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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We characterised the blood pressure (BP) and hormonal responses to the oral angiotensin II (Ang II) receptor antagonist irbesartan (SR47436/BMS-186295) or placebo in normal men with an activated renin-angiotensin system (RAS) during salt depletion. We also evaluated safety and tolerability. Twelve healthy, normotensive male volunteers followed a standardised salt-depletion regimen for 3 days before each study day. Six different single oral doses of irbesartan (1, 5, 10, 25, 50, and 100 mg) were administered double-blind in a three-panel, dose escalation with placebo randomised in each panel. Supine and erect BP and heart rate (HR), serum and urinary electrolytes: plasma renin activity (PRA), and Ang II were measured at intervals. Urinary electrolytes were measured for the 24-h period before dosing (to confirm salt depletion) and for 24 h afterward. No drug-related side effects were noted. There was a dose-related decrease in supine and erect systolic and diastolic BP (SBP, DBP) with irbesartan from 10 mg and beyond, with no change in HR. Supine mean arterial pressure (MAP) decreased by 18.8 mm Hg. There was a dose-related reactive increase in PRA (to 35 ng/ml/h) and Ang II (to 450 pg/ml) with irbesartan. Irbesartan is an orally active AT1 receptor antagonist. In salt-deplete normal men, it has a dose-related haemodynamic, hormonal, and electrolyte profile characteristic of AT1 antagonists. The dose range studied did not show a plateau or maximum effect.
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PMID:Dose-ranging study of the angiotensin II receptor antagonist irbesartan (SR 47436/BMS-186295) on blood pressure and neurohormonal effects in salt-deplete men. 879 43

Inhibition of the angiotensin-converting enzyme (ACE) in the setting of chronic left ventricular (LV) dysfunction has been demonstrated to have beneficial effects on survival and symptoms. However, whether ACE inhibition has direct effects on myocyte contractile processes and if these effects are mediated primarily through the AT1 angiotensin-II receptor subtype remains unclear. The present project examined the relationship between changes in LV and myocyte function and beta adrenergic receptor transduction in four groups of six dogs each: (1) Rapid Pace: LV failure induced by chronic rapid pacing (4 weeks; 216 +/- 2 bpm); (2) Rapid Pace/ACEI: concomitant ACE inhibition (ACEI: fosinopril 30 mg/kg b.i.d.) with chronic pacing; (3) Rapid Pace/AT1 Block: concomitant AT1 Ang-II receptor blockade [Irbesartan: SR 47436(BMS-186295) 30 mg/kg b.i.d.] with chronic pacing; and (4) CONTROL: sham controls. With Rapid Pace, the LV end-diastolic volume increased by 62% and the ejection fraction decreased by 53% from control. With Rapid Pace/ACEI, the LV end-diastolic volume was reduced by 24% and the ejection fraction increased by 26% from Rapid Pace only values. Rapid Pace/AT1 Block did not improve LV geometry or function from Rapid Pace values. Myocyte contractile function decreased by 40% with Rapid Pace and increased from this value by 32% with Rapid Pace/ACEI. Rapid Pace/AT1 Block had no effect on myocyte function when compared with Rapid Pace values. With Rapid Pace/ACEI, beta receptor density and cyclic AMP production were normalized and associated with an improvement in myocyte beta adrenergic response compared with Rapid Pace only. Although Rapid Pace/AT1 also normalized beta receptor density, cyclic AMP production was unchanged and myocyte beta adrenergic response was reduced by 15% compared with Rapid Pace only. ACE inhibition with chronic rapid pacing improved LV and myocyte geometry and function, and normalized beta receptor density and cyclic AMP production. However, AT1 Ang-II receptor blockade with chronic rapid pacing failed to provide similar protective effects on LV and myocyte geometry and function. These unique findings suggest that the effects of ACE inhibition on LV geometry and myocyte contractile processes in the setting of developing LV failure are not primarily caused by modulation of AT1 Ang-II receptor activation.
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PMID:Angiotensin-converting enzyme inhibition and angiotensin II subtype-1 receptor blockade during the progression of left ventricular dysfunction: differential effects on myocyte contractile processes. 939 80

