卡维地洛与培哚普利联合干预心梗后心衰对心肌肌浆网Ca2+泵活性和Ca2+释放通道密度的影响

目的 探讨β受体阻滞剂卡维地洛与血管紧张素转换酶抑制剂培哚普利联合干预心梗后慢性心衰对心肌肌浆网(SR)Ca~(2+)泵活性和Ca~(2+)释放通道(RyR2)密度的影响及意义.方法 通过结扎大鼠左冠脉建立慢性心衰模型,术后1周开始分别给以卡维地洛(6mg·kg~(-1)·d~(-1))、培哚普利(4mg·kg~(-1)·d~(-1))、特拉唑嗪(2mg·kg~(-1)·d~(-1))、卡维地洛(6mg·kg~(-1)·d~(-1))+培哚普利(4mg·kg~(-1)·d~(-1))联合干预9周,观察血流动力学、左室心肌SR Ca~(2+)泵活性和RyR_2密度的变化.结果 与假手术组相比,心衰组左室舒张末压(LVEDP)显著升高(P<0.01),+dp/dt_(max)、-dp/dt_(max)显著降低(P<0.01),左室心肌SR Ca~(2+)泵活性和RyR_2密度显著降低(P<0.01).卡维地洛、培哚普利单独及联合干预均降低LVEDP(P<0.01),升高+dp/dt_(max)、-dp/dt_(max)(P<0.01),并升高左室心肌SR Ca~(2+)泵活性和RyR_2密度(P<0.01),联合干预变化更明显(P<0.01).特拉唑嗪组对上述指标无明显影响(P>0.05).左室心肌sRCa~(2+)泵活性与+dp/dt_(max)、-dp/dt_(max)显著正相关(r=0.596,r=0.684,P<0.01).结论 β受体阻滞剂卡维地洛和血管紧张素转换酶抑制剂培哚普利长期联合干预心梗后慢性心衰,能够改善血流动力学和心肌SR Ca~(2+)泵活性,增加RyR_2密度,优于任何单一药物干预.

Abstract：

Objective To study the effects of carvedilol combined with perindopril on Ca~(2+) pump activity and the density of Ca~(2+)-release channel ryanodine receptor (RyR2) in the myocardial sarcoplasmic reticulum (SR) in rats with chronic heart failure caused by myocardial infarction. Methods Rat models of chronic heart failure established by left coronary artery ligation were divided into different groups and treated with carvedilol (6 mg·kg~(-1)·d~(-1)), perindopril (4 mg·kg~(-1)·d~(-1)), terazosin (2 mg·kg~(-1) ·d~(-1)), or the combination of carvedilol (6 mg·kg~(-1) ·d~(-1) and perindopril (4 mg·kg~(-1) ·d~(-1) for 9 weeks. Another 12 rats with sham operation served as the sham-operated group. The hemodynamic parameters, activity of SR Ca~(2+) pump, and RyR2 density were determined. Results Compared with shame-operated group, the rats with chronic heart failure showed significantly increased left ventricular end-diastolic pressure (LVEDP) (P<0.01) and decreased +dP/dtmax, -dp/dtmax, activity of SRCa~(2+)pump and density of RyR2 (P<0.01). Both monotherapies with carvedilol and perindopril attenuated the increment ofLVEDP, and significantly increased+dp/dtmax, -dp/dtmax, activity of SR Ca~(2+) pump and density of RyR2 (P<0.01). Combined treatment even further enhanced the therapeutic effects, whereas terazosin produced no obvious effect. The activity of SR Ca~(2+) pump was strongly correlated to +dp/dtmax and -dp/dtmax (r=0.596 and 0.684, respectively, P<0.01). Conclusion Prolonged treatment with p$-blocker carvedilol in combination with ACE inhibitor perindopril may improve the hemodynamic parameters, enhance Ca~(2+) pump activity and increase the density of RyR2 of myocardial SR more effectively than either monotherapy in preventing and treating chronic heart failure following myocardial infarction.     

