卡维地络联合缬沙坦逆转高血压左心室肥厚的临床观察

目的 比较β受体阻滞剂联用血管紧张素转换酶抑制剂（ACEI）与联用血管紧张素Ⅱ受体拮抗剂对逆转高血压患者左心室肥厚的疗效.方法 临床收集高血压伴左心室肥厚患者96例,随机分为卡维地络联合咪达普利组（A组）和卡维地络联合缬沙坦（B组）,每组各48例.观察两种治疗方法对于逆转左心室肥厚的疗效.结果 两组治疗后左室舒张末内径（LVDd）、舒张期室间隔厚度（IVST）、左室后壁厚度（LVPWT）、左室射血分（LVEF）、心排出量（CO）、A峰/E峰比值（A/E比值）、左室重量指数（LVMI）均明显下降,与治疗前比较差异有统计学意义（P＜0.01）,但两组间比较差异无统计学意义（P＞0.05）.结论 卡维地络联用缬沙坦与联用咪达普利一样能显著逆转原发性高血压伴左室肥厚,并能改善预后.     

咪达普利、缬沙坦抑制动脉粥样硬化的作用及机制

目的研究咪达普利，缬沙坦抑制动脉粥样硬化的作用及其机制。方法40只纯种大白兔随机分为4组。喂养8周后测定各组血清中总胴固醇（TC）、甘油三酯（TG）及低密度脂蛋白胆固醇（LDL），免疫组化观察粥样硬化斑块中STAT3、P21、CDK4的表达情况。结果高脂组、药物干预组血清TC、TG、LDL—C水平较对照组显著升高。STAT3、CDK4在药物干预组中表达较高脂组明显减少．而P21在药物干预组的表达较高脂组则明显升高。结论咪达普利、缬沙坦可明显抑制动脉粥样硬化的发生，其机制可能与抑制STAT3的信号传导和平滑肌增值有关。     

咪唑普利对高血压患者血压及有关生化因素的影响

目的 评估ACEI咪唑普利(Imidapril)对原发性高血压患者的降压效果及对有关因素(包括血脂、内皮素等)的影响。方法 选择31例高血压患者服用咪唑普利5～10mg/日,连续4～6周,观察比较服药前后血压、心率、生化指标及内皮素含量。结果 服药后血压、心率、TC、LDL-C及内皮素显著降低,血肌酐及其它指标无明显变化。结论 咪唑普利具有良好的降压效果,无反射性心率加快,对血脂、血糖无不良影响,并能降低内皮素含量。     

Molecular mechanism of imidapril for cardiovascular protection via inhibition of MMP-9

To investigate the inhibitory specificity of angiotensin converting enzyme (ACE) inhibitors to matrix metalloproteinase (MMP)-9, we predicted molecular interactions between an ACE inhibitor imidapril and MMP-9 active site based on recent X-ray structural analyses. Two binding modes differing in the orientation of imidapril on the active site were identified, and its hydrophobic group appeared to preferentially interact with the S1 site compared with the S1' site. Compared with the lisinopril-MMP-9 model in our previous study, imidapril was stabilized effectively on the active site with less of molecular distortions. We also measured ACE and MMP-9 inhibitory activities of imidapril and lisinopril after myocardial infarction. Imidapril had a stronger inhibitory activity against MMP-9 than lisinopril. These findings show that imidapril inhibits MMP-9 directly like lisinopril and its hydrophobic interactions with the S1 site of MMP-9 would be important for enhancing inhibitory activity.     

咪达普利的药理学特性和临床治疗意义

咪达普利不仅具有良好的降压效果 ,而且不良反应小 ,患者依从性好 ,作为新的血管紧张素转化酶抑制剂体现出不同于其它同类药物及肾上腺素能受体结合剂制剂的优越性 ,在心血管疾病治疗中具有广泛的应用前景。     

Pharmacokinetics and pharmacodynamics of a sustained-release biodegradable pellet containing imidapril, a new angiotensin-converting enzyme inhibitor in spontaneously hypertensive rats

The pharmacokinetics and pharmacodynamics (PK/PD) of a sustained-release biodegradable pellet containing imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated in comparison with those of an osmotic pump in male spontaneously hypertensive rats (SHRs). A pellet was prepared from copolymer of -lactic acid and glycolic acid by the melt-pressing technique. Imidapril was released in vitro from the pellet at an approximately zero-order rate and the release profile was similar to that of the osmotic pump. Imidapril was administered subcutaneously via a pellet or an osmotic pump implanted under the skin in the back of SHRs. Plasma concentrations of imidaprilat as an active metabolite of imidapril, plasma ACE activity and systolic blood pressure (SBP) were determined periodically. The plasma concentration of imidaprilat during the administration of a pellet was maintained for 4 weeks, and the plasma concentration profile was close to that of the osmotic pump. Both groups of pellet and osmotic pump significantly inhibited plasma ACE activity and reduced SBP for 4 weeks, and these action profiles were similar in both groups. In addition, in vivo release profile of the pellet was close to the in vitro release profile, and the in vivo release profiles of the pellet and the osmotic pump were similar to each other. From these results, it was found that the PK/PD of a biodegradable pellet were close to those of the osmotic pump, and it was shown that the pellet may be a useful system to maintain the plasma concentration of imidaprilat for a long time.     

