Bioequivalence, pharmacokinetic and pharmacodynamic response to combined extended release formulations of felodipine and metoprolol in healthy volunteers

Objective: The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol␣compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation. Methods: Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects. Results: Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding C_max of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination. Conclusion: The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination. Received: 29 October 1996 / Accepted in revised form: 21 March 1997     

心达康对老年高血压病人血清一氧化氮的影响

目的：观察老年高血压一氧化氮（NO）的水平变化及心达康对其的影响。方法：应用比色法测定52例老年高血压病人和30例正常人的血清（NO）水平,其中20例在应用心达康,26例用非洛地平治疗2－4周后,复查血清（NO）水平。结果：老年高血压病人血清（NO）水平较对照组明显降低（P＜0．01）,Ⅱ-Ⅲ级病人明显低于I级病人（P＜0．01）,经心达康治疗后血清NO水平明显升高（P＜0．01）,非洛地平治疗后血清NO无明显变化（P＞0．05）。结论：老年高血压病人体内（NO）水平显降低,且随病情加重而更为显。心达康治疗后（NO）水平明显升高。     

Renal failure in haemorrhagic shock in dogs: Salutary effects of the calcium entry blocker felodipine

Summary The efficacy of felodipine, a dihydropyridine calcium entry blocker to restore renal function was investigated in Wiggers model of haemorrhagic shock. Mongrel dogs were anaesthetized with sodium pentobarbital and subjected to haemorrhagic shock by allowing the animals to bleed into a reservoir. After maintaining the hypotensive state (mean blood pressure 40–45 mm Hg) for a period of 150 min, the blood was reinfused and the recovery of the various parameters were monitored for an additional 120 min. These studies were conducted in three different groups of dogs: (A) Solvent control, (B) Felodipine 0.01 mol/kg i. v., administered 10 min prior to reinfusion of the blood, and (C) Felodipine 0.01 mol/kg i. v., administered prior to haemorrhage. In all the three groups arterial blood pressure returned to similar basal levels following reinfusion. Felodipine administration prior to haemorrhage or before reinfusion (Group B and C) resulted in a 80–95% recovery in the renal blood flow, 60–65% in the glomerular filtration rate, 15–300% in the urine volume and 80–100% in the urinary sodium and potassium excretions. In the vehicle-treated control group, despite a 45% recovery in the renal blood flow, renal function was not restored following reinfusion.The observations made in these studies suggest that felodipine, an arteriolar dilator which also possesses natriuretic properties, could be clinically useful in the treatment of renal failure in haemorrhagic shock. Prevention of cellular calcium overload during ischaemia and reperfusion by this dihydropyridine derivative, may account for its ability to preserve vascular as well as tubular function. Send offprint requests to B. S. Jandhyala at the above address     

氯沙坦和非洛地平治疗中老年高血压合并高尿酸血症的疗效观察

[目的 ]　比较氯沙坦和非洛地平对中老年高血压合并高尿酸血症的疗效。　 [方法 ]　 60例中老年高血压合并高尿酸血症患者随机分成两组 ,分别服用氯沙坦 (氯沙坦组 ,n =3 0例 )和非洛地平 (非洛地平组 ,n =3 0例 ) ,分别测定两组患者治疗前后的血压、2 4h动态血压、血尿酸、空服血糖、血脂和肝肾功能。　 [结果 ]　氯沙坦和非洛地平均有明显的降压效果 (P <0 .0 1) ,两组的降压效果相似 (P <0 .0 5 ) ,但氯沙坦降低血尿酸的效果优于非洛地平 (P <0 .0 0 1) ,对血糖、肝肾功能、血脂均无明显作用 ,未发生明显不良反应。　 [结论 ]　氯沙坦治疗中老年高血压安全、有效 ,与非洛地平相似 ,并且有降低高血尿酸作用     

