Functional characterization of 21 CYP3A4 variants on amiodarone metabolism in vitro

1. Cytochrome P450 3A4 (CYP3A4) is an important member of the cytochrome P450 enzyme superfamily, with 33 allelic variants reported previously. Genetic polymorphisms of CYP3A4 can produce a significant effect on the efficacy and safety of some drugs, so the purpose of this study was to clarify the catalytic characteristics of 22 CYP3A4 allelic isoforms, including 6 novel variants in Han Chinese population, on the oxidative metabolism of amiodarone in vitro.

2. Wild-type CYP3A4*1 and other variants expressed by insect cells system were incubated respectively with 10–500?μM substrate for 40?min at 37?°C and terminated at ?80?°C immediately. Then these samples were treated as required and detected with ultra-performance liquid chromatography-tandem mass spectrometry used to analyze its major metabolite desethylamiodarone.

3. Among the 21 CYP3A4 variants, compared with the wild-type, the intrinsic clearance values (V_max/K_m) of two variants were apparently decreased (11.07 and 2.67% relative clearance) while twelve variants revealed markedly increased values (155.20～435.96%), and the remaining of seven variants exhibited no significant changes in enzyme activity.

4. This is the first time report describing all these infrequent alleles for amiodarone metabolism, which can provide fundamental data for further clinical studies on CYP3A4 alleles.     

围手术期使用胺碘酮对心房颤动转律的研究

目的探讨围手术期使用胺碘酮对二尖瓣置换手术患者心房颤动（房颤）的转复和维持窦性心律的作用。方法40例行二尖瓣置换手术房颤患者随机分为2组：胺碘酮组和安慰剂组，每组20例。胺碘酮组术前3d开始胺碘酮200mg口服，3次／d，术后当天通过微量输液泵持续静脉输注600mg胺碘酮，能进食后改为胺碘酮200mg口服，3次／d；1周后改为200mg口服，2次／d；再1周后改为200mg口服，1次／d，一直维持。安慰剂组以安慰剂代替胺碘酮，服药时间和方法同胺碘酮组。观察2组患者术后房颤转复率、ICU监护时间、住院时间及窦性心律维持情况。结果胺碘酮组房颤转复率明显高于安慰剂组（65％vs30％，P〈0．05）。随访6个月，胺碘酮组维持窦性心律明显优于安慰剂组（70％vs0，P〈0．05），而ICU监护时间和住院时间较安慰剂组缩短[（1．8±1．7）d vs（2．8±1．5）d，（11．3±2，4）d vs（13．4±3．2）d，P均〈0．05]。结论胺碘酮可以有效地将二尖瓣置换手术患者的房颤心律转复为窦性心律，缩短ICU监护时间和住院时间，并且在术后维持窦性心律方面疗效显著。     

Best Clinical Practice: Emergency Medicine Management of Stable Monomorphic Ventricular Tachycardia

Background

Ventricular tachycardia (VT) and ventricular fibrillation are the causes of approximately 300,000 deaths per year in the United States. VT is classified based on hemodynamic status and appearance. Stable, monomorphic VT treatment is controversial.

Ventricular Pacing Threshold and Time to Capture Postdefibrillation in Patients Undergoing Implantable Cardioverter-Defibrillator Implantation

To assess the effect of defibrillation and amiodarone on ventricular pacing threshold and time to capture in patients undergoing automatic implantable cardioverter-defibrillator (AICD) implantation, 28 patients were prospectively evaluated. The patients were entered into one of two protocols: la—epicardial ventricular pacing threshold measured at baseline (preventricular fibrillation induction) and 10 and 60 seconds postdefibrillation with 20 J, or Ib—two fibrillation-defibrillation sequences were performed 3 minutes apart and ventricular pacing thresholds were measured for each sequence at baseline and at 10 and 60 seconds postdefibrillation with 20 J. Ten patients also underwent asynchronous pacing at 1.1 times baseline threshold during ventricular fibrillation with measurement of time to capture postdefibrillation. All patients were randomly assigned to receive either amiodarone or no antiarrhythmic drug therapy. Ventricular fibrillation was induced with AC (applied for 1-2 seconds), and standard epicardial bipolar and epicardial patch electrodes of the AICD were used for pacing and defibrillation, respectively. Ventricular pacing threshold at baseline, 10 seconds, 60 seconds, and 3 minutes postdefibrillation did not differ significantly. There were no significant differences in patients with or without amiodarone therapy. Furthermore, there was no transient loss of ventricular capture postdefibrillation or significant difference in time to capture with amiodarone (≤ 2 seconds). We conclude that following internal defibrillation with 20 J: (1) ventricular pacing threshold at 10 seconds, 60 seconds, and 3 minutes were not significantly different from baseline with one or two fibrillation-defibrillation sequences, (2) time to capture was short, and (3) there was no significant difference in no drug versus amiodarone. These findings have direct clinical importance in considering device therapy with both pacing and defibrillating capabilities.     

