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Q1 アミオダロンによる心房細動のリモデリング予防効果およびリモデリング逆行効果について教えてください

P.3 掲載の参考文献

• 1) AFFIRM first antiarrhythmic drug substudy investigators. Maintenance of sinus rhythm in patients with atrial fibrillation:An AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003;42:20-9.
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• 2) Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Eng J Med 2000;342:913-20.

• 3) Manios EG, Mavrakis HE, Kanoupakis EM, et al. Effects of amiodarone and diltiazem on persistent atrial fibrillation conversion and recurrence rates:a randomized controlled study. Cardiovasc Drugs Ther 2003;17:31-9.

• 4) Shinagawa K, Shiroshita-Takeshita A, Schram G, et al. Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium:Insights into the mechanism of amiodarone's superior efficacy. Circulation 2003;107:1440-6.
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• 5) Fareh S, Benardeau A, Thibault B, et al. The T-type Ca2+ channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs. Circulation 1999;100:2191-97.

• 6) 大橋成孝ほか:T型Caチャネル遮断薬エホニジピンによる心房電気的リモデリングの抑制. 心電図 2003;23:323-31.
  Medical*Online

• 7) Ashikaga K, Kobayashi T, Kimura T, et al. Effects of amiodarone on electrical and structural remodeling induced in a canine rapid pacing-induced persistent atrial fibrillation model. Eur J Pharmacol 2006;536:148-53.

Q2 アミオダロンとACEI、もしくはARB併用に関する最新知見について、心房細動を中心に教えてください

P.6 掲載の参考文献

• 1) Members of the Sicilian Gambit. New approaches to antiarrhythmic therapy, Part I:emerging therapeutic applications of the cell biology of cardiac arrhythmias. Circulation 2001;104:2865-73

• 2) Nakashima H, Kumagai K, Urata H, Gondo N, Ideishi M, Arakawa K. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation. 2000;101:2612-7

• 3) Zankov DP, Omatsu-Kanbe M, Isono T, Toyoda F, Ding WG, Matsuura H, Horie M. Angiotensin II potentiates the slow component of delayed rectifier K+ current via the AT1 receptor in guinea pig atrial myocytes. Circulation 2006;113:1278-86

• 4) Kumagai K, Nakashima H, Urata H, et al. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol 2003;41:2197-204

• 5) Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers:a meta-analysis. J Am Coll Cardiol 2005;45:1832-9

• 6) Yin Y, Dalal D, Liu Z, et al. Prospective randomized study comparing amiodarone vs. amiodarone plus losartan vs. amiodarone plus perindopril for the prevention of atrial fibrillation recurrence in patients with lone paroxysmal atrial fibrillation. Eur Heart J 2006;27:1841-1846

• 7) Madrid AH, Marin IM, Cervantes CS, et al. Prevention of recurrences in patients with lone atrial fibrillation. The dose-dependent effect of angiotensin II receptor blockers. J Renin Angiotensin Aldosterone Syst 2004;5:114-120

Q3 心臓手術後にみられる術後不整脈はどのように予知・対処すべきでしょうか?

P.10 掲載の参考文献

• 1) Ishii Y, Schuessler RB, Gaynor SL, et al. Inflammation of atrium after cardiac surgery is associated with inhomogeneity of atrial conduction and atrial fibrillation. Circulation 2005;111:2881-8.
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• 2) Mitchell LB, Exner DV, Wyse DG, et al. Prophylactic oral amiodarone for the prevention of arrhythmias that begin early after revascularization, valve replacement, or repair. PAPABEAR:A randomized controlled trial. JAMA 2005;294:3093-100.
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• 3) Bagshaw SM, Galbraith PD, Mitchell LB, et al. Prophylactic amiodarone for prevention of atrial fibrillation after cardiac surgery:a meta-analysis. Ann Thorac Surg 2006;82:1927-37.
  pubmed

Q4 難治性の小児不整脈の治療法について教えてください

P.13 掲載の参考文献

• 1) Paul T and Guccione P:New antiarrhythmic drugs in pediatric use:amiodarone. Pediatr Cardiol, 1994;15 (3):132-8.
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• 2) Guccione P, Paul T, Garson A:Long-term follow-up of amiodarone therapy in the young:continued efficacy, unimpaired growth, moderate side effects. J Am Coll Cardiol, 1990;15 (5):1118-24.

