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。

BACKGROUND & AIMS: :Bone is a dynamic organ system that is directly related to calcium and phosphor metabolism. Imbalance in these two parameters upon aging or menopause leads to osteoporosis. Recently, it was also shown by researchers that high blood pressure in elderly women is statistically associated with decreased bone mineral content at the femoral neck, which may increase the susceptibility to fractures. The aim of our study was to investigate the effects of different doses of amlodipine and lacidipine on ovariectomized rat femurs' calcium and phosphor content. Bone calcium and phosphor concentration was measured by a Wavelength Dispersive Spectrometer. Calcium contents of the rat femurs were significantly lower in the ovariectomized group than in the sham group eight weeks after the operation. Amlodipine treatment at doses of 1 and 3 mg/kg significantly increased the calcium (P<0.01) and phosphor concentrations (P<0.01) in the femurs of ovariectomized rats, compared to those of control (ovariectomized) group. Both doses of lacidipine (1 and 3 mg/kg) also effectively increased calcium concentrations (P<0.01) significantly in ovariectomized rats. On the other hand amlodipine treatment at doses of 1 and 3 mg/kg significantly increased the calcium (P<0.01) and phosphor concentrations (P<0.01) in the femurs of ovariectomized rats compared with those of the sham group. In conclusion, amlodipine and lacidipine improved the bone loss in an ovariectomy induced osteopenic rat model. Our findings suggest that potent calcium channel blockers such as amlodipine and lacidipine have a beneficial effect on bone metabolism, and an antihypertensive effect.

背景与目标： : 骨骼是与钙和磷代谢直接相关的动态器官系统。衰老或更年期时，这两个参数的不平衡会导致骨质疏松症。最近，研究人员还发现，老年妇女的高血压与股骨颈骨矿物质含量降低在统计学上相关，这可能会增加骨折的敏感性。我们研究的目的是研究不同剂量的氨氯地平和拉西地平对去卵巢大鼠股骨钙和磷含量的影响。通过波长色散光谱仪测量骨钙和磷的浓度。术后8周，去卵巢组大鼠股骨的钙含量明显低于假手术组。与对照组 (卵巢切除组) 相比，1和3 mg/kg剂量的氨氯地平处理可显着增加去卵巢大鼠股骨中的钙 (P<0.01) 和磷浓度 (P<0.01)。两种剂量的拉西地平 (1和3 mg/kg) 也有效地增加了去卵巢大鼠的钙浓度 (P<0.01)。另一方面，与假手术组相比，1和3 mg/kg剂量的氨氯地平治疗可显着增加去卵巢大鼠股骨中的钙 (P<0.01) 和磷浓度 (P<0.01)。总之，氨氯地平和拉西地平改善了卵巢切除术诱导的骨质减少大鼠模型的骨丢失。我们的发现表明，有效的钙通道阻滞剂 (例如氨氯地平和拉西地平) 对骨代谢具有有益作用，并具有抗高血压作用。

BACKGROUND & AIMS: :Hypertension and dyslipidemia are important risk factors for cardiovascular disease. However, the clinical outcomes of fixed-dose combination (FDC) versus free-equivalent combination (FEC) of amlodipine and atorvastatin in the treatment of concurrent hypertension and dyslipidemia remain unknown. In this study, we included patients with newly diagnosed hypertension and dyslipidemia, without previously established cardiovascular disease, and treated with either FDC or FEC of amlodipine and atorvastatin were identified from the National Health Insurance Research Database of Taiwan and follow-up for 5 years. By using 1:1 propensity score matching, a total of 1756 patients were enrolled in this study. The composite of major adverse cardiovascular events, including all-cause mortality, myocardial infarction (MI), stroke, and coronary revascularization, occurred more frequently in the FEC group than in the FDC group (hazard ratio, 1.88; 95% confidence interval [CI], 1.42 to 2.5). Although the all-cause mortality did not differ (hazard ratio, 0.46; 95% CI, 0.36 to 1.59), the FEC group developed increased MI, stroke, and coronary revascularization (hazard ratio, 2.87; 95% CI, 1.07 to 7.68; hazard ratio, 1.97; 95% CI, 1.41 to 2.74; and hazard ratio, 2.44; 95% CI, 1.26 to 4.69, respectively). Furthermore, as an unexpected result, a higher risk to develop new-onset diabetes mellitus was observed with FEC regimens (hazard ratio, 2.19; 95% CI, 1.6 to 3.0). In conclusion, although the all-cause mortality did not differ between the two groups, the FDC regimen of amlodipine and atorvastatin improved clinical outcomes when compared to FEC in patients with newly diagnosed hypertension and dyslipidemia.

