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3 2) 100 / ST 3) 3) 5) 6) 7) 8) 9) ONO

4 ) ),11) / 12) 10.6 / 13) 10) 19 / ) 2 14) Ca Ca Ca ) 3

5 4 RPP Ca ONO-1101 Hypovolemia

6 1 9 Esmolol Hydrochloride 16) 19) 2 0.5mg/kg/min mg/kg/min mg/kg/min 0.05mg/kg/min 0.3mg/kg/min mg 1mg/kg mg/kg/min 0.3mg/kg/min 0.5mg/kg/min mg/kg/min mg/kg/min ONO-1101 ) 4 / ),21) ST 20) 5

7 ),21) Ca mg/kg/min ONO-1101 ONO-1101 M-1 6

8 1) Gann DS, Foster AH. : Endocrine and metabolic responses to injury. in Principles of Surgery, 5th edition by Schwartz, Shires, Spencer, McGraw-hill, New York, 1-68, ) Stoelting RK. : The 29th Rovenstine Lecture : Clinical challenges for the anesthesiologist. Anesthesiology. 74 : , ) Slogoff S, Keats AS. : Does perioperative myocardial ischemia lead to postoperative myocardial infarction Anesthesiology. 62 : , ) RW, Berger HJ, Barash PG, et al. : Continuous monitoring of left ventricular performance with the computerized nuclear probe during larynogoscopy and intubation before coronary artery bypass surgery. Am. J. Cardiol. 50 : , ) Geft JL, Fishbein MC, Ninomiya K, et al. : Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation. 66 : , ) Yurenev AP, et al. : Hypertensive heart disease. Am. Heart. J. 120 : , ) Dennis T.Mangano, Warren S.Browner, Milton Hollenberg et al. : Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. New Engl.J.Med. 323 : , ) Kannel WB. et al. :CHD risk factors : A Framingham Study update. Hosp. Pract. 25 : , ) Inoue I.,Massie,B.,Loge,D. et al. : Abnormal left ventricular filling : An early finding in mild to moderate systemic hypertension. Am.J.Cardiol. 53 : , ) 8 11) 8 12) 8 13) 8 14) : 13 : 17-32, ) Fox EJ, Sklar GS, Hill GH, et al. : Complications related to the pressor responses to endotracheal intubation. Anesthesiology. 47 : , ) Gorczynski RJ, Check Y. Quon, Richard W. Krasula, et al. : New Drugs Annual : Cardiavascular Drugs 3 : , ) Kaplan JA. : Role of ultrashort acting -blockers in the perioperative period. J. Cardiothorac. Anesth. 2 : , ) Menkhaus PG, Reves JG, Kissin I, et al. : Cardiovascular effects of esmolol in anesthetized humans. Anesth. and Analg. 64 : , ) Byrd R, Sung RJ, Marks J, Parmley WW. : Safety and efficacy of esmolol (ASL-8052 : an ultrashort - acting beta adrenergic blocking agent ) for control of ventricular rate in supraventricular tachycardias. J. Am. 7

9 Coll. Cardiol. 3 : 394, ) 1 ONO : ) 8

10 3 ONO µg/kg/min µg/kg/min 3 µg/kg/min ONO ONO mg/kg 100mg/kg 1 20mg/kg/min 24 5mg/kg/min 50mg/kg 12.5mg/kg 50mg/kg 50mg/kg 25mg/kg 50mg/kg 25mg/kg 25mg/kg,100mg/kg 3mg/mL 10mg/mL mg/mL mg/mL 0.3 mg/kg C ONO mg/kg , , pseudocholinesterase 9

11 carboxyesterase 10% P mg/ 0.001mg/kg/min mg/kg/min mg/kg/min mg/kg/min % mg/kg/min (EF) (CO) (SV) (negative inotropic action) 0.08mg/kg/min

12 mg/kg/min Cmax AUC T1/2 4 Tmax mg/kg/min mg/ 0.005, 0.01mg/kg/min mg/kg/min 20 (1/5) 0.04mg/kg/min 54.5 (6/11) 0.08 mg/kg/min 66.7 (8/12) Cmax T1/ mg/kg/min mg/kg/min Cmax mg/kg/min Bolus infusion Infusion 0.25mg/kg/min mg/kg/min mg/kg/min mg/kg/min

13 Cmax 2 5 Cmax 2 Cmax / 1 10 L 0.06mg/kg/min mg/kg/min 10 M 0.125mg/kg/min mg/kg/min 10 H 0.25mg/kg/min mg/kg/min mg/ L M H L 55.6 (10/18) M 60.0 (12/20) H 69.2 (9/13) L 15.4 (2/13) M 41.2 (7/17) H 50.0 (5/10) 80 / L 5.6 (1/18) M 55.0 (11/20) H 58.3 (7/12) 3 H 0.25mg/kg/min mg/kg/min CCU 12

14 300 g/kg/min P % 1) P / L 0.03mg/kg/min mg/kg/min 10 M 0.06mg/kg/min mg/kg/min 10 H 0.125mg/kg/min mg/kg/min mg/ L 67.4 (31/46) M 77.8 (35/45) H 90.7 (39/43) 3 30 H :0.125mg/kg/min mg/kg/min 100 / (1) (2) (3) ONO-1101 A 0.125mg/kg/min mg/kg/min 10 P 50mg/ 13

