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

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). Aliskiren is rapidly absorbed following oral administration, with maximum plasma concentrations reached within 1-3 hours. The absolute bioavailability of aliskiren is 2.6%. The binding of aliskiren to plasma proteins is moderate (47-51%) and is independent of the concentration. Once absorbed, aliskiren is eliminated through the hepatobiliary route as unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 (CYP) 3A4. Unchanged aliskiren accounts for approximately 80% of the drug in the plasma following oral administration, indicating low exposure to metabolites. The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. Aliskiren excretion is almost completely via the biliary/faecal route; 0.6% of the dose is recovered in the urine. Steady-state plasma concentrations of aliskiren are reached after 7-8 days of once-daily dosing, and the accumulation factor for aliskiren is approximately 2. After reaching the peak, the aliskiren plasma concentration declines in a multiphasic fashion. No clinically relevant effects of gender or race on the pharmacokinetics of aliskiren are observed, and no adjustment of the initial aliskiren dose is required for elderly patients or for patients with renal or hepatic impairment. Aliskiren showed no clinically significant increases in exposure during coadministration with a wide range of potential concomitant medications, although increases in exposure were observed with P-glycoprotein inhibitors. Aliskiren does not inhibit or induce CYP isoenzyme or P-glycoprotein activity, although aliskiren is a substrate for P-glycoprotein, which contributes to its relatively low bioavailability. Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg. Phase II and III clinical studies involving over 12,000 patients with hypertension have demonstrated that aliskiren provides effective long-term blood pressure (BP) lowering with a good safety and tolerability profile at these doses. Aliskiren inhibits plasma renin activity (PRA) by up to 80% following both single and multiple oral-dose administration. Similar reductions in PRA are observed when aliskiren is administered in combination with agents that alone increase PRA, including diuretics (hydrochlorothiazide, furosemide [frusemide]), ACE inhibitors (ramipril) and angiotensin receptor blockers (valsartan), despite greater increases in the plasma renin concentration. Moreover, PRA inhibition and BP reductions persist for 2-4 weeks after stopping treatment, which is likely to be of benefit in patients with hypertension who occasionally miss a dose of medication. Preliminary data on the antiproteinuric effects of aliskiren in type 2 diabetes mellitus suggest that renoprotective effects beyond BP lowering may be possible. Further studies to evaluate the effects of aliskiren on cardiovascular outcomes and target organ protection are ongoing and will provide important new data on the role of direct renin inhibition in the management of hypertension and other cardiovascular disease.
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PMID:Clinical pharmacokinetics and pharmacodynamics of aliskiren. 1861 Oct 61

Hypertension is the most common risk factor for cardiovascular disease, constituting the most common cause of death in industrialized countries. Therefore, the task of blood pressure reduction has significant importance in reducing vascular damage, myocardial infarctions, kidney damage and incidence of cerebrovascular accidents. The renin-angiotensin-aldosterone system (RAAS) plays a central role in control and function of the cardiovascular and renal systems, and is deeply involved in the pathophysiology of diseases of vasculature, heart, kidneys and others. Therefore, blockade of RAAS by angiotensin converting enzyme (ACE) inhibitors and blockers of angiotensin II type AT1 receptors (ARBs) is widely utilized by clinicians. Indeed, it has long been known that ACE inhibitors and ARBs protect different targets of angiotensin II, due to impedance of the negative effects of the hormone and the inhibition of aldosterone production, which contributes both directly and indirectly to the damages, independent of angiotensin II. Despite this, the morbidity and mortality resulting from the progression of cardiovascular diseases in patients treated with ACE inhibitors or ARBs remain high. As such, over the years, much effort has been dedicated to the development of direct inhibitors of renin. The earliest renin inhibitors, developed 30 years ago were not effective due to their protein nature, which prevents their oral administration and limited their clinical use. In the last decade, several non-protein renin inhibitors which could be given orally were developed, of which Aliskiren is the most well known representative. Due to the fact that neutralization of the RAAS by ACE inhibitors and ARBs has been reviewed at length many times, this review will focus on the renewed subject of renin inhibition. The earliest research, both in humans as well as in animal models, show that Aliskiren has therapeutic potential in treatment of patients with hypertension, cardiovascular disease and renal disease. However, the efficacy of Aliskiren in treating systolic and diastolic hypertension in patients was not better than that obtained using ACE inhibitors or ARBs. Even so, there is no need to lower levels of optimism for potential therapy using direct inhibitors of renin. Current research is still in its early stages and there is a need to remember that it took many years to prove the clinical usefulness of ACE inhibitors, which are now central to treatment of cardiovascular and renal diseases, including hypertension.
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PMID:[Oral inhibitors of renin and their potential use as therapeutic agents in treating hypertension]. 1869 32

Aliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. The development program has established that at the licensed doses of 150 mg and 300 mg, there are dose-related falls in blood pressure comparable to those seen with other major classes of antihypertensive drugs and that these falls are associated with a placebo level of side effects. Aliskiren was found to be effective either as monotherapy or in combination with drugs from the other major classes. As expected, there was a greater benefit from adding aliskiren to natriuretic drugs than to other blockers of the renin system. However, there was also some consistent benefit from dual renin blockade. Aliskiren is likely to be of most value in patients uncontrolled by, or intolerant of, other classes. Rational understanding of the renin system will maximize its value, for instance, by encouraging greater use of natriuretic agents in patients with resistant hypertension to render their hypertension renin dependent. Whether there are cardiovascular benefits other than blood pressure control in blocking the renin system remains to be demonstrated. It is hoped that long-term outcome studies with aliskiren will finally allow this question to be answered.
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PMID:Aliskiren. 1869 3

Chronic kidney disease (CKD), a major worldwide public-health problem which affects about 10% of the population, has an increased annual incidence rate of about 5-8%. This increased incidence is mainly due to type 2 diabetes and hypertension and the increasing incidence of elderly patients with CKD. Although the progression to end-stage renal failure (ESRF) is mainly based upon the underlying disease, comorbid conditions such as an initial low renal function, severe proteinuria, and high levels of blood pressure also play important roles in the development of ESRF. Since experimental and clinical evidence suggest that angiotensin II plays a central role in the progression of CKD, pharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists has been suggested as first-line treatment for hypertension and prevention of ESRF in these patients. Aliskiren, a novel renin inhibitor is also a promising medical intervention. However, independently of the category of the drugs used, low target blood pressure levels seem to be equally or more important for the delay or prevention of CKD. In this review the results of studies with pharmacological inhibition of the RAAS in patients with diabetic and nondiabetic nephropathy is discussed.
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PMID:Inhibition of the renin-angiotensin system and chronic kidney disease. 1880 6

High blood pressure is a major risk factor for cardiovascular disease worldwide. Drug treatments include those that target the renin-angiotensin system, a key hormone cascade in the regulation of blood pressure. One of these is aliskiren (Rasilez - Novartis), which belongs to a new class of drugs, direct renin inhibitors. Here we assess its place in managing adults with hypertension.
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PMID:Aliskiren for hypertension in adults. 1883 57

Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs) was recently approved for the treatment of hypertension. In this review, we discuss the history of the development of DRIs and available data regarding the effects of DRIs in the treatment of hypertension and related target organ damage.
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PMID:Renin inhibitors: novel agents for renoprotection or a better angiotensin receptor blocker for blood pressure lowering? 1892 29

Pharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure-lowering effects. We investigated the effect of aliskiren on cardiac remodeling, apoptosis, and left ventricular (LV) function after experimental myocardial infarction (MI). C57J/bl6 mice were subjected to coronary artery ligation and were treated for 10 days with vehicle or aliskiren (50 mg/kg per day via an SC osmopump), whereas sham-operated animals served as controls. This dose of aliskiren, which did not affect systemic blood pressure, improved systolic and diastolic LV function, as measured by the assessment of pressure-volume loops after MI. Furthermore, after MI LV dilatation, cardiac hypertrophy and lung weights were decreased in mice treated with aliskiren compared with placebo-treated mice after MI. This was associated with a normalization of the mitogen-activated protein kinase P38 and extracellular signal-regulated kinases 1/2, AKT, and the apoptotic markers bax and bcl-2 (all measured by Western blots), as well as the number of TUNEL-positive cells in histology. LV dilatation, as well as the associated upregulation of gene expression (mRNA abundance) and activity (by zymography) of the cardiac metalloproteinase 9 in the placebo group after MI, was also attenuated in the aliskiren-treated group. Aliskiren improved LV dysfunction after MI in a dose that did not affect blood pressure. This was associated with the amelioration of cardiac remodelling, hypertrophy, and apoptosis.
Hypertension 2008 Dec
PMID:Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure. 1895 59

