Ⅲ类抗心律失常药物研究近况

综述近年来Ⅲ类抗心律失常药物的研究进展，分类介绍单纯型ⅠKr阻滞剂、单纯型ⅠKs阻滞剂和复合型Ⅲ类抗心律失常药物的药理作用和药效学，探讨抗心律失常药物的新靶点和发展方向。     

阿魏酸钠抗心律失常机制的初步探讨

目的探讨阿魏酸钠是否具有抗心律失常作用及其可能的抗心律失常机制。方法应用哇巴因及乌头碱建立心律失常的动物模型 ,并观察阿魏酸钠对心律失常的影响。结果阿魏酸钠0 6g/kg静脉推注可对抗哇巴因诱发的室性心律失常 ,使室性早搏、室性心动过速、室颤的发生时间延长 ,并可提高哇巴因致室性早搏、室性心动过速、室颤的剂量 ,两组之间差异有显著意义 (P <0 0 1) ,但阿魏酸钠不能对抗乌头碱诱发的心律失常。结论阿魏酸钠具有对抗哇巴因诱发的心律失常作用 ,机制可能与其对钾离子通道的阻滞作用有关     

一种新心律失常大鼠模型的建立

目的建立一种新的心律失常动物模型。方法大鼠脂肪乳剂灌胃建立大鼠高脂血症模型后进行冠状动脉结扎，观察术后1 h心律失常发生情况，并进行心律失常评分。结果高脂血症大鼠冠脉结扎组同正常大鼠冠脉结扎组相比，室性早博二联律、室性心动过速持续时间均明显延长。胺碘酮、维拉帕米对单纯冠脉结扎诱发的心律失常个数及持续时间无明显作用。维拉帕米对高脂血症大鼠冠脉结扎诱发的心律失常个数及持续时间也无明显影响，而胺碘酮明显减少高脂血症大鼠冠脉结扎诱发的心律失常个数及持续时间。结论通过高脂血症大鼠冠脉结扎可以建立一种接近临床的心律失常动物模型。     

抗心律失常药物的致心律失常作用

随着新型抗心律失常药物的不断问世，该类药物的致心律失常作用日渐增多从而影响了其在临床的广泛应用，本文就其威胁生命的致心律失常作用类型。预测致心律失常作用加重的标志以及对致心律失常的药物动力学机制进行阐述。并对门诊，住院患者抗心律失常药物的选用原则进行简要的讨论。     

苦参总碱抗实验性心律失常的作用

目的：研究苦参总碱抗实验性心律失常的作用。方法：本研究采用冠脉结扎，BaCl2肾上腺素，乌头碱，哇巴因诱发的心律失常模型。结果：苦参总碱能明显对抗大鼠冠脉结扎后诱发的早期缺血性心律失常；对BaCl2诱发的大鼠心律失常有预防和治疗作用；缩短静注肾上腺素诱发的家兔心律失常持续时间；增加乌头碱诱发大鼠心律失常的剂量；增加哇巴因诱发豚鼠心律失常的剂量。结论：苦参总碱对多种心律失常模型有预防或治疗作用，其抗心律失常机制是多方面的。     

一种新的适合于筛选抗梭菌属药物的培养基

拟膜状结肠炎是一种死亡率很高的严重的传染病之一。它多发生于抗生素联合治疗,尤其是用广谱抗细菌抗生素治疗的病例。引起这种病的主要病原体是厌氧细菌艰难梭菌。这种菌在培养过程中对氧非常敏感,要求严格的厌氧条件。一旦暴露到空气中就再也不生长。因此在分离、培养和保藏艰难梭菌的所有过程中,都必须在厌氧箱和厌氧室中进行。这种条件对开展和进行筛选控制拟膜状结肠炎的药物带来极大的不便。本文描述了一种培养艰推梭菌的简单而便利的琼脂培养基。采用这种培养基培养艰难梭菌,可以在空气中操作几小时而后置于厌氧培养室中培养。实验中采用艰难梭菌KB-258(ATCC     

与抗心律失常药物相关的药物相互作用

心律失常是心动规律和频率的异常，此时心室心房正常激活和运动顺序发生障碍，是一种严重的、复杂的心脏疾患，目前临床缺乏特异的治疗药物。     

抗心律失常药物的非临床心血管系统安全性评价研究进展

抗心律失常药物作用于心肌细胞的离子通道,临床使用时常产生致心律失常等风险。药物非临床安全性评价过程中,除参考国内外指导原则外,应结合药物作用机制和适应症的特点,追加心血管系统安全性相关试验,有针对地完善试验设计,为后续试验中风险点的设置和临床使用风险的防控提供参考。     