Irbesartan is an angiotensin II receptor (AT1 subtype) antagonist that has been extensively studied in the Bristol-Myers Squibb/Sanofi clinical development program. As shown in seven placebo controlled clinical trials, irbesartan provides clinically significant dose related reductions in blood pressure in patients with mild-to-moderate hypertension. Once daily dosing provides full 24 h blood pressure control with blood pressure reductions equivalent to those of twice daily dosing, and long-term control with monotherapy in a high percentage of patients. The antihypertensive effect of irbesartan is comparable to or exceeds that of leading antihypertensive agents. Whereas irbesartan demonstrates a relationship between dose and antihypertensive effect, there is no such relationship between dose and rates of adverse events or discontinuations due to adverse events, the incidence of which are comparable to those with placebo. Thus, irbesartan provides significant dose related antihypertensive effects with placebo-like tolerability.
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PMID:Clinical overview of irbesartan: a new angiotensin II receptor antagonist. 943 76

In 10 healthy normotensive volunteers on a normal sodium diet, we evaluated the renal effects of a single oral dose of 50 mg of irbesartan (SR 47436, BMS 186295), an angiotensin II AT1-receptor antagonist, in baseline conditions and during an exogenous angiotensin II infusion (2.5 ng/kg/min). We used a double-blind, placebo-controlled, crossover design. Hormones, blood pressure, renal hemodynamics, and urinary electrolytes were measured during each phase. To examine further the determinants of glomerular filtration at the microcirculation level, fractional clearance of neutral dextran was performed, and sieving curves were applied on a hydrodynamic model of ultrafiltration. Irbesartan administration was followed by an increase in active renin and plasma angiotensin II concentrations and renal plasma flow without change of systemic blood pressure, glomerular filtration rate, or plasma aldosterone concentration. Irbesartan did not affect either sieving curves or glomerular ultrafiltration determinants. Angiotensin II infusion at 2.5 ng/kg/min elicited a slight pressor response accompanied by a decrease in glomerular filtration rate and renal plasma flow and an enhancement of fractional dextran clearance over the radius range explored (3.4-5.4 nm). The transcapillary glomerular pressure gradient deltaP and the ultrafiltration coefficient kf were computed to increase by 9% and to decrease by 23%, respectively, without change in intrinsic membrane properties. Pretreatment with irbesartan prevented all these effects of angiotensin II.
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PMID:Acute renal effects of AT1-receptor blockade after exogenous angiotensin II infusion in healthy subjects. 947 75

The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of the angiotensin II (AII) AT1 blocker irbesartan were assessed in healthy subjects. In this single-center, placebo-controlled, double-blind within dose group, sequential, dose-ascending study, 48 men were randomized to receive irbesartan at doses of 150 mg, 300 mg, 600 mg, or 900 mg daily. Subjects received a single dose of irbesartan (n = 9 per group) or placebo (n = 3 per group), followed by 3 days of placebo, and then multiple doses of irbesartan or placebo once daily for 7 days. The values for plasma area under the concentration-time curve (AUC) of irbesartan were dose proportional up to 600 mg. There were no significant differences between the dose groups in time to maximum concentration (tmax) or half-life (t1/2) after single and multiple doses. After multiple doses, urinary recovery was significantly lower in the 600-mg and 900-mg dose groups compared with the 150-mg and 300-mg dose groups. Steady-state concentrations of irbesartan were achieved within 3 days of administration with no clinically important accumulation. Irbesartan produced dose-dependent increases in plasma renin activity and AII levels. Irbesartan was well tolerated at doses from 150 mg to 900 mg daily; a maximally tolerated dose was not reached. Modest decreases in blood pressure without orthostatic symptoms were observed at irbesartan doses of 300 mg or higher. These results demonstrated the dose-proportionality of irbesartan 150 mg to 600 mg and indicated that doses up to 900 mg daily were well tolerated.
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PMID:Pharmacokinetics and pharmacodynamics of irbesartan in healthy subjects. 954 63