银杏叶滴丸联合非洛地平治疗冠心病心绞痛的临床研究

目的探讨银杏叶滴丸联合非洛地平治疗冠心病心绞痛的有效性与安全性。方法选取滨州医学院烟台附属医院2015年12月—2017年6月收治的冠心病心绞痛患者146例,根据治疗方案的不同分成对照组(73例)和治疗组(73例)。对照组患者口服非洛地平缓释片,1片/次,1次/d。治疗组患者在对照组的基础上口服银杏叶滴丸,5丸/次,3次/d。所有患者均治疗2个月。观察两组患者临床疗效,比较治疗前后两组患者心绞痛发作频率和平均持续时间,运动耐力、血清P选择素水平、生活质量评分、心脏指标和舒张期冠状动脉血流峰值速度及不良反应情况。结果治疗后,对照组临床总有效率为84.93%,显著低于治疗组的95.89%,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者心绞痛发作频率和平均持续时间均显著降低(P0.05);且治疗组患者发作频率和平均持续时间明显低于对照组患者(P0.05)。治疗后,两组患者6 min步行距离和生活质量评分均显著增加(P0.05),血清P选择素水平显著降低(P0.05);且治疗后治疗组上述指标明显优于对照组(P0.05)。治疗后,两组患者LVEF和舒张期冠状动脉血流峰值速度显著升高(P0.05),LVEDD显著降低(P0.05);且治疗组患者这些指标治疗后水平明显优于对照组(P0.05)。治疗组不良反应发生率为2.74%,明显低于对照组的13.70%,两组比较差异具有统计学意义(P0.05)。结论银杏叶滴丸联合非洛地平治疗冠心病心绞痛疗效显著,不良反应发生率低,具有一定的临床推广应用价值。     

非洛地平联合倍他洛克治疗34例高血压临床效果分析

目的：探究与分析非洛地平联合倍他洛克治疗34例高血压临床效果分析。方法高血压患者34例,将其作为临床研究对象,对其采用非洛地平联合倍他洛克治疗,观察该组患者治疗前后血压及生理指标变化情况。结果该组患者在治疗1周后较治疗前相比,收缩压及舒张压有了明显下降,治疗6~12周血压下降更加显著（P〈0.05）;该组患者治疗前后血清总胆固醇（TC）、甘油三酯（TG）、血尿素氮（BUN）、血肌酐（CR）指标差异无统计学意义（P〉0.05）;该组患者治疗后较治疗前相比,血尿酸（UA）和白蛋白（Alb）有了明显下降（P〈0.05）。该组患者共34例中出现3例面红（8.82%）、4例心悸（11.76%）、3例头痛（8.82%）、3例头晕（8.82%）,因症状较轻,未采取停药处理,数天后症状自行消失。结论对于高血压患者采用非洛地平联合倍他洛克治疗后的临床效果较为显著,能够有效降低患者血压,且在治疗过程中未出现不良反应,具有一定的安全性。     

缬沙坦、苯那普利、非洛地平治疗高血压左室肥厚

目的 研究缬沙坦、苯那普利、非洛地平的降压效果,对高血压左室肥厚(LVH)的逆转作用并观察治疗中的醛固酮(Ald)逃逸现象与 LVH关系.方法 入选高血压左室肥厚患者111例随机分成服用缬沙坦组(36例)或苯那普利组(39例)或非洛地平组(36例),监测治疗过程中的血压变化及服药10～14周、20～26周时血浆血管紧张素Ⅱ(Ang Ⅱ)、醛固酮(Ald)变化,治疗前后超声心动图检查及检测血尿常规、血糖、血脂、肝肾功能检查,记录药物不良反应.结果 3组均能有效降压,效果相当(组内治疗前后比较,P<0.01,组间比较,P>0.05).缬沙坦组、苯那普利组均能逆转LVH.左室质量(LVM)、左室质量指数(LVMI)下降(组内治疗前后比较P<0.01;组间P>0.05),舒张功能改善,二尖瓣血流舒张早期与晚期最大流速比值(E/A)升高(组内治疗前后比较,P<0.01;组间比较,P>0.05);非洛地平组虽有LVM下降(P<0.05),但LVMI、E/A无明显变化(P>0.05).缬沙坦组治疗后Ang Ⅱ显著上升(P<0.01);苯那普利组治疗10～14周Ang Ⅱ明显下降(P<0.01),20～26周Ald升高,接近治疗前水平(P>0.05),与10～14周比较明显升高(P<0.01);非洛地平组Ang Ⅱ较治疗前显著上升(P<0.01).缬沙坦组治疗后Ald浓度明显下降(P<0.01).苯那普利组Ald逃逸发生率36%,有逃逸者LVH逆转较差.结论 缬沙坦、苯那普利、非洛地平降压效果相当.3组对LVH均有逆转作用.缬沙坦、苯那普利作用优于非洛地平.缬沙坦长期应用无Ald逃逸.非洛地平治疗期间对血浆Ald无明显影响.     

