缬沙坦和卡托普利干预高血压左室心肌肥厚与血中某些活性因子的比较研究

目的：比较缬沙坦对心肌肥厚和纤维化的干预作用是否优于卡托普利，两联用是否更为有益，并对作用机理进行分析探讨。方法：79例伴有左室肥厚的轻、中度高血压病患，随机分为3组：缬沙坦组，缬沙坦80－160mg qd；卡托普利组，卡托普利25－50mg bid；卡托普利＋缬沙坦组，卡托普利12．5－25mg bid 缬沙坦40－80mg qd。治疗期为8个月。另设正常对照组。观测室间隔厚度、左室重量指数、左室相关壁厚度、左室射血分数、二尖瓣口舒张早期和晚期血流速度比（VE／VA）、血浆血管紧张素Ⅱ（Ang Ⅱ)、醛固酮（Ald)、血清I型前胶原羧基端肽（PI CP）和Ⅲ型前胶原氨基端肽（PⅢ NP）等指标，进行治疗前后及组间比较。另对各治疗组每组6例患，观察上述指标的动态变化。结果：各组治疗后反映心肌肥厚和纤维化以及左室舒张功能的各项指标均显改善（P＜0．05，P＜0．01），但未达正常。组间比较差异不显。动态观察卡托普利组Ang Ⅱ及Ald先下降，后出现“逃逸”现象，但此后血清PI CP、PⅢ NP及超声心动图改变仍继续好转。结论：（1）缬沙坦和卡托普利单用或联用均能抑制和逆转高血压心肌肥厚与纤维化，改善舒张功能；（2）缬沙坦组短期治疗的益处未见明显优于卡托普利，两联用未见明显优势；（3）卡托普利持续治疗后出现Ang Ⅱ及Ald“逃逸”现象，但心肌重塑却继续好转。其作用机制与降低Ang Ⅱ的确切关系还有待深入研究。     

The effect of valsartan on regression of left ventricular hypertrophy in type 2 diabetic patients

AIM: The aim of the present study was to examine the effects of an angiotensin II receptor antagonist, valsartan, on echocardiographically proven left ventricular hypertrophy (LVH) in patients with type 2 diabetes. METHODS: Outpatients with type 2 diabetes mellitus were recruited at Niigata University Hospital. The left ventricular mass index (LVMI) was calculated by echocardiography. LVH was considered to be present if the LVMI was > 131 g/m(2) in males and > 100 g/m(2) in females. Patients with LVH received a low dose (40 mg/day) of valsartan for 12 months. This low dose had no clinical effect on blood pressure. RESULTS: Of the 38 patients who entered the study, 14 (36.8%) had LVH. After only 6 months of valsartan therapy, the mean LVMI decreased significantly, from 126.5 +/- 27.8 to 119.0 +/- 23.5 g/m(2) (p < 0.01 vs. baseline). Also, a significant decrease was observed after 12 months (116.5 +/- 30.9 g/m(2), p < 0.05 vs. baseline). Compared to baseline, there were no significant differences after treatment in body mass index, glycosylated haemoglobin (HbA(1c)), systolic blood pressure and diastolic blood pressure. CONCLUSIONS: In type 2 diabetic patients with LVH, treatment with a low dose of valsartan, an angiotensin II receptor antagonist, for 12 months, reduced LVMI, with no reduction in systemic blood pressure. This drug may be safely administered to type 2 diabetic patients with LVH. The long-term risk-reduction effects will have to be evaluated in further trials.     

哮喘大鼠支气管肺泡灌洗液中血管内皮生长因子和血小板源性生长因子的变化及缬沙坦的干预

目的观察血管内皮生长因子（VEGF）和血小板源性生长因子（PDGF）在哮喘大鼠支气管肺泡灌洗液（BALF）中的变化，探讨两者与哮喘气道重塑的关系以及缬沙坦的干预作用。方法50只Wistar大鼠随机分成5组，每组10只：A组（正常对照组）、B组（哮喘组）、C组[15mg／（kg·d）缬沙坦]、D组[30mg／（kg·d）缬沙坦]和E组[50mg／（kg·d）缬沙坦]。分别观察各组肺组织切片的病理改变，用酶联免疫吸附法（EHSA）检测各组大鼠BALF中VEGF和PDGF的水平。结果哮喘大鼠肺组织出现了气道重塑的病理改变；与A组比，B组BALF中VEGF和PDGF水平显著增高（P〈0．01），与B组比，缬沙坦干预后的C组、D组和E组BALF中VEGF和PDGF均显著减少（P〈0．05或P〈0．01）。结论VEGF和PDGF在哮喘大鼠BALF中浓度增高，可能参与了哮喘发病和气道重塑过程。缬沙坦能明显降低哮喘大鼠BALF中VEGF和PDGF的水平，有助于改善哮喘大鼠气道重塑的病理生理过程，其作用机理还有待进一步研究。     

