Antiarrhythmic effects of coronary vasodilators on canine ventricular arrhythmia models

Antiarrhythmic effects of intravenous coronary vasodilators (verapamil, diltiazem, bepridil, trimetazidine and nicorandil) were evaluated using two canine ventricular arrhythmia models (halothane-adrenaline arrhythmia and digitalis arrhythmia), and the minimum effective plasma concentrations of the drugs were determined for each arrhythmia model. Verapamil (0.1 mg/kg), diltiazem (0.1 mg/kg), bepridil (1 mg/kg) and high dose trimetazidine (10 mg/kg) were effective on halothane-adrenaline arrhythmia; and the minimum effective plasma concentrations of the above drugs were less than 30 +/- 10 ng/ml, less than 18 +/- 5 ng/ml, 0.38 +/- 0.11 microgram/ml and 7.0 +/- 1.5 micrograms/ml, respectively. Nicorandil (1 mg/kg) did not suppress halothane-adrenaline arrhythmia. Verapamil, diltiazem and bepridil must have suppressed the halothane-adrenaline arrhythmia by blocking the Ca channel. Verapamil (1 mg/kg), diltiazem (1 mg/kg), bepridil (5 mg/kg), trimetazidine (3 mg/kg) and nicorandil (3 mg/kg) were ineffective on digitalis arrhythmia, even though their maximum hypotensive doses were used.     

Antiarrhythmic effects of a new drug, E-0747, on canine ventricular arrhythmia models

Antiarrhythmic effects of a new antiarrhythmic drug, E-0747, were examined using four canine ventricular arrhythmia models: digitalis-, adrenaline- and two-stage coronary ligation-induced arrhythmias and a newly developed locally-induced digitalis arrhythmia. The minimum effective plasma concentration of E-0747 was determined for the first three arrhythmia models. E-0747 suppressed those arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by digitalis, adrenaline, 24 hr coronary ligation, and 48 hr coronary ligation were 1.4 +/- 0.6, 1.8 +/- 0.4, 1.6 +/- 0.4 and 2.2 +/- 0.2 micrograms/ml, respectively (mean +/- S.D., n = 5-10). The aforementioned minimum effective plasma concentrations of E-0747 for these arrhythmias were almost equal to the reported concentration in vitro to suppress the Na channels of isolated canine ventricular tissues. The class 1 property of E-0747 was also shown in a newly developed locally-induced digitalis arrhythmia. Thus E-0747 suppresses arrhythmia by inhibiting Na channels of cardiac cells and is expected to become a clinically useful antiarrhythmic drug.     

Antiarrhythmic effects of MS-551, a new class III antiarrhythmic agent, on canine models of ventricular arrhythmia.

The antiarrhythmic effects of MS-551, which prolongs cardiac action potential duration without affecting the maximum upstroke velocity of the action potential, were assessed in three different canine ventricular arrhythmia models: 1) ventricular tachycardia (VT) induced by electrical stimuli 3-5 days after myocardial infarction, 2) spontaneous ventricular tachyarrhythmias 24-48 hr after two-stage coronary ligation and 3) ventricular tachyarrhythmias induced by digitalis. Intravenous administration of MS-551 (0.1-1 mg/kg) decreased the susceptibility in 10 dogs out of 13 to VT or ventricular fibrillation evoked by programmed electrical stimulation (PES) delivered to the ventricular septum 3-5 days after myocardial infarction. Oral administration of MS-551 (3 mg/kg) also decreased the susceptibility to VT evoked by PES in 7 out of 10 conscious postinfarction dogs. Concurrently, intravenous (0.1-1 mg/kg) or oral (3 mg/kg) administration of MS-551 produced increases in the ventricular effective refractory periods (ERP) by 7 +/- 1% - 17 +/- 3% or 13 +/- 2%, respectively. Similarly, d-sotalol (0.3-3 mg/kg, i.v. and 10 mg/kg, p.o.) decreased the susceptibility to VT with increased ERP. However, MS-551 (1 and 10 mg/kg, i.v.) failed to inhibit both canine two-stage coronary ligation arrhythmia and digitalis arrhythmia. These results suggest that MS-551 is a pure class III antiarrhythmic drug which may be effective in the treatment of life-threatening reentrant tachyarrhythmias, but not in automaticity arrhythmias.     

