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: EC:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BACKGROUND: The pharmacodynamics (plasma angiotensin II [AII], plasma renin activity [PRA], renal function, blood pressure [BP], urinary excretion of major metabolites of prostacyclin [PGI(2)-M], and thromboxane A(2) [TXA(2)-M]) and pharmacokinetics of irbesartan were assessed in hypertensive patients. METHODS AND RESULTS: Twenty-four white patients with seated diastolic blood pressure 95 to 110 mmHg were randomized to double-blind irbesartan 300 mg or placebo once daily for 4 weeks, following a placebo lead-in. Irbesartan-treated patients had significantly greater 24-hour area under the curve values for mean change from baseline in AII and PRA versus placebo-treated patients on day B15 (AII [pg |mZ h/mL]: 261 +/- 515 vs 12 +/- 51; PRA [(ng/mL/h); h]:74 +/-162 vs -2 +/-14; P values >.05). Irbesartan significantly lowered BP without clinically important changes in renal function. Irbesartan had no effect on 24-hour urinary TXA(2)-M excretion, but significantly increased 24-hour PGI(2)-M excretion versus placebo on day B29 (20.7 +/- 23 pg/mg creatinine vs _2.3 +/- 43 pg/mg creatinine; P <.05). Pharmacokinetics were comparable to those from previous studies. The hourly relationship between plasma irbesartan concentration and antihypertensive effect indicated a broad, clockwise hysteresis, with peak concentration occurring at 1.5 hours, whereas peak antihypertensive effect occurred at 4 hours. CONCLUSIONS: Irbesartan increases plasma AII and PRA and lowers BP consistent with AT(1) receptor blockade, without clinically important effects on renal function.
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PMID:Pharmacodynamics and Pharmacokinetics of Irbesartan in Patients With Mild to Moderate Hypertension. 1068 25

The recently developed and marketed angiotensin II type 1 (AT1) receptor blockers (ARBs) have demonstrated efficacy equivalent to that of other leading classes of antihypertensive agents, with superior tolerability profiles. The specific targeting of the AT1 receptor afforded by these agents has demonstrated more complete blockade of the renin-angiotensin system than that offered by angiotensin-converting enzyme inhibitors. These data notwithstanding, differentiation within the class of ARBs has been limited. With the accumulation of additional data with ARBs, it has recently become possible to make within-class distinctions, based in large part on the individual pharmacological profiles of the ARBs. To this end, absorption, distribution, half-life, dose response and level of angiotensin II antagonism are of special note. When these properties are viewed as a group, the ARB irbesartan appears to offer advantages beyond those attained with other ARBs. Irbesartan is well absorbed, does not require biotransformation to an active metabolite to exert its antihypertensive activity, offers a large volume of distribution, has a half-life that is sufficient to allow once-daily dosing, is associated with a strong and consistent dose-response and has been demonstrated to provide a level of angiotensin II antagonism that is statistically superior to that offered by some other ARBs. These pharmacological differences may explain the clinical superiority of irbesartan compared with losartan, the first member of the ARB class. As even more data on the ARBs become available, the ability to determine the advantages of specific members of this class will be enhanced, distinctions that already have begun to come to light.
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PMID:Irbesartan: review of pharmacology and comparative properties. 1082 10

Irbesartan interrupts the renin-angiotensin system via selective blockade of the angiotensin II subtype 1 receptor; the latter being responsible for the pressor related effects of angiotensin II. As treatment for mild to moderate hypertension, irbesartan 150 mg/day controlled diastolic BP in 56% of patients according to pooled data from several phase III studies and 77% of patients in a large phase IV study. in comparative trials, irbesartan was significantly more effective than losartan and valsartan as treatment for mild to moderate essential hypertension and as effective as enalapril or atenolol. Results from many studies show an additive antihypertensive effect when hydrochlorothiazide is added to irbesartan monotherapy. The drug also induces statistically significant regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy, and preliminary evidence suggests it has beneficial haemodynamic effects in patients with heart failure. Irbesartan is very well tolerated, exhibiting an adverse event profile similar to that seen with placebo in comparative trials. In conclusion, although the role of irbesartan as a treatment for heart failure is little clearer than it was 2 years ago, the place of the drug in the management of hypertension is now better established. There is evidence to suggest the drug may have a role as initial therapy for hypertension, although formal recommendation in management guidelines will almost certainly not occur until long term morbidity and mortality benefits are established.
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PMID:Irbesartan: an updated review of its use in cardiovascular disorders. 1085 48

