BACKGROUND & AIMS: :Background:  Chinese Hypertension Intervention Efficacy (CHIEF) study is a large-scale randomised clinical trial across China, which compares the efficacy of two combination regimens in reducing cardiovascular events associated with hypertension. Methods:  We reported the 48-week efficacy and tolerability of the two antihypertensive regimens in participants from Shandong Province, China. Eligible patients aged 50-79 years were randomised to receive amlodipine plus amiloride/hydrochlorothiazide (Group A) or amlodipine plus telmisartan (Group B). The doses of both regimens were titrated and other antihypertensive agents were added subsequently to achieve a blood pressure (BP) goal (<140/90 mmHg for general population, <130/80 mmHg for diabetics and <150/90 mmHg for elderly). Efficacy variables included the changes of BP, control rates (the proportion of patients achieving a BP goal), and response rates (the proportion of patients achieving a BP goal or a reduction of BP ≥20/10 mmHg). Safety was assessed by monitoring the incidence of adverse events (AEs). Results:  Of the 349 patients enrolled, 314 were randomised and 291 completed the study (141 in Group A and 150 in Group B). At week 48, the BP was reduced by 28.77/15.55 mmHg in Group A and by 31.38/16.07 mmHg in Group B (p > 0.05 for comparisons between Group A and Group B). The control rates (71.79% vs. 77.22%; p = 0.270) and response rates (79.49% vs. 84.81%; p = 0.218) were also similar. For both regimens, the control rates in diabetic patients were relatively lower (31.91% and 32.50%), while those in elderly patients were pretty higher (90.74% and 97.62%). AEs were mild to moderate in severity (17.95% vs. 12.66%, p = 0.193). Conclusion:  Both combination regimens, amlodipine plus amiloride/hydrochlorothiazide and amlodipine plus telmisartan, were effective and safe for the high-risk hypertensive patients.

背景与目标： 背景:   中国高血压干预疗效 (CHIEF) 研究是一项在中国各地进行的大规模随机临床试验，比较两种联合方案在降低高血压相关心血管事件方面的疗效。方法:   我们报告了来自中国山东省的两种降压方案的48周疗效和耐受性。50-79岁的符合条件的患者被随机分为氨氯地平联合阿米洛利/氢氯噻嗪 (A组) 或氨氯地平联合替米沙坦 (B组)。两种方案的剂量均进行滴定，随后添加其他降压药以达到血压 (BP) 目标 (普通人群 <140/90  mmHg，糖尿病患者 <130/80  mmHg，老年人 <150/90  mmHg)。疗效变量包括血压变化、控制率 (达到血压目标的患者比例) 和缓解率 (达到血压目标或降低血压 ≥ 20/10  mmHg的患者比例)。通过监测不良事件 (AEs) 的发生率来评估安全性。结果: 在纳入的349例患者中，314例被随机分组，291完成研究 (A组141例，B组150例)。48周时，A组血压降低28.77/15.55  mmHg，B组血压降低31.38/16.07  mmHg (A组与B组比较p  >  0.05)。控制率 (71.79% 对77.22%; P   =   0.270) 和应答率 (79.49% 对84.81%; P   =   0.218) 也相似。对于这两种方案，糖尿病患者的控制率相对较低 (31.91% 和32.50%)，而老年患者的控制率相对较高 (90.74% 和97.62%)。AEs的严重程度为轻至中度 (17.95% vs. 12.66%，p   =   0.193)。结论: 氨氯地平联合阿米洛利/氢氯噻嗪和氨氯地平联合替米沙坦治疗高危高血压患者均安全有效。

BACKGROUND & AIMS: :To investigate the effects of S- and R-amlodipine (Aml) on action potential (AP) and L-type calcium channel current (ICa-L), the whole-cell patch-clamp technique was used on rat ventricular myocytes to record AP, ICa-L, peak currents, steady-state activation currents, steady-state inactivation currents, and recovery currents from inactivation with S-Aml and R-Aml at various concentrations. Increasing concentrations of S-Aml gradually shortened AP durations (APDs). At concentrations of 0.1, 0.5, 1, 5, and 10 micromol/L, S-Aml blocked 1.5% +/- 0.2%, 25.4% +/- 5.3%, 65.2% +/- 7.3%, 78.4% +/- 8.1%, and 94.2% +/- 5.0% of ICa-L, respectively (p < 0.05), and the half-inhibited concentration was 0.62 +/- 0.12 micromol/L. Current-voltage curves were shifted upward; steady-state activation and inactivation curves were shifted to the left. At these concentrations of S-Aml, the half-activation voltages were -16.01 +/- 1.65, -17.61 +/- 1.60, -20.17 +/- 1.46, -21.87 +/- 1.69, and -24.09 +/- 1.87 mV, respectively, and the slope factors were increased (p < 0.05). The half-inactivation voltages were -27.16 +/- 4.48, -28.69 +/- 4.52, -31.19 +/- 4.17, -32.63 +/- 4.34, and -35.16 +/- 4.46 mV, respectively, and the slope factors were increased (p < 0.05). The recovery times from inactivation of S-Aml were prolonged (p < 0.05). In contrast, R-Aml had no effect on AP and ICa-L (p > 0.05) at the concentrations tested. Thus, only S-Aml has calcium channel blockade activity, whereas R-Aml has none of the pharmacologic actions associated with calcium channel blockers.

