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 Table of Contents  
REVIEW ARTICLE
Year : 2011  |  Volume : 3  |  Issue : 2  |  Page : 189-193  

Aliskiren: An orally active renin inhibitor


Pranveer Singh Institute of Technology, Kanpur, India

Date of Submission16-Jul-2010
Date of Decision02-Aug-2010
Date of Acceptance15-Oct-2010
Date of Web Publication12-May-2011

Correspondence Address:
Ankita Wal
Pranveer Singh Institute of Technology, Kanpur
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.80764

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   Abstract 

Renin inhibitors are antihypertensive drugs that block the first step in the renin-angiotensin system. Their mechanism of action differs from that of the angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists, but like these drugs, renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion. The renin-angiotensin-aldosterone system (RAAS) has long been recognized to play a significant role in hypertension pathophysiology. Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes. Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug. Aliskiren is the first of a new class of antihypertensive agents. Aliskiren is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. In short-term studies, it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide, and had a low incidence of serious adverse effects. It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives. Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin-receptor blocker. The most common adverse effects reported in clinical trials were headache, fatigue, dizziness, diarrhea, and nasopharyngitis. Aliskiren has not been studied in patients with moderate renal dysfunction; as an RAAS-acting drug, it should be prescribed for such patients only with caution.

Keywords: Aliskiren, hypertension, mechanism of action, renin-angiotensin-aldosterone system, renin inhibitors


How to cite this article:
Wal P, Wal A, Rai AK, Dixit A. Aliskiren: An orally active renin inhibitor. J Pharm Bioall Sci 2011;3:189-93

How to cite this URL:
Wal P, Wal A, Rai AK, Dixit A. Aliskiren: An orally active renin inhibitor. J Pharm Bioall Sci [serial online] 2011 [cited 2019 Aug 22];3:189-93. Available from: http://www.jpbsonline.org/text.asp?2011/3/2/189/80764

High blood pressure (BP) is a prevalent risk factor for cardiovascular disease, affecting more than 72 million people in India and more than 1 billion people worldwide. [1] The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends a BP treatment goal of <140/90 mmHg for most patients and <130/80 mmHg for patients with diabetes mellitus (DM) or kidney disease. [1] Despite the effort of JNC 7 to increase the awareness and treatment of hypertension in the United States, only 34% of patients with high BP are adequately controlled. [1] Choosing the appropriate medications for individual patients and adherence to these regimens are among the most important contributing factors to the success of hypertension control. Of all the different pharmacological agents that the JNC guidelines recommended for hypertension management, medications that work by inhibiting the renin-angiotensin-aldosterone system (RAAS) are among some of the most commonly prescribed drugs in the United States; these include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and aldosterone antagonists. [2] Not only do these agents help control BP, they have also been found to reduce cardiovascular events in some disease states. [1] ACE inhibitors and ARBs have been shown to reduce mortality and recurrent cardiovascular events in patients with heart failure, myocardial infarction, and previous stroke. [3],[4],[5] In patients with DM or kidney disease, ACE inhibitors and ARBs also reportedly preserve kidney function in addition to improving cardiovascular outcomes. [6] Aldosterone antagonists have been found to reduce mortality in patients with left ventricular dysfunction as well as myocardial infarction. [7] Aliskiren is a first-in-class oral renin inhibitor, developed by Novartis in conjunction with the biotech company Speedel. [8] It becomes the fourth class of pharmacological agents that modify the function of RAAS. It is an octanamide, is the first known representative of a new class of completely nonpeptide, low-molecular-weight, orally active transition-state renin inhibitors. Aliskiren has good water solubility and low lipophilicity, and is resistant to biodegradation by peptidases in the intestine, blood circulation, and the liver. Aliskiren provides significant antihypertensive efficacy in patients with hypertension, with no rebound effects on BP after the withdrawal of the treatment. Aliskiren has a half-life of approximately 40 h, [9],[10] making it suitable for once-daily dosing, with less potential for loss of efficacy between doses than shorter acting agents. Continuous 24-h BP control throughout the dosing period is clinically important, as it can reduce BP variability that may be suboptimally controlled in other drug classes. [11],[12],[13]


