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Advances in Enzyme Research 2014年第2期2卷 92-99页

作者： Sahar Kamal Pharmacology Department Faculty of Medicine Ain Shams University Cairo Egypt

Hypertension is a serious problem that is recently thought to be associated with damaging effects on target organs partially via oxidative stress. On the other hand, there is accumulating literature describing some sort of therapeutic interaction between antioxidant enzymes in vital organs and hypertension. Therefore, the aim of this study is to investigate the possible effect of a direct renin inhibitor, aliskiren, used in treatment of hypertension via renin-angiotensin-aldosterone system (RAAS), on selected anti-oxidant enzymes in hepatic homogenates in DOCA salt-induced hypertesnive albino rats. Thirty male wister albino rats were assigned randomly into 3 groups (n = 10/ group). Group 1 received no treatement and serves as control. Group 2 received 0.5% carboxymethylcellulose sodium ip as a solvent of aliskiren, as a direct renin inhibitor (DRI). Group 3 received aliskiren 100 mg/kg/day ip for 4 weeks through gastric tube. Systolic blood pressure (SBP) was measured every week and its mean was recorded at the end of the study. Superoxide dismutase (SOD) enzyme in RBCs lysates, activities of catalase (CAT) and glutathione peroxidase enzymes and thiobarbituric acid reactive substance (TBARS), as a marker of lipid peroxidation, in hepatic homogenates were measured at the end of the study. DRI produced a marked reduction in mean SBP of hypertensive rats. It also significantly (p aliskiren, in addition to its powerful anti-hypertensive effect, it could induce a great anti-oxidant effect in liver homogenates of DOCA salt-hypertensive rats.

关键词： aliskiren DOCA Hypertensive Rats Anti-Oxidant Enzymes TBARS Liver

aliskiren预处理对脑缺血再灌注损伤的保护及对脑能量代谢的影响

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中华神经外科杂志 2013年第6期29卷 626-631页

作者：张涛法志强郭燕舞天津市环湖医院重症医学科 300060 南方医科大学珠江医院神经外科

目的探讨aliskiren预处理对脑缺血再灌注（I／R）损伤的保护作用及对脑能量代谢的影响。方法将雄性ICR小鼠随机分为假手术组（Sham组）、溶剂对照组（Vehicle组）、低剂量aliskiren预处理组（Alis．L组）和高剂量aliskiren预处理组（Ali... 详细信息

目的探讨aliskiren预处理对脑缺血再灌注（I／R）损伤的保护作用及对脑能量代谢的影响。方法将雄性ICR小鼠随机分为假手术组（Sham组）、溶剂对照组（Vehicle组）、低剂量aliskiren预处理组（Alis．L组）和高剂量aliskiren预处理组（Alis—H组）；采用Zea—longa改良线栓法大脑中动脉闭塞（MCAO）制备局灶性脑I／R模型，于I／R24h后采用r137C染色法评估脑梗死面积、DHE染色观察脑活性氧自由基水平、乳酸及Na’．K’．ATPase检测试剂盒检测脑组织中乳酸水平及Na＋-K＋-ATPase活性；于I／R72h后腹腔注射Brdu检测海马DG区的神经细胞增殖情况；于I／R后不同时间采用神经行为学评分评价神经损伤情况，Morris水迷宫评价空间记忆能力。结果与Sham组相比，Vehicle组出现明显的梗死区域，梗死面积和梗死面树前脑面积均增加，脑活性氧自由基和乳酸水平升高，Na’．K’-ATPase活性降低，I／R后1—6d的神经行为学评分均降低，Morris水迷宫的逃避潜伏期延长，游泳速度减慢，海马DG区的BrdU’细胞数减少，差异均有统计学意义（P〈0．05）；aliskiren预处理可改善Vehicle组的各指标变化，差异均有统计学意义（P〈0．05）。Alis-H组以上I／R导致的异常改善程度高于Alis．L组，差异均有统计学意义（P〈0．05）。结论aliskiren预处理对脑缺血再灌注损伤有保护作用，并改善脑能量代谢情况。

关键词： aliskiren 脑缺血再灌注损伤能量代谢细胞凋亡

aliskiren: A New Harbinger of Hypotension?

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Open Journal of Anesthesiology 2013年第2期3卷 102-103页

作者： Elliot I. Palmer Andrew Oken Oregon Health & Science University (OHSU) Portland USA

We present a case of significant, persistent, and relatively refractory hypotension during general anesthesia in a reasonably healthy 50-year-old man thought to be caused by a direct rennin inhibitor. This case is of particular significance because the medication thought responsible for the hemodynamic abnormalities is a relatively novel antihypertensive agent and remains largely unknown to clinical anesthesia providers.