背景与目标： : 为研究S-和R-氨氯地平 (Aml) 对动作电位 (AP) 和L型钙通道电流 (ICa-L) 的影响，采用全细胞膜片钳技术对大鼠心室肌细胞进行记录AP，ICa-L，峰值电流，稳态激活电流，稳态失活电流以及不同浓度的S-Aml和R-Aml失活后的恢复电流。S-Aml浓度的增加逐渐缩短AP持续时间 (APDs)。在0.1、0.5、1、5和10微摩尔/升的浓度下，S-Aml阻断了1.5% +/- 0.2% 、25.4% +/- 5.3% 、65.2% +/- 7.3% 、78.4% +/- 8.1% 和94.2% +/- 5.0% 的ICa-L，分别 (p <0.05)，半抑制浓度为0.62 +/- 0.12 micromol/L。电流-电压曲线向上移动; 稳态激活和失活曲线向左移动。在这些S-Aml浓度下，半激活电压分别为-16.01 +/- 1.65、-17.61 +/- 1.60、-20.17 +/- 1.46、-21.87 +/- 1.69和-24.09 +/- 1.87 mV，坡度因子增加 (p <0.05)。半灭活电压分别为-27.16 +/- 4.48、-28.69 +/- 4.52、-31.19 +/- 4.17、-32.63 +/- 4.34和-35.16 +/- 4.46 mV，斜率因子增加 (p <0.05)。S-Aml失活恢复时间延长 (p <0.05)。相反，在所测试的浓度下，R-Aml对AP和ICa-L没有影响 (p> 0.05)。因此，只有S-Aml具有钙通道阻断活性，而R-Aml没有与钙通道阻滞剂相关的药理作用。

BACKGROUND & AIMS: BACKGROUND:Microalbuminuria (MA) is common in hypertensive population and is a marker for endothelial dysfunction and a predictor of increased cardiovascular risk. A great body of data shows the importance of MA as a strong predictor of renal and cardiovascular disease (CVD) risk in hypertensive population. AIM:In this study, we aimed to compare the anti-albuminuric effects of an angiotensin II receptor antagonist, valsartan, with a calcium channel blocker, amlodipine, in newly diagnosed hypertensive patients. MATERIAL AND METHODS:Totally, 20 patients were recruited into the study. Patients were randomized to one of the following intervention protocols: An (a) angiotensin II receptor blocker (valsartan, 80-320 mg/day) or (b) calcium channel blocker (amlodipine, 5-10 mg/day), for 12 weeks immediately after baseline measurements. Ten patients were randomized into valsartan group and 10 patients into the amlodipine group. Twenty-four-hour urinary albumin excretion (UAE) levels of the patient groups were measured before treatment and on the 12th week. RESULTS:Patients of the two groups were matched for age and body mass index. In the amlodipine group, baseline urine microalbumin levels were higher compared to valsartan group, although the difference was not statistically significant (p = 0.082). At the 12th week, there was a significant decrease in urine microalbumin levels in the amlodipine group, but no significant change was observed in the valsartan group. CONCLUSION:Amlodipine seems to be superior to valsartan in decreasing UAE. To reduce cardiovascular risks, endothelial dysfunction, and microinflammation, these factors are taken into consideration while prescribing antihypertensive drugs in hypertensive patients.

背景与目标：

BACKGROUND & AIMS: :The combination of benazepril plus amlodipine was shown to be more effective than benazepril plus hydrochlorothiazide in reducing cardiovascular events in the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial. There was a small difference in clinic systolic blood pressure between the treatment arms favoring benazepril plus amlodipine. Ambulatory blood pressure monitoring provides a more rigorous estimate of blood pressure effects. A subset of 573 subjects underwent ambulatory blood pressure monitoring during year 2. Readings were obtained every 20 minutes during a 24-hour period. Between-treatment differences (benazepril plus amlodipine versus benazepril plus hydrochlorothiazide) in mean values were analyzed using ANOVA. Treatment comparisons with respect to categorical variables were made using Pearson's χ². At year 2, the treatment groups did not differ significantly in 24-hour mean daytime or nighttime blood pressures (values of 123.9, 125.9, and 118.1 mm Hg for benazepril plus amlodipine group versus 122.3, 124.1, and 116.9 for the benazepril plus hydrochlorothiazide group), with mean between-group differences of 1.6, 1.8, and 1.2 mm Hg, respectively. Blood pressure control rates (24-hour mean systolic blood pressure <130 mm Hg on ambulatory blood pressure monitoring) were greater than 80% in both groups. Nighttime systolic blood pressure provided additional risk prediction after adjusting for the effects of drugs. The 24-hour blood pressure control was similar in both treatment arms, supporting the interpretation that the difference in cardiovascular outcomes favoring a renin angiotensin system blocker combined with amlodipine rather than hydrochlorothiazide shown in the ACCOMPLISH trial was not caused by differences in blood pressure, but instead intrinsic properties (metabolic or hemodynamic) of the combination therapies.

