Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Aliskiren, an octanamide, is nonpeptide, low molecular weight, orally active renin inhibitor effectively preventing angiotensin and aldosterone release. This drug has been recently approved for the treatment of hypertension. Considering potential links between hypertension, platelets, the coagulation cascade and fibrinolysis we sought to evaluate the effect of aliskiren on human biomarkers of hemostasis. In vitro effects of whole blood preincubation with escalating concentrations of aliskiren (500, 1,000 and 2,000 ng ml(-1)) were assessed in 20 aspirin-naive volunteers with multiple risk factors for vascular disease. A total of 33 biomarkers were measured, of which 18 are related to platelet function, 12 to coagulation and 3 to fibrinolysis. Pretreatment of blood samples with aliskiren 500 ng ml(-1) resulted in a significant increase of antithrombin-III (AT-III) activity (P=0.003). All other tested biomarkers were not significantly affected. Spiking whole blood with the higher aliskiren doses was associated with various trends in biomarker activity, where 1000 ng ml(-1) concentration mostly decreased (7/33), and 2,000 ng ml(-1) mostly increased (6/33) some biomarkers. In the therapeutic concentration of 500 ng ml(-1) aliskiren does not affect hemostatic biomarkers, except for a moderate but highly significant (P=0.003) increase of AT-III activity. Higher aliskiren doses were associated with more profound biomarker changes, but they are likely not to be clinically relevant since they show diverging (that is, both mild antiplatelet and platelet-activating) trends, and considering the 2- to 4-fold safety margin. It is suggested that antithrombotic properties of aliskiren be explored further in an ex vivo clinical setting.
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PMID:Effects of aliskiren, a renin inhibitor, on biomarkers of platelet activity, coagulation and fibrinolysis in subjects with multiple risk factors for vascular disease. 1827 42

The development of aliskiren, the first orally effective renin inhibitor, utilized molecular modeling based upon X-ray crystallographic analysis of renin's active site to design a potent, low molecular weight renin inhibitor with improved bioavailability (approximately 2.6%). In patients with hypertension, dose-dependent BP reduction occurs with aliskiren 75-300 mg once daily; at these doses, the safety and tolerability profile is comparable to placebo. In direct comparison studies, BP reduction with aliskiren is equivalent to commonly used antihypertensive agents including diuretics, ACE inhibitors, and ARBs. Persistent BP reduction and prolonged suppression of plasma renin activity (PRA) is observed after aliskiren withdrawal. Aliskiren suppresses PRA when given either as monotherapy or in combination with other agents. When added to an ARB, aliskiren blocks compensatory RAS activation and produces significant additional BP reduction. In patients with diabetic nephropathy, addition of aliskiren to losartan, 100 mg resulted in a 20% greater reduction in proteinuria. Ongoing studies evaluating the long-term renal protective effects of aliskiren and its effects on ventricular remodeling are currently planned or underway.
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PMID:Current concepts: renin inhibition in the treatment of hypertension. 1830 34

Hypertension is a major risk factor for cardiovascular morbidity and mortality and currently has been estimated at 30% of the US population. Of these, only 36.8% have their blood pressure reduced to recommended levels of lower than 140/90 mmHg for uncomplicated hypertension, or less than 130/80 mmHg for patients with diabetes mellitus or renal disease. Since monotherapy controls blood pressure in less than 50% of treated hypertensive patients, combination therapy is often required to bring blood pressure to the recommended levels of the 7th Joint National Committee report. One of the most effective and widely used combinations is the combination of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with hydrochlorothiazide (HCTZ). Aliskiren, a new blocker of the renin-angiotensin system has been developed and approved by the US FDA on 18th January 2008 for the treatment of hypertension. Aliskiren is a direct inhibitor of renin, the rate-limiting enzyme for the production of angiotensin II, a powerful vasoconstrictive peptide. Several randomized clinical trials have demonstrated that aliskiren administered in single daily doses of 150, 300 or 600 mg alone and in combination with HCTZ 12.5 and 25 mg is effective in lowering blood pressure, and is safe and well tolerated. In this article, the pharmacokinetic and pharmacodynamic profile and the clinical application of aliskiren alone and in combination with HCTZ will be discussed.
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PMID:Aliskiren-hydrochlorothiazide combination for the treatment of hypertension. 1832 92

