Eplerenone for the treatment of cardiovascular disorders

The clinical utility and ultimately guideline recommendations for aldosterone receptor-blocking agents in cardiovascular disorders is clearly mentioned by a number of major clinical outcome trials. This article reviews the pharmacology, clinical efficacy and safety of the two currently available receptor blocking agents: spironolactone and eplerenone. The potential utility of eplerenone and other mineralocorticoid receptor agents beyond current clinical indications will also be examined.     

Eplerenone: a selective aldosterone receptor antagonist for patients with heart failure

OBJECTIVE: To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF). DATA SOURCES: English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles. STUDY SELECTION AND DATA EXTRACTION: Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated. DATA SYNTHESIS: Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence. CONCLUSIONS: The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone-related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.     

Eplerenone--a novel selective aldosterone blocker

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of eplerenone, a new selective aldosterone blocker. DATA SOURCES: Primary literature and review articles were obtained via MEDLINE search (1966-April 2002). Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles related to eplerenone, aldosterone, aldosterone antagonist, and spironolactone were reviewed. Data pertinent to this article were included. DATA SYNTHESIS: Eplerenone is a selective aldosterone blocker. Recent data have demonstrated the deleterious effects of aldosterone in several chronic disease states including hypertension and heart failure. Animal studies using eplerenone have shown a positive role for aldosterone antagonism in the treatment of hypertension, heart failure, myocardial infarction, renal disease, and atherosclerosis. In humans, eplerenone appears to be effective for the treatment of hypertension. An ongoing study will examine the effect of eplerenone for heart failure. To date, the incidence of adverse effects with eplerenone has been slightly lower than with spironolactone. CONCLUSIONS: Eplerenone appears to be a promising drug in a new class of agents called selective aldosterone blockers. The drug may be approved for treatment of hypertension in 2002. Additional studies are ongoing that may provide information on other clinical uses for this medication.     

The cardiovascular effects of eplerenone, a selective aldosterone-receptor antagonist

BACKGROUND: The role of the renin-angiotensin-aldosterone system in the pathophysiology and treatment of hypertension and heart failure has been extensively studied. Angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers have been shown to effectively reduce blood pressure, protect the kidney, and reduce morbidity and mortality in patients with heart failure. Therefore, there is increased interest in the effects of aldosterone and the use of aldosterone-receptor antagonists in the treatment of cardiovascular disease. Eplerenone is the first selective aldosterone-receptor antagonist approved for the treatment of hypertension and left ventricular (LV) dysfunction after acute myocardial infarction (AMI). OBJECTIVE: The goal of this article was to review the pharmacologic properties, clinical efficacy, and tolerability of eplerenone in the treatment of hypertension, LV dysfunction, and proteinuria. METHODS: Relevant English-language articles were identified through searches of MEDLINE (1966-May 2003), Current Contents, and International Pharmaceutical Abstracts (1970-May 2003) using the terms hypertension, heart failure, eplerenone, aldosterone, and aldosterone antagonist. Other pertinent publications were identified from the reference lists of the identified articles. Information was also obtained from abstracts presented at national meetings and data on file with the manufacturer. RESULTS: In clinical trials, eplerenone alone and in combination with renin-angiotensin blockade significantly reduced both systolic and diastolic blood pressure compared with placebo (P < 0.05 to P < 0.001). In EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), the addition eplerenone to optimal medical therapy reduced morbidity and mortality in patients with AMI and LV dysfunction, although the incidence of serious hyperkalemia was also significantly greater. In comparisons with spironolactone, eplerenone was associated with a lower incidence of gynecomastia and other sex hormone-related adverse effects. CONCLUSIONS: Either alone or in combination with other antihypertensive agents, eplerenone appears to be effective for the treatment of hypertension. Morbidity and mortality were reduced when eplerenone was added to standard therapy for LV dysfunction complicating AMI. The use of eplerenone for hypertension or heart failure may be limited in patients at risk for hyperkalemia.     

