卡维地洛对老年舒张性心力衰竭患者心功能及糖、脂代谢的影响

目的：探讨卡维地洛对老年舒张性心力衰竭（DHF）患者心功能及糖、脂代谢的影响,阐明其改善心功能的作用。方法：将76例老年舒张性心力衰竭的患者随机分为治疗组34例及对照组42例,全部给予常规抗舒张性心力衰竭治疗,治疗组加用卡维地洛（从小剂量开始）,疗程3～6个月。应用超声心动图（UCG）及无创心功能检测仪（Bioz.com）测定两组治疗前后心脏舒张功能指标。检测两组空腹血糖及甘油三酯、胆固醇水平。结果：治疗组患者在治疗后总有效率明显高于对照组（P<0.05）,反映左室舒张功能的指标优于治疗前（P<0.05）,与对照组比较差异有显著性（P<0.05）。治疗组用药前后血糖、血脂变化差异无显著性(P>0.05),与对照组比较血糖、血脂均降低（P<0.05）。治疗过程中,两组均未发生明显不良反应,无一例停药。结论：应用卡维地洛可改善老年舒张性心力衰竭患者的左室功能,且对糖、脂代谢无明显影响。     

卡维地洛对HERG钾通道电生理功能及蛋白表达的影响

目的探讨卡维地洛对稳定转染HERG基因的HEK(human embryonic kidney)293细胞上的HERG钾通道的影响。方法应用全细胞膜片钳技术记录在HEK293细胞上稳定表达的HERG钾通道的电流和动力学曲线(激活、失活、复活和去激活),研究不同浓度卡维地洛对HERG电流及动力学的影响;用Western blot技术定量的观察不同浓度卡维地洛对定位于HERG-HEK细胞膜上的HERG钾通道蛋白表达的影响。结果卡维地洛(10、100nmol.L-1,1、10μmol.L-1)浓度依赖性的抑制HERG步阶电流(Istep)及其尾电流(Itail)。由Hill方程得出IC50为539.6nmol.L-1,Hillslope为-0.64。1μmol.L-1卡维地洛作用后瞬时失活、去激活时间常数明显降低(P<0.05,n=10),而激活、失活、复活动力学无明显改变;Western blot检测结果显示卡维地洛组与无加药对照组HERG蛋白的表达无差别。结论卡维地洛通过影响通道的开放状态抑制HERG钾电流,加速瞬时失活和去激活动力学,对HERG蛋白的表达及成熟无影响。     

卡维地洛在健康人体的生物等效性

目的 研究中国健康志愿者单次口服卡维地洛片(抗高血压药)的药代动力学.方法 20名健康志愿者随机分成2组,分别单次口服试验与参比卡维地洛20 mg.用LC-MS法测定给药后不同时间点血浆中的卡维地洛浓度,并用DAS Ver 2.0软件计算其药代动力学参数.结果 卡维地洛试验与参比制剂主要药代动力学参数如下:tmax分别为(0.69±0.24)和(0.76±0.39)h,t1/2分别为(7.21±5.10)和(7.99±4.70)h,Cmax分别为(63.70±21.45)和(60.02±22.34)μ·L-1,AUC0-t分别为(161.98±62.24)和(168.15±64.09)μg·h·L-1,AUC0-∞分别为(173.30±78.42)和(179.49±72.84)μg·h·L-1;卡维地洛的相对生物利用度为(99.3±25.9)%.结论 2种制剂具有生物等效性.     

Effect of oxidative stress on ventricular arrhythmia in rabbits with adriamycin-induced cardiomyopathy

