ESL ()-methyl 3-{4-[2-hydroxy-3-(isopropylamino)pro poxy]phenyl} propanoate monohydrochloride H 3 C O O JAN( ) JAN( )esmolol hydrochloride r-inn( )esm
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1 (1) (2) (ISAintrinsic sympathomimetic activity) 199 (3) ( MSAmembrane stabilizing activity) 2 (4) 21 (5) 212 (6) 216 (7) 219 (8) 224 (9) (ASL-8123) (1) d-esl l-esl (1) ESL 237 (2) (ASL-8123) 24 (3) d-esl l-esl 243
2 ESL ()-methyl 3-{4-[2-hydroxy-3-(isopropylamino)pro poxy]phenyl} propanoate monohydrochloride H 3 C O O JAN( ) JAN( )esmolol hydrochloride r-inn( )esmolol O H OH H N CH 3 CH 3 HCl d-esl ()-methyl 3-{4-[2-hydroxy-3-(isopropylamino)pro poxy]phenyl} propanoate monohydrochloride H 3 C O O O OH H N CH 3 CH 3 HCl ESL d l-esl ()-methyl 3-{4-[2-hydroxy-3-(isopropylamino)pro poxy]phenyl} propanoate monohydrochloride H 3 C O O O OH H N CH 3 CH 3 HCl ESL l ASL {4-[2-hydroxy-3-(isopropylamino) propoxy]phenyl}propanoic acid monohydrochloride HO O O OH H N CH 3 CH 3 HCl
3 ( ) APA AP5 AP1 EC5 EC8 EC95 HPLC i.v. IC5 ISA Kd Ki LD5 LOQ LV dp/dt MAC MSA NE NLA Post EC5 Pre EC5 QTc RMP RPP SNP TOF TTC Vmax WB % 8% 95% 5 (intrinsic sympathomimetic activity) 5 (minimal alveolar concentration) (membrane stabilized action) (Neurolept analgesia) 5% 5% QT (QT / ) (Rate Pressure Product) 2-([2,6- ]-1,4-
4 31-7 M pa2 ( 1)6.82 (in vitro- ) 31-5 M( ) 11-5 M ( 2)5.18 ( 2) M( 1/ 2 / ) / (in vitro- ) M 11-2 M 313 (in vivo) g/kg/ (i.v. ) 131 g/kg/ (i.v. ) 11-8 M 11-3 M 11-6 M 11-8 M 11-3 M 31-9 M (ISA) 11-3 M Ki (nm) / pa (5 ).19 g/ml 1) 5 1 g/kg/ g/kg/ g/kg/ M 11-4 M 11-7 M 31-8 M1 1-5 M(31-6 M 12.4) 5 ( 11 ( )5 6 MSA) 5 L( ).313 mg/kg 7 (i.v. ) PR 3mg/kg.3 3mg/kg ESL ( 1 ) g/ml(.3mg/kg) g/ml(1mg/kg) g/ml(3 mg/kg) 15 ISA (intrinsic sympathomimetic activity) MSA (membrane stabilizing activity) 1) 186
5 mg/kg (i.v. ) 1 mg/kg (i.v. ) NLA 1 mg/kg (i.v. ) g/kg/ (i.v. ) 31 g/kg (i.v. ) 11 g/kg (i.v. ).111 g/kg/ (i.v. ).313 mg/kg (i.v. 18 ) 8.3mg/kg 1mg/kg PR QTc 3mg/kg ( 1 ) g/ml(.3mg/kg) g/ml (1mg/kg) g/ml(3mg/kg) 3 PR ( 1 ) g/ml PR QT ( 1 ) g/ml 15 (5)35.6 g/kg/ (5)249 g/kg g/kg 1 1 g/kg/ 1 mg/kg mg/kg12.4 ( 42.1) mg/kg (i.v. ) 187