背景与目标： : 对于收缩期高血压患者，通过联合治疗避免心血管事件，贝那普利加氨氯地平的组合在减少心血管事件方面比贝那普利加氢氯噻嗪更有效 (完成) 试验。有利于贝那普利加氨氯地平的治疗组之间的临床收缩压差异很小。动态血压监测可更严格地估计血压影响。在第2年期间，573名受试者的一部分接受了动态血压监测。在24小时内每20分钟获得一次读数。使用ANOVA分析平均值的治疗间差异 (贝那普利加氨氯地平与贝那普利加氢氯噻嗪)。使用Pearson's χ ² 对分类变量进行治疗比较。在第2年时，治疗组在24小时平均白天或夜间血压 (贝那普利加氨氯地平组的123.9，125.9和118.1毫米Hg值与贝那普利加氢氯噻嗪组的122.3，124.1和116.9) 无显着差异，组间平均1.6差异，分别为1.8和1.2毫米Hg。两组的血压控制率 (动态血压监测的24小时平均收缩压 <130毫米Hg) 均大于80%。在调整药物的作用后，夜间收缩压提供了额外的风险预测。两个治疗组的24小时血压控制相似，支持以下解释: 在完成试验中显示的有利于肾素血管紧张素系统阻滞剂联合氨氯地平而不是氢氯噻嗪的心血管结局差异不是由血压差异引起的，而是组合疗法的内在特性 (代谢或血液动力学)。

BACKGROUND & AIMS: :In the present work, four different spectrophotometric methods for simultaneous estimation of losartan potassium, amlodipine besilate and hydrochlorothiazide in raw materials and in formulations are described. Overlapped data was quantitatively resolved by using chemometric methods, classical least squares (CLS), multiple linear regression (MLR), principal component regression (PCR) and partial least squares (PLS). Calibrations were constructed using the absorption data matrix corresponding to the concentration data matrix, with measurements in the range of 230.5-350.4 nm (Δλ = 0.1 nm) in their zero order spectra. The linearity range was found to be 8-40, 1-5 and 3-15 μg mL-1 for losartan potassium, amlodipine besilate and hydrochlorothiazide, respectively. The validity of the proposed methods was successfully assessed for analyses of drugs in the various prepared physical mixtures and in tablet formulations.

背景与目标： : 在目前的工作中，描述了四种不同的分光光度法，用于同时估算原料和配方中的氯沙坦钾，苯磺酸氨氯地平和氢氯噻嗪。使用化学计量学方法，经典最小二乘法 (CLS)，多元线性回归 (MLR)，主成分回归 (PCR) 和偏最小二乘法 (PLS) 对重叠数据进行定量解析。使用与浓度数据矩阵相对应的吸收数据矩阵来构建校准，其零级光谱中的测量范围为230.5-350.4 nm (Δ λ = 0.1 nm)。发现氯沙坦钾，苯磺酸氨氯地平和氢氯噻嗪的线性范围分别为8-40、1-5和3-15μg mL-1。已成功评估了所提出方法的有效性，以分析各种制备的物理混合物和片剂中的药物。

BACKGROUND & AIMS: :Structures of human cytochrome P450 2B6 and rabbit cytochrome P450 2B4 in complex with two molecules of the calcium channel blocker amlodipine have been determined by X-ray crystallography. The presence of two drug molecules suggests clear substrate access channels in each P450. According to a previously established nomenclature, amlodipine molecules were trapped in access pathway 2f in P450 2B6 and in pathway 2a or 2f in P450 2B4. These pathways overlap for part of the length and then diverge as they extend toward the protein surface. A previously described solvent channel was also found in each enzyme. The results indicate that key residues located on the surface and at the entrance of the substrate access channels in each of these P450s may play a crucial role in guiding substrate entry. In addition, the region of P450 2B6 and 2B4 involving helices B', F, F', and G' and part of helix G is substantially more open in the amlodipine complexes than in the corresponding 4-(4-chlorophenyl)imidazole complexes. The increased active site volume observed results from the major retraction of helices F, F', and B' and the β4 sheet region located close to the binding cavity to accommodate amlodipine. These structures demonstrate novel insight into distinct conformational states not observed with previous P450 2B structures and provide clear evidence of the substrate access channels in two drug-metabolizing P450s. In addition, the structures exhibit the versatility that can be exploited via in silico studies with other P450 2B6 ligands as large as raloxifene and itraconazole.