老年高血压患者每日口服一次卡维地洛片的临床研究

目的:评价卡维地洛治疗老年轻、中度原发性高血压的降压疗效和安全性。方法:39例轻、中度高血压患者经过停药1周、2周安慰剂清洗期后,口服卡维地洛片10mg qd,2周后舒张压≥90mmHg或血压下降<20mmHg,增加剂量10mg/2周,直至10周结束观察。结果:39例患者服药2周末舒张压即明显下降,治疗10周末平均剂量为20mg/日,收缩压和舒张压分别降低19.19mmHg(↓11.9％)和13.69mmHg(↓13.9％),总有效率为74.4％,总显效率为59.0％。服药后心率在正常范围内下降3.0次/分,血清总胆固醇和甘油三酯无明显改变,血糖在正常范围内轻度升高。不良反应主要是头晕、头疼、困倦,但均较轻微,停药后消失。结论:老年轻、中度原发性高血压患者每日口服卡维地洛片10～40mg安全有效。     

Chronic haemodynamic effects of carvedilol in essential hypertension at rest and during exercise.

Nineteen men (mean age 44 years) with essential hypertension, WHO stage I, were studied invasively at rest and during exercise. Blood pressure was recorded intra-arterially (brachial artery), cardiac output by dye dilution method and heart rate by electrocardiography. After initial pre-drug recordings, the patients received 25 mg carvedilol orally and central haemodynamics at rest and during exercise were recorded 1 and 2 h after tablet intake to evaluate the immediate effects of carvedilol. The results indicated a combined beta-blocking and vasodilating effect. After 6-9 months of treatment, supine haemodynamics were recorded 12-24 h after the last dose and then 1 and 2 h after an additional 25 mg dose. During chronic treatment (2 h after last dose at rest supine) mean arterial pressure was reduced by 17% (P less than 0.001) and total peripheral resistance index by 6% (NS) while heart rate and cardiac index were reduced by 12%. Exercise haemodynamics demonstrated a fall in blood pressure of 17% (P less than 0.001). Exercise stroke index increased by 5% (NS), partly compensating for the reduction in heart rate of 17%. Total peripheral resistance index was reduced by 5% (NS). It is concluded that carvedilol is an effective anti-hypertensive agent in a large proportion of patients with essential hypertension. The haemodynamic mode of action reflects an alpha 1-blocking activity, particularly in situations with low sympathetic tone. During exercise the beta 1-blocking activity (demonstrated by the reduction in heart rate) is more prominent.     

Pharmacokinetics and bioavailability of carvedilol,a vasodilating beta-blocker

Summary The pharmacokinetics and absolute bioavailability of carvedilol have been studied in 20 male healthy volunteers in a randomised 4-period, cross-over trial. Carvedilol 12,5 mg was given i.v., 50 mg was administered p.o. as a suspension and 25 and 50 mg were given in a capsule formulation. For the 50 mg capsule C_max was 66 µg·l^–1, t_max 1.2 h, t_1/2 6.4 h. The t_1/2 after i.v. administration was 2.4 h, CL 589 ml/min and V_z 132 l.The absolute bioavailability was 24% (50 mg capsule). The kinetics after the 25 and 50 mg capsules were consistent with dose linearity.     

卡维地洛对高血压的降压作用及对胰岛素抵抗的影响

目的探讨卡维地洛的降压作用及对胰岛素抵抗的影响。方法对58例高血压病Ⅰ期或Ⅱ期患者服用卡维地洛10 mg,bid,疗程为6 wk;治疗前后观察血压、空腹血糖(FBS)、血脂和胰岛素敏感性(ISI)的变化。结果服药前收缩压(158．3±13．5)mm Hg,舒张压(92．3±5．7)mm Hg;服药后收缩压(141．5±12．7)mm Hg,舒张压(81．8±6．4)mm Hg,服药前后比较(P< 0．05),治疗前后血糖、血脂无显著性改变(P>0．05),胰岛素敏感性增加(P<0．05)。结论卡维地洛能有效地降低收缩压和舒张压,能显著改善胰岛抵抗。     

