卡维地洛长期治疗充血性心力衰竭效果分析

目的　评价卡维地洛 (Carvedilol)治疗国人心力衰竭患者的疗效。方法　NYHAⅡ Ⅳ的住院心衰患者在常规治疗(强心、利尿、扩血管 )基础上加用卡维地洛起始剂量 5mg/d ,如能耐受则逐渐滴定到最大耐受量 ,观察其 1 2个月后的疗效 ,并与对照组比较。结果　 (1 )卡维地洛组心衰患者至随访结束后平均卡维地洛用量为 (31 .35± 7.5 6 )mg/d (1 0～ 4 0mg/d) ,临床疗效好 ;(2 ) 1例患者不能耐受卡维地洛治疗。结论　我国心衰患者对第 3代 β阻滞剂卡维地洛的疗效好。     

卡维地洛对不稳定型心绞痛患者内皮功能的影响

目的观察卡维地洛对不稳定型心绞痛患者内皮素(ET)、一氧化氮(NO)及血管性假血友病因子(vWF)水平的影响。方法不稳定型心绞痛患者62例采用完全随机化方法分成对照组(30例)和治疗组(32例),在常规抗血小板、扩血管治疗基础上,对照组予美托洛尔(12.5mg,每日2次×3d)口服,治疗组口服卡维地洛(6.25mg,每日2次×3d)。在治疗前后分别用放射免疫法测定ET;硝酸还原酶法比色测量血清NO浓度;ELISA法测定vWF值。结果对照组和治疗组在治疗前ET、NO、vWF差异均无显著性(P>0.05);用药后两组ET、NO、vWF与用药前比较,差异有显著性(P<0.05)。治疗组在用药后ET明显低于对照组,NO高于对照组(P<0.05)。结论卡维地洛可显著降低不稳定型心绞痛患者的ET、vWF水平,升高NO水平,改善内皮功能。     

卡维地洛对慢性收缩性心力衰竭患者心功能及血浆脑钠肽的影响

目的:观察卡维地洛对慢性收缩性心力衰竭(CHF)患者心功能、血浆脑钠肽(BNP)的影响。方法:慢性收缩性心力衰竭患者54例,随机分为常规治疗组和卡维地洛组各27例。常规治疗组使用血管紧张素转化酶抑制剂或血管紧张素拮抗剂、利尿药、硝酸酯类药和洋地黄类药,卡维地洛组在常规治疗基础上加用卡维地洛,疗程16周。观察心功能改善并测定治疗前后左心室射血分数(LVEF)、左心室舒张末期内径(LVEDd)和血浆BNP水平。结果:两组心功能均得到显著改善,血浆BNP水平明显下降,卡维地洛组更明显(P<0.05)。卡维地洛组LVEF和LVEDd虽较常规治疗组有所增加和下降,但差异无显著性。结论:在常规治疗心衰基础上加用卡维地洛能更有效地改善心功能和降低血浆BNP水平。     

卡维地洛治疗高血压的临床疗效及其对血脂、糖代谢的影响

目的观察卡维地洛对于高血压患者的临床疗效及其对患者血脂和糖代谢的影响。方法将78例Ⅰ、Ⅱ级原发性高血压患者随机分为2组,分别接受卡维地洛(研究组)及美托洛尔治疗(对照组),观察并对比2组患者血压控制情况以及空腹血糖、血脂、胰岛素水平和胰岛素指数。结果 2组患者血压控制疗效均令人满意,研究组显效率显著高于对照组,其他疗效评定相似。研究组患者的血脂、血糖以及胰岛素敏感性改善均显著优于对照组。2组患者均安全可靠,未发现严重不良反应。结论卡维地洛降压作用与美托洛尔相似,但其调节血糖、血脂代谢疗效更优,更适于合并血脂、血糖代谢功能紊乱的高血压患者。     

