1. 1) (1) in vitro i ii in vitro ex vivo (2) (3) ET i BALF ii CVF i ii BALF i ii iii BALF i ii ET 2) (1) in vitro (2) in vitro (3) in vitro (4)
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- ふじよし なぐも
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1 1. 1) (1) in vitro i ii in vitro ex vivo (2) (3) ET ibalf ii CVF i iibalf i ii iiibalf i ii ET 2) (1) in vitro (2) in vitro (3) in vitro (4)
2 ET CVF (5) (6) 3) (1)in vitro 2. 1)ONO-5046Na (1) (2) (3) (4) (5) (6) 2)ONO-5046Na ) 2) 3)
3 ONO-5046Na M-1 sodiumn-[2-[4-(2,2- dimethylpropionyloxy) phenylsulfonylamino] benzoyl]aminoacetate tetrahydrate N-[2-(4-hydroxyphenyl- I-1 sulfonylamino)benzoyl] aminoaceticacid I-2 I-3 I-4
4 Ki IC 50 50% SIRS OZ opsonized zymosan ET endotoxin CVF BALF α 1 -PI α 1 -protease inhibitor PaO 2 PaO 2 /F I O 2 pna p-nitroaniline fmlp N-formyl-methionyl-leucyl-phenylalanine PMA phorbol myristate acetate MPO myeloperoxidase AMC 7-amino-4-methylcoumarin
5 1 α α µ α µ µ µ µ α µ
6 µ µ µ
7
8
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10 2 µ µ α α α µ µ
11 µ µ µ µ µ
12
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14 SIRS SIRS IV SIRS ONO-5046Na 1in vitro Ki nM IC µM 2 IC 50 23µM 10µg/mL 39µM 17µg/mL 15µM 7µg/mL 3ex vivo 0.1mg/kg/hr 4in vivo 10mg/kg/hr ONO-5046Na in vitroex vivo in vivo ONO-5046Na ONO-5046Na 10.3mg/kg/hr ET BALF 3mg/kg/hr / 20.3mg/kg/hr CVF 30.1mg/kg/hr 1mg/kg/hr PaO 2 410mg/kg/hr - PaO 2 /F I O 2 ONO-5046Na BALF - PaO 2
15 ONO-5046Na M-1I-1 100µM I-2I-3 I-4 IC 50 ONO-5046Na 1/11/1 2/1 ONO-5046Na PhaseI M-1I-1 1/40 % ONO-5046Na 1) ONO-5046Na B 500µM ONO-5046Na 2 α 1 -protease inhibitorα 1 -PI HOCl ONO-5046Na HOCl 3 ONO-5046Na 4in vivo ONO-5046Na 5 ONO-5046Na BALF ONO-5046Na BALF ONO-5046Na α 1 -PI ONO-5046Na 1 ONO-5046Na 2 ONO-5046Na ET ONO-5046Na
16 ONO-5046Na in vitro ONO-5046Na in vitro ex vivo OZ in vitro i Meo-Suc-Ala-Ala-Pro-Val-pNA 0.5 M 0.1% M HEPES (ph 8.0) 37 p-nitroanilinepna 405nm Dixon Ki ONO-5046Na Ki 462nM ONO-5046Na α 1 -PI 1,000U/mL
17 ONO-5046Na 10 nm 30 nm 100 nm 300 nm Lineweaver-Burk α µ 2 3 NI1,000U/mL ii 0.5M 0.1% M HEPES ph 8.0 1mg/mL µM 37 60
18 490nm ONO-5046Na IC µm in vitro i OZ Meo-Suc-Ala-Ala-Pro-Val-pNA Tris Pro-Val-AMC AMC 1mL pna AMC ELISA α 1 -PI ii OZ ONO-5046Na 30M - α 1 -PI IC µM 10µg/mL pna 405 nm Meo-Suc-Ala-Ala- 2,500U/mL ONO- 5046Na IC µM 7µg/mL 398µM 17µg/mL
