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.     

预防输注胺碘酮致外周静脉炎的证据总结

目的 总结和评价预防输注胺碘酮所致外周静脉炎的证据,为临床干预方案的制订提供参考.方法 针对预防输注胺碘酮所致外周静脉炎的问题,计算机检索相关文献,包括指南、证据总结、专家共识、最佳实践、临床决策、系统评价及原始研究,检索时限为建库至2020年5月.由2名研究者独立完成纳入文献的质量评价,对符合质量标准的文献进行证据提...     

胺碘酮与苯那普利联合治疗对阵发性房颤复发率等的影响

目的评价ACEI制剂苯那普利（洛汀新）与小剂量胺碘酮联合治疗对减少阵发性心房颤动（房颤）复发率的作用。方法将有完整资料的共46例阵发性心房颤动（房颤）患者根据用药情况分为胺碘酮组（1组,n=22）、胺碘酮＋苯那普利组（Ⅱ组2,n=24）,治疗随访时间为1年,比较两种治疗方法对阵发性心房颤动患者窦性心律维持率的影响以及治疗前、治疗后12个月左心房内径大小的变化。结果治疗12个月后,Ⅰ组窦性心律维持率为59．09％．Ⅱ组窦性心律维持率为83．33％。即Ⅰ组明显低于Ⅱ组（P〈0．05）;而且Ⅰ组左心房内径大小的变化（治疗前左心房内径34．28±1．54mm;治疗后为38．48±1．68mm）,大于Ⅱ组（治疗前左心房内径为34．68±1．56mm;治疗后为35．28±1．42mm）（P〈0．05）。结论小剂量胺碘酮联合苯那普利对阵发性房颤的治疗,在窦性心律的维持、抑制左心房的扩大方面均优于单用胺碘酮．     

Ventricular tachycardia ablation remains treatment of last resort in structural heart disease: argument for earlier intervention

VT Ablation Treatment of Last Resort. Introduction: Despite advances in ablation of ventricular tachycardia (VT), recognized toxicity of amiodarone, and potential harm of implantable cardioverter defibrillator (ICD) shocks, there appears to be reluctance to pursue catheter ablation. Methods and Results: We tested the hypothesis that patients with structural heart disease and VT are referred late for ablation and may have worse outcomes as a result. Consecutive patients with VT and structural heart disease referred to a single center, between January 2008 and April 2009 were studied. Patients with prior VT ablations were excluded. Late referrals were defined as those with 2 or more episodes of VT, separated by at least 1 month. Ninety‐eight consecutive patients were analyzed. Ninety‐six percent of patients had an ICD implanted prior to ablation, 58% were in VT storm and 67% taking ≥400 mg daily of amiodarone or amiodarone intolerant (10%). Thirty‐six patients fit the definition of early referral and 62 late. Overall acute procedural success was achieved in 89%. Amiodarone dose decreased from a mean and median of 559 and 400 mg daily preablation to 98 and 0 postablation (P < 0.01). Mean and median VT episodes decreased from 17 and 6 in the month preceding ablation to 1 and 0 in the 6 months following ablation (P < 0.01). In Kaplan–Meier analysis, the early referral group had superior 1‐year VT free survival (P = 0.01). Conclusions: VT ablation is frequently reserved for patients receiving recurrent ICD shocks despite high dose amiodarone. Stronger consideration should be given to earlier referral for VT ablation in patients with structural heart disease. (J Cardiovasc Electrophysiol, Vol. 22, pp. 1123‐1128, October 2011)     

Effects of Antiarrhythmic Drugs on Epicardial Defibrillation Energy Requirements and the Rate of Defibrillator Discharges

Antiarrhythmic drugs are commonly used with the implantable cardioverter/defibrillator to treat recurrent ventricular tachyarrhythmias. Since various antiarrhythmic drugs have been reported to alter defibrillation threshold, an important question is whether the device will provide adequate energy for defibrillation during long-term follow-up and to what extent antiarrhythmic drug treatment will affect defibrillation energy requirements. To answer these questions, the defibrillation thresholds were determined in 20 patients using an epicardial patch-patch lead configuration at the time of implantation and at the time of pulse generator replacement. During a mean follow-up period of 24 ± 6 months, the defibrillation threshold increased significantly from 14.2 ± 3.7 joules to 18.3 ± 5.5 joules in the entire group (P < 0.05). This increase in defibrillation threshold was due to a marked elevation of defibrillation energy requirements in the subgroup of patients taking amiodarone compared with patients receiving mexiletine. Based on these results it is mandatory to retest defibrillation threshold at any time of pulse generator replacement to guarantee continued effectiveness. In particular, if amiodarone treatment is initiated after implantation of a defibrillator, it is recommended to reevaluate defibrillation threshold to ensure an adequate margin of safety.     