6 18 d 31-6 M 31-6 M 31-6 M 31-5 M 31-6 M 254 g/kg/ (i.v. ) ESL MAC ESL EC EC95 1 d EC d ESL SNP (ASL 8123) l ESL 31 - M (in vitro) 11-2 M (in vivo) mg/kg/ (i.v. ) pa (5 )293 g/ml 31-7 M (in vitro) 31-5 M ( ) (in vitro- ) 11-5 M 11-4 M ( ) M 11-2 M pa2 ( )desl6.7lesl 7.36ESL7.12 pa2 ( )lesl5.53esl5.41 desl Ki (nm) lesl Ki (nm) / 2 desl=1.74lesl=
7 ESL in vitro in vivo 2 ESL 3 ESL ESL ESL ESL ASL8123 ESL desllesl pa2 1/ 2 ESL 1 1 (ESL )ESL Ki ESL Ki 2/Ki 1 1 (ESL )ESL 1 In vivo ESL pa ESL ESL 6 ESL 11-6 M 11-7 M ESL 11-4 M ESL (11-7 M11-6 M) 189
8 ESL ISA M ESL MSA 5.2 MSA ESL.31 3mg/kg.3mg/kg 3mg/kg PR ESL.3mg/kg 1mg/kg 3mg/kg PR QTc ESL 1mg/kg PR NLA ESL 1mg/kg PR QT ESL 3mg/kg 1 3mg/kg 3 NLA 1mg/kg 1 3 ESL ESL g/kg/ 249 g/kg 1 1 g/kg 1 1 g/kg/ ESL 1 3mg/kg ( ) ( ) ESL rate pressure product ESL 19
9 ESL ESL.5 1 MAC ESL (4) ( NLA) ESL EC95 1 d EC95 3 ESL ESL ESL ESL SNP ASL8123 pa (ESL 6.82) ASL g/ml(esl.19.4 g/ml) ASL8123 ESL In vitro desl lesl pa desl lesl 1 (Ki ) nm desl lesl in vivo 1mg/kg desl 72 / lesl 87 / 191
10 ESL ( ) ( 1 WB411( 1 ) ( 2 ) in vitro in vivo (Hartley 1 6 ) ESL M M M M M M M M M ( 1) ( 2) pa2 ( EC5 ) 1 ( 1/ 2) ESL - pa2 ( 1) ( 2) ( 2) ( 1/ 2) / / ESL ESL pa2 ESL 1-1 ( 1) ( 2) ( 2) 1 ( 1/ 2) pa2 pa2 pa2 / / slope slope slope (95 ) (95 ) (95 ) ESL (.7.95) ( ) (.3.84) (.61.86) (.681.8) (.27.88) (.61.15) ( ) ( ) antilog( pa2 pa2 )
11 (Wistar ) ( 1- )( 2- ) ( 1-2- ) 23 ( ) ESL 11-2 M M 11-2 M( 1-2- ) M( 1-2- ) M M 11-3 M( 1-2- ) 11-6 M( 1-2- ) M M - WB M M (Ki ) Ki 1/Ki 2 ESL Ki (nm) 1-2- Ki 1- (Ki 1/ Ki 2) ESL ESL ESL 1- ( 3) - Ki ESL Ki 2/Ki ESL Ki (nm) Ki 2/ Ki ESL 45 (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) WB Ki 2/ Ki 1 Ki IC5/(1+[L]/Kd)[L] (M)Kd IC5 5 (M) WB4112-([2,6-Dimethoxyphenoxyethyl]-1,4-benzodioxane Hydrochloride
12 (1 5 ) ESL 31 3 g/kg/ g/kg 2 pa2 ( ED5 ) ESL ESL ( 1) pa ESL 4 µ 2 µ µ pa ( 4) ESL ESL in vivo µ µ 2 µ µ µ ESL µ µ µ µ µ µ µ µ
13 pa2( ) Slope( ) 95% ESL (1 56 ).5 g/kg ESL 13 1 g/kg/ 2.4 g/kg/ 18 1 () 1 5 ESL 13 1 g/kg/ g/kg/ ( 2) ESL µ µ µ µ