   Physiology of the Renin-Angiotensin-Aldosterone Top


System and hypertension

The RAAS plays a significant role in the pathophysiology of hypertension. The juxtaglomerular cells in the afferent renal arterioles secrete renin in response to low plasma volume, reduced renal perfusion, or increased sympathetic central nervous system activity. [14] Renin acts as a protease enzyme that catalyzes the conversion of angiotensinogen to angiotensin I, which is subsequently converted to angiotensin II by ACE. Angiotensin II induces adrenal secretion of aldosterone, which is a mineralocorticoid that leads to sodium and fluid retention, thus increasing BP. Angiotensin II also has a direct vasoconstrictive effect, which increases BP, and promotes inflammation and remodeling of the cardiovascular system, which leads to thrombosis or left ventricular hypertrophy. [15] Renin conversion of angiotensinogen to angiotensin I is the rate-limiting step in angiotensin II formation. Renin is therefore the primary determinant of RAAS activity. [15] ACE inhibitors hinder the systemic effect of angiotensin II by inhibiting ACE, which reduces the conversion of angiotensin I to angiotensin II. [16] ARBs directly inhibit the binding of angiotensin II to the receptor. [17] Aldosterone antagonists inhibit the action of the excessive aldosterone produced due to increases in angiotensin II. [18] However, both ACE inhibitors and ARBs can lead to increases in plasma renin activity. With ACE inhibitors, the angiotensin I level increases and may lead to accessory (i.e., non-ACE pathways) production of angiotensin II. [19],[20] These pathways convert angiotensin I to angiotensin II through alternative enzymes such as chymase and chymotrypsin-like angiotensin-generating enzyme. [21],[22] With ARBs, angiotensin II levels will increase to compete for receptor bindings. Such increases in angiotensin II levels may also continue to stimulate release of aldosterone from the adrenal gland. [21] Research has attempted to improve RAAS inhibition through the combination use of ACE inhibitors. Aldosterone breakthrough will occur at a far lower frequency during renin inhibition (0-10% over 9 months), alone or in combination with an ARB, compared to conventional ARB therapy (35-45% over 9 months). The investigators hypothesize that aldosterone breakthrough occurs due to accumulation of active precursor substances, most notably angiotensin II, produced in response to conventional RAAS blockade with ACE inhibitors and ARBs. The investigators believe that direct renin inhibition (DRI) should minimize this accumulation and therefore significantly lower or possibly eliminate the breakthrough effect. Interruption of the RAAS with angiotensin-converting enzyme inhibitors (ACE-Is) and ARBs, alone and in combination, has become a leading therapy to slow the progression of chronic heart and kidney disease. Both types of drugs inhibit the formation of aldosterone, a hormone, which has been shown to have harmful effects on patients with chronic heart and kidney disorders. This treatment is effective but not perfect since, even after an initial improvement, many patients become worse over the long term. This may be due to an unexpected increase in aldosterone, a phenomenon called "aldosterone breakthrough."

The aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) trial [23] was a randomized, double-blind, placebo-controlled, multinational study that aimed to evaluate the antiproteinuric effect of aliskiren (300 mg per day) in 599 hypertensive patients with type 2 diabetes and nephropathy who were on therapy with losartan at a fixed dose of 100 mg per day. The researchers found that treatment with aliskiren for 24 weeks was associated with a 20% reduction in albuminuria (compared with no change with placebo). Moreover, a reduction in urinary albumin:creatinine ratio of 50% or more occurred in 25% of patients on aliskiren compared with 12.5% of patients on placebo. Differences in BP between treatment groups at the end of the study period were small and not significant, and changes in albuminuria did not correlate with concomitant changes in arterial BP. These findings led the authors to conclude that aliskiren might have renoprotective effects that are independent of its blood pressure lowering effects in patients with hypertension, type 2 diabetes, and nephropathy. [23] The ALiskiren Trial In Type 2 diabetes Using cardio-renal Disease Endpoints (ALTITUDE) study (ClinicalTrials.gov registry number NCT00549757) aims to determine whether the addition of aliskiren (300 mg versus placebo) once daily for 4 years to treatment with ACE inhibitors or ARBs reduces renal and cardiovascular events in 8600 patients with type 2 diabetes and microalbuminuria, macroalbuminuria, or cardiovascular disease. A number of other key issues must also be addressed to determine whether aliskiren is a valuable alternative to currently available RAAS inhibitors.