19 4 p < 0.01OZ Dunnett ### p < Student t
20 ex vivo i ONO-5046Na 2 P.187 -i OZ ONO-5046Na ONO-5046Na 2 10 nmole pna/ml ii OZ ONO-5046Na mg/kg/hr OZ 7-8 p < 0.05 p < 0.01OZ Dunnett p < Student t
21 ONO-5046Na in vitro ONO- 5046Na in vitro ex vivo OZ ONO-5046 Na α 1 -PI
22 in vitro ONO-5046Na 5x10 5 4x10 6 fmlp1µm PMA10ng/mL LDH fmlp PMA ONO-5046Na 0.5µM O - 2 SOD10µg/mL ONO-5046Na LDH LDH p < 0.05 Student t ONO-5046Na in vitro
23 BALF - PaO 2 ONO-5046Na ONO-5046 ET ibalf ET 300µg/mL ET % BALF BALF BALF BALF Lowry BALF ONO-5046 Na ET 2 24 ET 3 ET 2 ET 8 ET ONO-5046Na 0.3mg/kg/hr ET BALF 3mg/kg/hr BALF ET 2 3mg/kg ivet 3 ET 24 BALF ET 2 10mg/kg iv ET 8
24 11-12 p < Student t p < 0.05 p < 0.01ET 24hr Dunnett
25 12 ONO-5046Na(3mg/kg/hr) p < Student t p < 0.01 p < 0.001ET24hr Student t
26 ii P.192 -i)- ET 30 ET 24 10% - ONO-5046 Na ET 2 24 ET ET 2 / ET 24 ONO-5046 Na 3mg/kg/hr
27 A ET 2hr B ET 24hr C ONO-5046 Na 24hr D 5-6
28 CVF i CVF(10 U/kg) I-BSA 30 1mL 1mL ONO-5046 Na CVF 90 CVF 3 CVF CVF 4.9 ONO-5046 Na mg/kg/hr CVF 0.3mg/kg/hr 3mg/kg 2,500 U/kg/hr
29 5-9 p < ( Student t p < 0.05 p < 0.01CVF Dunnett 7-8 ONO-5046Na1mg/kg/hr p < Student t p < 0.05 p < 0.001CVF Student t
30 iibalf P.197 -i)- ONO-5046 Na CVF CVF % BALF BALF MPO H 2 O 2 450nm 60 MPO CVF BALF ONO-5046 Na 1mg/kg/hr CVF BALF p < 0.01 p < ( Student t p < 0.05CVF Student t
31 i ONO-5046 Na (0.2N200µL) ONO-5046 Na ONO-5046Na mg/kg/hr mg/kg/hr 12 p < 0.05 p < 0.01 logrank
32 ii P.200 -i)- 8 PaO 2 PaO 2 PBS(-) 9 5 ONO-5046Na PaO 2 64 ONO-5046Na 1mg/kg/hr PaO p < PBS(-) Student t p < 0.05 p < 0.01 Student t NSNot Significant
33 iiibalf P.201ii)- PaO 2 BALF BALF P.173 -i)- PBS(-) BALF ONO-5046Na 1mg/kg/hr BALF ONO-5046Na BALF 4-9 p < 0.05 p < PBS(-) Student t p < 0.05 p < 0.01 p < Student t
34 i 12mL/kg/ 16 / Swan-Ganz mg/kg 10mg/kg/hr ONO-5046Na 10mg/kg/hr 3
35 ONO-5046Na 7 p < 0.05 Student t
36 ii P.203 -i)- / PaO 2 / F I O 2 PaO 2 / F I O 2 ONO-5046Na 10mg/kg/hr PaO 2 / F I O PaO 2 / F I O 2 ONO-5046Na 7 p < 0.05 Student t ONO-5046Na BALF - PaO 2
37 ET i ET2mg/kg 4 ONO-5046 ET 10 4 ET ii ET ET 4 ONO mg/kg/hr ET 6-13 # p < 0.05 Student t p < 0.05ET Dunnett
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