血管紧张素Ⅱ对心肌细胞缝隙连接蛋白Cx43表达的时相性调控

目的研究血管紧张素Ⅱ(AngⅡ)诱导心肌细胞肥大后缝隙连接蛋白Cx43表达的变化规律和机制。方法分离培养大鼠心肌细胞后分为正常对照组、AngⅡ组和缬沙坦组,用Westernblot和免疫荧光法观察不同时间(12、24、48、72h)和不同浓度(1.0×10-9～1.0×10-5mol/L)下心肌细胞Cx43表达的变化,采用免疫荧光法检测3组心肌细胞24和72hCx43的表达。结果AngⅡ组心肌细胞较正常对照组明显肥大,蛋白含量增加。AngⅡ组心肌细胞在24～48hCx43表达上调,72h则明显下调,较正常对照组减少30%,而且在AngⅡ作用下呈浓度依赖性下调,24hAngⅡ组荧光阳性细胞数较正常对照组和缬沙坦组明显上调,72h则较其他组明显下调。缬沙坦可拮抗AngⅡ对Cx43表达的作用。结论AngⅡ诱导心肌细胞肥大过程中Cx43的表达出现一定时相性变化,并和AngⅡ呈明显的量效关系,提示AngⅡ可能通过AT1受体调控Cx43的表达而参与心肌细胞缝隙连接重构。     

苯磺酸氨氯地平和缬沙坦治疗清晨高血压的疗效观察

目的：比较苯磺酸氨氯地平和缬沙坦控制清晨高血压的效果差异。方法：从社区高血压健康自我管理小组患者中选择原发性高血压患者200例,筛选出清晨高血压患者88例,入选患者停用抗高血压药物14 d,将入选患者分为2组,其中服用苯磺酸氨氯地平41例患者为观察组,服用缬沙坦47例患者为对照组,观察4周清晨血压（家庭自测血压）,比较2组患者清晨血压控制情况。结果：苯磺酸氨氯地平和缬沙坦2种药物均能明显降低收缩压（P〈0.01）,但观察组清晨血压控制更好,收缩压低于对照组（P〈0.01）。结论：苯磺酸氨氯地平和缬沙坦均为比较安全和有效的长效抗高血压药物,但在清晨高血压的控制方面,苯磺酸氨氯地平控制收缩压明显优于缬沙坦,而对舒张压无明显影响。     

缬沙坦联合硝苯地平缓释片治疗原发性高血压的临床疗效观察

目的：探讨缬沙坦联合硝苯地平缓释片治疗原发性高血压的临床疗效。方法：选择我院内科门诊治疗的86例原发性高血压患者,随机分为缬沙坦联合硝苯地平缓释片治疗组（A组,n=43）和单用缬沙坦对照组（B组,n=43）。对两组患者治疗4周后的有效性和安全性进行比较。结果：两组血压均有下降,A组下降明显,治疗总有效率95．3％,B组总有效率76．7％,两组比较差异有统计学意义（P〈0．05）。结论：缬沙坦联合硝苯地平缓释片治疗原发性高血压降压有效率优于单用缬沙坦。     

Efficacy and Safety of 30-Mg Fimasartan for the Treatment of Patients With Mild to Moderate Hypertension: An 8-Week,Multicenter, Randomized,Double-Blind,Phase III Clinical Study

Purpose

The standard 60-mg dose of fimasartan, a newly developed selective angiotensin II receptor blocker, is effective and safe for use in patients with mild to moderate hypertension. This study aimed to compare the efficacy and safety of low-dose (30 mg) fimasartan and placebo or valsartan (80 mg) for 8 weeks in patients with mild to moderate hypertension.

