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

The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.Cl and milrinone at A1 adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A1 adenosine receptors, all compounds inhibited 3H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations. As judged from the K1-values, the rank order of potency was saterinone greater than sulmazole greater than UD-CG 212.Cl greater than milrinone. The new inotropic agents also displaced the binding of 3H-QNB at m-cholinoceptors. Except for saterinone, the concentration ranges of mean Ki-values were considerably higher at m-cholinoceptors than at A1 adenosine receptors. The rank order of potency was saterinone greater than sulmazole greater than UD-CG 212.Cl greater than milrinone. Competition of the A1 adenosine receptor agonist R-PIA to 3H-DPCPX-binding showed a biphasic curve with a shallow slope (Hill coefficient nH = 0.63) and revealed two affinity states of the A1 adenosine receptor. In the presence of guanine nucleotides [Gpp(NH)p], the competition curve showed one low affinity class of binding sites and was shifted to the right. In contrast, the competition curves of the new inotropic agents were characterized by a monophasic, steeper slope (mean Hill coefficient nH = 0.98). Guanine nucleotides had no effect. Similar results were obtained with saterinone and carbachol at m-cholinoceptors. Competition with carbachol revealed three affinity states of the m-cholinoceptor, the super-high affinity binding was reversed by Gpp(NH)p. Competition with saterinone revealed one class of binding sites which was not influenced by Gpp(NH)p.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium. 239 60

Sympathomimetic stimulation, angiotensin II, or endothelin-1 is considered to be an essential stimulus mediating ventricular hypertrophy. Adenosine is known to protect the heart from excessive catecholamine exposure, reduce production of endothelin-1, and attenuate the activation of the renin-angiotensin system. These findings suggest that adenosine may also attenuate myocardial hypertrophy. To verify this hypothesis, we examined whether activation of adenosine receptors can attenuate cardiac hypertrophy and reduce the risk of heart failure. Our in vitro study of neonatal rat cardiomyocytes showed that 2-chloroadenosine (CADO), a stable adenosine analogue, inhibits protein synthesis of cardiomyocytes induced by phenylephrine, endothelin-1, angiotensin II, or isoproterenol, which were mimicked by the stimulation of adenosine A1 receptors. For our in vivo study, cardiac hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6 male mice. Four weeks after TAC, both heart to body weight ratio (6.80+/-0.18 versus 8.34+/-0.33 mg/g, P<0.0001) as well as lung to body weight ratio (6.23+/-0.27 versus 10.03+/-0.85 mg/g, P<0.0001) became significantly lower in CADO-treated mice than in the TAC group. Left ventricular fractional shortening and left ventricular dP/dtmax were improved significantly by CADO treatment. Similar results were obtained using the selective adenosine A1 agonist N6-cyclopentyladenosine (CPA). A nonselective adenosine antagonist, 8-(p-sulfophenyl)-theophylline, and a selective adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine, eliminated the antihypertrophic effect of CADO and CPA, respectively. The plasma norepinephrine level was decreased and myocardial expression of regulator of G protein signaling 4 was upregulated in CADO-treated mice. These results indicate that the stimulation of adenosine receptors attenuates both the cardiac hypertrophy and myocardial dysfunction via adenosine A1 receptor-mediated mechanisms.
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PMID:Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model. 1456 7

In heart failure, as the heart gets worse, often so do the kidneys, complicating the treatment of heart failure and worsening the prognosis. This article addresses challenges in the use of diuretics, angiotensin-converting enzyme (ACE) inhibitors, and other therapies in the cardiorenal syndrome, as well as novel therapies that hold promise, such as arginine vasopressin antagonists, adenosine A1 receptor antagonists, and ultrafiltration.
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PMID:Addressing the challenges of cardiorenal syndrome. 1684 71

