卡维地洛治疗心力衰竭对大鼠心肌细胞凋亡和Bcl-2、Bax蛋白表达水平的影响

目的 从细胞凋亡角度探讨卡维地洛治疗心力衰竭的机制。方法 采用结扎冠状动脉复制慢性心功能不全模型，观察卡维地洛治疗心力衰竭，对心肌细胞凋亡率、bcl-2、Bax蛋白表达水平的影响。结果 卡维地洛干预心功能不合可以剂量依赖地使心肌细胞凋亡率和Bax蛋白表达水平降低，使bcl-2蛋白表达水平增加。特拉唑嗪对心肌细胞凋亡和Bax、bcl-2的蛋白表达水平无影响。结论 抑制Bax蛋白表达水平，同时增加bcl-2蛋白表达水平，从而抑制心肌细胞凋亡，是卡维地洛治疗心力衰竭的重要机制之一。卡维地洛抑制心肌细胞凋亡的效应与α1－受体阻滞作用无关。     

Stereoselective analysis of carvedilol in human plasma and urine using HPLC after chiral derivatization

An enantioselective high-performance liquid chromatographic method for the analysis of carvedilol in plasma and urine was developed and validated using (-)-menthyl chloroformate (MCF) as a derivatizing reagent. Chloroform was used for extraction, and analysis was performed by HPLC on a C18 column with a fluorescence detector. The quantitation limit was 0.25 ng/ml for S(-)-carvedilol in plasma and 0.5 ng/ml for R(+)-carvedilol in plasma and for both enantiomers in urine. The method was applied to the study of enantioselectivity in the pharmacokinetics of carvedilol administered in a multiple dose regimen (25 mg/12 h) to a hypertensive elderly female patient. The data obtained demonstrated highest plasma levels for the R(+)-carvedilol (AUC(SS) (0-12) 75.64 vs 37.29 ng/ml). The enantiomeric ratio R(+)/S(-) was 2.03 for plasma and 1.49 for urine (Ae(0-12) 17.4 vs 11.7 microg).     

比索洛尔与卡维地洛治疗慢性心力衰竭的系统评价

目的系统评价比索洛尔与卡维地洛治疗慢性心力衰竭的疗效与安全性。方法计算机检索Cochrance图书馆(2012年第1期)、中国知网、中国生物医学文献数据库、中国科技期刊数据库、万方数据库、PubMed、Springer Link等中外生物医学数据库,纳入比索洛尔与卡维地洛治疗慢性心力衰竭的随机对照试验,检索日期截止到2012年3月31日。按照Cochrance系统评价方法,评价纳入研究的文献质量,并提取有效数据后采用RevMan 5.1软件对2组患者的收缩压、舒张压、心率、左室射血分数以及不良反应发生率等指标进行Meta分析。结果共纳入15个随机对照试验。Meta分析结果表明,2组患者分别在治疗第8周、第12周、第14周、第16周、第20²2周、第24周、第30周后收缩压、舒张压、心率、左室射血分数的变化水平以及不良反应发生率均无差异。结论目前的证据表明,比索洛尔具有与卡维地洛相似的治疗慢性心力衰竭的疗效和安全性。     

卡维地洛治疗慢性心力衰竭疗效预测参数研究

目的运用常用的临床指标预测卡维地洛（Carvedilol）治疗慢性心力衰竭（CHF）的效果。方法44例心衰患者（NYHAⅡ～Ⅳ）随机分为常规治疗组和卡维地洛组,并且根据治疗效果再将卡维地洛组分为疗效显著亚组（A组）和疗效不显著亚组（B组）,通过临床监测探讨卡维地洛疗效显著的预测参数。结果（1）卡维地洛治疗可以明显改善患者心功能、抑制心肌重构;（2）A组患者（n=13）收缩压明显高于B组（n=7）（P〈0．05）;（3）A组血清Na^＋浓度高于B组、血清K^＋低于B组（P〈0．05）。结论从卡维地洛治疗心衰疗效显著的患者分析中,提示治疗前的收缩压水平、血清Na^＋和血清K^＋浓度可以预测CHF的疗效。     

雷米普利、缬沙坦及卡维地洛联用对慢性心力衰竭自主神经功能的影响

目的 通过心率变异性（HRV）分析,观察雷米普利、缬沙坦及卡维地洛联用对慢性心力衰竭病人自主神经系统的影响。方法 对74例慢性心力衰竭病人（治疗组）联用雷米普利、缬沙坦及卡维地洛治疗6个月,测量冶疗前后HRV指标及左心室射血分数,并与60例健康者对照。结果 治疗组治疗前窦性RR间期的标准差、窦性RR间期平均值的标准差、窦性RR间期标准差的平均值、窦性RR间期差值的均方根、相邻两个正常窦性RR间期差值大于50ms的个数所占的百分数、左心室射血分数与对照组相比明显降低（t=3．322～3．371,P〈0．001）;治疗后各指标与治疗前比较差异有显著性（t=2．120～3．351,P〈0．001、0．05）。结论 雷米普利、缬沙坦并卡维地洛联用可明显改善慢性心力衰竭病人自主神经系统的功能。     

卡维地洛对急性心肌梗死QT离散度的影响

目的: 探讨卡维地洛对急性心肌梗死不同时期QT离散度(QTd)的影响及与心脏事件的关系。方法: 43例AMI患者分为卡维地洛组20例和对照组23例。分别在入院时及入院后1、3、7、14、21日记录静息12导联同步心电图及心电监护和动态心电图,计算QTd并分析其与心脏事件的关系。结果: AMI患者QTd于24h时显著增大,3天开始下降,后下降速度减慢。卡维地洛组QTd于3日后与对照组比较显著降低(P>0.05)。卡维地洛组心脏事件发生率20.0%,低于对照组34.8%,发生心脏事件的最大QTd为(77.19±10.81) ms (P>0.05),显著高于无心脏事件者(58.15±9.71) ms (P<0.01)。结论: AMI早期存在显著QTd增加。卡维地洛可显著降低AMI患者QT离散度。     

Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in a NG‐nitro‐l‐arginine methyl ester rat model of secondary hypertension

Objectives The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in N^G‐nitro‐l ‐arginine methyl ester (L‐NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic–pharmacodynamic (PK‐PD) modelling. Methods Male Wistar rats were randomly divided into two groups: control rats received tap water to drink for 2 weeks while L‐NAME rats received L‐NAME solution to drink for 2 weeks. The effects of carvedilol (1 and 5 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics were studied by means of traditional blood sampling. The relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by means of PK‐PD modelling. Vascular sympatholytic activity of carvedilol was assessed by the estimation of drug effects on low frequency blood pressure variability by means of spectral analysis. Key findings A dose‐dependent increase in volume of distribution, as well as a greater volume of distribution and clearance of S‐carvedilol as compared with the R‐enantiomer was found in both experimental groups. Although the PK‐PD properties of the S‐carvedilol chronotropic effect were not altered in L‐NAME rats, hypertensive rats showed greater potency and efficacy to the carvedilol hypotensive response. Greater potency of carvedilol for inhibition of sympathetic vascular activity was found in L‐NAME rats. Conclusions Carvedilol showed enantioselective non‐linear pharmacokinetic properties in both groups. An enhanced hypotensive activity of carvedilol was found in L‐NAME hypertensive rats compared with control rats, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition.     

卡维地洛与拉贝洛尔治疗轻中度高血压病的比较

目的 :评价国产卡维地洛与拉贝洛尔的降压疗效。方法 :轻、中度高血压病病人 2 0 0例 ,采用平行、随机、双盲对照方法 ,其中卡维地洛组 10 0例 ,给卡维地洛 10～ 2 0mg ,po ,bid ;拉贝洛尔组 10 0例给拉贝洛尔 50～ 10 0mg ,po ,bid ;对另 2 0例开放服卡维地洛 ,4 0mg ,po ,qd ;2药均服 4wk。结果 :2药均能明显降压、减慢心率 ;总有效率卡维地洛为 83% ,拉贝洛尔为 75% ,组间比较 (P >0 .0 5)。对 2 0例开放服卡维地洛者 ,治疗前后经 2 4h动态血压监测 ,发现日间平均血压下降及心率减慢差别均有显著意义 (P <0 .0 5或P <0 .0 1) ;对 2 0例中的10例计算血压谷 /峰比值 :SBP为 58% ,DBP为36 %。结论 :2药治疗轻、中度高血压病疗效均较好而安全。     

Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels

BACKGROUND AND PURPOSE

Human K_2P3.1 (TASK1) channels represent potential targets for pharmacological management of atrial fibrillation. K_2P channels control excitability by stabilizing membrane potential and by expediting repolarization. In the heart, inhibition of K_2P currents by class III antiarrhythmic drugs results in action potential prolongation and suppression of electrical automaticity. Carvedilol exerts antiarrhythmic activity and suppresses atrial fibrillation following cardiac surgery or cardioversion. The objective of this study was to investigate acute effects of carvedilol on human K_2P3.1 (hK_2P3.1) channels.

EXPERIMENTAL APPROACH

Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hK_2P3.1 currents from Xenopus oocytes, Chinese hamster ovary (CHO) cells and human pulmonary artery smooth muscle cells (hPASMC).

KEY RESULTS

Carvedilol concentration-dependently inhibited hK_2P3.1 currents in Xenopus oocytes (IC₅₀= 3.8 µM) and in mammalian CHO cells (IC₅₀= 0.83 µM). In addition, carvedilol sensitivity of native I_K2P3.1 was demonstrated in hPASMC. Channels were blocked in open and closed states in frequency-dependent fashion, resulting in resting membrane potential depolarization by 7.7 mV. Carvedilol shifted the current–voltage (I–V) relationship by −6.9 mV towards hyperpolarized potentials. Open rectification, characteristic of K_2P currents, was not affected.

CONCLUSIONS AND IMPLICATIONS

The antiarrhythmic drug carvedilol targets hK_2P3.1 background channels. We propose that cardiac hK_2P3.1 current blockade may suppress electrical automaticity, prolong atrial refractoriness and contribute to the class III antiarrhythmic action in patients treated with the drug.     

Development and validation of new discriminative dissolution method for carvedilol tablets

The objective of the present study was to develop and validate a discriminative dissolution method for evaluation of carvedilol tablets. Different conditions such as type of dissolution medium, volume of dissolution medium and rotation speed of paddle were evaluated. The best in vitro dissolution profile was obtained using Apparatus II (paddle), 50 rpm, 900 ml of pH 6.8 phosphate buffer as dissolution medium. The drug release was evaluated by high-performance liquid chromatographic method. The dissolution method was validated according to current ICH and FDA guidelines using parameters such as the specificity, accuracy, precision and stability were evaluated and obtained results were within the acceptable range. The comparison of the obtained dissolution profiles of three different products were investigated using ANOVA-based, model-dependent and model-independent methods, results showed that there is significant difference between the products. The dissolution test developed and validated was adequate for its higher discriminative capacity in differentiating the release characteristics of the products tested and could be applied for development and quality control of carvedilol tablets.