Mohiuddin S M, Hee T T, Hunter C B, Hilleman D E, Sketch M H
School of Medicine, Creighton University, Omaha, NE.
Ann Pharmacother. 1993 May;27(5):550-4. doi: 10.1177/106002809302700502.
To describe the possible development of antiarrhythmic resistance to cifenline, an investigational Class I agent.
Forty patients with chronic ventricular premature depolarizations (VPDs) underwent dose-ranging studies with cifenline, an investigational Class I antiarrhythmic agent. Patients had a minimum of 30 VPDs/h detected by ambulatory electrocardiographic (ECG) monitoring over a 48-hour baseline placebo lead-in period. Twenty-two patients (55 percent) who initially responded received long-term cifenline therapy. Ambulatory ECG monitoring over 24 hours was repeated during active cifenline therapy at three-month intervals and during placebo reintroduction at six-month intervals.
After an average follow-up of 28 months, VPD frequency during cifenline therapy was similar to that during initial baseline placebo therapy in 8 of the 22 patients (36 percent) who initially responded. Placebo reintroduction following cifenline failure showed a VPD frequency similar to that with active therapy. All patients had further cifenline dosage increases without success. Plasma cifenline concentrations increased in all patients and were in the high therapeutic range. All 8 patients were switched to other Class I antiarrhythmic agents with successful VPD suppression during treatment with the first alternative drug.
We conclude that antiarrhythmic resistance occurred with cifenline in these patients as (1) initial efficacy was established for a minimum of two years, (2) VPD frequency was similar during cifenline therapy and placebo reintroduction, (3) cifenline therapy failure continued despite further dosage titration, and (4) alternative Class I antiarrhythmic therapy was successful in all patients. Repeat intermittent ambulatory ECG monitoring is necessary not only to assess the continued need for antiarrhythmic drug therapy, but also to establish continued long-term efficacy.
描述对一种研究性I类药物西芬利产生抗心律失常耐药性的可能发展情况。
40例慢性室性早搏（VPDs）患者接受了西芬利的剂量范围研究，西芬利是一种研究性I类抗心律失常药物。在48小时的基线安慰剂导入期，通过动态心电图（ECG）监测，患者每小时至少检测到30次VPDs。22例（55%）最初有反应的患者接受了长期西芬利治疗。在西芬利积极治疗期间，每三个月重复进行24小时动态心电图监测，在六个月间隔重新引入安慰剂期间也进行监测。
平均随访28个月后，在最初有反应的22例患者中的8例（36%）中，西芬利治疗期间的VPD频率与初始基线安慰剂治疗期间相似。西芬利治疗失败后重新引入安慰剂时，VPD频率与积极治疗时相似。所有患者进一步增加西芬利剂量均未成功。所有患者的血浆西芬利浓度均升高，且处于高治疗范围内。所有8例患者均改用其他I类抗心律失常药物，在使用第一种替代药物治疗期间成功抑制了VPD。
我们得出结论，这些患者中出现了对西芬利的抗心律失常耐药性，原因如下：（1）最初的疗效至少维持了两年；（2）西芬利治疗期间和重新引入安慰剂期间的VPD频率相似；（3）尽管进一步调整剂量，西芬利治疗仍失败；（4）所有患者使用替代I类抗心律失常治疗均成功。重复间歇性动态心电图监测不仅对于评估抗心律失常药物治疗的持续需求是必要的，而且对于确定持续的长期疗效也是必要的。
