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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery of orally active nonpeptide angiotensin II (A II)-receptor antagonists has initiated a growing understanding of the physiologic and pathophysiologic roles of A II. Losartan is the first of the new class of antagonists that block all the well-known effects of A II, including vasoconstriction, aldosterone release, renin release (negative feedback), and the stimulation of thirst. A II-receptor subtypes have been described, with losartan antagonism defining the AT1 subtype and with PD123319 antagonism defining the AT2 subtype. The AT1 receptor is G-protein-coupled, involving PLC, PLA2, PLD, or adenylate cyclase and the release of intracellular calcium. The receptor-response coupling of the AT2 site remains elusive but may involve protein tyrosine phosphatase and subserve an antiproliferative role. Losartan as the prototype of an AT1-selective antagonist: i) inhibits A II binding, ii) antagonizes effects of A II in vivo and in vitro, and iii) lowers blood pressure in models of A II-dependent hypertension A II stimulates growth in vitro (DNA and protein synthesis) and in vivo (cardiac and vascular hypertrophy), and these effects are blocked by losartan. Losartan, like angiotensin-converting enzyme inhibitors, has significant renal, cardiac, and cerebral protective effects in models of renal failure, cardiac failure, and stroke, confirming the pathologic role of A II in these models. The pioneering studies in experimental animals are being confirmed by a growing number of other AT1-selective blockers and provide the basis of use of losartan for hypertension and its clinical trial in other disease states.
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PMID:The diversified pharmacology of angiotensin II-receptor blockade. 891 41

ACE inhibitors have been shown to be effective in reducing the morbidity and mortality of patients with left ventricular systolic dysfunction, but their application to clinical practice in this situation is still limited. In part, the failure to prescribe an ACE inhibitor to a patient with left ventricular systolic dysfunction is due to perceptions regarding their side effects, such as cough and renal dysfunction. Relatively few patients with left ventricular systolic dysfunction and a serum creatinine > or = 2 mg/dl receive an ACE inhibitor in clinical practice. In this situation one should consider an agent such as fosinopril, which is metabolized by the liver as well as secreted by the kidney. In patients with moderate renal dysfunction, fosinopril has been well tolerated without an increase in serum creatinine. In patients who develop cough due to an ACE inhibitor, consideration should be given to an angiotensin II type 1 receptor blocking agent, such as losartan. The relative safety and efficacy of an ACE inhibitor compared with an angiotensin II type 1 receptor blocking agent is being explored in a prospective randomized trial (Evaluation of Losartan In The Elderly [ELITE]), as well as the safety and pharmacological effectiveness of adding an angiotensin II receptor antagonist to an ACE inhibitor (Randomized Angiotensin receptor antagonists-ACE-inhibitor Study [RAAS]). There may also be a role for the combination of an aldosterone receptor antagonists and an ACE inhibitor in patients with left ventricular systolic dysfunction. Once an ACE inhibitor is administered to a patient with left ventricular systolic dysfunction it should be continued indefinitely. ACE inhibitors may be of value not only in preventing the progression of heart failure but also in reversing endothelial dysfunction and preventing the development of atherosclerosis and its consequences, such as myocardial infarction.
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PMID:ACE inhibitors in heart failure: prospects and limitations. 921 Oct 22

Health economy is often addressed in terms of acquisition cost, i.e. the cost of the pill. For various reasons, mainly the stricter demands from drug regulatory agencies (increased development costs), novel agents must be expected to be more expensive than older drugs. However, if the costs of changing therapy and the costs induced by side effects and extra clinic visits are considered, the economic aspects become less of a consideration. If compliance is enhanced and better blood pressure control is achieved with the newer agents, then the therapeutic gains must be weighed against the economic aspects. Losartan, the first agent of the new class of angiotensin II receptor antagonists of the AT1 type, has been available for clinical use for more than 2 years. Losartan has proven antihypertensive effects and its safety profile in the initial controlled trials (approximately 2900 patients) and in general practice (more than 14,000 patients in Sweden) has been very good. Its effect on long-term morbidity and mortality has not yet been established but a large mortality endpoint trial is underway in hypertensive patients with cardiac hypertrophy (the LIFE trial). In heart failure, losartan has been shown to reduce 3-month mortality (the ELITE trial). Although it is too early to assess the full therapeutic benefit of losartan in relation to the total patient costs, its efficacy and low incidence of side effects has made it a useful new therapy for the treatment of hypertension.
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PMID:Medical and cost-economy aspects of modern antihypertensive therapy--with special reference to 2 years of clinical experience with losartan. 928 10

