【作者】 吴文静；

【导师】 秦玲；

【作者基本信息】 吉林大学 ， 内科学， 2004， 硕士

【摘要】 高血压是最常见的心血管疾病，是全球范围内的重大公共卫生问题。我国高血压患者已达9千万人左右，且发病率不断增高，而知晓率、治疗率和控制率却很不理想。大量的动物实验和临床研究证实，血管紧张素转化酶抑制剂（angiotensin-converting enzyme inhibitor, ACEI）在高血压病的治疗中有重要贡献[1]，具有明确的降压效果及对靶器官的保护作用，被JNC7和ESC/ESH首次推荐作为单纯高血压或1期高血压患者的一线用药，并且是唯一拥有全部6个强适应症的抗高血压药物。它主要通过对循环RAAS及组织RAAS的抑制，阻断AngⅠ向AngⅡ的转化，使AngⅡ生成减少而产生降压作用。同时，它对激肽释放酶－激肽系统（Kallikrein-Kinin System, KKS）有保护作用，可以使缓激肽水平升高，引起血管扩张，并刺激前列环素（PGI2）、一氧化氮（NO）和内皮衍生超级化因子（Endothelium-derived hyperpolarizing factor, EDHF）等舒血管物质的合成[7]。依那普利作为其中一员，已在临床应用多年，有大量的循证医学及基础医学证明其卓越的降压效果及对靶器官的保护。氢氯噻嗪主要通过使细胞外液容量减低，心排血量降低产生降压作用，其一线抗高血压药的地位也早已确定。上述两者合用，通过作用于不同机制产生协同作用，在明显提高降压效果的同时，使各自的不良反应降低，是一种较好的配方。国外已进行了一些研究，比较由不同剂量上述两种药物所组成复方制剂的降压效果，但受试对象多为欧美人种，且使用的组合剂量及得出的结论各不相同，目前国内尚无研究比较不同剂量组合依那普利和氢氯噻嗪复方制剂对亚洲人种的降压效果。为了验证依那普利与氢氯噻嗪复方制剂对国人的有效性及安全性，寻找适合临床应用的剂量组合，本研究将126例受试者随机分为三组，进行双盲研究，观察不同剂量组合复方制剂及单药的降压效果、起效时间、有效剂量、安全性及依从性，并将三组间进行对比，以找到一种适合临床应用的剂量组合。 <WP=45> 入选的所有病例未用降压药或经过2周清洗期，随机分为依那普利10mg/氢氯噻嗪6.25mg组（A组）、依那普利10mg/氢氯噻嗪12.5mg组（B组）及依那普利10mg单药组（C组），各42例。三组病例每天上午7:00~10:00餐后服用一片药物，每2周一次上午8:00~10:00复诊。治疗4周后坐位舒张压仍不能降到小于90mmHg者，将剂量加倍，在8周观察期内不联用其他降压药物。126例患者中，16例中途退出试验。资料完整110例，男54例，女56例，年龄56.51±8.18岁。在试验前后对患者行血、尿常规、肝肾功、血脂、血糖、血离子及心电图检查，均无显著改变（P>0.05）。三组受试者在性别、年龄、体重指数等人口学特征以及基础血压、心率等临床体征上均无明显差异（P>0.05），三组间具有可比性。治疗2周后，三组受试者总有效率分别为64.3%、77.1%、39.4%，其中显效率分别为60.0%、54.3%、24.2%，A、B组明显优于C组（P<0.05），A、B组间无明显差异（P>.05）；治疗4周后，三组总有效率分别为64.3%、74.3%、42.4%，其中显效率分别为61.9%、65.7%、39.4%；治疗6周后，三组总有效率分别为90.5%、85.7%、72.7%，其中显效率分别为80.9%、82.9%、66.7%；治疗8周后，三组总有效率分别为90.5%、85.7%、72.7%，其中显效率分别为80.9%、85.7%、66.7%。A、B两组的总有效率及显效率在治疗4、6、8周时均无统计学差别（P>0.05），A组在治疗4、6、8周时与C组比较均有显著性差异（P<0.05）。在治疗4周时，C组中因舒张压未降至90mmHg以下而需要增加剂量的患者人数为23人，占C组总人数的69.7%，比例明显大于A、B两组（P<0.05），A、B两组间无统计学差别（P>.05）。在治疗第2、4、6、8周时，三组收缩压及舒张压均较基线值（0周）有明显下降（P<0.01），A、B两组间的降压幅度无统计学差异（P>.1），A组降压幅度明显大于C组（P<0.05）。治疗前后，三组的血钾、血糖、血脂、尿酸无明显改变（P>.05）。药物的不良反应主要为咳嗽，其发生率为19%-22%。完成研究的受试者依从性均在80%~120%之间。虽然经过此临床观察后，得到了依那普利10mg+氢氯噻嗪6.25mg是最佳剂量组合的循证医学证据，但是尚不能对其远期降压疗效及相关副作用进行准确评估，有<WP=46>待于更大规模的临床实践进行验证。此外，由于研究所选患者单一，无其他伴随疾病，且研究时间较短，依那普利对心室肥厚的逆转以及对心、脑、肾等保护作用未得以体现。 通过本研究我们认为：① 组成该复方制剂的药物通过不同作用机制降压；② 依那普利与氢氯噻嗪组成的复方制剂，与依那普利单药相比，起效快，总有效率及显效率高，降压幅度大（P<0.05）。③ 在治疗8周期间，依那普利与两种不同剂量氢氯噻嗪（6.25mg，12.5mg）组成的复方制剂组均未发生低钾血症以及血脂、血糖、尿酸代谢的紊乱。④ 依那普利与氢氯噻嗪复方制剂服用方便，患者不必自己分割药片，各自较小剂量即可很快产生满意的降压效果，避免了因依那普利单药疗效不佳所致的剂量增加，进而伴随副作用及治疗费用的增加。因此，有利于提高患者治疗的依从性。⑤ 依那普利与两种不同剂量氢氯噻嗪（6.25mg，12.5mg）组成的复方制剂在起效时间、总有效率、显效?更多还原