Two multicenter, double-blind, placebo-controlled, parallel group studies were conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of the angiotensin II receptor (AT1 subtype) antagonist irbesartan. The effect of irbesartan withdrawal and the effect of adding hydrochlorothiazide (HCTZ) to irbesartan were also assessed. After a placebo lead-in phase, all patients were randomized to 8 weeks of double-blind therapy with either placebo (n = 158) or irbesartan at doses of 1, 5, 10, 25, 50, 100, 200, or 300 mg (n = 731 total) orally once daily. Irbesartan reduced blood pressure in a dose-related manner. Reductions from baseline in trough seated diastolic blood pressure ranged from 7.5 mm Hg for 50 mg irbesartan to 11.6 mm Hg for 300 mg irbesartan. At week 8, statistically significant reductions over placebo were observed in trough seated blood pressure with all irbesartan doses > or = 50 mg. These reductions reached statistical significance versus placebo within 2 weeks with 100, 200, and 300 mg irbesartan. Plasma irbesartan concentrations correlated with dose. Angiotensin II and aldosterone levels generally showed dose-related changes, consistent with AT1 receptor blockade. In patients not controlled at 8 weeks, the addition of 12.5 mg HCTZ resulted in further dose-related reductions in blood pressure. Irbesartan demonstrated a placebo-like safety profile and no dose-related toxicity. Irbesartan, administered alone or in combination with HCTZ, was well tolerated. Withdrawal of irbesartan did not result in rebound hypertension or adverse events. Thus, once-daily irbesartan is both an effective and safe antihypertensive agent for the treatment of mild-to-moderate hypertension.
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PMID:Dose-related antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension. 960 85

Angiotensin AT1 receptor antagonists represent a novel class of cardiovascular drugs. In conscious, normotensive rats, irbesartan ((2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non) and losartan ((2 n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl -4-yl) methyl] imidazol), two specific, high- affinity angiotensin AT1 receptor antagonists administered intravenously (i.v.) at doses of 0.3, 1, 3 and 10 mg/kg body weight, or orally (p.o.) at doses of 1, 3, 10 and 30 mg/kg body weight, antagonized the pressor responses to i.v. angiotensin II (50 ng/kg body weight) in a dose-related manner and with similar potency. In the following sets of experiments, we tested the hypothesis that these angiotensin AT1 receptor antagonists, when applied systemically, can inhibit the effects of angiotensin AT1 receptor stimulation in the brain. Irbesartan and losartan were administered i.v. or p.o. at doses of 3, 10, 30 and 100 mg/kg body weight. The responses to 100 ng angiotensin II injected into the lateral brain ventricle (i.c.v.), namely blood pressure increase, vasopressin release into the circulation and drinking, were recorded for up to 3 h. While both angiotensin AT1 receptor antagonists dose-dependently attenuated the pressor responses to central angiotensin AT1 receptor stimulation to a similar degree (maximal inhibition, irbesartan: 62% i.v., 39% p.o.; losartan: 62% i.v., 46% p.o.; respectively), irbesartan was more effective with respect to the inhibition of vasopressin release (76% i.v., 65% p.o.) and drinking (63% i.v., 79% p.o.) than losartan (58% i.v., 33% p.o and 22% i.v., 56% p.o., respectively). We conclude that systemically administered angiotensin AT1 receptor antagonists have access to central angiotensin receptors. The degree of central angiotensin AT1 receptor blockade following peripheral application may vary between different representatives of this class of drugs.
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PMID:Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats. 1007

