Combined amiodarone and silymarin treatment,but not amiodarone alone,prevents sustained atrial flutter in dogs

Amiodarone/Silymarin Treatment for Sustained Atrial Flutter. INTRODUCTION: Because amiodarone generates free radicals that may mediate amiodarone's toxicity, simultaneous therapy with an antioxidant might be beneficial if the antioxidant did not impair amiodarone's antiarrhythmic action. We tested whether simultaneous administration of a flavonoid antioxidant, silymarin, altered the electrophysiologic (EP) actions of amiodarone in 62 open chest dogs with electrically induced atrial flutter created by a Y-shaped right atrial incision. METHODS AND RESULTS: Fifteen dogs received oral amiodarone (600 mg/day); 15 dogs received amiodarone (600 mg/day) and silymarin (70 mg bid); and 8 dogs received silymarin (70 mg bid) alone. All dosing was for 8 weeks; 24 control dogs received no drugs prior to induction of atrial flutter. Atrial flutter was induced by rapid right atrial pacing, and EP measurements were made before (presurgical) and after (postsurgical) creation of a Y-shaped right atrial incision. There was no difference in the frequency of induction of atrial flutter lasting >30 minutes among amiodarone-treated (8/15 53%]), silymarin-treated (4/6 67%]), and control (15/21 71%]) groups, whereas the frequency of induction in the amiodarone+silymarin dogs (2/15 13%]) was significantly reduced (P = 0.008) compared with the other three groups. Both amiodarone and amiodarone+silymarin treatment prolonged the presurgical and postsurgical right atrial effective refractory period (P = 0.012) compared with control; however, there was no significant difference in either parameter between the amiodarone+silymarin-treated and amiodarone-treated groups. The increase in atrial flutter mean cycle length (postsurgical minus presurgical) was significantly (P = 0.005) less in the amiodarone+silymarin-treated and control dogs compared with the amiodarone-treated dogs (16 +/- 11 msec for amiodarone+silymarin; 24 +/- 8 msec for control; and 42 +/- 14 msec for amiodarone treatment). Amiodarone+silymarin treatment resulted in a longer postsurgical right atrial refractory period (155 +/- 13 msec) than atrial flutter mean cycle length (154 +/- 19 msec), consistent with reduction and/or elimination of the excitable gap. Silymarin alone did not exert significant EP or antiarrhythmic action. CONCLUSION: Amiodarone exerted no preventative antiarrhythmic action in this atrial flutter model, probably because it could not reduce the excitable gap of atrial flutter. However, an antioxidant, silymarin, without a direct antiarrhythmic action, when administered together with amiodarone, potentiated amiodarone's antiarrhythmic actions and prevented sustained atrial flutter by reduction and/or elimination of the excitable gap.