14 ESL ( ) ESL M 345 ESL (NE.2.4g/mL.1.2g/mL) ESL M 615% 11-3 M g/ml NE ESL 11-7 M 11-6 M 78%.4g/mL NE ESL 11-7 M ( 3) ESL M ( 5).1.2 g/ml NE 658 ESL 11-7 M 325 NE 11-6 M ESL ( 4) ESL 11-3 M M 615% ESL ISA ESL 11-4 M NE 3 25 ESL ISA ESL 11-4 M M 1 ESL ( ) - 196
15 NE NE ESL () ESL () NE NE 197
16 ( ) 3M 1 ESL M 153 (RMP) (APA) (Vmax) 5 1 (AP5 AP1) ESL.2.5g/mL ESL M 153 ESL M (RMP) 11-3 M RMP ESL 11-4 M (APA) (Vmax) 5 1 (AP5AP1) ( 6 5).2.5 g/ml ESL 11-7 M 13 - ESL.2.5 g/ml 11-7 M 1-4 M ESL 1mg/kg 1. g/ml ( ) M 1/3 ESL M ESL RMP ESL ISA ESL (M) RMP APA Vmax AP1 AP p <.5 p <.5 RPM APA Vmax AP11% AP55% 198
17 (Hartley 1 47 ) ESL M ISA - ISA M M M M 1 ESL M (11-6 M 12.4) 11-5 M 31-5 M ( 7) ESL ISA ISA - ISA 199
18 p.5 p.1(unpaired t ) (Hartley 1 56 ) (5 L) (5 L) ESL ( ) ESL 5 MSA.2 1. MSA ( 6) ESL MSA ESL (1mg/kg 1. g/ml )5, ESL 2
19 () () ESL /5 /5 /5 1 /5 /5 /5 /6 /6 /6 2.5 /6 /6 /6 /6 /6 /6 /5 5 6/6 5/6 /6 /5 /6 /6 /6 /6 1 6/6 6/6 3/6 /6 /6 /6 /6.1 3/6 /6 /6 /6 /6 /6 /6.2 6/6 6/6 5/6 /6 /6 /6 /6 1 4/6 /6 /6 /6 /6 /6 /6 2 6/6 6/6 3/6 /6 / p.5(fisher ) (1 4 ) ESL.31 3mg/kg (PR QRS QT QTc) ( ) ESL HPLC ESL ESL ( 8 9) ESL 3mg/kg PR ( 1)ESL.33mg/kg ESL 1.3mg/kg g/ml 1mg/kg g/ml3mg/kg g/ml 15 (.11 g/ml 11) ESL 3mg/kg 3mg/kg PR.33mg/kg 21
20 (n=4) (n=4) ESL 3 22
21 (n=4) ESL 3 p.5 p.1(dunnett ) ESL.3mg/kg ESL 1mg/kg ESL 3mg/kg LOQ(.11µg/mL) ESL LOQ 23
22 1 4 (1.52.5) ( 73) 6mg/kg 24mg/kg/ ( 73) NLA (.75mg/mL) (.15mg/mL) (1mL/kg).5 1.5mg/kg/.1.3mg/kg/ ( 73) ESL (.31 3mg/kg NLA 1mg/kg) ( ) (PR QRS QT QTc) ESL 21 ESL 12 ESL ( ) 15 ( 14) (931) (1537) (252) ( 13)ESL 1 3mg/kg (3 23) (37 38) 5 ( 14)3mg/kg 1 PR (12) 5 QTc ( 1) ( 15) ESL 1.3mg/kg g/ml1mg/kg g/ml3mg/kg g/ml 3 ( 24) 16 ESL 1mg/kg 15 ( 16) 15 ( 4)( 17) 3 ( 18) 3 ( 24)( 18) PR 1 ( 13) ( 19) ESL g/ml 15 ( 24) NLA 2 NLA NLA ESL 1mg/kg 15 ( 17) ( 17) ( 21) ( 26)( 22) PR ( 16) QT ( 16) ( 23) ESL
23 g/ml 15 ( 24) NLA ESL.3 3mg/kg1mg/kg1mg/kg ESL - ) ESL 31 g/kg/ PR QRS 3 HV AH SH class 1 HV ESL ESL mg/kg 1.mg/kg ) (21 ) 3mg/kg ) ESL 31 g/kg/ LV dp/dtmaxrate pressure products ESL ESL - 25