Methods

In this randomized trial, 293 patients (219 men; mean age, 54.24 [9.77] years) with mild to moderate hypertension were enrolled. After randomization to receive 30-mg fimasartan (n = 115), placebo (n = 117), or 80-mg valsartan (n = 61), the treatment dose was kept constant without dose escalation for 8 weeks. The primary end point was improvement in sitting diastolic blood pressure (SiDBP) from baseline to 8 weeks that was compared between treatments with low-dose fimasartan and placebo. The secondary end point was the overall efficacy and safety of low-dose fimasartan compared with that of placebo or valsartan.

Findings

At week 8, SiDBP changed by –9.93 (8.86) mm Hg in the fimasartan group and by –2.08 (9.47) mm Hg in the placebo group, which indicated significant antihypertensive efficacy (P < 0.0001). Efficacy was shown at week 4 as measured by SiDBP (–9.96 [7.73] vs –2.27 [7.85] mm Hg; P < 0.0001) or sitting systolic blood pressure (SiSBP) (–16.18 [14.44] vs –1.95 [13.48] mmHg; P < 0.0001) and at week 8 as determined by SiSBP (–15.35 [16.63] vs –2.30 [14.91] mm Hg; P < 0.0001). The fimasartan group exhibited more potent antihypertensive efficacy than the valsartan group both at week 4 (SiDBP, –9.96 [7.73] vs –6.53 [9.58] mm Hg [P = 0.0123]; SiSBP, –16.18 [14.4] vs –7.65 [12.89] mm Hg [P = 0.0002]) and at week 8 (SiDBP, –9.93 [8.86] vs –5.47 [8.96] mm Hg [P = 0.0021]; SiSBP, –15.35 [16.63] vs –7.49 [13.68] mm Hg [P = 0.0021]). Most treatment-emergent adverse events (TEAEs) were mild (89 of 95), and there were no serious TEAEs. The incidence of TEAEs was 19.1% in the fimasartan group, 22.6% in the placebo group, and 13.6% in the valsartan group, with no significant differences.

Implications

Low-dose fimasartan (30 mg) was well tolerated during the study period with no significant TEAEs. Low-dose fimasartan had an effective blood pressure–lowering effect that was greater than that of 80-mg valsartan in patients with mild to moderate hypertension. ClinicalTrials.gov identifier: NCT01672476.     

缬沙坦对老年心力衰竭患者N端脑钠肽前体及和肽素的影响

目的观察老年慢性心力衰竭（简称“心衰”）患者缬沙坦治疗前后血浆N端脑钠肽前体（NT-proBNP）及和肽素的变化,探讨缬沙坦抑制心室重构的作用机制。方法纳入2011年6月至2012年9月在湖南株洲凯德心血管病医院心内科就诊的老年慢性心衰患者99例,随机分为治疗组（常规治疗＋缬沙坦,n＝50）和对照组（仅常规治疗,n＝49）,分别检测两组治疗前、治疗1个月、治疗6个月,血浆NT-proBNP、和肽素水平及心室结构功能的变化。结果两组患者治疗1个月与治疗前、治疗6个月与1个月比较,血浆NT-proBNP及和肽素水平均下降,差异均有统计学意义（P＜0.05或P＜0.01）;治疗组患者治疗1个月、6个月的血浆NT-proBNP、和肽素水平与同时间段对照组相比均下降,差异均有统计学意义（P＜0.05或P＜0.01）。治疗1个月,两组患者左室射血分数（LVEF）、左心室收缩末期内径（LVESD）及左心室舒张末期内径（LVEDD）与治疗前比较,以及两组间比较,差异均无统计学意义（P＞0.05）;治疗6个月,治疗组LVEF较对照组明显升高（P＜0.01）,LVESD及LVEDD较对照组明显减小（均P＜0.01）。结论血管紧张素Ⅱ受体拮抗剂缬沙坦能够抑制老年慢性心衰患者血浆NT-proBNP、和肽素的分泌,抑制神经内分泌因子,抑制心室重构,改善心功能。     

