A randomized cross-over study of enalapril in congestive heart failure: Haemodynamic and hormonal effects during rest and exercise

Summary We performed a randomized double-blind placebo controlled cross-over study of enalapril in 16 patients with chronic congestive heart failure, to assess haemodynamic and hormonal effects at rest and on exercise. Acute effects were measured 4 h after enalapril 10 mg, and chronic effects after 6 weeks treatment with enalapril 10–20 mg per day.Exercise tolerance, assessed by the duration of a maximal bicycle ergometer test, was not altered by enalapril. Mean blood pressure was reduced after enalapril, at rest and on exercise, acutely by 7% and 8% respectively, and chronically by 14% and 16%. Systemic vascular resistance was reduced by 16% at rest both acutely (NS) and chronically (p<0.05). The resting pulmonary capillary wedge pressure was reduced by 28% with chronic treatment. In the acute study, total body oxygen consumption on exercise was 26% higher after enalapril. Chronically, resting oxygen consumption was reduced by 13% after enalapril, with mixed venous oxygen saturation increasing by 16%.In the acute study enalapril increased plasma renin activity at rest and on exercise by 181% and by 189%, and reduced aldosterone by 49% (NS) and 39% (p<0.05), and these effects were sustained after 6 weeks. Enalapril increased antidiuretic hormone concentrations at rest acutely by 73% (NS) and chronically by 34% (p<0.05) but not on exercise; the increase in the acute study correlated with plasma enalaprilat levels (r=0.66, p<0.05). Enalapril did not alter plasma catecholamine concentrations.Patients preferred enalapril to placebo, and radiographic heart size was reduced during chronic treatment. There were no serious adverse effects.We conclude that enalapril is an effective angiotensin converting enzyme inhibitor of clinical value in chronic heart failure, but study design and methods of assessment of benefit can have a major influence on the results of pharmacological studies in such patients.     

Anaesthesia and angiotensin-converting enzyme inhibitors

The effect of enalapril pretreatment on the haemodynamic response to tracheal intubation and surgical stimulation has been studied in 22 patients. Enalapril 5 mg given 4 hours before operation was associated with a significant reduction in the pressor response associated with intubation (p less than 0.05) and surgical stimulation (p less than 0.005) compared with control. Heart rate changes were similar in the two groups. The role of the renin-angiotensin system in relation to the pressor response to sympathetic stimulation is discussed and it is concluded that angiotensin-converting enzyme inhibitors may help improve peri-operative cardiovascular stability.     

Effect of simvastatin given alone and in combination with valsartan or enalapril on blood pressure and the structure of mesenteric resistance arteries and the basilar artery in the genetically hypertensive rat model

1. The aims of the present study were to investigate, in the New Zealand genetically hypertensive (GH) rat model, the effects of treatment with simvastatin, alone or in combination with valsartan or enalapril, on blood pressure (BP) and structural remodelling of mesenteric resistance arteries (MRA) and of the basilar artery, an artery that plays a major role in the regulation of cerebral resistance. 2. Genetically hypertensive rats were treated with simvastatin at two dose levels (5 and 10 mg/kg per day) and simvastatin in combination with valsartan or enalapril (also 5 and 10 mg/kg per day) from the age of 7 to 12 weeks. Systolic BP and bodyweight were measured weekly. 3. At the end of the experiment, following fixation by perfusion, MRA and the basilar artery were excised and embedded in Technovit (a glycol methacrylate medium; Heraeus Kulzer, Werheim, Germany). Serial sections were cut and stereological techniques used to determine tunica media width and cross-sectional area (CSA), lumen diameter and the ratio of media width/lumen diameter. 4. Simvastatin monotherapy did not lower BP at either dose. In the high- and low-dose groups, the combination of simvastatin + enalapril lowered BP more than with enalapril alone; this was also true for the simvastatin + valsartan combination in the lower-dose group. 5. The MRA were hypotrophically remodelled by the 10 mg/kg per day dose of simvastatin; the 5 mg/kg per day dose caused hypotrophic remodelling with decreased media/lumen ratio. Valsartan and enalapril caused hypotrophic remodelling together with outward remodelling of the lumen in the 10 mg/kg per day valsartan group and, in all groups, a reduction in the media/lumen ratio, with the greatest effect observed in the high-dose groups. 6. The combination treatments of simvastatin + valsartan and simvastatin + enalapril did not have any consistent extra effect on MRA remodelling. 7. In the basilar artery, high-dose simvastatin had a hypotrophic effect on the media and both doses reduced the media/lumen ratio independently of any change in BP. 8. Simvastatin given in combination with valsartan produced a slight further reduction in medial CSA, media width and ratio. In combination with enalapril, there was little consistent additional effect. 9. Simvastatin monotherapy hypotrophically remodelled the media of the basilar artery in the GH rat model, even in the absence of changes in BP. A similar structural effect may explain, in part, the reduction in stroke seen in patients treated with statins.     