背景与目标： : 高血压和血脂异常是心血管疾病的重要危险因素。然而，氨氯地平和阿托伐他汀的固定剂量组合 (FDC) 与自由等效组合 (FEC) 治疗并发高血压和血脂异常的临床结果仍然未知。在这项研究中，我们从台湾国家健康保险研究数据库中确定了新诊断的高血压和血脂异常，没有先前确定的心血管疾病，并接受了FDC或氨氯地平和阿托伐他汀的FEC治疗，并进行了5年的随访。通过使用1:1倾向评分匹配，本研究共招募了1756名患者。与FDC组相比，FEC组的主要不良心血管事件 (包括全因死亡率，心肌梗死 (MI)，卒中和冠状动脉血运重建) 的发生率更高 (风险比，1.88; 95% 置信区间 [CI]，1.42至2.5)。尽管全因死亡率没有差异 (风险比，0.46; 95% CI，0.36至1.59)，但FEC组出现了MI，中风和冠状动脉血运重建 (风险比，2.87; 95% CI，1.07至7.68; 风险比，1.97; 95% CI，1.41至2.74; 和危险比，2.44; 95% CI，分别为1.26至4.69)。此外，作为意外的结果，使用FEC方案观察到发生新发糖尿病的较高风险 (风险比，2.19; 95% CI，1.6至3.0)。总之，尽管两组的全因死亡率没有差异，但与FEC相比，氨氯地平和阿托伐他汀的FDC方案在新诊断的高血压和血脂异常患者中改善了临床结局。

BACKGROUND & AIMS: :This study investigated the addition of the direct renin inhibitor aliskiren to amlodipine in patients with mild to moderate hypertension that was inadequately controlled with amlodipine alone. Following once-daily treatment with amlodipine 5 mg for 4 weeks, patients whose hypertension responded inadequately to therapy (mean sitting diastolic blood pressure [DBP] 90-109 mm Hg) (n=545) were randomized to 6 weeks of double-blind treatment with amlodipine 5 mg plus aliskiren 150 mg, amlodipine 5 mg, or amlodipine 10 mg. At the study's end, mean systolic blood pressure and DBP reductions with the combination of aliskiren 150 mg and amlodipine 5 mg (11.0/8.5 mm Hg) were significantly greater (P<.0001) than with amlodipine 5 mg (5.0/4.8 mm Hg)--the comparator group--but similar to amlodipine 10 mg (9.6/8.0 mm Hg). All treatments were well tolerated. Edema occurred more frequently with amlodipine 10 mg (11.2%) than with combination therapy (2.1%) or amlodipine 5 mg (3.4%). In conclusion, aliskiren 150 mg plus amlodipine 5 mg shows similar but not better blood pressure-lowering efficacy when compared with amlodipine 10 mg in patients not completely responsive to amlodipine 5 mg; less edema was noted with combination therapy.

背景与目标： : 这项研究调查了单独使用氨氯地平无法充分控制的轻度至中度高血压患者在氨氯地平中添加直接肾素抑制剂阿利吉仑的情况。每天用氨氯地平5 mg治疗4周后，高血压对治疗反应不充分的患者 (平均舒张压 [DBP] 90-109毫米Hg) (n = 545) 被随机分配到6周的双盲治疗氨氯地平5 mg加阿利吉仑150 mg，氨氯地平5 mg，或氨氯地平10 mg。在研究结束时，阿利吉仑150 mg和氨氯地平5 mg (11.0/8.5毫米Hg) 联合使用的平均收缩压和DBP降低显着高于 (P<.0001) 氨氯地平5 mg (5.0/4.8毫米Hg) (比较组)-但与氨氯地平10 mg (9.6/8.0毫米Hg) 相似。所有治疗均具有良好的耐受性。与联合治疗 (2.1%) 或氨氯地平5 mg (3.4%) 相比，氨氯地平10 mg (11.2%) 发生水肿的频率更高。总之，在对氨氯地平5 mg无完全反应的患者中，与氨氯地平10 mg相比，阿利吉仑150 mg加氨氯地平5 mg显示出相似但更好的降血压效果; 联合治疗可减少水肿。