24 (n=4) (n=4) ESL 3 p.5 p.1(dunnett )
25 (n=4) ESL 3 p.5 p.1(dunnett ) (n=4) ESL 3 p.5 p.1(dunnett ) 27
26 (n=4) (n=4) ESL 3 p.5(student t )
27 (n=4) ESL 3 p.5 p.1 (Student t ) (n=4) ESL 3 p.5(student t ) 29
28 (n=4) (n=4) ESL 3 p.5 p.1 (Student t ) 21
29 (n=4) ESL 3 p.5 p.1 (Student t ) (n=4) ESL 3 p.5 p.1 (Student t ) 211
30 1 1 ESL.3mg/kg ESL 1mg/kg ESL 3mg/kg 1 1 ESL 1mg/kg 1 1 ESL 1mg/kg.1 LOQ(.11µg/mL).1 LOQ(.11µg/mL).1 LOQ(.11µg/mL) ESL LOQ: ESL (1 35 ).5 g/kg ESL g/kg/ g/kg/ 6 () 1 5 ESL ( 25)ESL g/kg/ g/kg/ ESL 1/13 212
31 (1 6 ) 5 ESL g/kg g/kg( g/kg) ESL 1 5 () 1 () 5 ESL (19 )5 ESL ESL ESL 3 g/kg g/kg g/kg g/kg ( ) 1 g/kg g/kg g/kg g/kg ( 26)ESL g/kg 5 48 g/kg ESL 1/5 213
32 µ (1) 5 ) (1.55.5g/kg/) 3 ESL 1 1 g/kg 3 3 g/kg 3 3 g/kg ESL.1 1 g/kg/ 2 (2 ) ESL 1 g/kg 1 g/kg/ ( 27) 3 g/kg ( 28) ESL 214
33 µ µ µ µ µ (n=5) p.5 p.1(dunnett ) µ µ µ µ (n=5) p.5 p.1(dunnett ) 215
34 ESL (1 6 ) 2 cm 3 3 ESL.33mg/kg 2 3mg/kg ,3,5 (TTC) 1cm ( ) ( TTC ) ABC 3 D ESL 6 rate pressure product(rpp) ( 29) ( 7)ESL 1mg/kg 3mg/kg 3mg/kg ( ) ( ) ( 3) ESL 1 3 mg/kg ESL RPP ) (1 5 ) ESL.5mg/kg/ 2 4 () ESL
35 (A) (B) (C) RPP(rate pressure product) (n6) p.5 p.1(dunnett ) 217
36 (mg/kg) (ml//g) ESL (5) 6 6(5) (5) ESL.3 3.mg/kg 1 1cm 3 ABC D (ABC)/3 ()( / )1 (n6) p.5 p.1(dunnett ) 218
37 (1 45 ) ESL.3 1mg/kg ( ) g/kg/ 1 ESL.1.3 1mg/kg 1 (ESL )ESL mg/kg 3 / /3 ESL.3mg/kg 12 1 ESL1mg/kg mg/kg 33 ( 31) ESL.3 1mg/kg 15.3 mg/kg 11 3 ( 31) ( 32A) ( 32C) / ( 32D) ( 32E).1 g/kg/ ( 31) ( 32A) ( 32B) ( 32C) / ( 32D) ( 32E) ESL.11mg/kg / ESL.1 1mg/kg.3 mg/kg / 219
38 ESL ESL1mg/kg 2 / ESL ESL ESL ESL.11mg/kg 22
39 (A) (B) (C) µ µ (A)n=4(BC)n=5 p.5 p.1(dunnett test) 221
40 (A) (B) ().1 g/kg/ p.5(dunnett test) 222
41 (C) (D) (E) ().1 g/kg/ p.5 p.1(dunnett test) 223
42 (Hartley ) 5 (Pre EC5) ESL 31-6 M ( ).5 1. MAC ESL 31-6 M 1 5 (Post EC5) ESL ESL Post/Pre Post/Pre ESL Post/Pre MAC Post/Pre ( 8) ESL 1 MAC Pre EC5 (M) Post EC5 (M) Post/Pre ( ) Pre EC5(M)ESL 5 Post EC5(M)ESL 5 (Hartley 1 8 ) 5 (Pre EC5) ESL 31-6 M ESL M ( d )EC (Post EC5) ESL ESL Post/Pre Post/Pre