关键词： aliskiren Renin Inhibitor ACE Inhibitor Hypotension Anesthesia

Effect of aliskiren on arterial stiffness, compared with ramipril in patients with mild to moderate essential hypertension

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Chinese Medical Journal 2013年第7期126卷 1242-1246页

作者： GUO Jian-qiang WANG Hong-yi SUN Ning-ling Department of Cardiology Peking University People's Hospital Beijing 100044 China

Background aliskiren is a novel blood pressure-lowering agent acting as an oral direct renin inhibitor. The aim of this study was to assess the effect of aliskiren on arterial stiffness, compared with that of ramipril in mild to moderate essential hypertensive patients. Methods Following a two week placebo run-in period, patients with a mean sitting diastolic blood pressure （ms-DBP）〉95 and 〈110 mmHg （1 mmHg=0.133 kPa）, and a mean sitting systolic blood pressure （ms-SBP）〈180 mmHg were randomly allocated to treatment with aliskiren （150 mg/d, n=20） or ramipril （5 mg/d, n=20） for eight weeks. Blood pressure, plasma renin activity, and the brachial-ankle pulse wave velocity （ba-PWV） were measured before and after eight weeks of treatment. Results Eight weeks of treatment significantly decreased systolic blood pressure and diastolic blood pressure in both the aliskiren group and ramipril group. The hypotensJve effect did not differ between the two groups. Plasma renin activity decreased after aliskiren treatment and increased after ramipril treatment. There was no significant difference in baseline ba-PWV between the aliskiren and ramipril groups （P=-0.892）. The ba-PWV was significantly reduced in both the aliskiren group （1535 （1405-1666） vs. 1464 （1360-1506） cm/s）（P 〈0.01） and the ramipril group （1544 （1433-1673） vs. 1447 （1327-1549） cm/s）（P 〈0.01）. No statistically significant difference was found in the decline of ba-PWV between the two groups （P=0.766）. Conclusions The current study revealed that aliskiren （150 mg/d） could ameliorate arterial stiffness and its effect was similar to ramipril （5 mg/d） in mild to moderate hypertensive patients, indicating that in addition to lowering blood pressure, aliskiren had beneficial effect on vascular protection.

关键词： aliskiren arterial stiffness hypertension ramipril

A retrospective aliskiren and Losartan study in non-diabetic chronic kidney disease

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World Journal of Nephrology 2013年第4期2卷 129-135页

作者： Keng-Thye Woo Hui-Lin Choong Kok-Seng Wong Han-Kim Tan Marjorie Foo Fook-Chong Stephanie Evan JC Lee Vathsala Anantharaman Grace SL Lee Choong-Meng Chan Department of Renal Medicine Singapore General Hospital Department of Clinical Research Singapore General Hospital Department of Nephrology National University of Singapore

AIM： To assess the effcacy of combined aliskiren and Losartan vs high dose Losartan and aliskiren alone in chronic kidney disease （CKD）.METHODS： This is a retrospective study of 143 pa-tients with non-diabetic CKD comparing combined aliskiren （150 mg/d） with Losartan （100 mg/d） therapy vs High dose Angiotensin receptor blockers （ARB）（Losartan 200 mg/d） and the third group aliskiren （150 mg/d） alone. This study involved only patient medi-cal records. Entry criteria included those patients who had been treated with the above drugs for at least 36 mo within the 5 years period; other criteria included proteinuria of 1 g or more and or CKD Stage 3 at the start of the 36 mo period. The study utilised primary renal end points of estimated Glomerular Filtration Rate （eGFR）〈 15 mL/min or end stage renal failure. RESULTS： Patients treated with high dose ARB com-pared to the other two treatment groups had signifcantly less proteinuria at the end of 36 mo （ P 〈 0.007）. All 3 groups had signifcant reduction of proteinuria （ P 〈 0.043, P 〈 0.001）. Total urinary protein was signifcantly differ-ent between the 3 groups over the 3-year study period （ P = 0.008）, but not eGFR. The changes in eGFR from baseline to each year were not signifcantly different be-tween the 3 therapeutic groups （ P 〈 0.119）. There were no significant differences in the systolic and diastolic blood pressure between the 3 drug groups throughout the 3 years. The incidence of hyperkalemia （〉 5.5 mmol/L） was 14.2% （7/49） in the Combined aliskiren and ARB group, 8.7% （4/46） in the aliskiren alone group and 6.3% （3/48） in the High dose ARB group （ P 〈 0.001）.CONCLUSION： This study in non-diabetic CKD pa-tients showed that Combination therapy with aliskiren and ARB was effective but was not safe as it was asso-ciated with a high prevalence of hyperkalaemia.