丹参酮ⅡA磺酸钠联合卡维地洛对心力衰竭患者心功能及内分泌激素水平的影响

目的探讨丹参酮Ⅱ_A磺酸钠联合卡维地洛对心力衰竭患者心功能及内分泌激素水平的影响。方法选取医院2017年8月至2019年8月收治的心力衰竭患者96例,按随机数字表法分为观察组和对照组,各48例。两组均予卡维地洛治疗,观察组加用丹参酮Ⅱ_A磺酸钠治疗。两组均连续治疗2周。结果观察组总有效率为89.58%,显著高于对照组的72.92%(P <0.05);治疗后,观察组患者左室射血分数(LVEF)显著高于对照组,左室收缩末期内径(LVESd)、左室舒张末期内径(LVEDd)均显著低于对照组(P <0.05),内分泌激素[血管紧张素Ⅱ(Ang-Ⅱ)、醛固酮(ALD)、血管内皮素(ET)]水平均显著低于对照组(P <0.05),炎性因子[C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)、白细胞介素6(IL-6)]水平均显著低于对照组(P <0.05);治疗期间,观察组与对照组患者不良反应发生率相当(18.75%比10.42%,P> 0.05)。结论丹参酮Ⅱ_A磺酸钠联合卡维地洛治疗心力衰竭临床疗效显著,能改善患者心功能,降低内分泌激素和炎性因子水平,且安全性良好。     

Low-volume LC–MS/MS method for the pharmacokinetic investigation of carvedilol,enalapril and their metabolites in whole blood and plasma: Application to a paediatric clinical trial

Evidence-based pharmacotherapy with carvedilol and enalapril in children suffering from heart failure is insufficient owing to limited pharmacokinetic data. Although a few data sets regarding enalapril, its metabolite enalaprilat and carvedilol in children have been published, pharmacokinetic data on carvedilol metabolites are missing. However, for both drug substances, their active metabolites contribute substantially to drug efficacy. As data can hardly be derived from adults owing to the unknown impacts of enzymatic maturation and ontogeny during childhood, customised assays are important to facilitate paediatric evidence-based pharmacotherapy. Considering ethical paediatric constraints, a low-volume liquid chromatography coupled to mass spectrometry (LC–MS/MS) assay was developed using whole blood or plasma for the quantification of enalapril, enalaprilat, carvedilol, O-desmethyl carvedilol, 4- and 5-hydroxyphenyl carvedilol as well as 3- and 8-hydroxy carvedilol. To facilitate broader applications in adults, the elderly and children, a wide calibration range—between 0.024/0.049 and 50.000 ng/ml—was achieved with good linearity (r ≥ 0.995 for all analytes). In compliance with international bioanalytical guidelines, accuracy, precision, sensitivity and internal standard normalised matrix effects were further successfully validated with the exception of those for 3-hydroxy carvedilol, which was therefore assessed semi-quantitatively. Distinct haematocrits did not impact matrix effects or recoveries when analysing whole blood. Blood-to-plasma ratios were determined for all analytes to form the basis for pharmacokinetic modelling. Finally, incurred sample reanalysis of paediatric samples confirmed the reproducibility of the developed low-volume LC–MS/MS method during study sample analysis. The assay facilitates the reliable generation of important data and contributes towards a safe drug therapy in children.     

Population pharmacokinetics and dose simulation of carvedilol in paediatric patients with congestive heart failure

Aims

To investigate the ontogeny of carvedilol pharmacokinetics and to develop an age-appropriate carvedilol dosing strategy for paediatric patients.

Methods

Data were derived from a prospective, nonplacebo-controlled study of carvedilol for the treatment of paediatric patients with congestive heart failure and analysed using a nonlinear mixed-effects modelling approach (NONMEM, Version V 1.1). The population pharmacokinetic model was further utilized for simulations of different carvedilol dosing strategies.

Results

Four hundred and eighty carvedilol plasma concentrations of 41 patients (0.1–19.3 years; median 3.5) were included in the analysis. A two-compartment model with first-order absorption and absorption lag served as structural model. Weight and age were the most important covariates for carvedilol pharmacokinetics. The weight-adjusted clearance was highest for the younger patients with 2.7 l h⁻¹ kg⁻¹ for a 1-year-old patient compared with 0.7 l h⁻¹ kg⁻¹ for a 19.3-year-old patient. Dose simulations revealed that the area under the plasma concentration–time curve (AUC) as a measure of drug exposure increased with age despite constant doses with respect to body weight. For infants (28 days to 23 months), children (2–11 years) and adolescents (12–15 years) daily doses of 3, 2 and 1 mg kg⁻¹, administered in two or three discrete doses, were necessary to reach an exposure comparable to adults receiving 0.7 mg kg⁻¹ day⁻¹.

