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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aliskiren, the direct renin inhibitor, is the first new class of drug available in 13 years for the treatment of hypertension. Renin has long been recognized as a preferred site for blockade of the renin-angiotensin-aldosterone system because it prevents conversion of angiotensinogen to angiotensin I. Aliskiren binds to the active site of the renin molecule, blocking angiotensinogen cleavage, thus, preventing the formation of angiotensin I. Clinical studies have demonstrated at least equivalent or superior blood pressure lowering efficacy compared with existing drugs with a favorable side effect profile. Aliskiren possesses possible synergistic potential when combined with a thiazide diuretic, ACE inhibitor, angiotensin receptor blocker and calcium channel blocker both in terms of efficacy and tolerability. This review aims to define the role of aliskiren in the therapeutic management of hypertension.
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PMID:Aliskiren, the first in a new class of direct renin inhibitors for hypertension: present and future perspectives. 1795 3

At Ciba-Geigy (now Novartis), the clinical development of the CGP38560 renin inhibitor was halted due to insufficient pharmacokinetics. This indicated that the peptidomimetic approach to the development of antihypertensive agents was improper. Real non-peptide drug candidates were then expected to provide the necessary framework for obtaining the desired properties. For this purpose a homology model of the enzyme was used to characterize the binding mode of CGP38560 in complex with the renin model and served as a basis for the four chemistry laboratories that were assigned to this project. The renin team worked in a full structure-based perspective with this model, and four chemically-unrelated non-peptide series were discovered acting as renin inhibitors at the 1-3 nanomolar level. One of these leads was selected for further development and led to Aliskiren, which has been just approved by the FDA. Here is presented the successful structure-based strategy that enabled the discovery of several non-peptide inhibitors and the recent launch of a new drug that will be commercialized in the United States under the name Tekturna (for the treatment of high blood pressure as monotherapy or in combination with other high blood pressure medications).
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PMID:Structure-based drug design and the discovery of aliskiren (Tekturna): perseverance and creativity to overcome a R&D pipeline challenge. 1799 63

Aliskiren is the first member of a novel class of antihypertensive agents, the renin inhibitors, that has been approved by the US Food and Drug Administration for the treatment of hypertension. This review discusses its potential differences compared with existing renin-angiotensin-aldosterone system blockers, focusing also on the inactive precursor of renin, prorenin, and the recently discovered (pro)renin receptor. The review summarizes the findings from all clinical trials with aliskiren published so far, and provides an overview of the safety and tolerability of the new drug.
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PMID:Aliskiren: the first direct renin inhibitor for hypertension. 1799 72

Hypertension is a common chronic disease that leads to significant cardiovascular morbidity and mortality worldwide. Blood pressure control is critical in reducing the end-organ complications, such as stroke, myocardial infarction, heart failure, or kidney disease. Currently available antihypertensive agents work by different mechanisms to reduce blood pressure. Aliskiren, a novel direct renin inhibitor, lowers blood pressure by decreasing renin activity, and angiotensin I and II levels. At the approved dosage (150-300 mg once daily), it reduces systolic blood pressure by 12-16 mm Hg and diastolic blood pressure by 2-12 mm Hg. In studies its efficacy was comparable to losartan 100 mg, irbesartan 150 mg, and valsartan 80-320 mg. When used adjunctively with ramipril, an angiotensin-converting enzyme (ACE) inhibitor, valsartan, an angiotensin II receptor blocker (ARB), or hydrochlorothiazide, a diuretic, it provides additional blood pressure reduction compared with placebo or monotherapy. Aliskiren is well tolerated, with the most common side effects being gastrointestinal symptoms, fatigue, weakness, and headache. In short-term clinical trials, aliskiren caused fewer disturbances in potassium levels when compared with hydrochlorothiazide, ACE inhibitors and ARBs. Long-term data on morbidity and mortality outcomes are not currently available, thus it is unknown whether aliskiren would join ACE inhibitors and ARBs as the preferred hypertensive agents for end organ protection. At this time, aliskiren should be considered as an alternative agent for mild-to-moderate hypertension, or as an adjunctive therapy when preferred agents fail to maintain optimal blood pressure control. It is also an option for those patients who have contraindications or intolerability to other antihypertensive agents, including dry cough induced by ACE inhibitors.
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PMID:Aliskiren: an oral renin inhibitor for the treatment of hypertension. 1809 68

We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA- or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180+/-3 mm Hg) compared with dTGRs (208+/-5 mm Hg). Aliskiren-treated dTGRs and Sprague-Dawley rats were normotensive (110+/-3 and 119+/-6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QT(c) intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy.
Hypertension 2008 Feb
PMID:Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension. 1815 39

