27 JCOG http://www.jcog.jpjcog 0. 0.1. NCI Common
The Physics of Atmospheres CAPTER :
The Physics of Atmospheres CAPTER 4 1 4 2 41 : 2 42 14 43 17 44 25 45 27 46 3 47 31 48 32 49 34 41 35 411 36 maintex 23/11/28 The Physics of Atmospheres CAPTER 4 2 4 41 : 2 1 σ 2 (21) (22) k I = I exp(
卵巣癌の治療
K-net:2008.7.17 85 90 8 10 20 (FIGO) a (FIGO) b (FIGO) c (FIGO) a (FIGO) b (FIGO) c (FIGO) (FIGO) (FIGO) Risk factors Preventive factors Risk factors 35 PCO, Preventive factors? Relative risk
元素分析
: このマークが付してある著作物は 第三者が有する著作物ですので 同著作物の再使用 同著作物の二次的著作物の創作等については 著作権者より直接使用許諾を得る必要があります (PET) 1 18 1 18 H 2 13 14 15 16 17 He 1 2 Li Be B C N O F Ne 3 4 5 6 7 8 9 10 Na Mg 3 4 5 6 7 8 9 10 11 12 Al Si P
untitled
COLAK Mehmed 11000 305 305 180 10000 9000 8000 160 140 120 7000 100 6000 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 80 GH IGF-1 GH GH 5 4 3 2 1 0 2 3 4 5
II ( ) (7/31) II ( [ (3.4)] Navier Stokes [ (6/29)] Navier Stokes 3 [ (6/19)] Re
![II ( ) (7/31) II ( [ (3.4)] Navier Stokes [ (6/29)] Navier Stokes 3 [ (6/19)] Re](/thumbs/94/118770263.jpg "II ( ) (7/31) II ( [ (3.4)] Navier Stokes [ (6/29)] Navier Stokes 3 [ (6/19)] Re")
II 29 7 29-7-27 ( ) (7/31) II (http://www.damp.tottori-u.ac.jp/~ooshida/edu/fluid/) [ (3.4)] Navier Stokes [ (6/29)] Navier Stokes 3 [ (6/19)] Reynolds [ (4.6), (45.8)] [ p.186] Navier Stokes I Euler Navier
n 2 + π2 6 x [10 n x] x = lim n 10 n n 10 k x 1.1. a 1, a 2,, a n, (a n ) n=1 {a n } n=1 1.2 ( ). {a n } n=1 Q ε > 0 N N m, n N a m
![n 2 + π2 6 x [10 n x] x = lim n 10 n n 10 k x 1.1. a 1, a 2,, a n, (a n ) n=1 {a n } n=1 1.2 ( ). {a n } n=1 Q ε > 0 N N m, n N a m](/thumbs/94/118912662.jpg "n 2 + π2 6 x [10 n x] x = lim n 10 n n 10 k x 1.1. a 1, a 2,, a n, (a n ) n=1 {a n } n=1 1.2 ( ). {a n } n=1 Q ε > 0 N N m, n N a m")
1 1 1 + 1 4 + + 1 n 2 + π2 6 x [10 n x] x = lim n 10 n n 10 k x 1.1. a 1, a 2,, a n, (a n ) n=1 {a n } n=1 1.2 ( ). {a n } n=1 Q ε > 0 N N m, n N a m a n < ε 1 1. ε = 10 1 N m, n N a m a n < ε = 10 1 N