心力衰竭幼鼠心肌CaMKII表达及药物干预研究

【摘 要】目的：研究缬沙坦（Valsartan）对心力衰竭（Heart failure,HF）幼鼠心室肌内钙调素依赖性蛋白激酶II（Calmodulin KinaseII,CaMKII）表达的影响。方法：采用腹主动脉部分缩窄（Abdominal aortic constriction,AAC）的方法建立3周龄SD幼鼠的心力衰竭模型,同时设假手术组;术后4周将心衰鼠随机分为心衰组和缬沙坦治疗组,缬沙坦组每日灌胃给药,心衰组和假手术组给予安慰剂;术后8周使用高频超声检测大鼠左室收缩和舒张末期内径（LVIDs、LVIDd）、左室收缩和舒张末期容积（LVESV、LVEDV）、左室射血分数（LVEF）、左室短轴收缩率（LVFS）;左、右心室重量指数（LVMI、RVMI）;Western blot检测CaMKII及其亚型表达情况。结果：与假手术组（n=8）比较,心衰组（n=10）LVIDs、LVESV均明显升高（F =21.082,P <0.001;F =14.178,P =0.001）, LVEF、LVFS均明显降低（F =103.766,P <0.001;F =62.953,P <0.001）, LVIDd、LVEDV无明显差异;LVMI明显增加（F =13.272,P =0.01）;心室肌细胞内CaMKII表达升高1.95倍（F =7.541,P =0.026）,CaMKII亚型 (δB δ9) 表达升高1.93倍（F =7.042,P =0.029）,CaMKIIδC表达升高1.93倍（F =6.714,P =0.045）;经缬沙坦治疗后,缬沙坦组（n=8）与假手术组比较,超声结果（LVIDs、LVIDd 、LVESV、LVEDV 、LVEF 、LVFS ）、LVMI和CaMKII表达没有显著差异（P >0.05）。结论：心力衰竭幼鼠心室肌上CaMKII表达增高;缬沙坦改善HF心脏收缩功能,可能与其部分下调心室肌细胞内CaMKII的表达有关。     

Ambulatory Blood Pressure Response to Once-Daily Fimasartan: An 8-Week,Multicenter, Randomized,Double-Blind,Active-Comparator,Parallel-Group Study in Korean Patients With Mild To Moderate Essential Hypertension

Background

Fimasartan, a selective angiotensin II type 1 receptor blocker, was approved in Korea for the treatment of patients with mild to moderate hypertension.

Objective

The aim of this study was to evaluate the 24-hour blood pressure (BP) profiles before and after 8-week treatment with fimasartan and to compare them with those of valsartan.

Methods

A multicenter, randomized, double-blind, active-controlled, parallel-group study was conducted using ambulatory BP monitoring (ABPM). Korean patients with mild to moderate essential hypertension were enrolled and randomly received once-daily oral fimasartan 60 or 120 mg or valsartan 80 mg for 8 weeks. ABPM was performed before and after 8-week treatment, and clinic BP was also measured. Based on ABPM data, trough-to-peak ratio and smoothness index were derived. Tolerability was monitored throughout the study.

Results

Ninety-two patients were enrolled (mean [SD] age, 54.1 [8.2] years; weight, 67.9 [10.2] kg). After 8 weeks, 24-hour, daytime, and nighttime mean ambulatory systolic and diastolic BPs (SBP and DBP, respectively) were significantly decreased in all 3 treatment groups (range: SBP, –9.2 to –15.6 mm Hg; DBP, –5.0 to –10.7 mm Hg; P <0.0001–<0.05). The global trough-to-peak ratios of ambulatory DBP in the fimasartan groups were 0.74 (60 mg/d) and 0.81 (120 mg/d)—45.1% and 58.8% higher, respectively, than the ratio of 0.51 in the valsartan group. Fimasartan 60 mg/d was associated with 53.5% (SBP) and 68.3% (DBP) greater smoothness index scores compared with those with valsartan 80 mg/d (SBP, 1.52 vs. 0.99; DBP, 1.38 vs. 0.82). The decrease in clinic-measured DBP was significantly greater in the fimasartan 60-mg/d group compared with that in the valsartan 80-mg/d group (–14.0 vs –8.7 mm Hg; P = 0.0380). Fimasartan was well tolerated; headache was the most common adverse event.

Conclusion

Once-daily fimasartan effectively maintained a BP-reduction profile over the full 24-hour dosing interval; this profile was comparable to or slightly better than that of once-daily valsartan. Fimasartan was well tolerated; headache was the most common adverse event. ClinicalTrials.gov identifier: NCT00922441.