背景与目标： : 已通过x射线晶体学确定了人细胞色素P450 2B6和兔细胞色素P450 2B4与钙通道阻滞剂氨氯地平的两个分子复合物的结构。两个药物分子的存在表明每个p450中有清晰的底物进入通道。根据先前建立的命名法，氨氯地平分子被捕获在P450 2B6的通路2f和P450 2B4的通路2a或2f中。这些途径在部分长度上重叠，然后在向蛋白质表面延伸时发散。在每种酶中也发现了先前描述的溶剂通道。结果表明，这些p450中每个p450中位于基板进入通道的表面和入口处的关键残留物可能在引导基板进入中起关键作用。此外，涉及螺旋B'，F，F' 和G' 和部分螺旋G的P450 2B6和2B4的区域在氨氯地平络合物中比在相应的4-(4-氯苯基) 咪唑络合物中基本上更开放。观察到的活性位点体积增加是由于螺旋F的主要回缩导致的，f' 和B' 以及靠近结合腔的 β4片区域以容纳氨氯地平。这些结构展示了对先前P450 2B结构未观察到的不同构象状态的新见解，并提供了两个药物代谢P450中底物进入通道的明确证据。此外，该结构具有通用性，可以通过与雷洛昔芬和伊曲康唑等其他P450 2B6配体进行计算机研究来利用。

BACKGROUND & AIMS: :Patients with difficult to control hypertension typically require 2 or more agents to achieve goal blood pressure (BP) levels. Fixed-dose combination therapies with lower doses generally are well tolerated and more effective than higher-dose monotherapy. The authors performed prespecified and post hoc subgroup analyses of 2 double-blind, randomized, placebo-controlled trials that assessed the efficacy and safety of amlodipine and valsartan, alone and in combination, in patients with mild to moderate hypertension. Patients were randomized to amlodipine (study 1: 2.5 or 5 mg/d; study 2: 10 mg/d), valsartan (study 1: 40, 80, 160, or 320 mg/d; study 2: 160 or 320 mg/d), combination therapy across the same dose ranges, or placebo. Analyses were performed on changes from baseline in mean sitting systolic and diastolic BP and the occurrence of adverse events in specific subgroups of patients (ie, those with stage 2 hypertension [post hoc], the elderly [65 years or older], and blacks [both prespecified]). Amlodipine + valsartan combination therapy was associated with greater BP-lowering effects in the subgroups compared with each respective monotherapy and placebo. These findings were consistent with the primary efficacy analysis results from the overall study populations. Combination regimens were generally well tolerated by all patient subgroups.

背景与目标： : 难以控制的高血压患者通常需要2种或更多种药物才能达到目标血压 (BP) 水平。较低剂量的固定剂量联合疗法通常比较高剂量的单一疗法具有良好的耐受性和更有效。作者对2项双盲，随机，安慰剂对照试验进行了预设和事后亚组分析，这些试验评估了氨氯地平和缬沙坦单独或联合使用对轻度至中度高血压患者的疗效和安全性。患者随机接受氨氯地平 (研究1: 2.5或5 mg/d; 研究2: 10 mg/d)，缬沙坦 (研究1: 40、80、160或320 mg/d; 研究2: 160或320 mg/d)，相同剂量范围内的联合治疗，或安慰剂。分析平均静坐收缩压和舒张压相对于基线的变化以及特定亚组患者 (即2期高血压 [事后]，老年人 [65岁或以上] 和黑人 [均预先指定]) 中不良事件的发生。与每种单独疗法和安慰剂相比，氨氯地平 + 缬沙坦联合疗法在亚组中具有更大的BP降低作用。这些发现与总体研究人群的主要疗效分析结果一致。所有患者亚组对联合方案的耐受性普遍良好。