咪达普利联合托拉塞米治疗继发性高血压患者的疗效与安全性分析

目的探析咪达普利联合托拉塞米治疗继发性高血压患者的疗效与安全性。方法选取2018年6月至2019年6月在本院治疗的继发性高血压患者92例为研究对象,按随机数字法分为对照组和观察组,各46例。对照组采用咪达普利治疗,观察组在对照组基础上采用托拉塞米治疗。比较两组临床疗效和不良反应发生率。结果观察组治疗总有效率为95.65%,显著高于对照组的78.26%(P<0.05);观察组不良反应发生率为2.17%,显著低于对照组的17.39%(P<0.05)。结论继发性高血压患者临床治疗中给予咪达普利与托拉塞米联合治疗效果显著,可有效提高临床疗效,显著减少用药不良反应,安全有效。     

咪达普利对氯化铵所致急性肺损伤大鼠血气、MDA及AngⅡ、CD54蛋白表达的影响

 目的: 本研究通过复制氯化铵致大鼠肺损伤模型,研究咪达普利对肺损伤大鼠动脉血气、MDA、肺形态学和AngⅡ、CD54蛋白表达的影响。方法: 将30只雄性大鼠随机分为3组:空白对照组、肺损伤模型组和药物组。对照组大鼠腹腔注射生理盐水2 mL/kg;肺损伤模型组大鼠腹腔注射等量6%氯化铵;药物组大鼠在注射6%氯化铵后,每天1次灌胃咪达普利(3 mg/kg),连续灌胃7 d;在实验第7天,用2%的戊巴比妥钠麻醉,采集腹主动脉血和腹腔静脉血样本;肺组织经4%多聚甲醛灌注、固定、脱水、透明、浸蜡、包埋和切片。ELISA法测定血清TNF-α和IL-6水平,化学发光法测定血清MDA含量,HE染色观察肺部形态学变化,免疫组织化学染色法观察肺组织AngⅡ和CD54蛋白表达。结果: 与对照组相比,模型组PaCO₂明显升高(P < 0.05),血清TNF-α、IL-6和MDA浓度显著增加(P < 0.01),氯化铵腹腔注射的肺损伤模型组大鼠出现肺水肿、肺炎、肺泡壁瘀血、肺泡腔出血和肺泡壁增生等损伤,肺组织AngⅡ和CD54蛋白表达明显增高(P < 0.01);与模型组比较,药物组PaCO₂明显降低(P < 0.05),血清TNF-α、IL-6和MDA浓度以及肺组织AngⅡ、CD54蛋白表达显著降低(P<0.01)。结论: 咪达普利可显著改善氯化铵所致肺损伤大鼠血气,抑制脂质过氧化和血清炎症细胞因子,降低肺组织AngⅡ和CD54蛋白表达。     

咪达普利与氯沙坦对糖尿病大鼠心肌间质重构的对比研究

目的:研究在不同水平阻断肾素-血管紧张素系统(RAS)对糖尿病大鼠心肌间质重塑过程的影响及保护机制。方法:50只健康雄性SD大鼠随机分为空白对照组(10只)和糖尿病组(40只),糖尿病组用链脲佐菌素(STZ)50 mg/kg腹腔注射建立实验性糖尿病大鼠模型,将建模成功的39只大鼠随机分为咪达普利组10只、氯沙坦组10只、联合用药组10只及模型对照组9只,给药9周后麻醉处死,免疫组化SP法检测肿瘤坏死因子-α(TNF-α)、核因子-κB(NF-κB)、基质金属蛋白酶-9(MMP-9)的蛋白表达,RT-PCR法测NF-κB、MMP-9和TNF-α的mR-NA表达。VG染色观察心肌胶原容积分数(CVF)变化。结果:与空白对照组相比,糖尿病组大鼠心脏指数、左心室指数、心肌CVF明显升高,心肌间质发生重构,TNF-α、MMP-9、NF-κB含量和TNF-αmRNA、MMP-9 mRNA和NF-κB mRNA的表达均增高。咪达普利、氯沙坦及联合用药干预后,上述指标表达均明显降低,但咪达普利和氯沙坦的改善程度无明显差异,联合用药明显优于单独用药。结论:咪达普利和氯沙坦可能通过影响TNF-α、MMP-9的表达来改善糖尿病心肌间质重构,NF-κB参与了这一过程。     

LC-MS determination and bioavailability study of imidapril hydrochloride after the oral administration of imidapril tablets in human volunteers

The purpose of the present study was to develop a standard protocol for imidapril hydrochloride bioequivalence testing. For this reason, a specific LC-MS method was developed and validated for the determination of imidapril in human plasma. A solid-phase extraction cartridge, Sep-pak C18, was used to extract imidapril and ramipril (an internal standard) from deproteinized plasma. The compounds were separated using a XTerra MS C18 column (3.5 microm, 2.1 x 150 mm) and acetonitrile-0.1% formic acid (67:33, v/v) adjusted to pH 2.4 by 2 mmol/L ammonium formic acid, as mobile phase at 0.3 mL/min. Imidapril was detected as m/z 406 at a retention time of ca. 2.3 min, and ramipril as m/z 417 at ca. 3.6 min. The described method showed acceptable specificity, linearity from 0.5 to 100 ng/mL, precision (expressed as a relative standard deviation of less than 15%), accuracy, and stability. The plasma concentration-versus-time curves of eight healthy male volunteers administered a single dose of imidapril (10 mg), gave an AUC12hr of imidapril of 121.48 +/- 35.81 ng mL(-1) h, and Cmax and Tmax values of 32.59 +/- 9.76 ng/mL and 1.75 +/- 0.27 h. The developed method should be useful for the determination of imidapril in plasma with sufficient sensitivity and specificity in bioequivalence study.