   Mechanism of Action Top


Aliskiren exhibits oral bioavailability due to its low molecular weight (609.8 Da) and nonpeptide structure, making it more resistant to gastrointestinal enzyme disintegration. [24]

Aliskiren is one of the most potent, known renin inhibitors with high specificity for primate renin. [25]

Aliskiren effectively reduces functional plasma renin activity by binding to renin with high affinity, preventing it from converting angiotensinogen to angiotensin I. [26],[27]

The inhibition of renin by aliskiren is associated with a reduction in circulating levels of angiotensin I and II, with a resultant increase in plasma renin concentration and inhibit activation of mitogen-activated protein kinases ERK1 (p44) and ERK2 (p42). [27],[28]

It prevents hypertrophy and proliferation.


   Chemical Properties Top


Aliskiren is a low-molecular-weight hydrophilic nonpeptide, which exerts a potent and specific competitive inhibition on renin in primates. The adverse effects of aliskiren are uncertain due to its 10,000-fold higher affinity for renin than for other aspartic peptidases. Because renin is a water-soluble protein that can be studied with crystallographic analysis, the opportunity arose to examine systematically the crystals of renin bond to renin inhibitors. Aliskiren is a transition-state mimetic, with favorable physicochemical properties including high aqueous solubility (>350 mg/ml at pH 7.4) and high hydrophilicity (log Poct/water = 2.45, pH 7.4). These properties are important prerequisites for improved oral bioavailability. [29]


   Pharmacokinetics Top


Aliskiren is also metabolized by cytochrome P450 (CYP) 3A4 enzymes, but the exact extent of metabolism is unknown. [26],[27],[30],[31] Although aliskiren exhibits oral bioavailability compared with other previously synthesized renin inhibitors, it is still poorly absorbed (oral bioavailability, ~2.5%). [32] In nine healthy volunteers aged 20-34 years, after administration of oral aliskiren 40-640 mg daily, the plasma concentration exhibited dose-dependent increases, with peak concentrations achieved after 3-6 h of administration. [26] Aliskiren is 50% protein bound, and the apparent volume of distribution is 135 L. [31] The pharmacokinetics of aliskiren remains unaffected by ethnicity, age, gender, hepatic impairment, renal impairment, and diabetes. [32] The elimination t1/2 of aliskiren averaged 24 h (20-45 h) in healthy volunteers as well as in patients with DM. Plasma steady-state concentrations are therefore achieved in approximately 5-8 days (five times the half-life). This relatively long half-life makes aliskiren suitable for QD dosing. Peak plasma concentrations are reached 1-2 h after dosing, and steady state is reached after 5-8 days of once-daily administration. [27],[28] Conventional pharmacokinetic studies have been performed in rats, marmosets, and humans after single and multiple oral doses of aliskiren. Aliskiren shows low bioavailability, but the exact mechanism of this property has not been elucidated. The distribution volume of intravenously administered aliskiren is reported to be 135 L, in normal volunteers, indicating extensive tissue uptake of the drug. Aliskiren binds only moderately to plasma proteins, with the binding concentrations being independent in the range of 10-500 ng/ml. Approximately 47-51% of aliskiren is bound by plasma proteins in humans, independent of the concentration. In marmosets, aliskiren is highly bound to plasma proteins by approximately 92%. [27] Aliskiren is slightly metabolized in humans (about 20%) and is approximately 50% metabolized in rodents. The major metabolic pathway for aliskiren metabolism is O-demethylation at the phenyl-proxy side chain or at the 3-methoxypropoxy group, with further oxidation to the carboxylic acid derivative. The metabolism of aliskiren observed in liver microsomes is qualitatively comparable in humans, marmosets, and rats. [27],[31] The main pathway of elimination for aliskiren is via biliary excretion as unmetabolized drug. Less than 1% of an orally administered dose is excreted in urine. [33] Aliskiren is not metabolized by, and does not induce or inhibit, cytochrome P450 enzymes and shows no clinically relevant pharmacokinetic interactions with warfarin, lovastatin, atenolol, celecoxib, cimetidine, amlodipine, valsartan, hydrochlorothiazide (HCTZ), or ramipril. Coadministration of aliskiren with furosemide reduced the AUC of furosemide by 28% and Cmax by 49%, but clinical significance of this remains uncertain. Aliskiren pharmacokinetics has been studied in marmosets. After a single oral dose of 10 mg/kg, peak plasma concentrations were reached in 1-2 h. The calculated bioavailability was 16.3% and mean half-life 2.3 h. [34] Aliskiren accumulates following multiple once-daily administrations as indicated by the accumulation ratios of 1.4-3.9, with the accumulation being more pronounced at higher doses. Study in healthy volunteers showed that the plasma concentration increased dose-dependently after oral aliskiren in doses of 40-640 mg/day, with peak plasma concentrations reached in 3-6 h. The mean plasma half-life was 23.7 h.