Losartan is a novel orally active nonpeptidal antihypertensive agent that specifically blocks the angiotensin II type 1 receptor. This paper compares the short- and long-term safety and tolerability of losartan with those of placebo. Approximately 3800 patients with mild-to-severe essential hypertension were enrolled in 16 double-masked and 4 open clinical trials worldwide. Of these, approximately 2900 were treated with losartan either alone or in combination with other antihypertensive drugs. These trials included patients with diabetes mellitus (n = 133). An additional 5 trials enrolled hypertensive patients with compromised renal function (n = 115) or heart failure (n = 220). Losartan dosages primarily ranged from 10 to 150 mg once daily, with most patients receiving 50 to 100 mg per day. Hypertension trials generally lasted 12 weeks. The most frequently reported adverse events were headache, upper respiratory tract infection, dizziness, and asthenia/fatigue, but only dizziness occurred more frequently (> or = 1%) in the losartan-treated groups. Cough occurred in 3.1% of patients treated with losartan and 2.6% of patients treated with placebo. The overall incidence of clinical and laboratory adverse events in the losartan- and placebo-treated groups was similar among patients with hypertension and either diabetes mellitus, renal impairment, or heart failure. The data suggest that losartan can be safely administered in hypertensive patients with concomitant illnesses. It can be considered for first-line therapy and is suitable as an alternative therapy in patients already experiencing side effects with other agents.
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PMID:Clinical safety and tolerability of losartan. 937 6

The objective of this article is to give more information about the pharmacology of and recent clinical data on the angiotensin II receptors antagonists. The angiotensin II receptors antagonists, of which Losartan will be the first representative on the Belgian market, constitute a new therapeutic class in the treatment of hypertension and even heart failure. They are non peptic and orally active and their long mechanism of action allows one daily administration to improve therapeutic compliance. These agents block all known effects of the angiotensin II through binding to the AT1 receptors. Thanks to this unique mechanism of action they reduce blood pressure with a lower incidence of the adverse effects commonly associated with other antihypertensives. In controlled clinical trials, overall incidence of adverse experiences was comparable to placebo. Addition of thiazide-type diuretics provides additive efficacy.
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PMID:[The advent of a new class of antihypertensive agents: angiotensin II receptor antagonists]. 941 19

Patients with acute myocardial infarction and evidence of heart failure or left ventricular dysfunction during the acute phase have an excessive mortality risk. Therapy with angiotensin-converting enzyme inhibitors attenuates the detrimental effects of angiotensin II and has been shown to substantially reduce morbidity and mortality in this population. Selective, angiotensin type 1 receptor antagonism with losartan, which inhibits the effects of angiotensin II regardless of its source at the receptor level, may provide more complete blockade of the renin-angiotensin system. The Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) study is a multicenter, double-blind, randomized, parallel, captopril-controlled trial. The primary hypothesis is that, compared with captopril, losartan will decrease the risk for all-cause mortality by 20% in high-risk patients after acute myocardial infarction. The study population will consist of 5,000 patients, > or = 50 years of age, with heart failure during the acute phase or with a new Q-wave anterior infarction or reinfarction. Patients will be randomized to treatment with either losartan or captopril. All patients will be followed until 937 deaths occur (event-driven). The primary end point is total mortality (all-cause mortality). The secondary and tertiary end points are sudden death (and/or resuscitated cardiac death) and fatal/nonfatal reinfarction. Based on the assumed event rate, treatment effect and a 95% power to detect a 20% reduction in all-cause mortality at the 4.3% significance level (2-sided, adjusted for 2 interim analyses), the trial will enroll at least 5,004 patients and continue until a total number of 937 events has been reached (intention-to-treat analysis).
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PMID:Comparison of the effects of losartan and captopril on mortality in patients after acute myocardial infarction: the OPTIMAAL trial design. Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan. 1007 46

Losartan is a potent non-peptide, selective angiotensin II (AngII) type 1 (AT1) receptor antagonist. Losartan has been worldwide marketed as the first orally active AT1 receptor antagonist with once-daily dosing for treatment of hypertension. In a study of patients with heart failure, the mortality appeared to be lower with losartan than with the ACE inhibitor captopril. In healthy subjects, losartan produced a dose-dependent reduction in serum uric acid. The mechanism of action is considered to be the inhibition of reabsorption of uric acid in the proximal tubules of the kidney. Furthermore, it was recently reported that losartan has moderate affinity for the thromboxane (TX) A2 receptor in a competitive-inhibition manner in the platelets and vascular smooth muscle. The efficacy of losartan with regard to not only AT1 receptor blockade, but also the reduction of serum uric acid and the blockade of TXA2 receptors, may be advantageous to patients with hypertension having these cardiovascular risk factors.
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PMID:[Pharmacological properties and its significance in clinical practice]. 1036 45