BACKGROUND & AIMS: :Hypertension and hyperlipidaemia are major risk factors for the development of atherosclerosis. Calcium channel blockers (CCBs) have been used for decades and have established antihypertensive effects. Statins have been extensively used because of their potent lipid lowering properties. Amongst other factors, inflammation and oxidation are involved in enhanced progression of atherosclerosis and new lesion development. Therefore, research has been initiated focusing on the antioxidant and anti-inflammatory properties of CCBs and statins, beyond their primary effect, in order to evaluate the possible additive effects of combined treatment of CCBs with statins as antiatherosclerotic therapy. Clinical studies (e.g., the International Nifedipine Trial on Antiatherosclerotic Therapy [INTACT]) have demonstrated that the antiatherosclerotic action of CCBs is limited to the attenuation of the first stage of atherosclerogenesis (fatty streak formation or new lesion growth). The lesions that pre-existed at the start of CCB therapy did not demonstrate progression or regression on angiography. However, because the mechanisms of action of lipid-lowering drugs and CCBs, and their role in preventing the progression of atherosclerosis differ, it is conceivable to conclude that these two classes may have an additive or synergic effect, not only on new lesion formation but also on inhibiting the progression of established coronary atherosclerosis. Indeed, this combined effect of lipid-lowering therapy and CCBs on human coronary atherosclerosis has been reported in the Regression Growth Evaluation Statin Study (REGRESS) trial. This beneficial effect of combining CCBs with statins has now been replicated in transgenic atherosclerotic mice, where the combination of amlodipine and atorvastatin produced an additional 60% reduction of atherosclerosis compared with that observed with the statin alone. Serum markers of atherosclerosis and vascular integrity also improved most in the combination group. Synergistic effects of the combination of atorvastatin and amlodipine on acute nitric oxide release/endothelial function, and additive effects of the combination of amlodipine and atorvastatin in the improvement of arterial compliance in hypertensive hyperlipidaemic patients has been demonstrated. Collectively, these studies support the clinical antiatherosclerotic advantages of combination of CCBs and statins and in particular, of atorvastatin with amlodipine beyond their established antihyperlipidaemic and antihypertensive modes of action.

背景与目标： 高血压和高脂血症是动脉粥样硬化发展的主要危险因素。钙通道阻滞剂 (ccb) 已经使用了数十年，并已建立了抗高血压作用。他汀类药物因其有效的降脂特性而被广泛使用。除其他因素外，炎症和氧化参与动脉粥样硬化的进展和新的病变发展。因此，已经开始研究CCBs和他汀类药物的抗氧化和抗炎特性，超越其主要作用，以评估CCBs与他汀类药物联合治疗作为抗动脉粥样硬化疗法的可能的累加作用。临床研究 (例如，国际硝苯地平抗动脉粥样硬化治疗试验 [完整]) 表明，CCBs的抗动脉粥样硬化作用仅限于动脉粥样硬化发生的第一阶段 (脂肪条纹形成或新病变生长) 的衰减。CCB治疗开始时预先存在的病变在血管造影上没有显示出进展或消退。但是，由于降脂药物和ccb的作用机制以及它们在预防动脉粥样硬化进展中的作用不同，因此可以得出结论，这两类药物不仅对新的病变形成具有累加或协同作用，而且对抑制已建立的冠状动脉粥样硬化的进展。实际上，降脂治疗和CCBs对人冠状动脉粥样硬化的联合作用已在回归生长评估他汀研究 (REGRESS) 试验中报道。现在已经在转基因动脉粥样硬化小鼠中复制了将CCBs与他汀类药物组合的这种有益作用，其中与单独使用他汀类药物观察到的相比，氨氯地平和阿托伐他汀的组合产生了额外的动脉粥样硬化60% 降低。在联合组中，动脉粥样硬化和血管完整性的血清标志物也得到了最大的改善。已证明阿托伐他汀和氨氯地平联合使用对急性一氧化氮释放/内皮功能的协同作用，以及氨氯地平和阿托伐他汀联合使用对改善高血压高脂血症患者动脉顺应性的累加作用。总的来说，这些研究支持CCBs和他汀类药物，尤其是阿托伐他汀和氨氯地平的临床抗动脉粥样硬化优势，超出了其既定的抗高脂血症和抗高血压作用方式。

BACKGROUND & AIMS: BACKGROUND:Fixed-dose combination treatments using an angiotensin-converting enzyme (ACE) inhibitor, such as perindopril, plus a calcium channel blocker (CCB), such as amlodipine, have been endorsed by guidelines because they improve blood pressure control and cardiovascular outcomes in hypertensive patients, while being well tolerated and well adhered to by patients. OBJECTIVE:This study aimed to assess the blood pressure-lowering effects of fixed-combination perindopril/amlodipine in patients previously treated with an ACE inhibitor and/or a CCB. METHODS:This was a prospective, real-life, open-label, longitudinal, phase IV study conducted in 223 outpatient medical centres across Slovakia. 2132 previously treated patients whose hypertension was insufficiently controlled at baseline or who tolerated treatment poorly were included. Patients were treated for 3 months with fixed-combination perindopril/amlodipine 5 mg/5 mg, 5 mg/10 mg, 10 mg/5 mg and 10 mg/10 mg. The main outcome measure was a reduction in mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) and achievement of blood pressure targets (SBP/DBP <140/90 mmHg or <130/80 mmHg for patients with type 2 diabetes mellitus or high cardiovascular risk). RESULTS:After 3 months of treatment, mean ± SD SBP/DBP had decreased from 158.5 ± 17.5/93.6 ± 9.8 mmHg to 132.9 ± 10.6/80.7 ± 6.2 mmHg (p < 0.0001). In patients with grade 3 hypertension, mean ± SD changes from baseline in SBP/DBP were -45.4 ± 16.4/-20.0 ± 11.5 mmHg after 3 months (p < 0.0001). Blood pressure targets were reached by 74% of the overall patient population, 84% of patients with grade 1 hypertension, and 52% of difficult-to-treat patients with grade 3 hypertension. This treatment was associated with a 58% reduction in the number of patients with amlodipine-related ankle oedema compared with baseline. CONCLUSION:Fixed-combination perindopril/amlodipine was well tolerated and resulted in statistically significant and clinically meaningful decreases in blood pressure.