卡维地洛治疗高血压病的临床研究

目的：评价卡维地洛治疗各级原发性高血压病的临床疗效、安全性及副作用,并汉族、哈萨克族（哈族）两民族患者的临床疗效进行对照分析。方法：选择汉、哈族各级原发性高血压病患者各34例．均服用卡维地洛（10mg／d）进行降压治疗，2周后疗效不满意即加量至50mg／d，服药2、4、8、12周后分别观察血压、心率及副反应情况。结果：治疗12周后，汉族患者收缩压及舒张压的降压幅度分别为18．5％、16．3％．哈族患者收缩压及舒张压的降压幅度分别为19．5％、17．3％，与用药前相比差异有统计学意义（P〈0．01）。治疗8周后汉族患者心率不再变化，哈族患者心率呈进一步下降趋势，12周后两者心率变化差异有统计学意义（P〈0．01）。汉族和哈族患者用药前后血糖、血脂、肝肾功能均无明显变化。结论：卡维地洛对汉、哈族患者各级原发性高血压均有较好治疗作用，副作用少．但哈族患者应用时应注意监测心率变化。     

卡维地洛、螺内酯联合治疗慢性心力衰竭的临床研究

目的观察卡维地洛、螺内酯联合治疗慢性心力衰竭患者的临床疗效及对心肌重塑的影响。方法60例NYHA分级为Ⅲ~Ⅳ级的住院患者,随机分为治疗组31例及对照组29例,治疗组在常规抗心力衰竭〔强心剂、利尿剂及血管紧张素转换酶抑制剂(ACEI)〕的基础上加服卡维地洛及螺内酯,对照组仅予常规抗心力衰竭治疗,总疗程均为12周,并监测治疗前后临床指标变化。结果治疗组较对照组心率、血压明显降低(P<0.05),NYHA心功能分级、左室射血分数(LVEF)、左室舒张末期内径(LVEDD)、E/A均明显改善(P<0.05或P<0.01)。结论卡维地洛与螺内酯联合应用可以明显减轻心力衰竭患者临床症状,改善心功能及心肌重塑。     

Amorphous solid dispersions of carvedilol along with pH‐modifiers improved pharmacokinetic properties under hypochlorhydoria

Carvedilol (CAR) belongs to biopharmaceutics classification system class‐II drugs, with poor aqueous solubility and pH‐dependent solubility. The present study aimed to develop a novel amorphous solid dispersion (ASD) of CAR with acidic counter ions for pH modifications in microenvironment to improve the pharmacokinetic properties under hypochlorhydric conditions. CAR‐ASD was prepared by freeze‐drying in combination with counter ions and hydroxypropyl cellulose, and their physicochemical properties including dissolution behavior, storage stability, and photostability were characterized. Pharmacokinetic studies were carried out after oral administration of CAR samples in both normal and omeprazole‐treated (30 mg/kg, p.o.) rats as a hypochlorhydria model. Among the tested six counter ions, citric acid (CA) was found to be a preferable pH‐modifier of CAR with respect to the dissolution profile and photostability (both potency and colorimetric evaluation). In CAR‐ASD formulation with 50% loading of CA (CAR‐ASD/CA50), amorphization of CAR was observed during the preparation process. After the oral administration of crystalline CAR in rats under hypochlorhydric condition, there was a 34.4% reduction in the systemic exposure of CAR compared with that in normal rats. However, orally‐dosed CAR‐ASD/CA50 resulted in limited alterations of pharmacokinetic behavior between normal and omeprazole‐treated rats. From these findings, addition of CA as pH‐modifier in CAR‐ASD might provide consistent pharmacokinetic behavior of CAR even under hypochlorhydric conditions.