43 ESL Post/Pre EC d Post/Pre ( 9) d EC95 1 Post/Pre Post/Pre ( 1) EC95 1 ( 11) ESL EC95 1 d EC95 1 ESL (M) Pre EC5 (M) Post EC5 (M) Post/Pre ( ) d Pre EC5(M)ESL 5 Post EC5(M)ESL 5 (M) Pre EC5 (M) Post EC5 (M) Post/Pre ( ) d p.5(dunnett ) Pre EC5(M)ESL 5 Post EC5(M)ESL 5 (M) Pre EC5 (M) Post EC5 (M) Post/Pre ( ) Pre EC5(M)ESL 5 Post EC5(M)ESL 5 225
44 (Hartley 1 3 ) 2.2 2Hz 4 (TOF ) EC8 ( M) d ( M) ESL 31-6 M 31-5 M ESL TOF 1 (T1) 1 T1 d ( EC8 ) ESL 31-6 M 31-5 M ( 12) ESL ESL 1) 2) ESL (M) ESL 31-6 M ESL 31-5 M d p.1(dunnett ) T1 1 T1 1) Murthy V.S., et. al. : Effects of esmolol on circulatory response to intubation and succinylcholine-induced neuromuscular blockade in man. Anesthesiology, 63, 3A, ) Szmuk P., et. al. : The onset time of rocuronium is slowed by esmolol and accelerated by ephedrine. Anesth. Analg., 9, , 2 226
45 (Hartley 1 8 ) 5 (Pre EC5) ESL 31-6 M ( ) ESL 31-6 M 1 5 (Post EC5) ESL ESL Post/Pre Post/Pre M ESL 31-6 M Post/Pre M ESL 31-6 M Post/Pre ESL ( 13) ESL Ca 1) (M) Pre EC5 (M) Post EC5 (M) Post/Pre ( ) p.5(dunnett ) Pre EC5(M)ESL 5 Post EC5(M)ESL 5 1) 2.4 (199) 227
46 (1 1 ).3 (SNP) 6mmHg ESL 6mmHg 254 g/kg/ 6 6mmHg SNP SNP ESL 6mmHg SNP SNP g/kg/ ESL251 4 g/kg/ SNP g g/kg/( ) ESL SNP SNP 3 ( 33)ESL SNP ESL ESL SNP µ µ µ µ ESL ( g/kg/) SNP 9.6 ( g/kg/) (n1) ( ) p.5 p.1(dunnett ) 228
47 ESL ASL8123 in vitro in vivo ESL (148) ASL M 1 ( 1) ( 1) pa2( EC5 ) ASL M 11-2 M 257 / ASL8123 ( 34) pa ASL M ASL8123 ( 1) pa ESL pa (192 )ASL8123 ESL 1/1 (Shaffer J.E. et al.: -adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol. J. Cardiovasc. Pharm. 11, , 1988) 229
48 (1 6 ).5 g/kg 1 ASL mg/kg/ 2 ( mg/kg) ASL ASL8123 ASL mg/kg / ASL mg/kg ASL mg/kg ASL mg/kg 5 ASL g/ml( 35)(ESL.19.4 g/ml )) ASL8123 ESL 1/1 5 ASL8123 (Shaffer J.E. et al.: -adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol. J. Cardiovasc. Pharm. 11, , 1988) 23
49 ESL desllesl d lesl (Hartley 1 56 ) desl lesl ESL M 1 ( 1) 3 desllesl ESL M 1 ( 2) ( 1) ( 2) pa2 ( EC5 ) desllesl ESL ( 36) pa ( 14)lESL ESL ( 37) pa ( 14) desl 11-4 M pa2 desl lesl ESL 1 desl 2 lesl ESL 2 desl lesl in vivo 1mg/kg desl 72 / lesl 87 / (243 ) ESL d-esl l-esl pa2( ) Slope( ) 95% ) 1) 1) ) 1-4 M 231
