盐酸尼非卡兰的有关物质及含量测定方法

 目的分别用HPLC和非水酸碱滴定法建立起盐酸尼非卡兰有关物质检查及含量测定的方法,为原料的质量控制提供有效的分析方法。方法采用岛津CLC-ODS(6mm×150mm,5μm)柱,流动相:乙腈-0.02mol·L^-1的磷酸二氢钾溶液(NaOH溶液调pH至5.0)=25∶75;检测波长:268nm;流速:1.0mL·min^-1;柱温:30℃。结果在选定的色谱条件下,盐酸尼非卡兰与7个有关物质分离完全;盐酸尼非卡兰在5～100mg·L^-1内,峰面积与浓度线性关系良好,r=0.9999;检测限为0.2ng。结论方法简便,准确,专属性强,可用于盐酸尼非卡兰的有关物质检查及含量测定。     

尼非卡兰和胺碘酮治疗急性心肌梗死新发房颤有效性和安全性对比研究

目的:探讨尼非卡兰和胺碘酮治疗急性心肌梗死新发房颤的有效性和安全性。方法:纳入泰达国际心血管病医院重症监护室2017年1月- 2018年5月收治的急性心肌梗死合并新发房颤的患者共106例,按计算机产生的随机序号分为尼非卡兰组52例和胺碘酮组54例,分别予尼非卡兰（注射用盐酸尼非卡兰,50 mg）:负荷剂量:0.3 mg/kg输注5 min,维持剂量:0.4 mg/kg/h;胺碘酮（盐酸胺碘酮注射液,可达龙,3 mL:0.15 g）:负荷剂量:15 mg/min输注10 min,维持剂量:1 mg/min治疗,观察2组患者24 h房颤转复率及控制率,治疗前后血压、心率、左心室射血分数、不良反应等。结果:尼非卡兰组和胺碘酮组的房颤转复率分别为50（96%）、42（78%）,具有统计学差异（P=0.001）。尼非卡兰组转复时间较短（2.7±1.3,P=0.02）,24 h房颤发作控制率未见明显统计学差异（P=0.16）,但尼非卡兰组相对比例较高（77%）。尼非卡兰组对收缩压（P=0.24）、舒张压（P=0.32）、心率（P=0.23）未见明显影响,可升高LVEF（P=0.001）、延长QTc（P=0.001）。不良反应方面,尼非卡兰组发生率低,仅1例尖端扭转室速,停药后恢复,总体不良反应发生率与胺碘酮组无明显统计学差异（P=0.27）。结论:尼非卡兰对急性心肌梗死新发房颤的治疗效果显著,对血压心率影响小,不良反应发生率低。     

盐酸尼非卡兰的合成

以1，3－二甲基脲为原料，经环合、氯化、胺解和磺酸酯化反应合成中间体6－[[2－（p－甲苯磺酰基氧基）乙基]氨基]－1，3－二甲基－2，4（1H，3H）－嘧啶二酮，再与中间体2－[3-(4-硝苯基）再基氨基]乙醇缩合、成盐得盐酸尼非卡兰，总收率26．6％。     

Effects of pH on Nifekalant-Induced Electrophysiological Change Assessed in the Langendorff Heart Model of Guinea Pigs

Since information regarding the effects of pH on the extent of nifekalant-induced repolarization delay and torsades de pointes remains limited, we assessed it with a Langendorff heart model of guinea pigs. First, we investigated the effects of pH change from 7.4 to 6.4 on the bipolar electrogram simulating surface lead II ECG, monophasic action potential (MAP), effective refractory period (ERP), and terminal repolarization period (TRP) and found that acidic condition transiently enhanced the ventricular repolarization. Next, we investigated the effects of pH change from 6.4 to 7.4 in the presence of nifekalant (10 μM) on the ECG, MAP, ERP, TRP, and short-term variability (STV) of MAP₉₀ and found that the normalization of pH prolonged the MAP₉₀ and ERP while the TRP remained unchanged, suggesting the increase in electrical vulnerability of the ventricle. Meanwhile, the STV of MAP₉₀ was the largest at pH 6.4 in the presence of nifekalant, indicating the increase in temporal dispersion of repolarization, which gradually decreased with the return of pH to 7.4. Thus, a recovery period from acidosis might be more dangerous than during the acidosis, because electrical vulnerability may significantly increase for this period while temporal dispersion of repolarization remained increased.     

Analysis of arrhythmogenic profile in a canine model of chronic atrioventricular block by comparing in vitro effects of the class III antiarrhythmic drug nifekalant on the ventricular action potential indices between normal heart and atrioventricular block heart

The chronic atrioventricular block dog is a useful model for predicting the future onset of drug-induced long QT syndrome in clinical practice. To better understand the arrhythmogenic profile of this model, we recorded the action potentials of the isolated ventricular tissues in the presence and absence of the class III antiarrhythmic drug nifekalant. The action potential durations of the Purkinje fiber and free wall of the right ventricle were longer in the chronic atrioventricular block dogs than in the dogs with normal sinus rhythm. Nifekalant in concentrations of 1 and 10 microM prolonged the action potential durations of Purkinje fiber and the free wall in a concentration-dependent manner. The extent of prolongation was greater in the chronic atrioventricular block dogs than in the normal dogs. However, increase of temporal dispersion of ventricular repolarization including early afterdepolarization was not detected by nifekalant in either group of dogs, indicating lack of potential to trigger arrhythmias in vitro. These results suggest that the ventricular repolarization delay in the chronic atrioventricular block model by nifekalant may largely depend on the decreased myocardial repolarization reserve, whereas the trigger for lethal arrhythmia was not generated in the in vitro condition in contrast to the in vivo experiment.     