Comparative effects of drugs on four paw oedema models in the rat.

The development of novel anti-inflammatory drugs (AID) has been claimed to be dependent on the discovery of models of inflammation that differ from those currently used for drug screening, e.g. carrageenen paw oedema and u.v. erythema. We have thus evaluated the effect of a variety of drugs in a number of novel models of inflammation in the rat produced in the hind paw. We have utilized kaolin, zymosan, anti-rat IgG (anti-IgG) and the Reversed Passive Arthus (RPA) reaction to produce these oedema models. We found that the non-steroidal AID's, e.g. aspirin, flufenamic acid, indomethacin, naproxen, and phenylbutazone, were active in all four tests. Of the nine novel AID examined, levamisole and tetramisole demonstrated considerable activity in all four tests and dapsone was especially active in the anti-IgG and RPA tests. In contrast, the anti-rheumatic d-penicillamine was inactive in all four models. Each of the ten compounds tested which has been claimed to influence complement function, was active in the RPA but not in the kaolin model. These results are discussed in the context of the aetiology of each oedema and the suspected mode of action of the various drugs.     

In vitro effects of cadmium on two different animal cell models.

The aim of this study was to assess comparatively the effects of cadmium on two different in vitro cell models, a cell line derived from proximal tubule renal cells (LLC-PK1) and haemocytes or blood cells of mussels (Mytilus galloprovincialis). Cells were seeded in 96-well microplates and exposed in vitro to different concentrations of cadmium (CdCl(2)) ranging from 10 to 2000 microM for haemocytes and from 1 to 100 microM for LLC-PK1 cells, added to the culture medium. After 24 h of exposure, different assays were performed on haemocytes: neutral red uptake, phagocytosis of neutral red-stained zymosan, XTT assay, activity of lysosomal acid phosphatase and demonstration of the actin cytoskeleton using TRITC-labeled phalloidin. Cell viability expressed as LC50 was 750 microM when using the neutral red assay and 400 microM with the XTT assay. The phagocytic ability and the activity of acid phosphatase increased significantly in cells treated with Cd in a non dose-dependent manner. Doses of Cd above 100 microM caused disruption of the actin cytoskeleton. In LLC-PK1 cells, cell viability expressed as LC50 was found to be around 40 microM when using the neutral red assay and 50-60 microM with MTT and LDH assays, respectively. These results show that mussel haemocytes are in general more resistant to Cd exposure than LLC-PK1 cells. Furthermore, Cd appears to stimulate phagocytic and lysosomal activities in haemocytes in vitro.     

哌唑嗪在不同实验模型上的抗心律失常作用

用不同的心律失常模型来研究α受体阻断药哌唑嗪的作用,结果表明,哌唑嗪对氯仿,氯化钡,乌头碱,毒毛花甙G及冠状动脉结扎-再灌注所引起的室性心律失常均有抗心律失常作用,预先用普蔡洛尔本身并不产生抗心律失常的作用,也不影响哌唑嗪的抗心律失常作用,但用普蔡洛尔反而使乌头碱及氯化钡诱发大鼠室性心律失常更为明显,提示α受体阻断药是通过多种机理产生抗心律失常作用的。     