背景与目标：

BACKGROUND & AIMS: AIM:We aimed to investigate the effect of the ABCB1 gene on the pharmacokinetics of amlodipine. METHODS:Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 26 healthy male participants were divided into three groups: subjects with 2677GG/3435CC (n = 9), 2677GT/3435CT (n = 9) and 2677TT/3435TT (n = 8). After a single-dose administration of 5 mg amlodipine, plasma concentrations of amlodipine were measured and its pharmacokinetic characteristics were compared according to ABCB1 genotype. RESULTS:The area under the plasma concentration-time curve was significantly lower in subjects with 2677TT/3435TT (140.8 +/- 35.6 ng h(-1) ml(-1)) and 2677GT/3435CT (149.8 +/- 40.1 ng h(-1) ml(-1)) than in those with 2677GG/3435CC (208.6 +/- 39.2 ng h(-1) ml(-1)) [95% confidence interval (CI) on the difference, 2677GG/3435CC vs. 2677GT/3435CT 12.0, 105.6, P < 0.01; 2677GG/3435CC vs. 2677TT/3435TT 19.6, 116.0, P < 0.01; 2677GT/3435CT vs. 2677TT/3435TT - 39.2, 57.2, P > 0.05]. The peak plasma concentrations were highest in subjects with 2677GG/3435CC (3.8 +/- 0.5 ng ml(-1)), lower in subjects with 2677GT/3435CT (3.2 +/- 0.5 ng ml(-1)) and 2677TT/3435TT (2.7 +/- 0.5 ng ml(-1)) in rank and showed a significant difference between those with 2677GG/3435CC and with 2677TT/3435TT (95% CI on the difference 0.4, 2.0, P < 0.01). However, the oral clearance was higher in subjects with 2677TT/3435TT (37.7 +/- 10.2 l h(-1)) than in those with 2677GT/3435CT (35.7 +/- 9.9 l h(-1)) and with 2677GG/3435CC (24.8 +/- 5.4 l h(-1)) and exhibited a significant difference between ABCB1 genotype groups (95% CI on the difference, 2677GG/3435CC vs. 2677GT/3435CT - 21.5, - 0.3, P < 0.05; 2677GG/3435CC vs. 2677TT/3435TT - 23.8, - 2.0, P < 0.05). CONCLUSION:Amlodipine pharmacokinetics was affected by the genetic polymorphisms of the ABCB1 gene in humans. These findings may provide a plausible explanation for interindividual variation in the disposition of amlodipine, although our study could not explain the exact mechanism(s) by which the polymorphic ABCB1 gene paradoxically reduces the plasma levels of amlodipine. Further evaluation is thus warranted.

背景与目标：

BACKGROUND & AIMS: :It has been suggested that the combination of dietary Ca and Ca2+ channel antagonists could have a synergic antihypertensive effect. In this study, 3-week-old male spontaneously hypertensive rats (SHR) were randomized into four groups of animals. Two of these groups were fed on a normal Ca diet (Ca 1%) and the other two groups were fed on a Ca-enriched diet (Ca 2.5%). One of the groups fed on each diet also received amlodipine (1 mg/kg/day) in their drinking water. Systolic and diastolic arterial blood pressure were measured weekly in the rats, from the 6th week of life until the 25th week of life, by the tail-cuff method, and we also calculated the corresponding pulse pressure values (systolic blood pressure-diastolic blood pressure). Determination of plasma Ca levels by colourimetric methods, and measurement in pithed rats of the pressor responses to the alpha-adrenoceptor agonists methoxamine and B-HT 920 (5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d)-acepin-dihydrochloride, talixepole) were also performed using 16- and 23-week-old animals from the different groups. The Ca-enriched diet decreased systolic and diastolic blood pressure in SHR. Almodipine also decreased systolic and diastolic blood pressure in SHR, and this drug intensified the antihypertensive effect of the Ca 2.5% diet in the SHR between weeks 13 and 18. Nevertheless, in the 19- to 25-week-old SHR amlodipine antagonized the effect of dietary Ca on arterial blood pressure. A decrease in the pulse pressure was seen only in the 15- to 20-week-old SHR which had been simultaneously treated with dietary Ca and amlodipine. All the treatments used increased calcaemia, and the highest plasma Ca levels were obtained in the animals which had received the combined treatment with Ca and amlodipine. The responses to methoxamine and to B-HT 920 in the pithed 16-week-old SHR were similar in the four groups of animals. The responses to these agonists in the pithed 23-week-old SHR fed on the Ca-enriched diet were smaller than the corresponding responses in 23-week-old SHR of the untreated group. By contrast, the responses to these agonists were slightly higher in the pithed 23-week-old SHR which were treated with amlodipine than in the pithed 23-week-old SHR in the untreated group. Moreover, amlodipine partially reversed the effect of dietary Ca on alpha-vascular reactivity. According to our results, it would seem inadvisable to use dietary Ca with a Ca2+ channel antagonist with the aim of controlling arterial blood pressure.