Hypertension in Dahl S rats on high-salt intake is in general considered a model of "low-renin hypertension," unresponsive to treatment with blockers of the renin-angiotensin system. However, direct central administration of an angiotensin II type 1 (AT(1)) receptor blocker prevents both the sympathoexcitation and hypertension caused by high-salt intake in Dahl S rats. In the present study, we tested the hypothesis that chronic peripheral administration of an AT(1) receptor blocker inhibits the salt-induced hypertension relative to the extent of central AT(1) receptor blockade that is induced. Dahl S rats received a high-salt (1370 micromol Na(+)/g) or regular (101 micromol Na(+)/g) diet from 4 to 8 weeks of age. In 3 different sets of experiments, Dahl S on high salt were randomized to intracerebroventricular (ICV) treatment with control infusion versus irbesartan at 50 or 250 microg. kg(-1). d(-1), oral treatment with control versus irbesartan at 125 or 500 mg. kg(-1). d(-1) once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg. kg(-1). d(-1) by once daily injection. At 8 weeks of age, MAP was measured in conscious rats at rest and in response to angiotensin II ICV or IV. On high-salt intake, Dahl S developed the anticipated marked increase in MAP to approximately 160 mm Hg. Irbesartan ICV did not affect pressor responses to angiotensin II IV, but irbesartan administered subcutaneously or by gavage markedly inhibited these responses. Irbesartan ICV or by gavage partially inhibited pressor responses to angiotensin II ICV and the development of hypertension. Irbesartan subcutaneously at the higher dose more completely inhibited pressor responses to angiotensin II ICV and fully prevented the salt-induced hypertension. The degree of central but not peripheral AT(1) receptor blockade parallels the antihypertensive effect of irbesartan, indicating that inhibition of the brain renin-angiotensin system can contribute to a significant extent to the therapeutic effectiveness of AT(1) receptor blockers such as irbesartan when administered in sufficiently high doses to cause central AT(1) receptor blockade.
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PMID:Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade. 1124 27

Irbesartan (SR 47436, BMS 186295) is an imidazole derivative that specifically binds to the angiotensin type 1 receptor. The purpose of this study was to assess the inhibitory effect of irbesartan on the pressor action of exogenous angiotensin II in healthy subjects, to evaluate the dose dependency and duration of this inhibition, and to determine the effect of irbesartan on plasma components of the renin-angiotensin system. Forty-two healthy male volunteers maintained on ad libitum sodium intake were enrolled in a randomized, double-blind, placebo-controlled, parallel-design, dose-ranging study. On 2 study days 1 week apart, volunteers were given either a placebo or the active drug at one of the chosen doses (5, 25, 50, 75, 100, 150, or 300 mg). The pressor effects of an individually titrated test dose of exogenous angiotensin II as well as plasma levels of angiotensin II, active renin, aldosterone, and treatment drug were determined before and throughout the 24 h after drug administration. The inhibitory effect of irbesartan on the pressor response to angiotensin II was observed within 1 h after dosing, peaked between 2 and 4 h, and lasted more than 24 h for doses of 25 mg and more. The effect was clearly dose related. Two and 24 h after administration of irbesartan, 300 mg, the response of arterial blood pressure (systolic and diastolic) to a given dose of angiotensin II was reduced by approximately 100% and 60%, respectively. Plasma concentrations of angiotensin II and active renin increased markedly after irbesartan administration, whereas plasma concentrations of aldosterone decreased. No evidence was found that the high levels of circulating angiotensin II observed after irbesartan administration could override the inhibitory effect of irbesartan on any of the measured parameters up to 24 h after dose. In conclusion, irbesartan appears to be a well-tolerated, orally active, potent antagonist of the renin-angiotensin system in men.
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PMID:Inhibition of the acute effects of angiotensin II by the receptor antagonist irbesartan in normotensive men. 1130 Jun 58

Blood pressure reduction is the most significant factor in delaying onset and progression of renal disease. Blockade of the renin-angiotensin system (RAS) using angiotensin-converting enzyme inhibitors (ACEIs) delays renal disease progression. More recently, agents that block the RAS by preventing angiotensin II from binding to its subtype 1 receptor (ARBs) have been developed in an effort to prevent deleterious consequences of pathologic levels of angiotensin II and to reduce the adverse effects of RAS blockade associated with ACEIs. Human studies with a variety of ARBs have clearly demonstrated the antihypertensive and antiproteinuric efficacy of these agents in patients with progressive renal diseases. Moreover, the effects of ARBs are similar or identical to those of ACEIs. Ongoing long-term clinical trials are designed to determine whether ARBs also preserve renal function similar to ACEIs. Specifically, the role of ARBs in patients with hypertension and type 2 diabetes is being evaluated in 3 large trials, including Appropriate Blood Pressure Control in Diabetes-Part 2 With Valsartan, the Losartan Renal Protection Study, and the Irbesartan Diabetic Nephropathy Trial. Definitive evidence of the long-term protective effects of ARBs in chronic progressive renal disease is expected from these important studies.
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PMID:Angiotensin II subtype 1 receptor blockers and renal function. 1142 96