The purpose of the present study was to examine the effects of oxidative stress on ventricular arrhythmias in rabbits with adriamycin-induced cardiomyopathy and the relationship between oxidative stress and ventricular arrhythmia. Forty Japanese white rabbits were randomly divided into four groups (n=10 in each): control group, metoprolol (a selective β1 receptor blocker) group, carvedilol (a nonselective β blocker/α-1 blocker) group and adriamycin group. Models of adriamycin-induced car-diomyopathy were established by intravenously injecting adriamycin hydrochloride (1 mg/kg) to rabbits via the auri-edge vein twice a week for 8 weeks in the adriamycin, metoprolol and carvedilol groups. Rabbits in the control group were given equal volume of saline through the auri-edge vein. Rabbits in the metoprolol and carvedilol groups were then intragastrically administrated metoprolol (5 mg/kg/d) and carvedilol (5 mg/kg/d) respectively for 2 months, while those in the adriamycin and control groups were treated with equal volume of saline in the same manner as in the metroprolol and carvedilol groups. Left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) were measured by echocardiography. Plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), malondialdehyde (MAD) and superoxide dismutase (SOD) were detected. The left ventricular wedge preparations were perfused with Tyrode’s solution. The transmural electrocardiogram, transmural action potentials from epicardium (Epi) and endocardium (Endo), transmural repolarization dispersion (TDR) were recorded, and the incidences of triggered activity and ventricular arrhythmias were obtained at rapid cycle lengths. The results showed that TDR and the serum MDA and NT-proBNP levels were increased, and LVEF and the serum SOD level decreased in the adriamycin group compared with the control group. The incidences of triggered activity and ventricular arrhythmia were significantly higher in the adriamycin group than those in the control group (P<0.05). In the carvedilol group as compared with the adriamycin group, the serum SOD level and the LVEF were substantially increased; the TDR, and the serum MDA and NT-proBNP levels were significantly decreased; the incidences of triggered activity and ventricular arrhythmia were obviously reduced (P<0.05). There were no significant differences in the levels of MDA and SOD, LVEF, TDR and the incidences of triggered activity and ventricular arrhythmia between the adriamycin group and the metoprolol group. It was concluded that carvedilol may inhibit triggered activity and ventricular arrhythmias in rabbit with adriamycin-induced cardiomyopathy, which is related to the decrease in oxygen free radials.     

Lung function with carvedilol and bisoprolol in chronic heart failure: Is β selectivity relevant?

BACKGROUND: Carvedilol is a beta-blocker with similar affinity for beta1- and beta2 receptors, while bisoprolol has higher beta1 affinity. The respiratory system is characterized by beta2-receptor prevalence. Airway beta receptors regulate bronchial tone and alveolar beta receptors regulate alveolar fluid re-absorption which influences gas diffusion. AIMS: To compare the effects of carvedilol and bisoprolol on lung function in patients with chronic heart failure (CHF). METHODS AND RESULTS: We performed a double-blind, cross-over study in 53 CHF patients. After 2 months of full dose treatment with either carvedilol or bisoprolol, we assessed lung function by salbutamol challenge, carbon monoxide lung diffusion (DLCO), including membrane conductance (DM), and gas exchange during exercise. FEV1 and FVC were similar; after salbutamol FEV1 was higher with bisoprolol (p<0.04). DLco was 82+/-21% of predicted with carvedilol and 90+/-20% with bisoprolol (p<0.01) due to DM changes. Peak VO2 was 17.8+/-4.5 mL/min/kg on bisoprolol and 17.0+/-4.6 on carvedilol, (p<0.05) with no differences in bronchial tone (same expiratory time) throughout exercise. Differences were greater in the 22 subjects with DLCO<80%. CONCLUSION: Carvedilol and bisoprolol have different effects on DLCO and response to salbutamol. DLCO differences, being DM related, are due to changes in active membrane transport which is under alveolar beta2-receptor control. Peak VO2 was slightly higher with bisoprolol particularly in CHF patients with reduced DLCO.     

Carvedilol,A Novel Cardiovascular Agent,Inhibits Development of Vascular and Ventricular Hypertrophy in Spontaneously Hypertensive Rats

The effects of carvedilol, a novel cardiovascular agent, were evaluated in developing spontaneously hypertensive rats (SHR) for effects on hemodynamics, and the ability to effect the development of left ventricular, and vascular hypertrophy associated with chronic hypertension. Chronic oral administration of low dose carvedilol (20 mg/kg/day) was initiated when rats were 5 weeks of age, and experiments progressed until 14 weeks of age. Carvedilol-treated SHR had significantly reduced systolic blood pressures and heart rates throughout the duration of the experiment, and had significantly reduced ventricle/body weights by approximately 9.0%. Morphologic analysis of tertiary branches of the mesenteric artery revealed that carvedilol-treated     