The effects of carbamazepine on two animal models of depression

Some clinical reports on antimanic, antidepressant and prophylactic effects of carbamazepine (CBZ) in manic-depressive illness have appeared since its initial use as an anticonvulsant drug. The present report deals with the effects of CBZ on two animal models of depression, namely the potentiation of amphetamine-induced anorexia, and the behavioral despair model. Carbamazepine (10, 20 or 40 mg/kg) neither modified the methamphetamine anorectic effect, nor induced anorexia when administered alone. Subacute and chronic administration of imipramine (4 or 15 mg/kg) decreased immobility of rats in the behavioral despair model. Subacute and chronic administration of CBZ (40 mg/kg) also decreased immobility, whereas the dose of 10 mg/kg CBZ was effective only after chronic treatment. It was concluded that CBZ is similar to atypical anti-depressants, since it did not potentiate the amphetamine-induced behavioral effect, but did have an effect on the behavioral despair model of depression.     

Antiarrhythmic profile of a new class 1 drug, AHR 10718, on canine atrial and ventricular arrhythmia models

Antiarrhythmic effects of AHR 10718 were examined using two-stage coronary ligation, digitalis and adrenaline-induced canine ventricular arrhythmias and aconitine-induced canine atrial arrhythmia. The minimum effective plasma concentration for each arrhythmia model was determined for quantitative analysis of the antiarrhythmic effects. AHR 10718 suppressed the above arrhythmias except for adrenaline-induced arrhythmia. The minimum effective plasma concentrations for arrhythmias induced by 24 hr coronary ligation, 48 hr coronary ligation and digitalis were 8.1 +/- 0.7 (by 10 mg/kg, i.v.), 2.9 +/- 0.9 (by 5 mg/kg, i.v.) and 2.8 +/- 0.6 (by 5 mg/kg, i.v.) microgram/ml, respectively (mean +/- S.D., n = 6). The correlation coefficients between the antiarrhythmic effects of AHR 10718 and its plasma concentrations were not high. This pharmacological profile is characteristic of class 1 Na channel blockers, and in particular, it is similar to those of disopyramide, procainamide and SUN 1165 from our previous studies. AHR 10718 is expected to become a clinically useful antiarrhythmic drug.     

Effects of antiarrhythmic drugs on canine ventricular arrhythmia models

In order to compare and clarify the effects of various antiarrhythmic drugs, we examined drug effects on several canine arrhythmia models, simultaneously determining the minimum effective plasma concentrations. We used 1) two-stage coronary ligation arrhythmia, 2) digitalis arrhythmia, and 3) halothane-adrenaline arrhythmia. The following are, a summary of our results: Antiarrhythmic drugs of class 1 all suppressed digitalis arrhythmia, and except for lidocaine, also suppressed coronary ligation arrhythmia. Class 2 antiarrhythmic drugs, beta blockers, and class 4 antiarrhythmic drugs, Ca channel blockers, had common features of effectiveness, where they suppressed adrenaline arrhythmia in relatively low concentrations. Some differences among the antiarrhythmic effects of class 1 drugs could not be explained by their subclassification based either on action potential duration or kinetic properties of dissociation or association with Na channels. A new arrhythmia model for triggered activity in in vivo canine heart was developed, but drug effects on it does not seem to be very different from the effects on the other three arrhythmia models.     

心律失常患者中心律平药动学研究

用ＨＰＬＣ测定血浆中心律平的浓度，灵敏度高，准确度好，在５０～４０００ｎｇ／ｍｌ范围内线性关系良好，最低检测限５０ｎｇ／ｍｌ。６名心律失常患者口服６００ｍｇ心律平后，药时曲线拟合均呈一室模型，平均消除半衰期为２．３±０．６ｈ，平均达峰时间３．０±０．７ｈ，血浓最大个体差异相差７．９倍，峰浓最大相差２．５倍，提示心律平存在明显个体差异。     