背景与目标： : 有人认为，饮食中的Ca和Ca2通道拮抗剂的组合可能具有协同降压作用。在这项研究中，将3周龄的雄性自发性高血压大鼠 (SHR) 随机分为四组动物。这些组中的两组以正常Ca饮食 (Ca 1%) 喂养，另外两组以富含Ca的饮食 (Ca 2.5%) 喂养。每种饮食喂养的一组还在饮用水中接受氨氯地平 (1 mg/kg/天)。从生命的第6周到生命的第25周，通过尾袖法每周测量大鼠的收缩压和舒张压，我们还计算了相应的脉压值 (收缩压-舒张压)。通过比色法测定血浆Ca水平，并在大鼠中测量对 α-肾上腺素受体激动剂甲氧明和B-HT 920 (5-烯丙基-2-氨基-5，6,7，8-四氢-4h-噻唑-(4,5-d)-乙酰-二盐酸盐，talixepole) 也使用来自不同组的16周和23周大的动物进行。富含Ca的饮食可降低SHR的收缩压和舒张压。Almodipine还降低了SHR的收缩压和舒张压，并且该药物在第13周至第18周之间增强了Ca 2.5% 饮食在SHR中的降压作用。然而，在19至25周龄的SHR氨氯地平拮抗饮食Ca对动脉血压的影响。仅在15至20周龄的SHR中观察到脉压降低，该SHR已同时用饮食中的Ca和氨氯地平治疗。所有使用的治疗都会增加钙血症，并且在接受Ca和氨氯地平联合治疗的动物中获得了最高的血浆Ca水平。在四组动物中，在16周龄的SHR中，对甲氧胺和对b-ht 920的反应相似。在富含Ca的饮食中喂养的23周龄SHR中，对这些激动剂的反应小于未治疗组的23周龄SHR中的相应反应。相比之下，在用氨氯地平治疗的23周龄SHR中，对这些激动剂的反应略高于未治疗组的23周龄SHR。此外，氨氯地平部分逆转了饮食中Ca对 α-血管反应性的影响。根据我们的结果，为了控制动脉血压，将饮食中的Ca与Ca2通道拮抗剂一起使用似乎是不明智的。

BACKGROUND & AIMS: BACKGROUND:The coexistence of type 2 diabetes mellitus and hypertension increases the risk of cardiovascular diseases. The U.K. Prospective Diabetes Study has shown that blood pressure control as well as blood glucose control is efficient for prevention of complications in hypertensive patients with diabetes mellitus. However, some reports have shown that it is difficult to control the blood pressure and the concomitant use of a plurality of drugs is needed in hypertensive patients with diabetes mellitus. In recent years renin-angiotensin system depressants are increasingly used for the blood pressure control in diabetic patients. Particularly in Japan, angiotensin II (A II) antagonists are increasingly used. However, there is no definite evidence of the point of which is efficient for the control, the increase in dose of A II antagonist or the concomitant use of another drug, in hypertensive patients whose blood pressure levels are inadequately controlled with A II antagonist. METHODS/DESIGN:Hypertensive patients of age 20 years or over with type 2 diabetes mellitus who have been treated by the single use of AII antagonist at usual doses for at least 8 weeks or patients who have been treated by the concomitant use of AII antagonist and an antihypertensive drug other than calcium channel blockers and ACE inhibitors at usual doses for at least 8 weeks are included. DISCUSSION:We designed a multi-center, prospective, randomized, open label, blinded-endpoint trial, ADVANCED-J, to compare the increases in dose of A II antagonist and the concomitant use of a Ca-channel blocker (amlodipine) and A II antagonist in hypertensive patients with diabetes mellitus, whose blood pressure levels were inadequately controlled with A II antagonist. This study is different from the usual previous studies in that home blood pressures are assessed as indicators of evaluation of blood pressure. The ADVANCED-J study may have much influence on selection of antihypertensive drugs for treatment in hypertensive patients with diabetes mellitus. It is expected to give an important hint for considering the validity of selection of antihypertensive drugs from the aspects not only of the antihypertensive effect but medical cost-effectiveness.