HPLC-MS测定Beagle犬血浆中非洛地平的浓度

目的探讨测定Beagle犬血浆内微量非洛地平浓度的方法。方法采用反相高效液相色谱-质谱联用法检测。以尼莫地平为内标,Cosmosil ODS(150 mm×2.0 mm,5μm)为色谱柱,流动相为乙腈-0.1%醋酸铵水溶液(85∶15),柱温40℃,流速0.2 m.lm in-1。结果非洛地平的线性范围为0.5~200.0 ng.m l-1(r2=0.9992),最低定量限为0.5 n.gm l-1,批内、批间RSD均小于15%,提取回收率大于90%。结论所建方法方便、快速,灵敏度高,精密度和重复性好,测定准确,适用于Beagle犬血浆中微量非洛地平的测定及生物利用度试验。     

非洛地平对载脂蛋白E基因敲除小鼠动脉粥样硬化斑块及烟酰胺腺嘌呤二核苷酸氧化酶的影响

目的:探讨钙通道阻断剂(CCB)非洛地平对载脂蛋白E基因敲除(apoEKO)小鼠动脉粥样硬化斑块及烟酰胺腺嘌呤二核苷酸[NAD(P)H]氧化酶的影响。方法:apoEKO小鼠随机分为普通饮食组、高胆固醇饮食组、高胆固醇饮食加非洛地平组。无创血压系统测小鼠血压;内眦动脉取血检测血清TC和TG水平;冷冻切片光镜下定位主动脉根部,油红O染色评估斑块大小;实时定量PCR和Western blot方法检测主动脉中NAD(P)H氧化酶亚基p47phox和Rac-1表达。结果:高胆固醇饮食组小鼠血压没有明显变化,血脂明显升高(P<0.01),且斑块面积明显高于普食组(P<0.01);非洛地平可以明显减小斑块面积(P<0.01),同时还可以降低NAD(P)H氧化酶亚基p47phox和Rac-1表达(P<0.01)。结论:非洛地平可能通过阻断氧化应激反应抑制动脉粥样硬化发生发展。     

不同时间联合使用非洛地平和替米沙坦对高血压患者血压昼夜节律的影响及对左室肥厚的逆转作用

目的:研究不同时间联合使用非洛地平和替米沙坦对高血压患者血压昼夜节律的影响及对高血压左室肥厚的逆转作用。方法:将入选的86例高血压并发左室肥厚的患者随机分为2组,A组清晨顿服非洛地平和替米沙坦,B组清晨服用非洛地平,晚间服用替米沙坦,服药前及服药后每隔4周时分别测定患者诊室血压和24 h动态血压,测定用药前及用药36周时舒张期室间隔厚度(LVST),左室后壁厚度(LPWT)及舒张期左室内径(LVDd),并计算出心室重量(LVMT)。结果:2组用药后各时点收缩压及舒张压均低于用药前。B组夜间平均收缩压、夜间平均舒张压、晨峰血压升高程度、清晨收缩压、清晨舒张压、清晨脉压均较A组低。并且治疗36周后,B组的LVDd,LVST,LPWT均较A组减小(P<0.05)。结论:不同时间联合使用非洛地平和替米沙坦比清晨同时联合使用非洛地平和替米沙坦更能降低夜间血压、遏制清晨血压过度升高,改善高血压患者血压昼夜节律,并且在逆转左室肥厚方面,更有优势。