依那普利降低老龄鼠心房颤动诱发率的研究

目的:研究依那普利对老龄鼠心房颤动(房颤)诱发率的影响.方法:雄性老龄Wistar大鼠随机分为对照组和实验组,对照组常规饲养,实验组加喂依那普利.3个月后动物麻醉开胸暴露心脏.测量右房有效不应期.测量窦房结传导时间(SCT)和窦房结恢复时间(SRT)评价窦房结功能.采用心房短阵刺激评价房间传导时间(IACT)和心房对刺激的反应.用放免法测量血浆和心房组织血管紧张素Ⅱ(AngⅡ)浓度.取心房组织制作切片,Masson染色,测量纤维组织占总区域的百分比.结果:实验组IACT和SRT较对照组缩短(P ＜ 0.01或P ＜ 0.05).对照组有9例诱发出房颤,实验组有4例诱发出房颤(P ＜ 0.05).实验组左、右房组织匀浆AngⅡ浓度较对照组降低(均 P ＜ 0.01).实验组大鼠左房和右房纤维化程度均较对照组明显减轻(均P ＜ 0.01).结论:老龄鼠长期应用依那普利后房颤诱发率降低,窦房结功能改善.     

Preparation and Characterization of Salt Forms of Enalapril

Selection of an optimal salt form of a drug candidate is a vital component of preformulation stage of drug development. In this study, six salts of enalapril – citrate, mesylate, tartrate, malate, besylate and tosylate – were prepared and characterized by Mass Spectroscopy, Differential Scanning Calorimetry, Thermogravimetric Analysis, Microscopy, Powder X-ray Diffraction, Karl Fischer Titration, High Performance Liquid Chromatography, Fourier-Transform Infra-red Spectroscopy and Head Space Gas Chromatography. All the six salts were subjected to a tiered screening involving five stages in the following order: crystallinity, hygroscopicity, solubility, stability and flow/compactability. Enalapril malate showed encouraging profile because of its lower hygroscopicity, higher solubility, good solid state stability, and better flow and compactability, in comparison to the marketed maleate salt.     

缬沙坦与依那普利治疗急性心肌梗死合并心功能不全对照研究

目的探讨缬沙坦与依那普利治疗急性心肌梗死合并心功能不全的临床疗效和安全性。方法将122例急性心肌梗死合并心功能不全患者随机分为观察组与对照组,每组61例,两组均接受溶栓、扩容、调脂、抗凝等常规治疗,在此基础上观察组联合缬沙坦治疗,对照组联合依那普利治疗,观察6个月。于治疗前及治疗6个月末,检测两组收缩压、舒张压、左心射血分数,及时记录治疗过程中出现的不良反应。结果治疗6个月末两组收缩压、舒张压均较治疗前显著下降（P〈0．01）,左心射血分数均较治疗前显著升高（P〈0．01）,同期两组间比较差异均无显著性（P〉0．05）。治疗后观察组未出现明显的不良反应,对照组不良反应发生率显著高于观察组（χ^2=18．42,P〈0．01）。结论急性心肌梗死合并心功能不全患者在接受溶栓、扩容、调脂、抗凝等常规治疗的基础上,联合缬沙坦与依那普利治疗效果显著且相当,但联合缬沙坦安全性更高。     

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.     

两种药物在冠心病患者心功能及血浆同型半胱氨酸水平变化中的疗效比较

目的 :探析冠心病(CHD)患者经依那普利叶酸片治疗后其心功能及血浆同型半胱氨酸(Hcy)水平的变化.方法 :分析2015年2月~2016年3月在我院接受诊治的120例高度疑似为CHD患者的临床资料.根据CAG检查结果,将入选者分成对照组(CAG检查结果显示为正常者,42例)和CHD组(CAG检查结果显示为CHD的患者,78例).根据用药方式的不同,将CHD组分成依叶片组(马来酸依那普利叶酸片,40例)和依片组(依那普利片,38例)两组.比较三组患者的一般资料、治疗前后肝功能、心功能及血浆Hcy水平的变化.结果 :三组患者的一般资料及入院前后的肝肾功能均无显著性差异.入院时CHD组患者的血浆Hcy水平明显较对照组高;依叶片组服药6个月后的血浆Hcy水平显著较入院时低,但依片组服药前后的血浆Hcy水平却无显著变化.依叶片组和依片组服药6个月后心功能均得到了明显改善,但依叶片组的效果好于依片组.结论 :在CHD患者血浆Hcy水平的降低方面及其心功能改善方面,依那普利叶酸片较依那普利片更为优秀,值得推广.     

比索洛尔、依那普利和螺内酯联合治疗风湿性心脏病慢性心力衰竭的效果

目的:观察比索洛尔、依那普利和螺内酯联合治疗风湿性心脏病（风心病）慢性心力衰竭（心衰,CHF）对心脏重构的影响。方法: 风心病并发心衰患者86例,随机分为比索洛尔、依那普利和螺内酯联合治疗组（试药组）以及常规治疗方案对照组（对照组）。在治疗后1年测定心功能与左室内径等指标。结果: 试药组左室舒张末期内径（LVEDD）、左室收缩末期内径（LVESD）显著下降,左室射血分数（LVEF）增加显著,与对照组比较有显著差异（均P<0．05）。结论: 比索洛尔、依那普利和螺内酯联合治疗治疗风心病心力衰竭较常规治疗方法在改善心衰,阻止心脏重构方面效果更好。     

Effect of enalapril injected in the early period of postnatal ontogeny on structure of adrenal glands in mature hypertensive NISAG rats

Blood pressure in 6-month hypertensive NISAG rats daily treated with enalapril in the early postnatal period was lower than in control rats. Enalapril produced significant morphological alterations only in the zona glomerulosa of the adrenal cortex. The volumes of this area and the corresponding endocrine cells were lower than in the control. Enalapril produced a delayed modifying effect on the structure of the adrenal zona glomerulosa by moderating hyperplasic alterations, which are characteristic of intact mature NISAG rats. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 2, pp. 133–136, February, 2006