   Drug Interactions Top


Effects of other drugs on aliskiren

Based on in vitro studies, aliskiren is metabolized by CYP 3A4.

Irbesartan: Coadministration of irbesartan reduced aliskiren Cmax up to 50% after multiple dosing. P-glycoprotein Effects: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in absorption and disposition of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of this transporter.

Atorvastatin: Coadministration of atorvastatin resulted in about a 50% increase in aliskiren Cmax and AUC after multiple dosing.

Ketoconazole: Coadministration of 200 mg twice-daily ketoconazole with aliskiren resulted in an approximate 80% increase in plasma levels of aliskiren. A 400-mg once-daily dose was not studied but would be expected to increase aliskiren blood levels further.

Itraconazole: Coadministration of 100 mg itraconazole with 150 mg aliskiren resulted in approximately 5.8-fold increase in Cmax and 6.5-fold increase in AUC of aliskiren. Concomitant use of aliskiren with itraconazole is not recommended.

Cyclosporine: Coadministration of 200 and 600 mg cyclosporine with 75 mg aliskiren resulted in an approximately 2.5-fold increase in Cmax and fivefold increase in AUC of aliskiren. Concomitant use of aliskiren with cyclosporine is not recommended.

Verapamil: Coadministration of 240 mg of verapamil with 300 mg aliskiren resulted in an approximately twofold increase in Cmax and AUC of aliskiren. However, no dosage adjustment is necessary.

Drugs with no clinically significant effects: Coadministration of lovastatin, atenolol, warfarin, furosemide, digoxin, celecoxib, hydrochlorothiazide, ramipril, valsartan, metformin, and amlodipine did not result in clinically significant increases in aliskiren exposure.

Adverse events, contraindications, and precautions for aliskiren

Aliskiren has been shown to be well tolerated in healthy subjects and in patients with hypertension, when given as single and multiple oral doses. The clinical trials do not report any major adverse effects of aliskiren. Aliskiren-based therapy was well tolerated and produced sustained BP reductions in patients with hypertension during 6 months, greater than those with ramipril-based therapy. The incidence of adverse events with aliskiren and the number of study discontinuations as a result of adverse events during aliskiren treatment have been relatively low and were similar to results obtained in patients treated with placebo. The most commonly reported adverse events included headache, dizziness, and fatigue (incidence ranged from 2.4% to 8.5% among studies). [33],[35],[36],[37],[38],[39],[40],[41],[42] Aliskiren is also associated with dose-related gastrointestinal adverse events. Although the incidence of diarrhea reported with aliskiren up to 300 mg daily did not differ significantly from placebo, when aliskiren 600 mg daily was administered in one study, the incidence of diarrhea was significantly higher than that of placebo (11.4% vs 0.2%; P < 0.001). [35] Aliskiren use was associated with a slight increase in cough in placebo-controlled studies (1.1% for any aliskiren use vs 0.6% for placebo). [35],[36],[39] In studies comparing aliskiren and ACE inhibitors, the rates of cough for aliskiren were about one-third to one-half the rates of ACE inhibitors. Hyperkalemia was reported infrequently in aliskiren use (~0.9% vs ~0.6% in placebo). However, when used in combination with an ACE inhibitor, hyperkalemia occurred more frequently (~5.5%). [43] Aliskiren had no clinically important effects on total cholesterol, HDL, fasting triglycerides, or fasting glucose. Laboratory abnormalities that may occur in some patients include a minor increase in blood urea nitrogen (BUN) and serum creatinine, small reductions in hemoglobin and hematocrit, an increase in serum potassium greater than 5.5 mEq/L, elevated uric acid levels, and renal stones.