Effect of Lidocaine and Amiodarone on Transmural Heterogeneity of Ventricular Repolarization in Isolated Rabbit Hearts Model of Sustained Global Ischemia

Someresultsofmeta analysesofrandomizedcontroltrialsonmyocardialinfarctionfoundthatlidocaineandamiodaronecanbeusedforthetreat mentofventriculartachyarrhythmias,butlido cainedonotreducemortalityinpatientswithven triculararrhythmiasaftermyocardialinfarctionwhileamiodaronecan[1,2].Themechanismisnotfullyunderstood.Inrecentyears,discoveryoftheMcells,andthreelayersmyocardiumtheorybeendrawed,thatmostelectrophysiologicalphenomenahadgotnewexplains[3,4].Thisexperimentthemonophasicactionpotentials(MAPs)…     

Parenteral Antiarrhythmic Drug Therapy in Ventricular Tachycardia/Ventricular Fibrillation: Evolving Role of Class III Agents—Focus on Amiodarone

Intravenous Amiodarone. More effective intravenous antiarrhythmic agents are required for treatment of patients with refractory malignant ventricular arrhythmias. More recently, a great deal of interest has been focused on use of intravenous amiodarone for these patients. Uncontrolled early studies showed that intravenous amiodarone was effective in 42% to 81% of treated patients. Recent large cooperative trials have documented the efficacy of intravenous amiodarone in these patients and have shown an efficacy comparable to bretylium in patients with refractory sustained ventricular tachycardia or fibrillation.     

Sudden cardiac death while taking amiodarone therapy: the role of abnormal repolarization

Torsade depointes may occur as a complication of amiodaronetherapy. We report a patient receiving amiodarone who was resuscitatedfrom cardiovascular collapse and documented ventricular fibrillation.At subsequent electrophysiology study, while the patient wastaking amiodarone therapy, monophasic action potentials withearly after depolarisations were recorded which were not presentwhen the patient was restudied 6 weeks after discontinuationof amiodarone. Early after-depolarisations may be importantin the genesis of polymorphic ventricular tachycardia complicatingamiodarone therapy.     

预激综合征经旁路前传的心房颤动患者静脉注射胺碘酮的安全性分析

目的　探讨预激综合征(W P W)合并心房颤动(房颤)患者静脉注射胺碘酮的安全性。方法　选择接受射频消融治疗的W P W患者及同期行隐匿性房室旁路射频消融治疗的患者(对照组)各16例,测量W P W组患者预激旁路前传有效不应期(ERPAP)和对照组的房室结有效不应期(ERPAVN)。在10min内缓慢静脉注射胺碘酮150mg,10min后重复上述测量,并对结果进行对比分析。结果　W P W组用药后ERPAP有轻微延长(P<0 05),其中1例用药后缩短了60ms;对照组ERPAVN用药后明显延长(P<0 05)。结论　部分W P W合并房颤的患者静脉注射胺碘酮时,可能会促进激动经旁路下传,使心室率加快或引发心室颤动,需格外慎重。     

Modifications in the evolution of the dominant frequency in ventricular fibrillation induced by amiodarone, diltiazem, and flecainide: An experimental study

In 22 anesthetized mongrel dogs, spectral methods were used to analyze the surface electrocardiogram (ECG) for the time course of the dominant frequency in ventricular fibrillation and its modifications under the influence of amiodarone, diltiazem, and flecainide. The ECG was recorded over 5 minutes after triggering ventricular fibrillation. Following A/D conversion and by applying the Fourier fast transform, the frequency spectrum of the signals was obtained. In group 1 (5 dogs), the ECGs were obtained without prior drug administration; group 2 (5 dogs) first received amiodarone, 5 mg/kg; group 3 (7 dogs) received diltiazem, 0.2 mg/kg; and group 4 (5 dogs) received flecainide, 2 mg/kg. All drugs were administered intravenously. An initial increase in the dominant frequency of ventricular fibrillation was found in the control group and also in the groups that received amiodarone, diltiazem, or flecainide. Diltiazem significantly increased the dominant frequency and diminished the arrhythmia-slowing process. Amiodarone and flecainide tended to diminish the dominant frequency.