异丙酚对大鼠离体心脏再灌注心律失常的影响

目的：实验观察异丙酚对大鼠离体心脏再灌注心律失常的影响。方法：SD大鼠Langendorff离体心脏灌注后,建立冠状动脉左前降支局部心肌缺血和再灌注心律失常模型。分6组：对照组;异丙酚1μg/ml组;异丙酚3μg/ml组;维拉帕米10ng/ml组;异丙酚1μg/ml加维拉帕米10ng/ml组;异丙酚3μg/ml加维拉帕米10ng/ml组。定时测量冠脉流量、心率和连续监测ECG,以比较各组再灌注期室性期前收缩（VPB）、心室纤颤（VF）、室性心动过速（VT）的发生率以及正常窦性节律（NSR）的持续时间。结果：与对照组相比,后4组再灌注期的VF发生率均有非常显著地降低（P＜0．01）,VF的持续时间显著缩短（P＜0．01）,NSR的时间明显延长,而VT的发生率仅有下降趋势。结论：3μg/ml的异丙酚与10ng/ml的维拉帕米相似,对大鼠离体心脏再灌注期VF的发生率和持续时间具有非常显著的抑制作用。     

人类免疫缺陷病毒动物模型在相关神经病变的研究应用

人免疫缺陷病毒(human immunodeficiency virus,HIV)感染引起全身免疫系统严重损害。HIV感染后病毒产物本身及高效抗逆转录病毒治疗均可引起相关神经病变,包括神经认知功能障碍综合征(HIV associated neurocognitive disorders,HAND)、外周神经病变等并发症。HIV动物模型可对其相关神经病变的发病机制研究提供帮助,该文主要介绍HIV-1动物模型在相关神经病变病理机制的研究应用。     

宁心宝胶囊联合普罗帕酮治疗室性心律失常的临床研究

目的观察宁心宝胶囊联合普罗帕酮治疗室性心律失常的安全性与有效性。方法选取2016年7月—2017年7月于重庆市巴南区人民医院治疗的室性心律失常患者151例,随机分成对照组(75例)和治疗组(76例)。对照组患者口服盐酸普罗帕酮片,6片/次,3次/d;治疗组患者在对照组基础上口服宁心宝胶囊,2粒/次,2次/d。两组患者连续治疗2个月。观察两组患者临床疗效,同时比较治疗前后两组患者动态心电图指标、心功能指标和不良反应情况。结果治疗后,对照组和治疗组临床有效率分别为85.33%和96.05%,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者QRS波时限、室性早搏及短阵室速较治疗前显著降低(P0.05),且治疗组这些动态心电图指标明显低于对照组(P0.05)。治疗后,两组患者6min步行距离和左心室射血分数(LEVF)水平较治疗前显著升高(P0.05),脑尿钠肽(BNP)水平显著降低(P0.05),且治疗组这些心功能指标明显好于对照组(P0.05)。治疗期间,治疗组患者药物不良反应发生率为3.95%,显著低于对照组患者的14.67%,两组比较差异具有统计学意义(P0.05)。结论宁心宝胶囊联合普罗帕酮治疗室性心律失常效果显著、安全性高,且能够显著改善患者心功能,具有一定的临床推广应用价值。     

Anxiolytic effects of mecamylamine in two animal models of anxiety

Clinical and preclinical evidence suggests that mecamylamine, a nicotinic receptor antagonist, may have anxiolytic properties. The purpose of this study was to further investigate the anxiolytic properties of mecamylamine in rats as measured by the Elevated Plus Maze and the Social Interaction models of anxiety and to determine if manipulation of the testing environment (either brightly lit or dimly lit conditions) influenced the results. Results indicated that mecamylamine had significant anxiolytic effects in both the Elevated Plus Maze and Social Interaction Tests and that these effects were dependent on dose administered and the level of anxiety produced under different testing conditions. If confirmed by further clinical research, nicotinic receptor antagonists like mecamylamine may represent a novel class of anxiolytics.     