• 3) Bucknall CA, Keeton BR, Curry PV, Tynan MJ, Sutherland GR, Holt DW:Intravenous and oral amiodarone for arrhythmias in children. Br Heart J, 1986;56 (3):278-84.
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• 4) Fenrich AL, Perry JC, Friedman RA:Flecainide and amiodarone:combined therapy for refractory tachyarrhythmias in infancy. J Am Coll Cardiol, 1995;25 (5):1195-8.
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• 5) Drago F, Mazza A, Guccione P, Mafrici A, Di Liso G, Ragonese P:Amiodarone used alone or in combination with propranolol:a very effective therapy for tachyarrhythmias in infants and children. Pediatr Cardiol, 1998;19 (6):445-9.
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• 6) Coumel P and Fidelle J:Amiodarone in the treatment of cardiac arrhythmias in children:one hundred thirty-five cases. Am Heart J, 1980;100 (6 Pt 2):1063-9.

• 7) Kotake T, Takada M, Goto T, Komamura K, Kamakura S, Morishita H:Serum amiodarone and desethyl-amiodarone concentrations following nasogastric versus oral administration. J Clin Pharm Ther, 2006;31 (3):237-43.

• 8) Etheridge SP, Craig JE, Compton SJ:Amiodarone is safe and highly effective therapy for supraventricular tachycardia in infants. Am Heart J, 2001;141 (1):105-10.
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• 9) Burri S, Hug MI, Bauersfeld U:Efficacy and safety of intravenous amiodarone for incessant tachycardias in infants. Eur J Pediatr, 2003;162 (12):880-4.
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• 10) Strasburger JF, Cuneo BF, Michon MM, Gotteiner NL, Deal BJ, McGregor SN, Oudijk MA, Meijboom EJ, Feinkind L, Hussey M, Parilla BV:Amiodarone therapy for drug-refractory fetal tachycardia. Circulation, 2004;109 (3):375-9.
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• 11) Saul JP, Scott WA, Brown S, Marantz P, Acevedo V, Etheridge SP, Perry JC, Triedman JK, Burriss SW, Cargo P, Graepel J, Koskelo EK, Wang R:Intravenous Amiodarone Pediatric Investigators. Intravenous amiodarone for incessant tachyarrhythmias in children:a randomized, double-blind, antiarrhythmic drug trial. Circulation, 2005;112:3470-7.
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• 12) Thorne SA, Barnes I, Cullinan P, Somerville J:Amiodarone-associated thyroid dysfunction:risk factors in adults with congenital heart disease. Circulation, 1999;100 (2):149-54.
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Q5 アミオダロン誘発性肺毒性とその予知法について検査間隔も含めて教えてください

P.16 掲載の参考文献

• 1) Pitcher WD:Southwestern Internal Medicine Conference:Amiodarone pulmonary toxicity. Am J Med Sci, 1992;303:206-212.

• 2) Camus P, Bonniaud P, Fanton A, et al:Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med, 2004;25:65-75

• 3) Olshansky B, Sami M, Rubin A, et al:Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol, 2005;95:404-5.
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• 4) Mason JW:Prediction of amiodarone-induced pulmonary toxicity. Am J Med, 1989;86:2-3

• 5) Endoh Y, Hanai R, Uto K, Uno M, Nagashima H, Narimatsu A, Takizawa T, Onishi S, Kasanuki H:KL-6 as a potential new marker for amiodarone-induced pulmonary toxicity. Am J Cardiol, 2000;86:229-231.
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• 6) 坂巻文雄:アミオダロンによる肺合併症への対応. 心電図, 2002;22 (2):91-96.
  Medical*Online

• 7) Martin WJ and Rosenow EC:Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part 1). Chest, 1988;93:1067-1075.

