卡维地洛的抗高血压及对左室肥厚的逆转作用

目的 :观察卡维地洛降压疗效及其对原发性高血压 (EH)左室肥厚 (LVH)的逆转作用。方法 :60例患者口服卡维地洛 1 0～ 2 0 mg,2次 / d,治疗半年 ,用动态血压仪记录卡维地洛治疗 EH的降压效果 ,用超声心动图测量 LVH的逆转情况。结果 :卡维地洛可使 2 4 h血压平稳下降 ,且左室质量指数较治疗前减低 (P<0 .0 1 )。结论 :卡维地洛能有效地控制血压的升高 ,对 EH的 LVH有逆转作用     

卡维地洛对体外柯萨奇病毒B3致心肌细胞凋亡与Bcl-2/Bax蛋白表达的影响

目的探讨卡维地洛对体外柯萨奇病毒B3(CVB3)致心肌细胞凋亡的抑制作用及其机制。方法采用差速贴壁法培养原代Wistar乳鼠心肌细胞。实验分为正常对照组、病毒组、卡维地洛组及美托洛尔组。正常对照组仅加入不含血清的DMEM培养液,后3组于CVB3感染心肌细胞后分别加入不含血清的DMEM培养液、无血清培养基配制的卡维地洛、美托洛尔溶液。72h后在倒置相差显微镜下观察各组心肌细胞的形态、搏动速率;采用黄嘌呤氧化酶法测定其心肌细胞培养液中超氧化物歧化酶(SOD)活性,硫代巴比妥酸法测定其心肌细胞培养液中丙二醛(MDA)水平,流式细胞术检测其心肌细胞凋亡率,免疫细胞化学法检测其心肌细胞内Bcl-2及Bax蛋白表达水平。结果1.与病毒组比较,卡维地洛组心肌细胞搏动速率明显提高(P<0.05)、凋亡率明显降低(P<0.05),心肌细胞培养液中SOD活性显著升高(P<0.05)、MDA水平明显降低(P<0.05);美托洛尔组与病毒组比较,心肌细胞搏动速率、凋亡率、心肌细胞培养液中SOD活性、MDA水平均无统计学差异(Pa>0.05);2.与病毒组及美托洛尔组比较,卡维地洛组心肌细胞内Bcl-2蛋白表达增多,而Bax蛋白表达减...     

Carvedilol Inhibits Na^＋ Current in Rat Ventricular Myocytes

Objectives The effects of carvedilol on sodium current （INa） were investigated in isolated adult rat ventricular myocytes. Methods Single ventricular myocytes were enzymatically dissociated. INa was recorded by whole-cell patch- clamp recording technique. Results an IC50of （6. 35 - 0.40） mol . L^- 1. Carvedilol reversibly inhibited INa in a concentration-dependent manner, with 2. This inhibition was voltage- and frequency-dependent. 3. Carvedilol decreased the peak of the I-V relationship curve at -35 mV from （17.31± 1.68） pA/pF to （6. 58 ± 1.35） pA/pF, but did not change active potential, peak potential and the reverse potential significantly. 4. The steady-state inactivation curve of INa was shifted to more negative potentials. Conclusions Carvedilol inhibits INa in adult rat ventricular myocytes by mechanisms involving preferential interaction with the inactivated state of sodium channel.     

卡维地洛标准红外光谱的研究

目的对国内卡维地洛原料的红外光谱进行考察,建立转晶方法以得到标准红外光谱。方法经溴化钾压片后用红外分光光度法（IR）扫描,得到其红外光谱,通过比较分析原料的晶型。结果不同厂家生产的卡维地洛原料的红外光谱不同,并与现行标准图谱有差异。结论用建立的转晶方法处理后能得到一致的红外光谱。     

Effects of carvedilol on delayed rectifier and transient inactivating potassium currents in rat hippocampal CA1 neurons

1. The aims of the present study were to investigate the mechanism(s) underlying the protective effect of carvedilol against neural damage. 2. The transient inactivating potassium current (I_A) and the delayed rectifier potassium current (I_K) in rat hippocampal CA1 pyramidal neurons were recorded using whole‐cell patch‐clamp techniques. 3. Carvedilol (0.1–3 μmol/L) significantly inhibited I_K with an IC₅₀ of 1.3 μmol/L and the inhibition was voltage independent. Over the same concentration range, carvedilol had no effect on the amplitude of I_A. At 1 μmol/L, carvedilol did not significantly change the steady state activation curves of I_A and I_K, but did negatively shift their steady state inactivation curves. Recovery from inactivation was slowed for both I_A and I_K. The inhibitory effect of carvedilol on I_K was not affected by the adrenoceptor agonists phenylephrine and prazosin or the adrenoceptor antagonist isoproterenol, but propranolol was able to shift the dose–response curve of carvedilol for I_K to the right. 4. Because I_K is the main pathway for loss of intracellular potassium from depolarized neurons, selective obstruction of I_K by carvedilol could be useful for neuroprotection.     

Effect of renal sympathetic nerve on adrenergically and angiotensin II-induced renal vasoconstriction in normal Wistar-Kyoto rats

Abstract

Background. This study examined the effect of renal sympathetic innervation on adrenergically and angiotensin II (Ang II)-induced renal vasoconstriction in Wistar-Kyoto (WKY) rats.