Nephropathy associated with type 2 diabetes mellitus is a rising cause of end-stage renal disease and is a major public health problem. If blocking of the renin angiotensin system has a well established nephroprotective effect in type 1 diabetic nephropathy, this remained to be shown for type 2 diabetes. Two large outcome trials using angiotensin II receptor antagonists (ARA's) in proteinuric chronic renal impairment and hypertensive type 2 diabetic patients have now closed this gap: the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan (RENAAL) trial. Both trials showed a significant reduction in the primary pre-specified end-point of death, or worsening of renal function (doubling of serum creatinine) or the development of end-stage renal disease. This effect goes beyond the reduction in blood pressure and makes of ARA's one of the important tools in the treatment of type 2 diabetic nephropathy.
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PMID:[Clinical study of the month. Nephroprotective role of angiotensin II receptor antagonists in type 2 diabetes: results of the IDNT and RENAAL trials]. 1176 85

The Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan Diabetic Nephropathy Trial (IDNT) are two recently reported trials with hard end points, conducted in patients in advanced stages of diabetic nephropathy. Two other studies--the Irbesartan Microalbuminuria Study (IRMA)-2 and the Microalbuminuria Reduction with Valsartan study (MARVAL)--were trials conducted in patients with type 2 diabetes with microalbuminuria, a cardiovascular risk factor associated with early-stage diabetic nephropathy. These trials all had a common theme--that is, does an angiotensin receptor blocker (ARB) interfere with the natural history of diabetic nephropathy in a blood pressure-independent fashion? Without question, the results of these trials legitimatize the use of the ARB class in forestalling the deterioration in renal function, which is almost inevitable in the patient with untreated diabetic nephropathy. These data can now be added to the vast array of evidence supporting angiotensin-converting enzyme (ACE) inhibitor use in patients with nephropathy associated with type 1 diabetes. It now appears a safe conclusion that the patient with diabetic nephropathy should receive therapy with an agent that interrupts the renin-angiotensin system. These studies have not resolved the question as to whether an ACE inhibitor or an ARB is the preferred agent in people with nephropathy from type 1 diabetes, though the optimal doses of these drugs remain to be determined. Head-to-head studies comparing ACE inhibitors to ARBs in diabetic nephropathy are not likely to occur, so it is unlikely that comparable information will be forthcoming with ACE inhibitors. An evidence-based therapeutic approach derived from these trials would argue for ARBs to be the foundation of therapy in the patient with type 2 diabetes and nephropathy.
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PMID:Type 2 diabetes: RENAAL and IDNT--the emergence of new treatment options. 1182 41

The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.
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PMID:Angiotensin II receptor blockers for the treatment of hypertension. 1182 17

Irbesartan (SR 47436; BMS-186295) is a selective non-peptide antagonist of angiotensin II type 1 receptor (AT1). Irbesartan inhibits the action of angiotensin II, which acts through the binding to the AT1 receptor. Many experimental and clinical data show that activation of AT1 receptors plays the crucial role in the development of hypertension, hypertrophy of left ventricle, progression of lipid disorders and impairment of renal function. Therefore, the pharmacological intervention with angiotensin II type 1 receptor antagonists could be used as a new therapeutic option in treatment of hypertension and its complications. The advantage of irbesartan is its long lasting blood pressure lowering action and the possibility of taking it once a day. The principle of its action is not only limited to blocking the AT1 receptor, but it also participates in many other reactions of the renin-angiotensin-aldosterone system. According to the reports published, irbesartan and other antagonists of angiotensin II type 1 receptor seem to be a promising complement in the treatment of idiopathic hypertension, especially in patients with heart failure, diabetes and impaired renal function. Several studies showed that in addition to its long blood pressure lowering action (study of Pool, Fogari, Stumlple, Minran)--(possibility of taking the drug once a day), the AT1 antagonists reduced proteinuria (Sica et al.) without decreasing the creatinine clearance, improved the function of endothelium and inhibited the mitogen and proliferative action of angiotensin II on cardio-vascular system (Kahan et al., Tonkon et al., SILVER and ELITE trail).
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PMID:[Irbesartan--antihypertensive treatment in patients with heart failure and diabetes mellitus]. 1218 30


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