Acceptance of the notion that physiologically specific interruption of the renin-angiotensin-aldosterone system (RAAS) is of considerable therapeutic benefit in the treatment of hypertension and congestive heart failure has generated great interest in the search for novel pharmacological inhibitors. The RAAS is expressed at the whole body, organ/tissue and cellular level through the action of the octapeptide angiotensin II (Ang II), the primary effector molecule of the RAAS. The availability of selective, potent, orally active and long-acting nonpeptide Ang II type 1 (AT1) receptor antagonists provided the opportunity to obtain the benefits of selectively blocking the RAAS at the level of the AT1 receptor that mediates most, if not all, of the important actions of Ang II, and avoid the nonspecificity of the Ang I converting enzyme (ACE) inhibitors. Losartan was the first, but by no means remained the only nonpeptide AT1 receptor antagonist. Numerous other "sartans" have emerged in the past several years and successfully completed clinical development. With the exception of Eprosartan, all others, i.e. Candesartan, Irbesartan, Saprisartan, Tasosartan, Telmisartan, Valsartan and Zolasartan, are based on modifications of Losartan's prototypic chemical structure. AT1 receptor antagonists represent the newest addition to the arsenal of cardiovascular therapeutics. The predominant role of the AT1 receptor in mediating the pathophysiological role of Ang II underlies the effectiveness of this novel class of agents to lower arterial blood pressure, reduce pre- and afterload, inhibit sympathetic nervous system activity and prevent cardiovascular hypertrophy and cardiac failure induced by inappropriate control of the RAAS.
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PMID:Angiotensin II receptor antagonists: an emerging new class of cardiovascular therapeutics. 1048 32

We evaluate the acute hemodynamic and neurohormonal effects of losartan in 15 patients with symptomatic chronic heart failure (CHF), mean age 72+/-8 years, which were classified in two subgroups: (A) Patients with left ventricular ejection fraction (LVEF)< or =0.35 (n = 7); (B) subjects with LVEF>0.35 (n = 8). Sympathetic reactivity (blood pressure, heart rate and plasma norepinephrine) and plasma endothelin-1 (ET-1) were evaluated by a cold pressor test (CPT). Single doses of losartan (50 mg p.o.) lowered delta DBP in both subgroups (A, 8+/-9 to 0+/-5 mm Hg, P<0.05; B, 10+/-6 to 3+/-4 mm Hg, P<0.05) and attenuated the rise of HR in patients with mild (4+/-6 to -1+/-2 bpm, P<0.05) but not with severe (4+/-5 to 2+/-5 bpm, n.s.) impairment of left ventricular function. Losartan blunted the response (delta) of PNE during CPT (A, 142+/-131 to 10+/-74 pg/ml, P<0.05; B, 129+/-72 to 1+/-144 pg/ml, P<0.01). A significant rise in plasma ET-1 was observed during CPT in patients from subgroup B (0.64+/-0.40 to 0.81+/-0.40 fmol/ml, P<0.05) but not in patients with LVEF< or =0.35 (1.79+/-0.44 to 1.51+/-0.66 fmol/ml, n.s.). Losartan attenuated the rise in ET-1 during CPT in patients with LVEF>0.35 (delta ET-1 0.17+/-0.86 to 0.03+/-0.11 fmol/ml, P<0.05), with no significant changes in subgroup A. Acute effects of losartan were characterized by a more favorable hemodynamic and neurohumoral response in patients with chronic heart failure and preserved systolic ventricular function related to subjects with lower ejection fractions.
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PMID:Effects of the angiotensin II antagonist losartan on endothelin-1 and norepinephrine plasma levels during cold pressor test in patients with chronic heart failure. 1050 44

The Losartan Heart Failure ELITE Study recently found that in patients with symptomatic heart failure and a left ventricular ejection fraction of </=0.40, losartan compared to captopril improved survival with better tolerability. The objective of this study was to perform an economic evaluation of losartan versus captopril based on the results of the Losartan Heart Failure ELITE Study. The Losartan Heart Failure ELITE Study was a multinational, double-blind, randomized 48-week study comparing the safety and efficacy of losartan to captopril in angiotensin-converting enzyme-inhibitor-naive patients >/=65 years with symptomatic heart failure. Data on health care resource utilization were collected as part of the trial. We conducted a cost-effectiveness analysis to estimate the lifetime benefits of treatment and the associated costs. We observed no differences between treatments in the number of hospitalizations, hospital days, and emergency room visits per patient over the trial period. We estimated the total cost of losartan to be USD 54 (95% CI: USD -1,717, USD 1,755) less per patient than captopril over this time frame. We also estimated that over the projected remaining lifetime of the study population, losartan compared to captopril would increase survival by 0.20 years (undiscounted) at an average cost of USD 769 (discounted) more per patient. This cost increase translated into a cost-effectiveness ratio of USD 4,047 per year of life gained for losartan relative to captopril. In patients with symptomatic heart failure, losartan compared to captopril increased survival with better tolerability at a cost well within the range accepted as cost-effective.
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PMID:The cost-effectiveness of losartan versus captopril in patients with symptomatic heart failure. 1051 13


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