硬化剂注射联合药物治疗食管静脉曲张破裂出血疗效的研究

目的观察肝硬化食管静脉曲张患者硬化剂注射联合口服卡维地洛与单纯硬化剂注射后的再出血发生率、死亡率和治疗前后食管静脉曲张程度以及肝功能的分级变化。方法入选有效随访患者159例,其中82例患者采用硬化剂注射联合口服卡维地洛治疗,77例患者采用硬化剂注射治疗,两组患者给予多次注射硬化剂,直至曲张静脉消失,联合组同时给予卡维地洛,起始剂量为6.25 mg,每日2次,逐渐增加剂量至最大耐受量12.5 mg,每日2次。全部患者观察12月,对比两组间的出血在发生率和死亡率,治疗前后静脉曲张程度以及肝功能分级变化。结果联合治疗组82例,期间发生出血9例（10.9%,6月内）、16（19.5%,6月后）,死亡3例（3.7%）,硬化治疗组77例,期间发生出血13例（16.9%,6月内）、22（28.6%,6月后）,死亡8例（10.4%）。组间出血发生率（近、远期）和死亡率差异有统计学意义（P〈0.05）。两组治疗前后肝功能Child-Pugh评分比较差异无统计学意义（P〉0.05）。结论与单纯硬化剂注射治疗组相比,联合治疗组治疗可以降低出血率、死亡率和静脉曲张程度,同时患者肝功能无明显损害。     

Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension

Portal hypertension (PH) is the most common complication ofcirrhosis and represents the main driver of hepatic decompensation. The overarching goal of PH treatments in patients with compensated cirrhosis is to reduce the risk of hepatic decompensation (i.e development of ascites, variceal bleeding and/or hepatic encephalopathy). In decompensated patients, PH-directed therapies aim at avoiding further decompensation (i.e. recurrent/refractory ascites, variceal rebleeding, recurrent encephalopathy, spontaneous bacterial peritonitis or hepatorenal syndrome) and at improving survival. Carvedilol is a non-selective beta-blocker (NSBB) acting on hyperdynamic circulation/splanchnic vasodilation and on intrahepatic resistance. It has shown superior efficacy than traditional NSBBs in lowering PH in patients with cirrhosis and may be, therefore, the NSBB of choice for the treatment of clinically significant portal hypertension. In primary prophylaxis of variceal bleeding, carvedilol has been demonstrated to be more effective than endoscopic variceal ligation (EVL). In patients with compensated cirrhosis carvedilol achieves higher rate of hemodynamic response than propranolol, resulting in a decreased risk of hepatic decompensation. In secondary prophylaxis, the combination of EVL with carvedilol may prevent rebleeding and non-bleeding further decompensation better than that with propranolol. In patients with ascites and gastroesophageal varices, carvedilol is safe and may improve survival, as long as no impairment of the systemic hemodynamic or renal dysfunction occurs, with maintained arterial blood pressure as suitable safety surrogate. The target dose of carvedilol to treat PH should be 12.5 mg/day. This review summarizes the evidence behind Baveno-VII recommendations on the use of carvedilol in patients with cirrhosis.     

A comparative study between angiotensin receptor neprilysin inhibitor (thiorphan/irbesartan) with each of nitrate and carvedilol in a rat model of myocardial ischemic reperfusion injury

The combined angiotensin receptor neprilysin inhibitor is a promising cardioprotective pharmacological agent. This study investigated the beneficial effects of thiorphan (TH)/irbesartan (IRB), in myocardial ischemia–reperfusion (IR) injury, compared to each of nitroglycerin and carvedilol. Male Wistar rats were divided into five groups (10 rats/group): Sham, untreated I/R, TH/IRB + IR (0.1/10 mg/kg), nitroglycerin + IR (0.2 mg/kg), and carvedilol + IR (10 mg/kg). Mean arterial blood pressure, cardiac functions and arrhythmia incidence, duration and score were assessed. Cardiac levels of creatine kinase-MB (CK-MB), oxidative stress, endothelin-1, ATP, Na⁺/K⁺ ATPase pump activity and mitochondria complexes activities were measured. Histopathological examination, Bcl/Bax immunohistochemistry studies and electron microscopy examination of left ventricle were performed. TH/IRB preserved the cardiac functions and mitochondrial complexes activities, mitigated cardiac damage, reduced oxidative stress and arrhythmia severity, improved the histopathological changes and decreased cardiac apoptosis. TH/IRB showed a comparable effect to each of nitroglycerin and carvedilol in alleviating the IR injury consequences. TH/IRB showed significant preservation of mitochondrial complexes activity I and II compared to nitroglycerin. TH/IRB significantly increased LVdP/dtmax and decreased oxidative stress, cardiac damage and endothelin-1 along with increasing the ATP content, Na⁺/K⁺ ATPase pump activity and mitochondrial complexes activity when compared to carvedilol. TH/IRB showed a cardioprotective effect in reducing IR injury that is comparable to each of nitroglycerin and carvedilol that could be explained in part by its ability to preserve mitochondrial function, increase ATP, decrease oxidative stress as well as endothelin 1.