The vascular effects of aliskiren last longer than expected based on its half life, and this renin inhibitor has been reported to cause a greater renin rise than other renin-angiotensin system blockers. To investigate whether aliskiren accumulation in secretory granules contributes to these phenomena, renin-synthesizing mast cells were incubated with aliskiren, washed, and exposed to forskolin in medium without aliskiren (0.1 to 1000 nmol/L). (Pro)renin concentrations were measured by renin- and prorenin-specific immunoradiometric assays, and renin activity was measured by enzyme-kinetic assay. Without aliskiren, the culture medium predominantly contained prorenin, the cells exclusively stored renin, and forskolin doubled renin release. Aliskiren dose-dependently bound to (pro)renin in the medium and cell lysates and did not alter the effect of forskolin. The aliskiren concentrations required to bind prorenin were 1 to 2 orders of magnitude higher than those needed to bind renin. Blockade of cell lysate renin activity ranged from 27+/-15% to 79+/-5%, and these percentages were identical for the renin that was released by forskolin, indicating that they represented the same renin pool, ie, the renin storage granules. Comparison of renin and prorenin measurements in blood samples obtained from human volunteers treated with aliskiren, both before and after prorenin activation, revealed that <or=30% of prorenin was detected in renin-specific assays. In conclusion, aliskiren accumulates in renin granules, thus allowing long-lasting renin-angiotensin system blockade beyond the half-life of this drug. Aliskiren also binds to prorenin. This allows its detection as renin, and might explain, in part, the renin rise during renin inhibition.
Hypertension 2008 Dec
PMID:Aliskiren accumulates in Renin secretory granules and binds plasma prorenin. 1912 76

Intensive efforts have been spent to discover therapeutic, non-peptide and orally effective hypertensive drugs. One drug that emerged from this effort is aliskiren, a direct human renin inhibitor that blocks the conversion of angiotensinogen to angiotensin I (Ang I). In contrast to other antihypertensive agents, aliskiren decreases plasma renin activity (PRA). In healthy human subjects, doses of between 40 and 640 mg of aliskiren exert a dose-dependent reduction in PRA and Ang I and Ang II levels. The bioavailability of aliskiren is low (2%), peak plasma concentrations are reached within one to three hours and the binding with plasma proteins achieves approximately 47-51%. Aliskiren is slightly metabolized (20%) by CYP3A4. The most common adverse events include diarrhea, headache, back pain and gastrointestinal disorders. Aliskiren is well tolerated, and may be used alone or in combination with other antihypertensive agents. Aliskiren belongs to a new class of agents that effectively and specifically inhibit the RAS. This drug functions through a novel mechanism of action and has the potential to become a true alternative to angiotensin converting enzyme inhibitors and angiotensin receptor blockers in the therapy of hypertension and other cardiovascular and renal disorders.
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PMID:Pharmacokinetics and pharmacodynamics of aliskiren, an oral direct renin inhibitor. 1906 8

Aliskiren is the first member of the new class of orally active direct renin inhibitors to receive approval from the United States Food and Drug Administration for the treatment of hypertension. In patients with hypertension, aliskiren can be used either as monotherapy or in combination with other antihypertensive agents. By inhibiting renin, aliskiren blocks the conversion of angiotensinogen to angiotensin I, which subsequently results in a reduction in angiotensin II concentrations. Unlike the angiotensin-converting enzyme inhibitors and the angiotensin II receptor blockers (ARBs), which reactively stimulate an increase in plasma renin activity, aliskiren suppresses the effects of renin and leads to a reduction in plasma renin activity. In clinical trials involving patients with mild-to-moderate hypertension, aliskiren provided antihypertensive efficacy that was comparable to that of an ARB. Combination therapy with aliskiren and an ARB may provide additional blood pressure-lowering effects compared with the respective monotherapies with each of the agents. The results from surrogate outcome studies have also alluded to the potential for aliskiren to prevent target organ damage. Because aliskiren does not significantly affect the cytochrome P450 system, it has been associated with few drug interactions. In clinical studies, aliskiren was well tolerated, and its adverse-effect profile was similar to that of placebo. Fatigue, headache, dizziness, diarrhea, nasopharyngitis, and back pain were the most commonly reported adverse events. Overall, aliskiren appears to be a reasonable treatment option for patients with mild-to-moderate hypertension who are intolerant of first-line antihypertensive therapies. Aliskiren may also be a promising renoprotective strategy in patients with concomitant hypertension and diabetes mellitus. Its potential as a first-line antihypertensive agent will have to be further examined once studies evaluating its effects on long-term clinical outcomes are completed.
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PMID:Aliskiren: an oral direct renin inhibitor for the treatment of hypertension. 1917 May 89


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