Q6 アミオダロン誘発性甲状腺中毒症の対処法について教えてください

P.19 掲載の参考文献

• 1) Martino E, Bartalena L, Bogazzi F, Braverman LE. The Effects of amiodarone on the thyroid. Endocr Rev, 2001;22:240-254.
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• 2) Shiga T, Wakaumi N, Matsuda N, Shoda M, Hagiwara N, Sato K, Kasanuki H. Amiodarone-induced thyroid dysfunction and ventricular tachyarrhythmias during long-term therapy in Japan. Jpn Circ J, 2001;65:958-960.

• 3) Sato K, Miyakawa M, Eto M, Inaba T, Matsuda N, Shiga T, Ohnishi S, Kasanuki H. Clinical characteristics of amiodarone-induced thyrotoxicosis and hypothyroidism in Japan. Endocr J, 1999;46:443-451.
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• 4) Sato K, Yamazaki K, Kanaji Y, Ohnishi S, Kasanuki H. Amiodarone-induced thyrotoxicosis associated with thyrotropin receptor antibody. Thyroid, 1998;8:1123-1126.
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• 5) Nakajima K, Yamazaki K, Yamada E, Kanaji Y, Kosaka S, Sato K, Takano K. Amiodarone stimulates interleukin-6 production in cultured human thyrocytes, exerting cytotoxic effects on thyroid follicles in suspension culture. Thyroid, 2001;11:101-109.
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• 6) Sato K, Shiga T, Matsuda N, Onoda N, Takano K, Hagiwara N, Kasanuki H. Mild and short recurrence of type II amiodarone-induced thyrotoxicosis in three patients receiving amiodarone continuously for more than 10 years. Endocr J, 2006;53:531-538.
  pubmed

Q7 アミオダロンによる肝障害(肝毒性)について対策も含めて教えてください

P.23 掲載の参考文献

• 1) Plomteux G, Heusghem C, Ernould H, et al. Long-term hepatic tolerance of amiodarone in the clinic. Eur J Phamacol 1969;8, 369-376

• 2) Lewis JH, Ranard R, Caruso A, et al. Amiodarone hepatotoxicity:plevalence and clinicopathologiCc correrations among 104 patients. Hepatology 1989;9:679-685

• 3) Hyatt RH, Sinha B, Vallon A et al. Noncardiac side effects of long term oral amiodarone in the elderly Age. Ageing 1988;17:116-122

• 4) Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone:a meta-analysis. J Am Coll Cardiol 1997;30:791-798

• 5) Fink R, Clemens MR, Marjot DH, et al. Increased free-radical activity in alcoholics. Lancet 1985;2:291-294

• 6) Grech-Belanger O. Depressive effect of amiodarone on hepatic drug metabolism in the rat. Res Commun Chem Pathol Pharmacol 1984;44:15-30

• 7) Pessayre D, Mansouri A, Haouzi D, Fromenty B. Hepatotoxicity due to mitochondrial dysfunction. Cell Biol Toxicol 1999;15:367-373

• 8) Kalantzis N, Gabriel P, Mouzas J, et al. Acute Amiodarone-induced Hepatitis. Hepato-Gastroenterol 1991;38:71-74

• 9) Kaufmann P, Torok M, Hanni A, et al. Mechanisms of Benzarone and Benzbromarone induced Hepatic Toxicity. Hepatology 2005;41:925-935

• 10) Shenasa M, Vaisman U, Wojciechowski M et al. Abnormal Abdominal computerized tomography with amiodarone therapy and clinical significance. Am Heart Journal 1984;107:929-933

• 11) 平川浩一, 阿部光一郎, 綾部善治, 西村昌雄. アミオダロン服用に伴う肝臓CT値の上昇についての検討. 日本医放会誌2003;63:221-224

• 12) Pollak PT, You YD. Monitoring of hepatic function during amiodarone therapy. Am J Cardiol 2003;91:613-616

• 13) Ratz Bravo AE, Drewe J, Schlienger RG, et al. Hepatotoxicity during rapid intravenous loading with amiodarone:Description of three cases and review of the literature. Crit Care Med 2005;33:128-134

Q8 アミオダロン維持量は低用量にすべきですか?維持量の設定について教えてください

P.28 掲載の参考文献

• 1) 志賀 剛. アミオダロン:日本人における有効性と安全性. 循環器科 2006;59:599-604.