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at Heart Rhythm 2007 organised by the Heart Rhythm Society which was held in Denver, USA and Heart Failure 2007 organised by the Heart Failure Association of the European Society of Cardiology which was held in Hamburg, Germany. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication. The CARISMA study suggests that non-invasive screening tests may help to identify post-MI patients who may benefit from ICD therapy. Data from the PREPARE study show that more conservative ICD programming can reduce morbidity at the cost of an increased risk of arrhythmic syncope. DAVID II indicates that atrial pacing may be a safe alternative to ventricular back-up pacing in patients with left ventricular dysfunction and standard indications for an ICD. The incidence of persistent atrial fibrillation in patients with sinus node disease in SAVE-PACE was reduced by dual chamber minimal ventricular pacing compared to conventional dual chamber pacing. The pilot phase of the PROTECT studies confirmed 30 mg as the dose of the selective A1 adenosine receptor antagonist KW-3902 to be used in pivotal studies. AREA-IN-CHF failed to show a beneficial effect of canrenone on LV volumes compared to placebo however some beneficial effects on secondary clinical endpoints were observed.
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PMID:Clinical trials update from Heart Rhythm 2007 and Heart Failure 2007: CARISMA, PREPARE, DAVID II, SAVE-PACE, PROTECT and AREA-IN-CHF. 1764 12

Acute decompensated heart failure (ADHF), generally related to signs and symptoms of volume overload, is one the most common reasons for hospitalization in the United States. Recently, it has been observed that the majority of patients with ADHF have baseline renal dysfunction. Moreover, heart failure (HF) treatment is limited by worsening renal function despite persistent volume overload. This connection between HF and renal dysfunction has been termed the cardiorenal syndrome and has made treatment of patients with stable and unstable HF challenging. Selective adenosine A1 receptor antagonists are novel pharmacologic agents that are currently under development to treat volume overload in HF while protecting or possibly improving renal function. In this article, we review the cardiorenal syndrome, the role of adenosine in renal function, and emerging data regarding the safety and efficacy of adenosine A1 receptor antagonists in patients with advanced HF.
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PMID:Role of adenosine antagonism in the cardiorenal syndrome. 1903 79

The majority of patients with acute decompensated heart failure are admitted with symptoms of congestion. The classic symptoms of "congestive" heart failure reflect fluid overload, that is, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema; these symptoms can be so dramatic that it is not surprising that patients seek hospitalization. Activation of the renin angiotensin system coupled with sympathetic hyperactivity results in marked sodium retention and high filling pressures that ultimately bring about these congestive symptoms. The treatment goal of patients hospitalized with volume overload and high filling pressures is to improve symptoms by normalizing the filling pressure and volume status without worsening renal function. The current use of diuretics, vasodilators, and ultrafiltration, as well as potential future use of investigational agents such as oral vasopressin antagonists and adenosine A1-receptor antagonists, is surrounded by the important issues of when to stop intravenous therapy in hospitalized patients and the exact mechanism by which the filling pressures are normalized. New data from evidence-based clinical trials and optimal strategies for monitoring fluid overload will help define this issue and ultimately reduce mortality in these patients.
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PMID:Inpatient management of patients with volume overload and high filling pressures. 1908 92

Rolofylline (KW-3902 or MK-7418) is an adenosine A1-receptor antagonist that exerts its effect by blocking adenosine-mediated constriction of the afferent glomerular arteriole. By blocking A1 receptors, rolofylline increases the glomerular blood flow and filtration and inhibits sodium reabsorption in the proximal tubule, thereby enhancing natriuresis and diuresis. Early phase clinical research data provided the proof-of-concept of an incremental effect beyond standard diuretic therapy. A large Phase III program is currently ongoing for the intravenous formulation of rolofylline in the treatment of acute heart failure.
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PMID:Rolofylline (KW-3902): a new adenosine A1-receptor antagonist for acute congestive heart failure. 1980 90

Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute decompensated heart failure and renal function impairment. The 30-mg dose of rolofylline administered by intravenous infusion over 4 hours for 3 days represented the anticipated recommended clinical regimen of rolofylline. This was a randomized, double-blind, double-dummy, placebo-controlled, three-period crossover study performed with a single 2-hour intravenous infusion of 60 mg rolofylline, placebo, or oral moxifloxacin in healthy subjects. Plasma samples were collected for determination of rolofylline, M1-trans, and M1-cis pharmacokinetic parameters. The upper limit of the two-sided 90% confidence interval for the placebo-adjusted least squares mean change from baseline in QTcF interval for rolofylline was less than 5 msec at every time point. Moxifloxacin demonstrated an increase in QTcF of greater than 10 msec at 2, 2.5, and 3 hours postdose, thus establishing the sensitivity of the assay to detect modest increases in QTcF interval. Mean Cmax values of 1947.4, 739.2, and 54.8 nM were attained for rolofylline and its metabolites M1-trans and M1-cis, respectively, which were 2.2- to 3.1-fold higher than historic Cmax values seen at the anticipated clinical dose and regimen. Adenosine A1 receptor antagonism from a single supratherapeutic intravenous dose of 60 mg rolofylline over 2 hours was generally well tolerated and did not prolong the QTcF interval relative to placebo.
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PMID:A single supratherapeutic dose of rolofylline does not prolong the QTcF interval in healthy volunteers. 2002 5

Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute decompensated heart failure and renal function impairment. This was a phase I, randomized, open-label, 2-period, fixed-sequence study in 19 healthy adult volunteers to examine the effect of multiple intravenous rolofylline doses on the single-dose pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. In period 1, subjects received a single oral dose of midazolam 7.5 mg on day 1. In period 2, subjects received 30 mg, 4-hour infusions of rolofylline (intended clinical dose and duration) once daily for 4 consecutive days; midazolam 7.5 mg was coadministered on day 4. The geometric mean ratios and 90% confidence intervals for AUC0-infinity and Cmax of midazolam in the presence/absence of rolofylline were 1.20 (1.12-1.29) and 1.17 (1.03-1.32), respectively. The apparent terminal half-life (t1/2) for midazolam was similar in the presence/absence of rolofylline (4.31 and 4.27 hours, respectively). The geometric mean ratios (90% confidence intervals) for AUC0-infinity and Cmax of 1'-hydroxymidazolam in the presence/absence of rolofylline were 1.04 (0.96-1.13) and 0.98 (0.84-1.14), respectively. The t1/2 for 1'-hydroxymidazolam was slightly higher in the presence relative to absence of rolofylline (4.24 and 3.17 hours, respectively). Multiple doses of intravenous rolofylline 30 mg for 4 days were generally well tolerated and did not result in clinically important inhibition of CYP3A4 as indicated by little or no change in the pharmacokinetics of midazolam.
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PMID:The effects of multiple doses of rolofylline on the single-dose pharmacokinetics of midazolam in healthy subjects. 2002 8

Selective adenosine A1 receptor antagonists targeting renal microcirculation are novel pharmacologic agents that are currently under development for the treatment of acute heart failure as well as for chronic heart failure. Despite several studies showing improvement of renal function and/or increased diuresis with adenosine A1 antagonists, particularly in chronic heart failure, these findings were not confirmed in a large phase III trial in acute heart failure patients. However, lessons can be learned from these and other studies, and there might still be a potential role for the clinical use of adenosine A1 antagonists.We review the role of adenosine A1 receptors in the regulation of renal function, and emerging data regarding the safety and efficacy of A1 adenosine receptor antagonists based on all available completed and reported clinical trials using A1 adenosine receptor antagonists. The majority of trials were done in heart failure patients. However, there is clear clinical evidence for a role of this new class in hepatorenal syndrome, hypotension on dialysis, and radiocontrast media-induced nephropathy.
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PMID:Adenosine A1 receptor antagonists in clinical research and development. 2059 13


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