邻卤代苄基异喹啉碘盐抗心律失常作用的研究

目的：比较1-(邻-碘苄基)-6，7-甲二氧基-2-甲基-3，4-二氢异喹啉碘盐(O-BIMMDI)与1-(邻-溴苄基)-6，7-甲二氧基-2-甲基-3，4-二氢异喹啉碘盐(O-BBMMDI)，对实验性心律失常模型的影响。方法：采用乌头碱、氯化钡和结扎左冠状动脉前降支方法制备大鼠心律失常模型，观察并比较O-BIMMDI与O-BBMMDI的保护作用。结果：O-BIMMDI和O-BBMMDI可对抗乌头碱、氯化钡所致的大鼠心律失常，延长心律失常诱发时间，缩短心律失常持续时间；对结扎左冠状动脉前降支所诱发的大鼠心律失常也有一定的对抗作用，并可减轻结扎造成的心肌缺血。O-BBMMDI抗心律失常作用优于O-BBMMDI。结论：O-BBMMDI和O-BBMMDI均可对抗大鼠心律失常模型，而O-BBMMDI抗心律失常作用优于O-BBMMDI．     

Establishment of liver specific glucokinase gene knockout mice： a new animal model for screening anti-diabetic drugs

AIM:Tocharacterizetheliver-specificroleofglucokinaseinmaintainingglucosehomeostasisandtocreateananimalmodelfordiabetes.METHODS:Weperformedhepatocyte-specificgeneknockoutofglucokinaseinmiceusingCre-loxPgenetargetingstrategy.First,twodirectlyrepeatedloxPsequenceswereinsertedtoflanktheexon9andexon10ofglucokinaseingenomicDNA.Toachievethis,linearizedtargetingvectorwaselectroporatedintoEScells.ThenG418-andGancyclovir-double-resistantcloneswerepickedandscreenedbyPCRanalysisandthepositivesid…     

Inhibition of aconitine-induced mortality in the conscious rat: a screening test for antiarrhythmic drugs

A test for inhibition of mortality induced by intravenous injection of aconitine in rats is proposed as a particularly valid method, owing to its simplicity and degree of specificity, for inclusion among the preliminary screening tests for antiarrhythmic activity. LD50 (63.5 micrograms/kg, i.v.) and LD99 (118.9 micrograms/kg, i.v.) values of aconitine were determined. The dose employed for screening was 100 micrograms/kg i.v., which in control animals produced a death rate of 97.7% (293 deaths/300 treated animals). The protection produced by various drugs belonging to different groups of antiarrhythmics was studied. ED50s, expressed in mg/kg i.p., were as follows: Class I antiarrhythmics: flecainide, 5.5; E-4017, 30.0; lorcainide, 30.9; quinidine, 41.1; diphenylhydantoin, 42.3; lidocaine, 48.5; ajmaline: 53.9; procainamide, 61.3. Class II antiarrhythmics: pindolol 22.8; propranolol, 24.9; oxprenolol, 38.0; labetalol, 60.7; atenolol, 100.0; metoprolol, approximately 160; acebutalol, greater than 160; timolol, greater than 160. Class III antiarrhythmics: amiodarone, greater than 160. Class IV antiarrhythmics: verapamil, diltiazem and nifedipine were inactive up to 40 mg/kg. The test would appear to be selective for membrane-stabilizing agents (class I) and beta-blockers (class II), but in view of the magnitudes of activity found, it should be used in combination with other antiarrhythmic tests.     

磷酸喹哌抗实验性心律失常作用

磷酸喹哌(PQP)9mg·kg~(-1)iv明显降低小鼠室颤的死亡率;PQP 18mg·kg~(-1)ip对氯仿诱发小鼠室颤具有保护作用;PQP 6.3mg·kg~(-1)ip显著增加恒速(10mg·L~(-1)·min~(-1)滴注乌头碱引起麻醉大鼠室性早搏(VE)、室性心动过速(VT)、室性纤颤(VF)所需的乌头碱用量;PQP5.4 mg·kg~(-1)iv显著增加恒速(50mg·L~(-1)·min~(-1))滴注哇巴因引起麻醉豚鼠VE、VT和VF所需哇巴因用量;PQP3.36mg·kg~(-1)iv明显缩短肾上腺素诱发家兔室性心律失常的持续时间.结果表明PQP具有抗心律失常作用。小鼠PQPLD_(50)iv为93.33 mg·kg~(-1)。     

Investigational antiarrhythmic agents: promising drugs in early clinical development

Introduction: Although there have been important technological advances for the treatment of cardiac arrhythmias (e.g., catheter ablation technology), antiarrhythmic drugs (AADs) remain the cornerstone therapy for the majority of patients with arrhythmias. Most of the currently available AADs were coincidental findings and did not result from a systematic development process based on known arrhythmogenic mechanisms and specific targets. During the last 20 years, our understanding of cardiac electrophysiology and fundamental arrhythmia mechanisms has increased significantly, resulting in the identification of new potential targets for mechanism-based antiarrhythmic therapy.