BACKGROUND & AIMS: BACKGROUND:Hypoxia-induced rise in intracellular calcium concentration is a causative agent of apoptosis and oxidative damage in cardiomyocytes. We examined the efficacy of calcium channel blocker amlodipine in preventing hypoxia-induced apoptosis in H9c2 cells and restoring oxidative balance. METHODS:H9c2 cells were exposed to hypoxia (0.5% oxygen) to evaluate the efficacy of amlodipine in restoring cellular calcium levels. Cellular markers of apoptosis (Bax/Bcl2 and caspase-3, -7, and -9) and pro-survival markers (Akt/p-Akt levels) were evaluated under hypoxia. Redox damage was evaluated by assessing markers of oxidative damage, that is, glutathione reduced, glutathione oxidized, lipid peroxidation, reactive oxygen species, and manganese superoxide dismutase activity. Cellular adenosine triphosphate (ATP) pool and AMPKα levels were measured to evaluate regulation of metabolism under hypoxia. RESULTS:Amlodipine treatment at 25 nM prevented apoptosis and restored cellular calcium levels and oxidative damage in cardiomyocytes. Stabilization of caspase-3, -7, and -9 along with restoration of Akt/p-Akt levels depicted pro-survival efficacy of amlodipine. Also, restoration of cellular ATP and AMPKα levels indicates that amlodipine prevents cardiomyocytes from hypoxia-induced metabolic stress. CONCLUSIONS:Amlodipine thus protects H9c2 cells from hypoxia-induced apoptosis by regulating Akt/p-Akt-mediated caspase-3, -7, and -9 activation and restoring cellular ATP and redox status.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:The aim of this study was to compare the antihypertensive efficacy and tolerability of the calcium channel antagonist amlodipine besylate versus the angiotensin II type 1 receptor antagonist candesartan cilexetil in hypertensive patients. PATIENTS AND METHODS:After a 2-week placebo washout period, 326 patients with essential hypertension were randomised to receive amlodipine 5mg once daily or candesartan cilexetil 8mg once daily in a double-blind, parallel-group design with a 12-week active treatment period followed by a 4-day placebo drug-free period. The initial daily dose could be doubled at week 6 if office diastolic blood pressure (DBP) was still >/=90mm Hg. BP changes were assessed daily through patient self-measurements, and fortnightly by office BP measurements. RESULTS:A total of 294 patients (151 amlodipine and 143 candesartan cilexetil) were included in the per-protocol analysis of the primary endpoint of BP change from baseline at 12 weeks. Reductions in sitting office systolic BP (SBP) [amlodipine 24.4mm Hg, candesartan cilexetil 22.3mm Hg] and DBP (amlodipine 14.9mm Hg, candesartan cilexetil 14.8mm Hg) were statistically equivalent within the chosen range of equivalence (5mm Hg for SBP and 3mm Hg for DBP). The proportion of controlled patients (office BP <140/90mm Hg) at the end of therapy was similar in both treatment groups (amlodipine 46.9%, candesartan cilexetil 44.4%). The reduction in self-measured DBP was significantly greater (p < 0.05) for amlodipine (7.2mm Hg) compared with candesartan cilexetil (4.8mm Hg). There was no significant difference between the two treatments in the incidence of adverse events reported. CONCLUSIONS:Amlodipine besylate and candesartan cilexetil were both very effective in lowering office BP after 12 weeks of treatment. There was a trend towards a better self-measured BP reduction with amlodipine compared with candesartan cilexetil. The overall incidence of adverse events was comparable between the two treatments.

背景与目标：