Effect of nifekalant for acute conversion of atrial flutter: the possible termination mechanism of typical atrial flutter

BACKGROUND: Nifekalant is a class III antiarrhythmic drug, which is usually used for suppression of ventricular tachycardia (VT) and fibrillation. We studied the efficacy of nifekalant for acute conversion of atrial flutter (AFL) in a prospective, open label study in the intensive care unit (ICU) of cardiovascular medicine. METHODS: This study consisted of 31 patients. Twenty-six patients (84%) suffered from structural heart diseases. AFL was developed in 15 patients (48%) while on antiarrhythmic therapy with class IA or IC drugs (I-AFL group) for suppressing atrial fibrillation (AF) and in the remaining patients without such drugs (S-AFL group). Patients with prolonged QT interval, hypokalemia were excluded. All patients received one dose of 0.3 mg/kg of nifekalant over 10 minutes under continuous ambulatory monitoring. Four patients with common AFL in each group received nifekalant during electrophysiologic (EP) study. RESULTS: Nifekalant had an overall AFL conversion efficacy of 77.4% within 60 minutes. Eleven patients in S-AFL group (68.8%) and 13 patients in I-AFL group (86.7%) could be converted with mean conversion times of 10.8 +/- 6.2 and 15.0 +/- 8.0 minutes, respectively (n.s.). Conversion rate was significantly higher in patients with a short duration of arrhythmia. The two modes of AFL termination were mainly demonstrated and the preferential mode significantly differed between the two groups. One patient in each group with excessive QT prolongation (6.5%) developed torsade de pointes (TdP), requiring electrical shock in one patient (3.3%). CONCLUSIONS: Nifekalant can be used for conversion of AFL with a potent efficacy even in patients with structural heart diseases. However, caution should be required for developing TdP.     

Effect of nifekalant on acute electrical remodelling in rapid atrial pacing canine model

Atpresent, treatment of atrial fibrillation (AF) with antiarrhythmic drugs is problematic, a better understanding of the mechanisms determining antiarrhythmic drug efficacy would help in improving therapy.1 Recent evidence indicates that disease or arrhythmic induced alterations in cardiac electrophysiology (electrical remodelling) are central in arrhythmic genesis, Aparticularly for AF, which alters cardiac electrophysiology to promote its own maintenance.2,3 Pharmacological therapy to prev…     

Nifekalant hydrochloride terminating sustained ventricular tachycardia accompanied with QT dispersion prolongation

Background Ventricular tachycardia （VT） and ventricular fibrillation are the main reasons causing sudden cardiac death.This study aimed to investigate the effects of nifekalant hydrochloride （NIF） on QT dispersion （QTd） in treating VT.Methods A total of 16 consecutive patients suffered sustained VT was included and then randomly divided into two groups according to the administration duration of NIF.In long-time group （group L）, patients were injected with NIF continuously for at least 12 hours after a bolus dose.The patients in short-time group （group S） were injected with NIF just for 1 hour.Results There were 7 of all 10 episodes of VT which were terminated by NIF, including 4 episodes in group L were stopped over 1 hour after continuous infusion of NIF.One patient suffered from torsade de pointes.Electrocardiography analysis indicated that QTd was significantly decreased 12 hours after stopping of infusing NIF compared with that when VT stopped （（45.4±22.1） ms vs.（73.4±33.2） ms, P 〈0.01）, and the corrected QTd （QTcd） decreased too （（47.8±22.9） ms vs.（78.3±36.5） ms, P 〈0.01 ）.There was a positive correlation between the increase in QTd and dose of administrating NIF （P 〈0.01）, so was QTcd （P 〈0.01）.Conclusions More administration of NIF indicates higher terminating rate of VT and more QTd prolongation.However,the safety is acceptable if several important issues were noticed in using NIF, such as serum potassium concentration,stopping side-effect related agents, and carefully observing clinical responses.     

Nifekalant and disopyramide in a patient with short QT syndrome: evaluation of pharmacological effects and electrophysiological properties

We assessed several pharmacological effects on electrocardiogram parameters and effective refractory period (ERP) in a patient with a short QT syndrome (SQTS). Pharmacological challenge tests revealed that disopyramide and selective I_kr blocker, nifekalant normalized QT interval, and ERP of the atrial and ventricular myocardium. This study suggested that disopyramide and nifekalant should be feasible for the drug treatment of the SQTS. Moreover, QT interval was paradoxically prolonged at higher heart rates induced with isoproterenol infusion or an exercise test, although the mechanism of this QT prolongation remains to be investigated.