50 M 1-9 M 1-1 M 1-9 M M 1-7 M 1-6 M 1-5 M M 1-7 M 1-6 M 1-5 M M 1-9 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-8 M 1-7 M 1-6 M 1-5 M M 1-9 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-8 M 1-7 M 1-6 M 1-5 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 232
51 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M M 1-9 M 1-8 M 1-7 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-6 M 1-5 M 1-4 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 233
52 (Wistar ) ( 1 ) ( 2 ) ( 1 2 ) ESLdESL lesl 23 ( ) ESLdESL lesl 11-2 M M WB M M (Ki ) Ki desl lesl (nm) desl lesl Ki 1 2 Ki desl lesl 1/ Ki desl lesl (nm) ( 15) 1 2 leslesldesl 1/ 2 ESLlESLdESL 1 2 ESL desl lesl Ki(nM) Ki 2/ Ki (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) (1 3 ) WB Ki 2/ Ki 1 Ki IC5/(1+[L]/Kd)[L] (M)Kd IC5 5 (M) WB4112-([2,6-Dimethoxyphenoxyethyl]-1,4-benzodioxane Hydrochloride
53 ESL ASL8123 desllesl ESL 1mg/kg ESL 11-5 g/ml(31-5 M) 11-4 g/ml(31-4 M) 11-3 g/ml(31-3 M) 11-4 g/ml(31-4 M) 11-4 g/ml(31-4 M) ESL 11mg/kg 3mg/kg 3mg/kg 1 mg/kg 11-4 g/ml ESL 1mg/mL ASL8123 1mg/kg 6 ASL8123 1mg/kg ASL ASL g/ml 11-4 g/ml 11-5 g/ml ASL8123 1mg/kg ASL8123 3mg/mL ASL g/ml ESL desllesl 2.52mg/kg 6 desl lesl 11-4 g/ml 11-4 g/ml desl 52mg/kg lesl 2.51mg/kg desl 1mg/kg 15 2mg/kg 1 desl lesl desl lesl 11-4 g/ml 235
54 ESL desl lesl ASL g/ml ESL M31-6 M( g/ml192 ) ESL 11 ESLdESL lesl (192 ) leslesld-esl ( 22) l d-esl ESL ASL8123 1mg/kg 11-3 g/ml ASL8123 ESL ESL ESLASL8123dESL lesl 236
55 16 ESL 11-4 g/ml(31-4 M) 11-3 g/ml(31-3 M) 11-5 g/ml(31-5 M) g/ml(31-4 M) 11-3 g/ml(3 1-3 M) 11-4 g/ml(3 1-4 M) 11-4 g/ml(31-4 M) 11-4 g/ml(31-4 M) ESL 13 1mg/kg 3mg/kg PR 3 mg/kg QT QRS QTc mg/kg 45 3 mg/kg 1 mg/kg ) ESL 1.258mg/kg mg/kg ESL 1mg/mL 237