关键词： aliskiren Chronic kidney disease disease Clinical trial

Antiproteinuric Effect of aliskiren versus Losartan in Primary Glomerulonephritis

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Open Journal of Nephrology 2014年第2期4卷 61-68页

作者： Abdul Halim Abdul Gafor Azrini Abdul Aziz Rozita Mohd Rizna Abdul Cader Kong Wei Yen Shamsul Azhar Shah Norella C. T. Kong Department of Epidemiology and Biostatistics University Kebangsaan Malaysia Medical Centre Jalan Yaacob Latif Bandar Tun Razak Cheras Kuala Lumpur Malaysia Nephrology Unit Department of Medicine University Kebangsaan Malaysia Medical Centre Jalan Yaacob Latif Bandar Tun Razak Cheras Kuala Lumpur Malaysia

Introduction: Treatment with renin-angiotensin-aldosterone-system (RAAS) blockers plays a major role in halting chonic kidney disease (CKD) progression. aliskiren is the first orally available direct renin inhibitor (DRI). Objective: We studied the efficacy of aliskiren compared to losartan in patients with primary GN. Design and Method: This was a prospective open-label randomized control trial in patients with primary GN. Patients were randomized to receive either aliskiren or losartan to maximum tolerated doses for 24 weeks. Blood and urine investigations were measured at baseline and at 4-weekly intervals. Adverse effects were recorded. Results: 22 patients were recruited (aliskiren-11 and losartan-11). Their baseline characteristics were comparable with the exception of a higher proteinuria (uPCI) in the aliskiren arm. There were no significant differences in proteinuria, blood pressure and other renal parameters between both groups. At end-study, only patients in the aliskiren arm showed significant reductions in both the systolic blood pressure and in proteinuria. There were no changes in the other parameters of renal function over time and no adverse events occurred. Conclusion: aliskiren appears to be as efficacious and tolerable as losartan both as an antihypertensive and antiproteinuric agent in this study.

关键词： Primary Glomerulonephritis Hypertension Proteinuria aliskiren Losartan

Inhibition of renin activity by aliskiren ameliorates diabetic nephropathy in type 1 diabetes mouse model

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Journal of Diabetes Mellitus 2012年第3期2卷 353-360页

作者： Yan Zhang Youli Wang Yunzi Chen Dilip K. Deb Tao Sun Qun Zhao Yan Chun Li Department of Medicine Division of Biological Sciences The University of Chicago Chicago USA Ministry of Health Key Laboratory of Congenital Malformation Shengjing Hospital China Medical University Shenyang China

Renin is the rate-limiting enzyme of the reninangiotensin system (RAS). In addition to its enzymatic activity to generate angiotensin I, renin also signals through the (pro)renin receptor to exert angiotensin II-independent effects. In this study we examined the effect of renin inhibition on the development of diabetic nephropathy. Male DBA/2J mice were induced to diabetes with streptozotocin, and the diabetic mice were treated for 16 weeks with saline or aliskiren, a renin enzymatic inhibitor. aliskiren treatment had little effects on blood glucose and blood pressure in diabetic mice. Saline-treated mice developed progressive albuminuria and glome-rulosclerosis, and aliskiren treatment effectively alleviated albumiuria and glomerulosclerosis. Morphologically aliskiren treatment prevented the thickening of the glomerular basement membrane and reduced podocyte loss. At the molecular levels, aliskiren prevented the decline of slit diaphragm proteins and blocked the synthesis of extracellular matrix and pro-fibrotic factors in the diabetic kidney. aliskiren treatment results in compensatory renin increase in the glomeruli due to blockade of the negative feedback loop, and also partially suppressed the intracellular signaling mediated by the (pro)renin receptor activated in hyperglycemia. These observations suggest that the therapeutic activity of aliskiren to prevent diabetic renal injury is contributed by inhibition of both the angiotensin II-dependent and -independent pathways. Taken together, it is concluded that inhibition of renin enzymatic activity ameliorates diabetic renal injury in type 1 diabetes, and support the use of aliskiren in diabetes kidney disease.