• 2) Herre JM, Sauve MJ, Malone P, et al. Long-term results of amiodarone therapy in patients with recurrent sustained ventricular tachycardia or ventricular fibrillation. J Am Coll Cardiol 1989;13:442-449
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• 3) Shiga T, Wakaumi M, Imai T, et al. Effect of low-dose amiodarone on atrial fibrillation or flutter in Japanese patients with heart failure. Circ J 2002;66:600-604
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• 4) Khand AU, Rankin AC, Kaye GC, et al. Systematic review of the management of atrial fibrillation in patients with heart failure. Eur Heart J 2000;21:614-632

• 5) Yamada Y, Shiga T, Matsuda N, et al. Incidence and predictors of pulmonary toxicity in Japanese patients receiving low-dose amiodarone. Circ J 2007;21:(in press)

• 6) Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation. 1990;82:51-59

Q9 植込み型除細動器治療例におけるアミオダロン併用の役割について教えてください

P.32 掲載の参考文献

• 1) Hohnloser SH, Dorian P, Roberts R, et al. Effect of amiodarone and sotalol on ventricular defibrillation threshold. The Optimal Pharmacological Therapy in Cardioverer Defibrillator Patients (OPTIC) Trial. Circulation 2006;114:104-109.
  pubmed

• 2) Ho AT, Pai SM, Timothy P, et al. Effect of concomitant antiarrhythmic therapy on survival in patients with implantable cardioverter defibrillators. PACE 2005;28:647-653.

• 3) Satomi K, Kurita T, Takatsuki S, et al. Amiodarone therapy in patients implanted with cardioverter-defibrillator for life-threatening ventricular arrhythmias. Circ J 2006;70:977-84.
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• 4) Connolly SJ, Dorian P, Roberts RS, et al., for the Optimal Pharmacological Therapy in Cardioverer Defibrillator Patients (OPTIC) Investigators. Comparison of β-blockers, amiodarone plus β-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators. The OPTIC study:a dandomized trial. JAMA 2006;295:165-171.

• 5) Ferreira-Gonzalez I, Dos-Subira L, Guyatt GH. Adjunctive antiarrhythmic drug therapy in patients with implantable cardioverter defibrillators:a systemic review. Eur Heart J 2007;28:469-477.

• 6) Maisel WH, Stevenson LW. Atrial fibrillation in heart failure:epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91 (suppl):2D-8D.

• 7) Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death-executive summary. Circulation 2006;114:1088-1132.

Q10 最近の大規模臨床試験(アミオダロントライアル)から何が明らかになりましたか?

P.40 掲載の参考文献

• 1) Kudenchuk PJ, Cobb LA, Copass MK, et al.:Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med 1999;341:871-8

• 2) Dorian P, Cass D, Schwartz B, et al.:Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med 2002;346:884-90

• 3) The CASCADE Investigators:Randomized anti-arrhythmic-drug therapy in survivors of cardiac arrest (the CASCADE Study). Am J Cardiol 1993;72:280-7

• 4) The AVID Investigators:A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997;337:1621-3

• 5) Connolly SJ, Gent M, Roberts RS, Dorian P, Roy D, et al:Canadian implantable defibrillator study (CIDS):a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000;101:1297-302

• 6) OPTIC Investigators:Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators:the OPTIC Study:a randomized trial JAMA. 2006;295:165-71
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• 7) EMIAT Investigators:Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction. Lancet 1997;349:667-74

• 8) GESICA Group:Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994;344:493-8

• 9) MADIT-II Research Group:Temporal aspects of improved survival with the implanted defibrillator (MADIT-II).

• 10) SCD-HeFT Investigators:Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37

• 11) AFFIRM Investigators:A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-33

• 12) RACE Study Group:A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834-40.

• 13) J-RHYTHM Investigators:Investigation of the optimal treatment strategy for atrial fibrillation in Japan. Circ J 2003;67:738-41

• 14) CTAF Investigators:Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000;342:913-20

• 15) SAFE-T Investigators:Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861-72