56 (1 ) (Irwin (6) ) (15) ( (6) ) ( ) (6) ( Writhing ) (6) mg/kg 131 mg/kg 131 mg/kg 131 mg/kg 131 mg/kg 131 (6) mg/kg ( ) 131 (1) mg/kg in vitro 11-6 (4) 11-4 g/ml ( M) in vitro 11-5 (6) 11-3 g/ml ( M) in vitro 11-6 (4) 11-4 g/ml ( M) in vitro 11-6 (4) 11-4 g/ml ( M) in vitro 11-6 (6) 11-3 g/ml ( M) 11-5 g/ml(31-5 M) g/ml(3 1-4 M) 11-3 g/ml(31-3 M) 11-4 g/ml(31-4 M) 11-4 g/ml(31-4 M) 11-4 g/ml(31-4 M)
57 239 (1 ) ( ) (3) 131 mg/kg (3) 131 mg/kg 3mg/kg ( ) (3) 131 mg/kg 3mg/kg PR QT QRS QTc (3) 131 mg/kg 11mg/kg 45 (3) 131 mg/kg 3mg/kg (3) 131 mg/kg 1mg/kg (6) 131 mg/kg (67) 131 mg/kg (56) 131 mg/kg (6) 131 mg/kg (46) 131 mg/kg (56) 131 mg/kg (67) 131 mg/kg (6) in vitro 131 mg/ml 1mg/mL
58 ASL8123 1mg/kg ASL8123 1mg/kg ASL g/ml 11-3 g/ml 11-3 g/ml 11-4 g/ml 11-3 g/ml g/ml 11-5 g/ml 11-3 g/ml ASL8123 1mg/kg g/ml 11-3 g/ml 3mg/mL 24
59 (1 ) 131 (Irwin (6) ) 13 1mg/kg 1 3mg/kg 1 mg/kg mg/kg (6) 31 mg/kg ( (6) ) ( ) (6) ( Writhing ) (6) (6) (6) ( ) 13 1mg/kg 13 1mg/kg 13 1mg/kg 13 1mg/kg in vitro 11-5 (6) 11-3 g/ml in vitro 11-5 (6) 11-3 g/ml in vitro 11-5 (6) 11-3 g/ml in vitro 11-6 (6) 11-3 g/ml in vitro 11-5 (6) 11-3 g/ml ( ) 11-3 g/ml 11-3 g/ml 11-3 g/ml g/ml 11-3 g/ml g/ml g/ml g/ml 241
60 (1 ) (6) mg/kg (6) mg/kg (6) mg/kg (6) mg/kg in vitro 11-5 (6) 11-3 g/ml (6) mg/kg (6) mg/kg in vitro (6) 131 mg/ml 1 mg/kg 1 mg/kg g/ml 11-3 g/ml 3 mg/ml 242
61 18 desl 52mg/kg 12mg/kg 5 2mg/kg 2mg/kg lesl 2.51mg/kg 2.5 1mg/kg 1mg/kg desl lesl 5 1 desl lesl 1 desl lesl g/ml g/ml g/ml g/ml desl lesl g/ml 11-3 g/ml desl 1mg/kg 15 2mg/kg 1 desl lesl desl 52mg/kg (1mg/kg 1 72 / ) lesl 2.51mg/kg (1mg/kg 1 87 / ) lesl desl desl lesl 1mg/mL 243
62 (1 ) (4) (Irwin ) g/ml lesl (desl) 512 (lesl) mg/kg (6) in vitro 11-6 (4) 11-4 g/ml ( 1) in vitro 11-6 (4) 11-4 g/ml in vitro 11-6 (4) 11-4 g/ml ( 1) in vitro 11-6 (6) 11-3 g/ml ( 3) (desl) (6) 512 (lesl) mg/kg in vitro (6) desl 52mg/kg 12mg/kg 5 2mg/kg 2mg/kg lesl 2.51mg/kg 2.5 1mg/kg 1mg/kg desl lesl mg/ml desl lesl 11-4 g/ml desl lesl g/ml g/ml desl lesl desl lesl 11-4 g/ml g/ml desl 1mg/kg 15 2mg/kg 1 desl desl 1mg/kg 72 /( 1 ) lesl 1mg/kg 87 /( 1 ) 1mg/mL 244
1 1)
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(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
1999年3月作成(新様式第１版)