关键词： Renin Inhibitor Renin-Angiotensin System Diabetic Nephropathy aliskiren

直接肾素阻滞剂aliskiren预防早产儿视网膜病变

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眼科新进展 2015年第4期35卷 393-396页

作者：马誉铷刘鹤南底煜陈晓隆中国医科大学附属盛京医院眼科辽宁省沈阳市110004

肾素作为肾素-血管紧张素系统(renin-angiotensin system,RAS)中上游生长因子,对RAS链起着特异性限速的作用。在早产儿视网膜病变等缺血性视网膜病变中,RAS上调,视网膜RAS被激活,刺激血管内皮生长因子等上调,导致血管渗漏、血管内皮细... 详细信息

肾素作为肾素-血管紧张素系统(renin-angiotensin system,RAS)中上游生长因子,对RAS链起着特异性限速的作用。在早产儿视网膜病变等缺血性视网膜病变中,RAS上调,视网膜RAS被激活,刺激血管内皮生长因子等上调,导致血管渗漏、血管内皮细胞增生和新生血管形成等血管病理性改变。直接肾素抑制剂aliskiren作为阻断RAS的新途径,在防止和减弱病理性血管生成的过程中发挥了明显作用。

关键词：肾素-血管紧张素系统视网膜病早产儿 aliskiren 血管内皮生长因子

美国FDA批准aliskiren／valsartan单片合剂Valturna（R）上市

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中国新药杂志 2009年第20期18卷 1921-1922页

Vahurna（R）（aliskiren／valsartan片）获得FDA批准，成为第一个且目前惟一的针对肾素-血管紧张素-醛固酮系统中两个关键点的药物。这是Valturna（R）的首次获批作为aliskiren或angiotensin受体抑制剂单药治疗高血压控制不足，以及作... 详细信息

Vahurna（R）（aliskiren／valsartan片）获得FDA批准，成为第一个且目前惟一的针对肾素-血管紧张素-醛固酮系统中两个关键点的药物。这是Valturna（R）的首次获批作为aliskiren或angiotensin受体抑制剂单药治疗高血压控制不足，以及作为可能需要多种药物达到血压目标患者的治疗药物。该许可主要是基于一项关键的随机双盲安慰剂对照的为期8周的临床试验，约包括1800例患者。

关键词： valsartan aliskiren FDA批准肾素-血管紧张素-醛固酮系统 angiotensin 高血压控制上市合剂

aliskiren单用及联用氟伐他汀对动脉粥样硬化斑块稳定性的影响

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现代生物医学进展 2019年第12期19卷 2201-2206页

作者：吴宏宪成宪武马元吉 Murohara Toyoaki 钱菊英葛均波复旦大学附属中山医院心内科上海市心血管病研究所名古屋大学医学部循环器内科学

目的:观察和比较肾素抑制剂aliskiren单用或与氟伐他汀(fluvastatin)联用对动脉粥样硬化斑块稳定性的影响。方法:选择4周龄雄性ApoE-/-小鼠通过喂以高脂饮食8周建立动脉粥样硬化模型,将其随机分为5组:模型对照组、aliskiren组、肼屈嗪... 详细信息

目的:观察和比较肾素抑制剂aliskiren单用或与氟伐他汀(fluvastatin)联用对动脉粥样硬化斑块稳定性的影响。方法:选择4周龄雄性ApoE-/-小鼠通过喂以高脂饮食8周建立动脉粥样硬化模型,将其随机分为5组:模型对照组、aliskiren组、肼屈嗪组、氟伐他汀组、aliskiren与氟伐他汀联合用药组,所有组别均治疗12周。取主动脉根部组织评估斑块面积(HE染色)、斑块内新生血管数量(CD31染色)及斑块稳定性指标(胶原蛋白染色、弹力纤维染色、Mac-3染色、MCP-1染色)。结果:与模型对照组比较,aliskiren单用显著降低动脉粥样硬化斑块面积,减少斑块内新生血管数量以及巨噬细胞浸润、炎症因子表达,增加斑块内弹力纤维及胶原蛋白含量(Paliskiren单用组比较,aliskiren与氟伐他汀联用进一步降低斑块面积,改善斑块的稳定性(Paliskiren组比较,肼屈嗪组降压幅度相似(P>0.05)。与模型对照组比较,肼屈嗪没有明显抑制斑块进展以及改善斑块的稳定性(P>0.05)。结论:aliskiren能够抑制动脉粥样硬化斑块的进展,减少斑块内新生血管形成,改善斑块的稳定性,而其与氟伐他汀联用的治疗效果更佳。

关键词：肾素抑制剂 aliskiren 动脉粥样硬化氟伐他汀血管新生斑块稳定性