Hypertension is associated with increased risk of cardiovascular diseases. Antihypertensive treatment, particularly blockade of the renin-angiotensin system, contributes to prevent atherosclerosis-mediated cardiovascular events. Direct comparison of different antihypertensive treatments on atherosclerosis and particularly plaque stabilization is sparse. ApoE(-/-) mice with vulnerable (2-kidney, 1-clip renovascular hypertension model) or stable (1-kidney, 1-clip renovascular hypertension model) atherosclerotic plaques were used. Mice were treated with aliskiren (renin inhibitor), irbesartan (angiotensin-receptor blocker), atenolol (beta-blocker), or amlodipine (calcium channel blocker). Atherosclerosis characteristics were assessed. Hemodynamic and hormonal parameters were measured. Aliskiren and irbesartan significantly prevented atherosclerosis progression in 2-kidney, 1-clip mice. Indeed, compared with untreated animals, plaques showed thinner fibrous cap (P<0.05); smaller lipid core (P<0.05); decreased media degeneration, layering, and macrophage content (P<0.05); and increased smooth muscle cell content (P<0.05). Interestingly, aliskiren significantly increased the smooth muscle cell compared with irbesartan. Despite similar blood pressure lowering, only partial plaque stabilization was attained by atenolol and amlodipine. Amlodipine increased plaque smooth muscle cell content (P<0.05), whereas atenolol decreased plaque inflammation (P<0.05). This divergent effect was also observed in 1-kidney, 1-clip mice. Normalizing blood pressure by irbesartan increased the plasma renin concentration (5932+/-1512 ng/mL per hour) more than normalizing it by aliskiren (16085+/-5628 ng/mL per hour). Specific renin-angiotensin system blockade prevents atherosclerosis progression. First, evidence is provided that direct renin inhibition mediates atherosclerotic plaque stabilization. In contrast, beta-blocker and calcium channel blocker treatment only partially stabilize plaques differently influencing atherogenesis. Angiotensin II decisively mediates plaque vulnerability. The plasma renin concentration measurement by an indirect method did not confirm the excessive increase of plasma renin concentration reported in the literature during aliskiren compared with irbesartan or amlodipine treatment.
Hypertension 2008 May
PMID:Renin inhibition by aliskiren prevents atherosclerosis progression: comparison with irbesartan, atenolol, and amlodipine. 1839 Oct 92

Hypertension is one of the major health care problems worldwide since it markedly increases the risk for development of heart disease, stroke, generalized vascular disease, and renal failure. The renin-angiotensin system (RAS) with its major end-product angiotensin II (Ang II) plays a fundamental role in blood pressure regulation through direct and indirect mechanisms. Pharmacologically, we can inhibit the RAS using angiotensin-converting enzyme inhibitors and AT1 receptor blocker. Inhibiting renin directly with a clinically useful drug eluded pharmacologists until recently. However, the once-daily, orally effective, small-molecule, direct renin inhibitor aliskiren has recently changed this state of affairs. Aliskiren, with its 40-h half-life and ideal pharmacokinetics, can now address angiotensin production directly at its rate-limiting step. A novel transgenic rat model outfitted with the human renin and angiotensinogen genes allowed the testing of aliskiren in an animal model. Preclinical data demonstrated that aliskiren prolonged survival, decreased cardiac hypertrophy and the inducibility of arrhythmias, proteinuria, and attenuated inflammation. All these features might result in improved target-organ damage. Studies in humans attest to an effective blood pressure-lowering action, a largely side effect-free profile, and the option of several combination therapies. Aliskiren is the first of a novel antihypertensive drug class. The preclinical data is very promising. Nevertheless, for the evaluation of its potency in humans, we have to wait for more clinical data.
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PMID:Aliskiren--mode of action and preclinical data. 1844 51

Aliskiren, a renin inhibitor, is the first in a new class of drugs interfering with the renin angiotensin system. Aliskiren was approved by the US Food and Drug Administration (FDA) in March 2007, and in Europe in August 2007 for the treatment of hypertension (marketed as Tekturna and Rasilez, respectively). Several clinical trials demonstrated effective blood pressure reduction due to aliskiren treatment. Whether aliskiren exhibits morbidity and mortality benefits for patients beyond its blood pressure reduction capability, can only be judged after realization of comparative long-term clinical trials. Furthermore, it remains to be seen, whether the use of aliskiren will be indicated for treatment of additional diseases, as it was the case for other inhibitors of the renin angiotensin system. In fact, recent and ongoing clinical trials regarding heart failure and diabetic nephropathy demonstrated first beneficial effects of aliskiren in these conditions (reduction of urinary albumin/creatinine-ratio and NTproBNP, respectively).
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PMID:[Aliskiren hemifumarate]. 1846 84