200622 19989 871313 1mL4mg JAN oxybuprocaine hydrochloridejan 2002621 20037 4 19667 1 FAX 2005 10 29607 05 1 63 () 103 2 3 49 111 4 Drug Safety Update 1. -------------------------------------1 2. -----------------------1
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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
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Kw 1-12 1-13 Kw van t Hoff 0 0 0 H S d ln K H ln K = + = RT R d(1/ T ) R ln KW 1/T H 0 /R H 0 = 51.0 kj mol -1 HCl H + + Cl - H2O H + + OH - [] [H + ] [OH - ]=10-14 M 2 25 OH - x OH - [OH - ]=x [H + ]
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1 9924 2260 CAS 107186 H 2 C CH CH 2 OH 2- -1- C 3 H 6 O 58.08 1 99 1. 2, 3 3, 4, 5-129 96-97 2 21c.c. 24o.c. 2 6, 7 378 6, 7 2.5-18 d 20 4 0.8540 2, 5 2.00 = 1 2.7 kpa 20 mmhg204.3 kpa 32 mmhg30 4 log
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er. 3.0SJ ver.3.0 SJ 3 2 1 ver.3.0 SJ 900 1200 () 400 2 ver.3.0 SJ OH OMe OMe O O O MeO O MeO OMe O O OMe O OMe OMe O O MeO O O H O O MeO OMe O H O OH OMe O CH 2 HO O O O O CH 3 OH HO OH OH HO OH O 1 3
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2007 12 1 871146 IF 1998 9 350mg 250mg 100mg 10mg 10mg Sodium Salicylate Sulpyrine Hydrate Caffeine Hydrate Allobarbital Procaine Hydrochloride 2007 8 31 2007 12 21 1955 2 FAX TEL FAX IF 2007 12 6 IF 1
取扱説明書
ED-601 ED-501 ED-401 2 3 4 23 14 5 6 18 10 7 1 2 6 3 4 8 9 16 16 16 12 1 2 18 10 2 1 5 12 11 1 2 1 2 12 1 2 13 16 14 3 2 4 1 1 2 16 3 4 18 15 1 2 16 2 3 1 1 2 3 18 17 18 22 19 D A C 20 A B 22 B C D 22
JA2008
A1 1 10 vs 3 2 1 3 2 0 3 2 10 2 0 0 2 1 0 3 A2 3 11 vs 0 4 4 0 0 0 0 0 3 6 0 1 4 x 11 A3 5 4 vs 5 6 5 1 0 0 3 0 4 6 0 0 1 0 4 5 A4 7 11 vs 2 8 8 2 0 0 0 0 2 7 2 7 0 2 x 11 A5 9 5 vs 3 10 9 4 0 1 0 0 5
ver5.1 HS 1. ALPHA LIPOIC ACID () S S COOH HS 1. α - SH COOH - ( 1) CoA -( 2)- - --P80 (--WSP8-L1-WSPC8 -LC1) - 1
ORYZA OIL & FAT CHEMICAL CO., LTD. ALPHA LIPOIC ACID --P () --P80 () --WSP8 () --L1 () --PC () --PC80 () --WSPC8 () --LC1 () ver. 5.1HS ver5.1 HS 1. ALPHA LIPOIC ACID 16 3 31 0331009 - () 19 5 24 0524001