Aliskiren (CGP-60536 or SPP100) is the first oral direct renin inhibitor and the first new class of antihypertensive agents to be introduced in more than a decade. Aliskiren taken once a day, alone or in combination with other antihypertensive agents, has been shown to be effective in reducing blood pressure and is generally well tolerated. Based on an extensive clinical trials program, aliskiren was approved for the treatment of hypertension in March 2007 (as Tekturna; Novartis Pharmaceuticals, East Hanover, NJ, USA) by the U.S. Food and Drug Administration and in August 2007 (as Rasilez, Enviage, Sprimeo, Tekturna and Riprazo, all from Novartis) for the treatment of essential hypertension by the European Commission. Although the indication for aliskiren is treatment of essential hypertension, benefits similar to those demonstrated with certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are anticipated for aliskiren. Some of the 44 trials with aliskiren are listed in Table II. Inhibition of renin, which is the first and rate-limiting step in the renin-angiotensin pathway has theoretical advantages over either ACE inhibitors or ARBs.
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PMID:Aliskiren. 1817 70

Diabetic nephropathy and hypertension are the major causes of chronic kidney disease. The renin system plays a key role in the control of blood pressure (BP), as well as in the regulation of renal and adrenal function. Chronic activation of the renin system can lead to organ damage, particularly renal damage; increasing evidence indicates that suppression of the renin system can provide renal protection. Despite the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), the renin system is not completely suppressed. The direct renin inhibitors (DRIs) provide suppression of the entire renin system at the rate-limiting step. Studies in humans with early DRIs indicated potential renoprotective effects, but these agents failed in clinical development due to poor oral bioavailability. Aliskiren is a new orally active DRI with proven BP-lowering effects. Animal studies indicate that aliskiren may provide renal protection, and data from human studies are anticipated.
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PMID:Renin inhibitors: optimal strategy for renal protection. 1817 90

The importance of renin-angiotensin-aldosterone system (RAAS) in diseases such as hypertension, congestive heart failure and chronic renal failure has long ago been recognized. It has also been established that inhibition of RAAS, using inhibitors of the angiotensin-converting enzyme (ACE) or angiotensin II receptor blockers (ARB), is an effective way to intervene with the pathogenesis of these disorders. Renin inhibitors block the RAAS at the highest level, at its origin, and might thus offer a new exciting approach for pharmacotherapy of arterial hypertension. Aliskiren is the first in a new class of orally active, non-peptide, low molecular weight renin inhibitors, and so far the only renin inhibitor that has progressed to phase III clinical trials. This review summarizes the available data on the pharmacokinetic and pharmacodynamic properties of aliskiren and its clinical development for treatment of arterial hypertension.
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PMID:Aliskiren--an orally active renin inhibitor. Review of pharmacology, pharmacodynamics, kinetics, and clinical potential in the treatment of hypertension. 1820 Aug 1

The recently cloned (pro)renin receptor [(P)RR] mediates renin-stimulated cellular effects by activating mitogen-activated protein kinases and promotes nonproteolytic prorenin activation. In vivo, (P)RR is said to be blocked with a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP). We tested whether human prorenin and renin induce extracellular signal-regulated kinase (ERK) 1/2 activation and whether the direct renin inhibitor aliskiren or the HRP inhibits the receptor. We detected the (P)RR mRNA and protein in isolated human monocytes and in U937 monocytes. In U937 cells, we found that both human renin and prorenin induced a long-lasting ERK 1/2 phosphorylation despite angiotensin II type 1 and 2 receptor blockade. In contrast to angiotensin II-ERK signaling, renin and prorenin signaling did not involve the epidermal growth factor receptor. A mitogen-activated protein kinase kinase 1/2 inhibitor inhibited both renin and prorenin-induced ERK 1/2 phosphorylation. Neither aliskiren nor HRP inhibited binding of (125)I-renin or (125)I-prorenin to (P)RR. Aliskiren did not inhibit renin and prorenin-induced ERK 1/2 phosphorylation and kinase activity. Fluorescence-activated cell sorter analysis showed that, although fluorescein isothiocyanate-labeled HRP bound to U937 cells, HRP did not inhibit renin or prorenin-induced ERK 1/2 activation. In conclusion, prorenin and renin-induced ERK 1/2 activation are independent of angiotensin II. The signal transduction is different from that evoked by angiotensin II. Aliskiren has no (P)RR blocking effect and did not inhibit ERK 1/2 phosphorylation or kinase activity. Finally, we found no evidence that HRP affects renin or prorenin binding and signaling.
Hypertension 2008 Mar
PMID:Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. 1821 69

The renin-angiotensin aldosterone system (RAAS) plays a key role in the regulation of blood pressure, acting via the effects of the hormone angiotensin (Ang) II. Ang II increases blood pressure and can exert growth-promoting effects leading to end-organ damage. Excess RAAS activity has been shown to be a major underlying cause of hypertension, heart failure, and related cardiovascular disorders. Inhibitors of renin block the RAAS at its first and rate-limiting step and thus appear to offer an excellent opportunity for blood pressure control. In the past two decades various potential renin inhibitors have been developed but have not been clinically useful. This review discusses a recent patent in the development of a novel class of non-peptide renin inhibitors: an alkanecarboxamide, aliskiren (SPP-100; Novartis). Aliskiren is effective in animal models, while recent results from studies in humans indicate that aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension.
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PMID:The renin inhibitor aliskiren as novel treatment for cardiovascular disease. 1822 Oct 88


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