Hypertension is one of the major risk factors for cardiovascular morbidity and mortality. Lowering blood pressure (BP) may reduce the risk of stroke by 40% and the risk of ischemic heart disease by 20%. Despite the varied drugs available to lower BP, more than 50% of the hypertensive patients are not well-controlled. The major reason for the failure to control BP is noncompliance which is related to the side effects and inconvenience of drug administration. Aliskiren, a new oral direct renin inhibitor is very effective in BP reduction. It is given once daily and has very few side effects, almost like a placebo. It is well combined with diuretics, angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers. Unlike ACE inhibitors and angiotensin receptor blockers that block the renin angiotensin axis in its last part and thereby raise the rein-levels, the direct renin inhibitor block the renin-angiotensin axis in its beginning and keep the renin levels suppressed. Aliskiren is a promising agent but further prospective studies with morbidity and mortality data as endpoints are required, before the drug can be recommended as a first choice agent.
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PMID:[Is there a need for direct renin inhibitors?]. 1848 62

This multicenter, double-blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo-adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time-matched analysis) and for values averaged across the dosing period (baseline-averaged analysis). In time-matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <10 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline-averaged analysis was consistent with time-matched analysis. Instances of QTcF interval >450 milliseconds or a >30-millisecond increase from baseline with aliskiren (< or = 1%) were similar or lower than placebo (< or = 4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4-fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.
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PMID:Effects of aliskiren, a direct Renin inhibitor, on cardiac repolarization and conduction in healthy subjects. 1849 Apr 95

The aim of this study was to explore the effects of the renin inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between renin and the (pro)renin receptor and between aliskiren and prorenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-beta and collagen I expression versus vehicle. Aliskiren reduced (pro)renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 micromol/L to 10 micromol/L) did not inhibit binding of (125)I-renin to the (pro)renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)renin receptor. Evidence was obtained that aliskiren binds to the active site of prorenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)renin receptor and that it may block prorenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this renin inhibitor.
Hypertension 2008 Jul
PMID:Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. 1849 May 20

(1) Pharmacological management of arterial hypertension is based on antihypertensive drugs with proven efficacy on morbidity and/or mortality endpoints. (2) Aliskiren is the first renin inhibitor to reach the market. (3) There are no published trials of aliskiren with clinical endpoints. Five double-blind short-term (8 weeks) placebo-controlled trials showed a moderate effect on blood pressure. This effect was not superior to that of other antihypertensive drugs with which aliskiren was compared: hydrochlorothiazide, amlodipine, irbesartan, losartan, valsartan, lisinopril and rampiril. (4) When added to another antihypertensive drug, aliskiren had little or no additional effect on blood pressure. In particular, there is no firm evidence that adding aliskiren to amlodipine 5 mg/day is any more effective than doubling the dose of amlodipine. (5) Aliskiren has not been tested in patients with renovascular hypertension or severe hypertension, but pharmacological data suggest that aliskiren might be less effective in these individuals. (6) Overall, the adverse effect profile of aliskiren does not seem to be any better than that of other antihypertensive drugs. Aliskiren contributes to the onset of angioedema, cough, diarrhea and abdominal pain, hyperuricaemia, gout attacks, kidney stones and skin rash. Pharmacovigilance should focus specifically on certain adverse effects that are known to occur with other drugs acting on renin-angiotensin axis, such as angioedema, muscle disorders and anaemia, even though few such cases were observed with aliskiren during clinical trials. (7) Aliskiren is contraindicated during pregnancy, as are other antihypertensive drugs acting on the renin-angiotensin axis. (8) In practice, it is better not to use aliskiren to treat hypertensive patients because better-assessed antihypertensive drugs with longer follow-up are available.
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PMID:Aliskiren: new drug. Arterial hypertension: no evidence of clinical efficacy. 1851 3


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