Antiarrhythmic and antifibrillatory properties of McN-4130 in several animal models

McN-4130 is an experimental compound having antiarrhythmic and antifibrillatory activity in several animal models. In anesthetized, open-chest pigs subjected to total occlusion and subsequent reperfusion of the left anterior descending coronary artery, McN-4130 dose-dependently (2.5-10.0 mg/kg i.v.) protected against fibrillation and death. Mean arterial pressure was not significantly affected, but heart rate was dose-dependently reduced. In anesthetized normal dogs, McN-4130 increased ventricular fibrillation threshold for up to 45 min. This increase in fibrillation threshold was associated with concurrent increases in ventricular conduction time and ventricular effective refractory period. In conscious dogs subjected to occlusion of the left anterior descending coronary artery 24 h previously, McN-4130, 2.5 and 5.0 mg/kg i.v., significantly reduced the rate of ventricular arrhythmias for up to 45 min. McN-4130 was more effective and had a longer duration of action than comparable doses of lidocaine and disopyramide. McN-4130 was orally effective in this model at 10 mg/kg. These results indicate that McN-4130, a structurally unique experimental antiarrhythmic compound, may be useful as a ventricular antiarrhythmic agent with antifibrillatory properties.     

Comparative efficacy and safety of intravenous non-steroidal anti-inflammatory drugs in two animal models of pain

In this study, the antinociceptive activity of five non-steroidal anti-inflammatory drugs (NSAIDs) was determined in two animal models of different pain intensity and compared with their capacity to produce motor incoordination and death. Intravenous clonixine, diclofenac, dipyrone (metamizole), ketorolac, and piroxicam produced dose-dependent antinociception in the acetylcholine-induced writhing test with ED₅₀ values ranging from 14 (clonixine) to 205 (dipyrone) μmol/kg. The behavioral responses in the 55°C hot plate assay were also inhibited in a dosedependent manner, but significantly higher doses were required to display antinociceptive activity, the ED₅₀ values ranging from 116 (clonixine) to 2, 263 (dipyrone) μmol/kg. In the writhing test, the antinociceptive effects of NSAIDs were present at doses far below those producing toxic effects. In contrast, their ED₅₀ values against a more intense nociceptive stimulus approached those producing lethal effects so that the therapeutic ratios were very small, ranging from 1.3 (diclofenac) to 3.0 (dipyrone). The antinociceptive activity of the reference drug morphine is striking, since both types of nociceptive responses were eliminated at doses substantially lower than those producing death (therapeutic ratios of 502 and 121). Morphine exhibited the highest antinociceptive efficacy, followed by dipyrone, ketorolac, clonixine, and piroxicam. Diclofenac showed a more limited efficacy. These findings imply potential risks for patients treated iv with this class of drugs and suggest caution in the use of high doses of NSAIDs. Future development of injectable NSAID formulations should include a detailed analysis of adverse reactions following iv administration of high doses. © 1995 Wiley-Liss, Inc.     

Effects of a new antiarrhythmic drug TYB-3823 on canine ventricular arrhythmia models.

The antiarrhythmic and direct cardiovascular effects of a new antiarrhythmic agent, TYB-3823 [1-(2,6-dimethylphenyl)-4,4-dimethyl-aminoguanidine hydrochloride], were investigated. To determine the antiarrhythmic effects, spontaneously occurring adrenaline-, digitalis-, and two-stage coronary ligation-induced arrhythmias were used. TYB-3823 suppressed these three arrhythmia models. The antiarrhythmic plasma concentrations, IC50, of TYB-3823 for digitalis-, coronary ligation-, and adrenaline-induced arrhythmias were 7.8, 16.8, and 5.0 micrograms/ml, respectively. In the blood perfused sinoatrial (SA) node and papillary muscle (PM) preparations, TYB-3823 decreased the sinoatrial rate (SAR) and contractile force following an initial small positive inotropic effect and increased the intraventricular conduction time and coronary blood flow. These results indicate that TYB-3823 is similar to other class I antiarrhythmic agents, such as aprindine and nicainoprol, in the antiarrhythmic profile and is expected to become a clinically useful antiarrhythmic drug.