   Dosage and Administration Top


Aliskiren is available in 150- and 300-mg tablets. The usual recommended starting dose of aliskiren is 150 mg QD. Doses >300 mg did not provide an increased BP response but did increase the rate of diarrhea by approximately threefold in one study. The antihypertensive effect of a given dose of aliskiren is attained after 2 weeks of therapy. [44] No dosage adjustment is required when used in elderly patients (i.e., those aged >65 years) or those with mild to severe renal impairment (creatinine clearance, <80 mL/min) or hepatic impairment (Child-Pugh Clinical Assessment score, 5-15). [45]


   Future Perspectives Top


Medications that have direct effects on the RAAS, such as ACE inhibitors, ARBs, and aldosterone antagonists, have been found to not only effectively lower BP but also to improve mortality and morbidity in patients with heart failure (ACE inhibitors, ARBs, and aldosterone antagonists), history of myocardial infarction (ACE inhibitors, ARBs, and aldosterone antagonists), and nephropathy (ACE inhibitors and ARBs). Aliskiren directly inhibits renin and, from a mechanism of action point of view, offers an advantage over ACE inhibitors and ARBs by inhibiting the rate-limiting step of angiotensin II formation and producing more effective and complete inhibition of angiotensin II. Whether such effects result in better protection from heart attack, stroke, myocardial infarction, and nephropathy is unknown. Whether the additive benefit in hypertension with the combination of aliskiren and ACE inhibitors or ARBs will extend to other indications is also unknown. Furthermore, it is not known whether patients who cannot tolerate ACE inhibitors or ARBs can be safely switched to aliskiren. Further research investigating these potential roles will help establish a place for aliskiren in cardiovascular disease management. There are ongoing studies evaluating the use of aliskiren in patients with postmyocardial infarction as well as in those with diabetic nephropathy. [46]


   Conclusions Top


Aliskiren is an orally effective, long-lasting renin inhibitor that shows antihypertensive efficacy in animals superior to previous renin inhibitors and at least equivalent to ACE inhibitors and AT 1 -receptor blockers. Aliskiren may therefore represent an effective, novel approach to the treatment of hypertension and related disorders, alone or in combination with other antihypertensive agents. [34] Aliskiren is well tolerated, with the most common adverse events reported as headache, dizziness, and fatigue. Clinical studies support the use of aliskiren in patients with mild to moderate hypertension, alone or in combination with ACE inhibitors, amlodipine, or diuretics. Future studies will provide more insights into the long-term effects of the use of renin inhibitors in hypertension treatment, as well as whether such treatment may alter cardiovascular outcomes.

 
   References Top

1.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [US Dept of Health and Human Services Web site]. Available from: http://www.nhlbi.nih.gov/guidelines/ hypertension/jnc7full.pdf. [Last accessed on 2010 Jul 02].  Back to cited text no. 1
    
2.Top 300 Prescriptions for 2005 [RxList.com Web site]. Available from: http://www.rxlist.com/script/main/art.asp?articlekey= 79509. [Last accessed on 2010 Jul 02].  Back to cited text no. 2
    
3.Linn WD. Angiotensin-converting enzyme inhibitors in left ventricular dysfunction. Pharmacotherapy 1996;16:50S-8.  Back to cited text no. 3
[PUBMED]    
4.Maggioni AP. Efficacy of angiotensin receptor blockers in cardiovascular disease. Cardiovasc Drugs Ther 2006;20:295-308.  Back to cited text no. 4
[PUBMED]  [FULLTEXT]  
5.Hilleman DE, Lucas BD Jr. Angiotensin-converting enzyme inhibitors and stroke risk: Benefit beyond blood pressure reduction? Pharmacotherapy 2004;24:1064-76.  Back to cited text no. 5
[PUBMED]    
6.Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: Systematic review. BMJ 2004;329:828.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Greenberg B, Zannad F, Pitt B. Role of aldosterone blockade for treatment of heart failure and post-acute myocardial infarction. Am J Cardiol 2006;97:34F-40.  Back to cited text no. 7
[PUBMED]  [FULLTEXT]  
8.Yokokawa F, Maibaum J. Recent advances in the discovery of non-peptidic direct renin inhibitors as antihypertensives: New patent applications in years 2000-2008. Expert Opin Ther Patents 2008;18:581-602.  Back to cited text no. 8
    