Conclusion

The ontogeny of carvedilol pharmacokinetics in paediatric patients depends on age and weight. Dose simulations revealed that younger patients have to be treated with higher doses with respect to body weight to reach the same exposure as adults.

What is already known about this subject

• Applying in silico tools such as population pharmacokinetic analysis and simulation will help to find adequate dosing strategies and increase the probability of success for a randomized controlled trial.
• Up to now, for carvedilol in paediatric patients with congestive heart failure (CHF) the dose has been linearly extrapolated from adults, but the results with this dosing strategy are ambiguous.
• Further trials are necessary to establish carvedilol for paediatric patients with CHF.

What this study adds

• Carvedilol pharmacokinetics in paediatric patients with CHF depends on the weight and age of the patient.
• Therefore, the drug exposure differs substantially between patients of different ages receiving the same dose with respect to body weight.
• Simulations revealed that an age-adjusted carvedilol dosing strategy with higher doses for younger patients with respect to body weight is preferable to a uniform one.

     

4-羟基咔唑的新合成方法

以邻溴硝基苯和邻碘苯甲醚为原料经3卡反应制得4-羟基咔唑,总收率为37.4%。     

两种β阻滞剂治疗轻、中度原发性高血压的比较

目的 :比较国产卡维地洛与柳胺苄心定治疗轻、中度原发性高血压患者的降压疗效和安全性。方法 :轻中度原性高血压患者 5 0例 ,随机分为卡维地洛组 (n=2 5 )与柳胺苄心定组 (n =2 5 ) ,分别口服卡维地洛 10mgbid,柳胺苄心定 5 0mgbid (均 8AM与 8PM)。治疗 2周后卡维地洛组 9例与柳胺苄心定组 4例因血压降低不满意 (舒张压>90mmHg)而分别增加剂量到 2 0mg和 10 0mgbid。共观察4周。结果 :卡维地洛组舒张压下降 11.2± 6 .7mmHg(P <0 0 1) ,收缩压下降 6 .9± 16 .2mmHg。柳胺苄心定组舒张压下降 1.1± 6 .2mmHg(P <0 0 1)。卡维地洛组总有效率 88%与柳胺苄心定组 84%相似。两组用药前后心率、血糖及血清胆固醇、甘油三酯均无明显变化 ;卡维地洛组HDL虽明显下降 ,但仍在正常范围内 ,不良反应少。结论 :国产卡维地洛治疗高血压的疗效与对照药柳胺苄心定相似 ,其疗效确切 ,不良反应少 ,耐受性好。     

Predictors of improvement in left ventricular ejection fraction with carvedilol for congestive heart failure

BACKGROUND: Beta-blocker therapy has been reported to improve survival and left ventricular ejection fraction (LVEF) in the setting of congestive heart failure (CHF). The magnitude and predictors of improved LVEF are unclear. METHODS: A total of 295 patients were enrolled in the study. Inclusion criteria were LVEF <35% at baseline and symptomatic (New York Heart Association class II to IV) CHF despite treatment with at minimum an angiotensin-converting enzyme inhibitor. Carvedilol was initiated at 3.125 mg twice daily and titrated to a target dose of 25 or 50 mg twice daily, depending on the patient's weight. Paired pretreatment baseline and 9 months with treatment follow-up quantitative LVEFs (assessed by resting radionuclide ventriculograms) were obtained in 161 (55 %) of the patients. RESULTS: LVEF improved from 25% +/- 6% at baseline to 36%+/-12% at follow-up (P<.001). Mean change in LVEF (deltaLVEF) was greater for nonischemic cardiomyopathy (NICM) (+14.5+/-2 LVEF points) than ischemic cardiomyopathy (deltaLVEF +/- 7.6+/-10 EF points, P = .001). The deltaLVEF was > or =21 LVEF points in 30% of the NICM group versus 10% of the ischemic cardiomyopathy group. Conversely, the deltaLVEF was unchanged to minimally improved (< or =5 LVEF points) in 21% of the NICM group versus 52% of the ischemic cardiomyopathy group. Multivariable analysis identified NICM and recent onset of congestive heart failure as correlates of improved LVEF. CONCLUSIONS: Carvedilol significantly improved LVEF, especially in patients with NICM and those with recent onset of CHF.