Areas covered: Here, we review the state-of-the-art in arrhythmogenic mechanisms and AAD therapy. Thereafter, we focus on a number of antiarrhythmic targets that have received significant attention recently: atrial-specific K⁺-channels, the late Na⁺-current, the cardiac ryanodine-receptor channel type-2, and the small-conductance Ca²⁺-activated K⁺-channel. We highlight for each of these targets available antiarrhythmic agents and the evidence for their antiarrhythmic effect in animal models and early clinical development.

Expert opinion: Targeting AADs to specific subgroups of well-phenotyped patients is likely necessary to detect improved outcomes that may be obscured in the population at large. In addition, specific combinations of selective AADs may have synergistic effects and may enable a mechanism-based tailored antiarrhythmic therapy.     

A classification of antiarrhythmic actions reassessed after a decade of new drugs

The past decade has seen the introduction of many new class 1 drugs, restricting fast inward current. Confirmative evidence has been obtained that the antiarrthymic action of lidocaine and diphenylhydantoin is indeed due to their effect as class 1 agents depressing conduction. The original class 3 drug, amiodarone, is increasingly in use as an antiarrhythmic of first choice for WPW and for arrhythmias associated with hypertrophic myopathy, and as a reserve drug in resistant arrhythmias of other types. Other compounds delaying repolarization have proved to be clinically effective as antiarrhythmics. In addition to their class 2 antiarrhythymic action exhibited acutely, on long-term treatment beta blockers have a class 3 action, which might be, at least in part, responsible for the protection of postinfarction patients against sudden death. Recent research suggests that inhibition of slow inward current may lead, as a secondary consequence of lowered [Ca]i, to improved cell-to-cell conduction. Finally, all but one of the new antiarrhythmic drugs, none of which existed in 1972, have turned out to possess one or more of the four classes of action originally described. This can hardly be a coincidence. The single exception, alinidine, a selective bradycardic agent, may restrict anionic currents, which would constitute a fifth class of action, but this is far from proved.     

Piceatannol, a derivative of resveratrol, moderately slows INa inactivation and exerts antiarrhythmic action in ischaemia-reperfused rat hearts

Background and purpose:

Piceatannol is more potent than resveratrol in free radical scavenging in association with antiarrhythmic and cardioprotective activities in ischaemic-reperfused rat hearts. The present study aimed to investigate the antiarrhythmic efficacy and the underlying ionic mechanisms of piceatannol in rat hearts.

Experimental approach:

Action potentials and membrane currents were recorded by the whole-cell patch clamp techniques. Fluo-3 fluorimetry was used to measure cellular Ca²⁺ transients. Antiarrhythmic activity was examined from isolated Langendorff-perfused rat hearts.

Key results:

In rat ventricular cells, piceatannol (3–30 µmol·L⁻¹) prolonged the action potential durations (APDs) and decreased the maximal rate of upstroke (V_max) without altering Ca²⁺ transients. Piceatannol decreased peak I_Na and slowed I_Na inactivation, rather than induced a persistent non-inactivating current, which could be reverted by lidocaine. Resveratrol (100 µmol·L⁻¹) decreased peak I_Na without slowing I_Na inactivation. The inhibition of peak I_Na or V_max was associated with a negative shift of the voltage-dependent steady-state I_Na inactivation curve without altering the activation threshold. At the concentrations more than 30 µmol·L⁻¹, piceatannol could inhibit I_Ca,L, I_to, I_Kr, Ca²⁺ transients and Na⁺-Ca²⁺ exchange except I_K1. Piceatannol (1–10 µmol·L⁻¹) exerted antiarrhythmic activity in isolated rat hearts subjected to ischaemia-reperfusion injury.

Conclusions and implications:

The additional hydroxyl group on resveratrol makes piceatannol possessing more potent in I_Na inhibition and uniquely slowing I_Na inactivation, which may contribute to its antiarrhythmic actions at low concentrations less than 10 µmol·L⁻¹.     

Arrhythmia models for drug research: classification of antiarrhythmic drugs

The aim of this study was to classify antiarrhythmic drugs based on their effectiveness on 6 in vivo arrhythmia models, mainly using dogs. The models were produced by two-stage coronary ligation, digitalis, halothane-adrenaline, programmed electrical stimulation in old myocardial infarction dogs, coronary artery occlusion/reperfusion, or chronic atrioventricular block. Na(+)-channel-blocking drugs suppressed two-stage coronary ligation and digitalis arrhythmias. Ca(2+)-channel blockers and beta-blockers suppressed halothane-adrenaline arrhythmia. Positive inotropic drugs aggravated halothane-adrenaline arrhythmia, but did not aggravate digitalis arrhythmia. K(+)-channel blockers suppressed programmed electrical stimulation induced arrhythmia, but induced torsades de pointes type arrhythmia in chronic atrioventricular block dogs and aggravated halothane-adrenaline arrhythmia. Na(+)/H(+)-exchange blockers suppressed coronary artery occlusion/reperfusion arrhythmias. This classification may be useful for predicting the clinical effectiveness in the preclinical stage of drug development.