15 5 5 A 9.9 (11/111) P 67.4 (62/92) A 80.3 (94/117) P 9.4 (12/127) A 3 30 A P A P 20 A P ST ST -0.05mV ) P A ST ONO

16 WHO ST RPP Rate Pressure Product ST ONO-1101 A 0.125mg/kg/min mg/kg/min 10 P 50mg/ A 85.7% 18/21 P 10.0% 2/20 P A 87.8% 43/49 P 2 60 RPP P 17,187 3,318bpm mmhg A 18,697 3,062bpm mmhg P 16,309 3,784bpm mmhg A 9,665 2,935bpm mmhg P A 90 / RPP12,000bpm mmhg ST RPP 2) RPP12,000bpm mmhg A RPP 9,665bpm mmhg A 74.1% 20/27 P 85.2% 23/27 34 A 19 P A % P % A 7/ % 30 15

17 0.25mg/kg/min mg/kg/min 0.125mg/kg/min mg/kg/min 50mg/ (PIP EEP SpO2 PETCO2) 1 ONO-1101 L 0.03mg/kg/min mg/kg/min 10 M 0.06mg/kg/min mg/kg/min 10 H 0.125mg/kg/min mg/kg/min mg/ 7 ONO mg/kg/min (FAC CFS Vcfc LVESWS) (Peak E Peak A Peak E/Peak A) 0.125mg/kg/min mg/kg/min 50mg/ mg/kg/min 16

18 TKS 50 mg/ mg/kg/min 0.04 mg/kg/min mg/kg/min Loading dose ( 1 ) Infusion dose mg/kg/min mg/kg/min 1) Simon Gelaman : General anesthesia and hepatic circulation. Can.J.Physiol.Pharmacol. 65: , ) Kaplan.J.A., Dunbar.R.W., Jones.E.L. : Nitroglycerin infusion during coronary artery surgery. Anesthesiology. 45 : 14,

19 18 19

20 1 P Ki ,890nM in vitro 1 2 pa in vitro 1 2 Ki M in vitro P.210 ONO P.185 ONO-1101 (MSA membrane stabilizing activity) in vitro (ISA Intrinsic sympathomimetic activity) in vitro P P P P.416 ST (-0.05mV ) P.442 ST 0.1mV 20

21 2 60 P P.464 P.479 (PIP EEP SpO2 PETCO2) P.496 (FAC CFS Vcfc LVESWS) (Peak E Peak A Peak E/Peak A) P mg/kg/min P

22 Esmolol ASL-8052 JAN JAN landiolol hydrochloride (-)-3-[4-[(S) (2- ) ] ] [(S)-2,2- -1, ] (-)-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(S)-2-hydroxy-3-(2- INN landiolol morpholinocarbonylamino)ethylamino]propoxy]phenylpropionate monohydrochloride r-inn List 37, WHO Drug Information Vol.11.(1)(1997)) ONO

23 -2 50mg/ 2mg/ ) ) ) (1) (2) mg/kg/min 0.04mg/kg/min mg 1 5mg mg/kg/min< > (1) (2) (3) (4) (1) (1) (2) (2) (3) (3) (4) (4) (5) (5) (6) (6) (7) (7) (8) 1 (9) (1) (10) (2) 1 2 (11) (12) (3) (13) 3. (4) 1. (5) (1) (6) 1 (2) 2 (3) (7) (4) 2 (5) (1) (6) (4) PQ (7) (8) 5. (2) 2 (1) (3) (2) 5 5 1mg (4) QRS 5 10 (3) 24 (4) (5) CYP2D6 CYP1A2 CYP2C19 1) (1)

24 -2 landiolol hydrochloride) propranolol hydrochloride) 3 2) (1) (1) ( (2) ( ) (2) ( ) (3) ( ) (3) ( ) (4) 48 (4) (5) ( ) (5) ( ) (6) ( ) (6) (7) (8) (7) ( ) (9) (8) ( ) (10) (11) (9) (12) (13) (10) (14) 4 (15) (15.6 ) (16) ST % (17) ALT GPT AST GOT (18) LDH (1) (8.6%) ( ) 5 (2.9%) (0.2 ) (1) (2) 1) ) 0.1 5% 0.1% 2) 0.1% 3) 0.1 5% 0.1% 2 (2) 0.1 5% 0.1% 1) 2) ) 5 GOT GPT AL-P LDH 6 [ ] (1) (2) mg 1 ( µg/kg ) 10mg (1) 2 ( - ) ( ( ) (1 2mg (2) 1 50mg 5mL 10mg/mL ) (1) (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( )esm

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 1 186 186 (1) - 192 (2) (ISAintrinsic sympathomimetic activity) 199 (3) ( MSAmembrane stabilizing activity) 2 (4) 21 (5) 212 (6) 216 (7) 219 (8) 224 (9) (ASL-8123) - 229 (1) d-esl l-esl - 231 2 235 235