背景与目标：

BACKGROUND & AIMS: OBJECTIVES:Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases. METHODS:We studied effects of amlodipine, atorvastatin, and their combination on carotid arteriosclerotic processes in a metabolic syndrome model of Zucker fatty rats. Zucker fatty rats were treated with vehicle, amlodipine, atorvastatin, or combination amlodipine plus atorvastatin for 28 days. RESULTS:Compared with the single treatment with amlodipine or atorvastatin, the combination of amlodipine plus atorvastatin treatment prevented arteriosclerotic processes, and induced a strong recovery of Sirtuin1 (Sirt1) expression and a marked reduction in p53, p21, and monocyte chemoattractant protein-1 (MCP-1). DISCUSSION:As Sirt1 is a longevity gene that prevents endothelial atherosclerotic processes, and p53, p21, and MCP-1 play pivotal roles in the initiation and development of atherosclerosis, these data suggest a strong synergistic benefit of combination therapy with amlodipine and atorvastatin for preventing atherosclerotic processes, and potentially reducing the clinical risk of cerebrovascular events in metabolic obesity patients.

背景与目标：

BACKGROUND & AIMS: :The pharmacokinetics of amlodipine was studied in 27 subjects with renal function ranging from normal to dialysis-dependent. Amlodipine (as a single 5-mg capsule) was administered once daily for 14 days and its plasma concentrations were measured by gas chromatography during and after treatment. Renal impairment had little or no effect on the pharmacokinetics of amlodipine. The elimination half-life was of the order of 50 h, similar to previously observed values, and did not vary with differences in renal function. Steady-state predose concentrations were observed after the ninth dose. Accumulation of amlodipine to steady-state levels was not significantly different from that expected on theoretical grounds and did not significantly change with renal function. These results suggest that once-daily administration of amlodipine is suitable for all degrees of renal function and that dosage adjustment is not necessary in renal impairment.

背景与目标： : 在27名肾功能从正常到透析依赖的受试者中研究了氨氯地平的药代动力学。每天给药一次氨氯地平 (作为单个5 mg胶囊)，持续14天，并在治疗期间和治疗后通过气相色谱法测量其血浆浓度。肾功能损害对氨氯地平的药代动力学几乎没有影响。消除半衰期约为50小时，与先前观察到的值相似，并且没有随肾功能的差异而变化。第9次给药后观察到稳态给药前浓度。氨氯地平积累到稳态水平与理论上的预期无显着差异，并且随肾功能无显着变化。这些结果表明，每天一次氨氯地平适用于所有程度的肾功能，并且在肾功能不全时无需调整剂量。

BACKGROUND & AIMS: :This study investigated whether pulmonary vascular remodelling in hypoxic pulmonary hypertensive rats (10% oxygen; 4 weeks) could be prevented by treatment, during hypoxia, with amlodipine (10 mg/kg/day, p.o.), either alone or in combination with the angiotensin converting enzyme inhibitor, perindopril (30 mg/kg/day, p.o.). Medial thickening of pulmonary arteries (30-500 microm o.d.) was attenuated by amlodipine whereas it was totally prevented by the combination treatment (amlodipine plus perindopril); neomuscularisation of small alveolar arteries (assessed from critical closing pressure in isolated perfused lungs) was not affected. Pulmonary vascular resistance (isolated perfused lungs) was reduced by both treatment regimes but only combination treatment reduced right ventricular hypertrophy. Thus, amlodipine has anti-remodelling properties in pulmonary hypertensive rats. The finding that combining amlodipine with another anti-remodelling drug produced effects on vascular structure that were additive raises the question of whether combination therapy with two different anti-remodelling drugs may be of value in the treatment of patients with hypoxic (and possibly other forms of) pulmonary hypertension.

背景与目标： : 这项研究调查了在缺氧期间，单独或联合使用氨氯地平 (10 mg/kg/天，p.o.) 是否可以预防低氧性肺动脉高压大鼠 (10% 氧气; 4周) 的肺血管重塑。血管紧张素转化酶抑制剂，培哚普利 (30 mg/kg/天，p.o.)。氨氯地平可减轻肺动脉内侧增厚 (30-500 microm o.d.)，而联合治疗 (氨氯地平加培哚普利) 可完全预防; 小肺泡动脉的新血管形成 (根据孤立的灌注肺中的临界闭合压力评估) 不受影响。两种治疗方案均降低了肺血管阻力 (孤立的灌注肺)，但仅联合治疗可降低右心室肥大。因此，氨氯地平在肺动脉高压大鼠中具有抗重塑特性。氨氯地平与另一种抗重塑药物联合使用对血管结构产生累加作用的发现提出了一个问题，即与两种不同的抗重塑药物联合治疗在治疗低氧 (可能还有其他形式) 的患者中是否有价值肺动脉高压。