Effect of amiodarone on dispersion of atrial refractoriness and cycle length in patients with atrial fibrillation

INTRODUCTION: Amiodarone is effective in preventing the recurrence of atrial fibrillation (AF) after cardioversion (CV). Dispersion of atrial refractoriness may be relevant to the generation of AF. We designed a study to determine the electrophysiologic effects of amiodarone in patients with previous early recurrence of AF after CV. METHODS AND RESULTS: Fifteen patients with previous AF recurrence (without antiarrhythmic drugs) after CV (CV1) were selected for amiodarone therapy and repeat CV (CVamio). Prior to CV1, mean AF cycle length (AFCL) had been recorded at four atrial sites (right atrial appendage [RAA], distal coronary sinus [DCS], right atrial lateral wall [LAT], and interatrial septum [IAS]) and dispersion of AFCL had been calculated. These patients were treated with amiodarone and, prior to CVamio, AFCL was recorded at the four atrial sites as for CV1. Between CV1 and CVamio, AFCL increased at all atrial sites: 153 +/- 13 msec to 179 +/- 14 msec at RAA, 144 +/- 12 msec to 174 +/- 18 msec at DCS, 158 +/- 13 msec to 182 +/- 16 msec at LAT, and 161 +/- 18 msec to 181 +/- 17 msec at IAS. Dispersion of AFCL decreased from 24 +/- 10 msec at CV1 to 15 +/- 11 msec at CVamio (P = 0.01). The median time in sinus rhythm increased from 3.12 hours post CV1 to 28 days post CVamio, (P < 0.02). CONCLUSION: Amiodarone causes a reduction in the dispersion of AFCL. This action may be relevant to the beneficial effects of amiodarone in patients with AF.     

An evaluation of postoperative P-wave variables after cardiothoracic surgery

Postoperative atrial fibrillation is common after cardiac surgery. Prediction of which patients will develop postoperative atrial fibrillation would be clinically useful. Increased P-wave duration, suggesting atrial conduction delay and measured from preoperative electrocardiograms, predicts postoperative atrial fibrillation. However, postoperative P-wave duration has not been evaluated after cardiac surgery. In this study, we evaluated postoperative P-wave variables (maximum P-wave duration and P-wave dispersion) over 5 days in cardiac surgery patients receiving amiodarone, pacing or no atrial fibrillation prophylaxis. P-wave variables gradually shortened as time passed from surgery. Amiodarone did not shorten P-wave measurements throughout therapy, while pacing shortened P-waves in the immediate postoperative period; however, shortening was not sustained. P-waves did not differ between those who did and did not develop atrial fibrillation with amiodarone or pacing. Our findings suggest that atrial conduction delay resulting from cardiothoracic surgery tends to resolve over time and may not play a critical role in the etiology of postoperative atrial fibrillation.     

Combination of flecainide and propranolol for congenital junctional ectopic tachycardia

Congenital junctional ectopic tachycardia is a rare tachyarrhythmia with high mortality. A pharmacological approach in early infancy is regarded as the first‐line therapeutic option. Pharmacologically, amiodarone alone or in combination with other drugs is the most commonly reported effective agent for congenital junctional ectopic tachycardia, but it has many adverse effects. Here we report the case of a 40‐day‐old infant. The clinical course suggests that combined oral flecainide and propranolol is an effective alternative therapy for early infants. Esophageal lead electrocardiography may give a clear diagnosis of junctional ectopic tachycardia.     

心律平与胺碘酮治疗心律失常疗效比较的Meta分析

目的 评价文献中运用心律平与胺碘酮治疗心律失常的疗效.方法 运用计算机检索Pubmed、EMbase、Cochrane图书馆、中国生物医学文献数据库中关于心律平和胺碘酮在治疗心律失常疗效的随机对照试验,将检索时限定为2000年1月～2014年7月.对检索到的论文进行客观质量评价,应用Cochrane协作网提供的Rev Man 5.3软件进行Meta分析.结果 通过药物静脉注射给药,2组心律失常总有效率差异有统计学意义(OR=1.68,95％ CI:1.25 ～2.26,P＜0.0001);药物口服给药,2组心律失常总有效率差异有统计学意义(OR=1.49,95％ CI:1.09 ～ 2.03,P=0.010);2组不良反应发生率比较差异无统计学意义(OR=0.85,95％ CI:0.62 ～ 1.16,P＞0.05).结论 胺碘酮组治疗心率失常的疗效优于心律平,但对于药物的不良反应率并不增加.