Irbesartan is a novel AT1 subtype angiotensin II receptor antagonist. Blockade of AT1 receptors by irbesartan is not competitive, but "insurmountable". The drug inhibits in a significant dose-dependent manner the maximal contractile response that can be induced by angiotensin II in isolated strips of rabbit aorta. Even high doses of angiotensin II are unable to overcome the AT1 specific receptor blockade. The drug is directly active and requires no prior biotransformation. Its bioavaility after oral administration is excellent (60-80%) and is not altered by meals. The maximal hypotensive effect is measured 3-6 h after intake. The long half life (11-15 h) allows administration in one single daily dose. Irbesartan is registered in Belgium fot the treatment of essential arterial hypertension only. The hypotensive clinical effects, present from the start, become obvious after 1-2 weeks and maximal after 4-6 weeks. The usual daily dose is 150 mg. If needed, it can be increased up to 300 mg/day or, else, be decreased to 75 mg daily in the dialysed or aged patient. Side effects are negligible.
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PMID:[Drug clinics. Drug of the month. Irbesartan (Aprovel)]. 1022 Oct 67

A lot of evidence points to the important role of the renin-angiotensin system in the physiopathology of hypertension and the progression of chronic renal failure. In this review, the authors report the data concerning the protective effects of antagonists of angiotensin II AT1 receptors (AT1ra). The AT1 ra have been shown to have beneficial effects in most experimental models of nephropathy in which they have been tested (renal ischaemia, essential or induced hypertension, glomerulonephritis, 5/6 nephrectomy, renal transplantation, induced diabetes, toxic and radiotherapy-induced nephropathy). Clinical trials confirm these beneficial effects. In healthy subjects and hypertensive patients, the AT1 ra have identical effects to those of angiotensin converting enzyme (ACE) inhibitors on renal haemodynamics. In hypertensives, Candesartan and Irbesartan increase renal blood flow and the glomerular filtration rate and decrease the filtration fraction. Two studies have also shown that Candesartan and Irbesartan reduce proteinuria in diabetic patients. Similar results have been reported in essential hypertension with renal failure. These data suggest that AT1 ra have beneficial effects on the progression of experimental kidney disease and on proteinuria in the clinical setting. Of the pharmacological agents available for use in this class, it is essential to propose molecules whose efficacy in antagonising the effects of angiotensin II lasts throughout the 24 hour period. Clinical trials are under way to evaluate the effects of AT1 ra on renal function in man over a long period.
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PMID:[Are the antagonists of angiotensin II AT1 receptors protectors of the kidney?]. 1044 11

Multiple factors are involved in thrombus formation and require complex and highly therapeutic strategies. Platelet activation plays a critical role in the genesis of acute coronary syndromes involving not only platelets but also endothelial cells, leucocytes and erythrocytes. Angiotensin II (Ang II) is a vasoconstrictor that could participate in the thrombotic process. Platelets also express Ang II AT1 type receptors on their surface. Losartan is a non-peptidic inhibitor of AT1 receptors. It has been demonstrated that losartan reduced platelet aggregation induced by the thromboxane A2 (TXA2) analogue U46619. This effect was not observed with the losartan metabolite EXP 3174. The effect of losartan was assessed in binding studies in which losartan competitively inhibited the binding of [3H]U46619 to platelets in a dose-dependent manner. Irbesartan also inhibits the TXA2 receptor in platelets, an effect that was not obtained with the active form of candesartan, CV11974, and with valsartan. These results suggest that the structural requirements necessary to antagonize the TXA2/PGH2 platelet receptor may be different from those involved in AT1 receptor antagonism. The in vivo relevance of the in vitro findings has been confirmed by the fact that in vivo administration of losartan decreases P-selectin expression in platelets obtained from stroke-prone spontaneously hypertensive rats.
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PMID:Angiotensin II AT(1) receptor antagonists and platelet activation. 1136 20


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