Methods. Forty-eight WKY rats were treated with either losartan (10 mg/kg/day p.o.) or carvedilol (5 mg/kg/day p.o.) or a combination of them (10 mg/kg/day + 5 mg/kg/day p.o.) for 7 days. On day 8, the rats were anaesthetized, and renal vasoconstrictor experiments were carried out. A group of rats was subjected to acute unilateral renal denervation during the acute study. Changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by Ang II, noradrenaline (NA), and methoxamine (ME).

Results. In normal animals, losartan decreased (P < 0.05) the renal vasoconstrictor response to Ang II but not to NA or ME. Carvedilol treatment, however, blunted (P < 0.05) the renal vasoconstrictor responses to Ang II and adrenergic agonists. Combination of losartan and carvedilol blunted (P < 0.05) the renal vasoconstrictor response to Ang II but augmented the responses to NA and ME (all P < 0.05). Interestingly, when denervated rats were treated with the same combination, there was a reduction (P < 0.05) in the renal vasoconstrictor responses to Ang II and adrenergic agonists.

Conclusions. Data suggest that the renal sympathetic nerve contributes to adrenergic agonist-mediated renal vasoconstrictions in normal rats. The data further indicate an interactive relationship between renin-angiotensin and sympathetic nervous systems in modulating adrenergically and Ang II-induced renal vasoconstriction in WKY rats.     

卡维地洛治疗急性心肌梗死患者左室功能的疗效观察

目的探讨卡维地洛治疗急性心肌梗死（AMI）患者左室功能的疗效。方法对于2005年1月～2009年7月在我院住院及出院后门诊随访的100例AMI患者随机分为卡维地洛组和美托洛尔组各50例,于入院后24小时内和治疗后1个月行超声心动图检查。比较2组间收缩功能和舒张功能的各种指标。结果治疗1个月后,在收缩功能方面,与美托洛尔组相比,卡维地洛组的改善更为明显（P<0.05）,在舒张功能方面,两组的改善程度一样（P>0.05）。结论在治疗1个月后,卡维地洛和美托洛尔均显著改善左心室功能,但卡维地洛疗效更好。     

β-blocker therapy of heart failure: an update

The beneficial effects of β-blocker therapy in patients with heart failure have been consistently shown by multi-center randomised trials. These agents are effective and also relatively well tolerated in the elderly and in patients with diabetes and advanced heart failure – traditionally considered as relative contraindications to their administration. However, the use of β-blockers in clinical practice remains low. The difficulties in their initiation and up-titration may be overcome by patient and physician education, as well as by their initiation during hospitalisation and/or the involvement of non-physician providers (i.e., a nurse facilitator). Forthcoming advances in the pharmacokinetic and pharmacodynamic characteristics of some β-blockers, and testing of novel methods for patient and drug selection may be based on genetic testing, and may allow further improvement of β-blocker therapy in the next future.     

Elucidation of intestinal absorption mechanism of carvedilol-loaded solid lipid nanoparticles using Caco-2 cell line as an in-vitro model

Abstract

Enhanced oral bioavailability of poorly aqueous soluble drugs encapsulated in solid lipid nanoparticles (SLNs) via lymphatic delivery has been documented. Since no in-vitro lymphoid tissue is currently available, human excised Caco-2 cell monolayer could be alternative tissue for development of an in-vitro model to be used as a screening tool before animal studies are undertaken. Therefore, optimized carvedilol-loaded SLNs (FOPT-SLNs) were prepared, characterized, and evaluated using Caco-2 cell line as an in-vitro model. Physical mixture of components of FOPT-SLNs (FOPT-PM) and carvedilol solution were used as control groups. From the studies of effect of SLNs concentration and cells incubation time, suitable carvedilol concentration and incubation time were selected for the model in which cells were subjected to five pretreatments for 24?h or 1?h of cell incubation and then followed with treatment of FOPT-SLNs, FOPT-PM or 100?µg/mL solution of carvedilol, for additional 24?h of cell incubation. The results obtained in this model suggest that main absorption mechanism of FOPT-SLNs could be endocytosis and, more specifically, clathrin-mediated endocytosis. When Transwell® permeable supports were used for the cells, carrier-mediated mechanism for FOPT-SLNs and passive absorption mechanism (transcellular and paracellular) for FOPT-PM and drug solution were concluded.     

Development and characterization of a carvedilol-loaded self-microemulsifying delivery system

The objective of the work was to develop, optimize, and evaluate a self-microemulsifying drug delivery system of the poorly water-soluble drug, carvedilol. Solubility of carvedilol was determined in various vehicles. Ternary and pseudo-ternary phase diagrams were constructed to indentify the efficient self-emulsification region using oils, surfactants, and co-surfactants in aqueous environment. Optimized formulations were assessed for drug content, spectroscopic clarity, emulsification time, contact angle, zeta potential, particle size, and dissolution studies. Zeta potential was measured in the absence and presence of oleylamine, a positive charge inducer. On the basis of similarity and dissimilarity of particle size distribution, formulations were characterized using PCA and AHCA, a multivariate statistical analysis. Decrease in t_50% and increase in DE attributed to small globule size and eventually higher surface area. The relevance of differences in t_50% and DE was evaluated statistically by two-way ANOVA. DRIFTS, DSC, and X-RD studies indicated no incompatibility between drug, oil, and surfactants. The results of this study indicate that the SMEDD formulations of carvedilol owing to nanosize have the potential to enhance its absorption, without interaction or incompatibility between the ingredients.