9.Vaidyanathan S, Limoges D, Yeh CM, Dieterich HA. Aliskiren, an orally effective renin inhibitor, shows dose linear pharmacokinetics in healthy volunteers, Clin Pharmacol Ther 2006;79:64 .  Back to cited text no. 9
    
10.Vaidyanathan S, Zhao C, Yeh CM, Dieterich HA. Pharmacokinetics and safety of the novel oral renin inhibitor aliskiren in patients with type 2 diabetes. Clin Pharmacol Ther 2006;79:12.  Back to cited text no. 10
    
11.Meredith PA. Organ protection and optimal blood pressure control. Am J Hypertens 1995;8:59S-62.   Back to cited text no. 11
[PUBMED]    
12.Myers MG. Twenty-four-hour blood pressure control: A brief review of aspects of target-organ protection, J Hypertens Suppl 1996;14:S7-10.   Back to cited text no. 12
    
13.Frattola A, Parati G, Cuspidi C, Albini F, Mancia G. Prognostic value of 24-hour blood pressure variability. J Hypertens 1993;11:1133-7.   Back to cited text no. 13
[PUBMED]    
14.Jandeleit-Dahm K, Cooper ME. Hypertension and diabetes: Role of the renin-angiotensin system. Endocrinol Metab Clin North Am 2006;35:469-90,   Back to cited text no. 14
    
15.Dzau VJ. Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: A unifying hypothesis. Hypertension 2001;37:1047-52.  Back to cited text no. 15
[PUBMED]  [FULLTEXT]  
16.Kostis JB. Angiotensin converting enzyme inhibitors. I. Pharmacology. Am Heart J 1988;116:1580-91.  Back to cited text no. 16
    
17.Mimran A, Ribstein J. Angiotensin receptor blockers: Pharmacology and clinical significance. J Am Soc Nephrol 1999;10:S273-7.  Back to cited text no. 17
[PUBMED]    
18.Brown NJ. Eplerenone: Cardiovascular protection. Circulation 2003;107:2512-8.  Back to cited text no. 18
[PUBMED]  [FULLTEXT]  
19.Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A. Identification of a highly specific chymase as the major angiotensin II- forming enzyme in the human heart. J Biol Chem 1990;265:22348-57.  Back to cited text no. 19
[PUBMED]  [FULLTEXT]  
20.Okunishi H, Miyazaki M, Toda N. Evidence for a putatively new angiotensin II-generating enzyme in the vascular wall. J Hypertens 1984;2:277-84.  Back to cited text no. 20
[PUBMED]    
21.Hollenberg NK, Fisher ND, Price DA. Pathways for angiotensin II generation in intact human tissue: Evidence from comparative pharmacological interruption of the renin system. Hypertension 1998;32:387-92.  Back to cited text no. 21
[PUBMED]  [FULLTEXT]  
22.Saris JJ, van Dijk MA, Kroon I, Schalekamp MA, Danser AH. Functional importance of angiotensin-converting enzyme-dependent in situ angiotensin II generation in the human forearm. Hypertension 2000;35:764-8.  Back to cited text no. 22
[PUBMED]  [FULLTEXT]  
23.Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358:2433-46.  Back to cited text no. 23
[PUBMED]  [FULLTEXT]  
24.Azizi M, Ménard J, Bissery A, Guyenne TT, Bura-Rivière A, Vaidyanathan S, et al. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-rennin feedback interruption. J Am Soc Nephrol 2004;15:3126-33.   Back to cited text no. 24
    