【Abstract】 Hypertension is one of the most common cardiovascular diseases. And it is a serious health problem in the world. There are 90 million patients with hypertension in our country, with incidence increasing continuously, while without ideal awareness rate, treatment rate and controlling rate. Large amount of animal experiments and clinical trials have demonstrated that angiotensin-converting enzyme inhibitor (ACEI) contributes a lot in the treatment of hypertension. It has explicit effect on hypertension and excellent protection of target organ. It is recommended for the first time by JNC7 as the first-line medication for simple hypertension and stage 1 hypertension. And it is the only one that has all the 6 compelling indications. It acts by inhibiting circulating and histologic RAAS. Thus it inhibits transformation of AngI to AngII and leads to lowering of blood pressure by decreasing production of AngII. At the same time, it protects Kallikrein-Kinin system and increases bradykinin. So it can lead to dilation of blood vessel and production of vascular dilating factor such as prostaglandin I2, nitric oxygen, endothelium-derived hyperpolarizing factor. As a member of ACEI, enalapril has been used in clinical work for many years. Lots of trials and experiments have demonstrated its excellent effect and protection of target organ. Dihydrochlorothiazide (DHCT) lowers blood pressure by decreasing cardiac output. The first-line position of DHCT in the treatment of hypertension has also been settled. The compound medication by the two mentioned drugs acts by different mechanisms. Thus it is a good prescription because two drugs work in coordination which increase effectiveness and decrease adverse events. Some trials have been performed in other countries to compare the effectiveness of compound prescription with different dosage. But the patients were from Europe and American.Dosage and conclusions were different among those trials. There are no such studies in our country at present. In order to verify the effectiveness and safety of compound agent and to find a suitable dose for clinical work, 126 patients with mild or moderate hypertension were dual-blinded randomized into 3 groups. The range of blood pressure lowering, the time when the medicine began to work, the <WP=48>effective dose, safety and compliance were recorded. Results were compared between different groups to find an appropriate dose for clinical application. All the 126 patients did not use antihypertensive drugs and ran in for 2 weeks. They were randomized into 3 groups: enalapril 10mg+DHCT 6.25mg (group A), enalapril 10mg +DHCT12.5mg (group B), enalapril 10mg +placebo (group C). Each has 42cases. All the patients took 1 tablet at 7:00-10:00 every morning, and followed up at 8:00-10:00 every 2 weeks. After 4 weeks’ therapy, the dosage was doubled in those whose diastolic blood pressure at sitting position were equal or higher than 90mmHg. All the patients did not use any other antihypertensive drugs during the study.In the end, 16 patients quitted,so we had 110 patients with complete data,among which there were 54 males and 56 females,with mean age of 56.51±8.18 yesrs. We performed blood, urine, blood chemistry and ECG examination in patients before and after the trial and no difference was found. No difference in bsaeline characters including age, sex, BMI, heart rate and blood pressure was found. So the three groups were comparable. After 2 weeks’therapy, the total response rate was 64.3%, 77.1%, 39.4%, with a markedly effective rate of 60.0%, 54.3%, 24.2% respectively. Group A and group B were better than group C (P<0.05). There were no difference between group A and group B (P>.05). After 4 weeks’therapy, the total response rate was 64.3%, 74.3%, 42.4%, with a markedly effective rate of 61.9%, 65.7%, 39.4% respectively. After 6 weeks’therapy, the total response rate was 90.5%, 85.7%, 72.7%, with a markedly effective rate of 80.9%, 82.9%, 66.7% respectively. After 8 weeks’ therapy, the total response rate was 90.5%, 85.7%, 72.7%, with a更多还原