25.Buczko W, Hermanowicz JM. Pharmacokinetics and pharmacodynamics of aliskiren, an oral direct renin inhibitor. Pharmacol Rep 2008;60:623-31.   Back to cited text no. 25
[PUBMED]  [FULLTEXT]  
26.Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor aliskiren (SPP100): Comparison with enalapril. Hypertension 2002;39:E1-8.  Back to cited text no. 26
[PUBMED]  [FULLTEXT]  
27.Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet 2006;368:1449-56.  Back to cited text no. 27
[PUBMED]  [FULLTEXT]  
28.Pool JL. Direct renin inhibition: Focus on aliskiren. J Manag Care Pharm 2007;13:21-33.  Back to cited text no. 28
[PUBMED]  [FULLTEXT]  
29.Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC, Rasetti V, et al. Structure-based design of aliskiren: A novel orally effective renin inhibitor. Biochem Biophys Res Commun 2003;308:698-705.   Back to cited text no. 29
    
30.Judy WM, Cheng BS. Aliskiren: Renin inhibitor for hypertension management. Clinical Therapeutics 2008;30:31-47  Back to cited text no. 30
    
31.Waldmeier F, Glaenzel U, Wirz B, Oberer L, Schmid D, Seiberling M, et al. Absorption, distribution, metabolism, and elimination of the direct renin inhibitor aliskiren in healthy volunteers. Drug Metab Dispos 2007;35:1418-28.  Back to cited text no. 31
[PUBMED]  [FULLTEXT]  
32.Zhao C, Vaidyanathan S, Yeh CM, Maboudian M, Armin Dieterich H. Aliskiren exhibits similar pharmacokinetics in healthy volunteers and patients with type 2 diabetes mellitus. Clin Pharmacokinet 2006;45:1125-34.  Back to cited text no. 32
[PUBMED]  [FULLTEXT]  
33.Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005;111:1012-8.  Back to cited text no. 33
[PUBMED]  [FULLTEXT]  
34.Wood JM, Schnell CR, Cumin F, Menard J, Webb RL. Aliskiren: A novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats. J Hypertens 2005;23:417-26.   Back to cited text no. 34
[PUBMED]  [FULLTEXT]  
35.Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 2003;42:1137-43.  Back to cited text no. 35
[PUBMED]  [FULLTEXT]  
36.Kushiro T, Itakura H, Abo Y, Gotou H, Terao S, Keefe DL, et al. Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension. Hypertens Res 2006;29:997-1005.  Back to cited text no. 36
    
37.O'Brien E, Barton J, Nussberger J, Mulcahy D, Jensen C, Dicker P, et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension 2007;49:276-84.  Back to cited text no. 37
[PUBMED]  [FULLTEXT]  
38.Villamil A, Chrysant SG, Calhoun D, Schober B, Hsu H, Matrisciano-Dimichino L, et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens 2007;25:217-26.  Back to cited text no. 38
[PUBMED]  [FULLTEXT]  
39.Pool JL, Schmieder RE, Azizi M, Aldigier JC, Januszewicz A, Zidek W, et al. Aliskiren, an orally effective rennin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 2007;20:11-20.  Back to cited text no. 39
[PUBMED]  [FULLTEXT]  
40.Oh BH, Mitchell J, Herron JR, Chung J, Khan M, Keefe DL. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 2007;49:1157-63.  Back to cited text no. 40
[PUBMED]  [FULLTEXT]  
41.Jordan J, Engeli S, Boye SW, Le Breton S, Keefe DL. Direct renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension 2007;49:1047-55.  Back to cited text no. 41
[PUBMED]  [FULLTEXT]  
42.Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: A randomised, double-blind trial. Lancet 2007;370:221-9.   Back to cited text no. 42
[PUBMED]  [FULLTEXT]  
43.Tekturna (aliskiren) tablets [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; September 2007. http:// www.pharma.us.novartis.com/ product/pi/pdf/tekturna.pdf. Accessed April 16, 2007.  Back to cited text no. 43
    
44.Cada DJ, Levien T, Baker DE. Aliskiren. Hosp Pharmacy 2007;42:737-49.   Back to cited text no. 44
    
45.Vaidyanathan S, Bigler H, Yeh C, Bizot MN, Dieterich HA, Howard D, et al. Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment. Clin Pharmacokinet 2007;46:661-75.  Back to cited text no. 45
[PUBMED]  [FULLTEXT]  
46.Aliskiren Clinical Trials. Available from: http://www.clinicaltrials.gov/ct/action/GetStudy. [Last accessed on 2007 Sep 26].  Back to cited text no. 46
    



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