Aldosteron und Aldosteronrezeptorantagonisten in der Herzinsuffizienztherapie

In addition to the classical effects exerted by aldosterone on water and electrolyte haemostasis, recent data suggest additional roles in the pathophysiology of cardiovascular diseases. Examples are the regulation of blood pressure (by direct aldosterone effects on vessels and the CNS), myocardial hypertrophy and remodelling. Two aldosterone receptor antagonists, spironolactone and eplerenone, are currently available for the long-term therapy of chronic heart failure. Both compounds have clearly demonstrated their efficacy in heart failure treatment in end-point based clinical trials. Spironolactone, in addition to its antagonistic effects on the mineralocorticoid receptor, has anti-androgenic and gestagenic actions which can lead to endocrine side effects. Eplerenone selectively blocks aldosterone receptors and thus lacks adverse effects caused by non-specific steroid receptor blockade. The elimination half-life of eplerenone is shorter than the half-life of the active metabolites of spironolactone. Eplerenone is metabolised by CYP3A4, and pharmacokinetic interactions with inhibitors and inducers of this enzyme have to be considered. Essential for the clinical use of aldosterone antagonists in heart failure is the careful monitoring of potassium levels and renal function. The recommended doses should be followed precisely. Higher doses increase the risk of developing life-threatening hyperkalemia. Particular attention has to be paid to patients with impaired renal function. Aldosterone receptor antagonists should not be used when the glomerular filtration rate is below 50 ml/min.     

The role of aldosterone receptor antagonists in the management of heart failure: An update

The aldosterone receptor antagonists (ARAs) spironolactone (Aldactone) and eplerenone (Inspra) have become part of standard medical therapy for heart failure, having shown clinical efficacy in randomized trials in patients with advanced symptomatic systolic heart failure, postinfarction heart failure with cardiac dysfunction, and systolic heart failure with mild symptoms. The benefits include a lower rate of death. Yet to be answered is whether the two drugs are clinically equivalent; another question is whether they may benefit everyone with symptomatic heart failure, including diastolic heart failure.     

Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases?

Selective non-peptide antagonists for the neurokinin 3 (NK₃) receptor first became available about twenty years ago. Although the understanding of the role of the NK₃ receptor in the brain has been greatly complicated by marked species differences in its distribution and by pharmacological heterogeneity, studies with brain-penetrant non-peptide NK₃ receptor antagonists in animals have indicated that these compounds may find utility in a number of psychiatric diseases, including schizophrenia, anxiety and depressive disorders. However, clinical studies with selective NK₃ receptor antagonists in these psychiatric conditions have been disappointing and they were unable to confirm the promising therapeutic potential from animal studies, thereby questioning the therapeutic utility of these compounds for CNS disorders. The purpose of this article is to provide a critical overview of the available data on NK₃ receptor antagonists in the psychiatry research and development field, by reviewing the behavioral and neurochemical effects of these agents in both preclinical and clinical studies.     

Mineralocorticoid receptor blocker eplerenone improves endothelial function and inhibits Rho-associated kinase activity in patients with hypertension

Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs). The purpose of this study was to evaluate the effects of the selective mineralocorticoid receptor blocker, eplerenone, on endothelial function and ROCK activity in patients with hypertension. The study was carried out over 48 weeks in 60 untreated patients with hypertension who were randomly assigned to eplerenone, nifedipine, and losartan groups. We evaluated the effects of each treatment on flow-mediated vasodilation (FMD) and ROCK activity in peripheral leukocytes. Eplerenone increased FMD and decreased leukocyte ROCK activity. Nifedipine decreased ROCK activity but did not alter FMD. Losartan increased FMD but did not alter ROCK activity. Hypotensive effects were similar in the three groups, as was nitroglycerin-induced vasodilation during the follow-up period. There were no significant differences between the groups with respect to other parameters. The study results show that eplerenone improves endothelial function and inhibits ROCK activity in patients with essential hypertension.     

Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting

Better tolerated and more effective means of controlling chemotherapy-induced nausea and vomiting have been introduced over the past decade. Despite the progress made, incompletely controlled emesis is a persistent problem for significant numbers of patients receiving chemotherapy. Efforts to improve antiemetic control further are ongoing. The most interesting new class of antiemetics under development focuses on antagonism of the neurotransmitter substance P. Substance P exerts its effects by binding to the tachykinin neurokinin NK1 receptor. A number of selective antagonists of the NK1 receptor have been synthesized and, when used in preclinical models, have demonstrated an ability to antagonize the emetic effects of a number of stimuli, including chemotherapy agents such as cisplatin. Over the past 3 years, results of the initial studies evaluating this class of agents for cisplatin-induced emesis in cancer patients have begun to appear. These agents have been well tolerated. As single agents, they appear to be no more effective than 5-HT3 receptor antagonists in preventing acute cisplatin-induced emesis. Their real value may be found in combination with existing agents and in the treatment of delayed emesis. The results of ongoing clinical trials will hopefully define the utility and appropriate place for this new class of agents in the management of chemotherapy-induced nausea and vomiting.     

Aldosterone receptor antagonists for heart failure: current status, future indications

Many patients with heart failure should receive an aldosterone receptor antagonist, ie, either spironolactone (Aldactone) or the newer agent eplerenone (Inspra)--in addition to an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) or both, and a beta-blocker. We review the evidence and indications.     

Eplerenone in the treatment of chronic heart failure

There has been a recent revival of interest in aldosterone receptor antagonists for the treatment of chronic heart failure. This was largely triggered by fresh insights into the role of aldosterone in a number of key pathophysiological processes, including fibrosis and remodeling, inflammation, and the potentiation of catecholamine effects. The therapeutic efficacy of spironolactone (Aldactone), Pfizer) in severe chronic heart failure was established by the Randomized Aldactone Evaluation Study, but hormonal side effects (gynecomastia) associated with the drug posed a problem. More recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study has provided firm support for the use of eplerenone (Inspra, Pfizer) in heart failure following acute myocardial infarction in addition to neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and beta-blockers. This strategy can be expected to benefit both mortality and morbidity. Due to the fact that eplerenone is a selective aldosterone receptor antagonist, it does not cause troublesome hormonal side effects. This is an important feature of the drug that is likely to help maintain compliance.     

依普利酮片治疗轻中度高血压的疗效和安全性

【目的】评估依普利酮片治疗轻、中度原发性高血压的临床疗效和安全性。[方法]本研究为随机、双盲、平行对照的多中心II期临床试验,235例轻、中度高血压患者,随机分为两组：（1）氯沙坦组（n=118）,（2）依普利酮组（n=117）。分别接受氯沙坦和依普利酮治疗,治疗4周后,若血压未达标,药物剂量加倍后继续治疗4周;若血压达标,维持原剂量继续治疗4周。观察两组疗效及不良反应。【结果】治疗8周后：①依普利酮组平均坐位舒张压下降（14．09±7．84）mmHg,收缩压下降（19．77±10．89）mmHg,氯沙坦组分别下降（12．87±8．04）mmHg,（18．63±9．66）mmHg,两组间差异无统计学意义（P均〉0．05）;依普利酮组及氯沙坦组平均坐位血压达标率分别为77．6％和73．50％,降压显效率分别为65．5％和56．6％,总有效率分别为87．9％和82．3％,两组间均无统计学意义（P〉0．05）。②两组的不良事件及不良反应发生率均无显著性差异（P〉0．05）。【结论】依普利酮能有效降压,疗效与氯沙坦相当,且其安全性良好。     

Eplerenone in the treatment of chronic heart failure

There has been a recent revival of interest in aldosterone receptor antagonists for the treatment of chronic heart failure. This was largely triggered by fresh insights into the role of aldosterone in a number of key pathophysiological processes, including fibrosis and remodeling, inflammation, and the potentiation of catecholamine effects. The therapeutic efficacy of spironolactone (Aldactone^®, Pfizer) in severe chronic heart failure was established by the Randomized Aldactone Evaluation Study, but hormonal side effects (gynecomastia) associated with the drug posed a problem. More recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study has provided firm support for the use of eplerenone (Inspra?, Pfizer) in heart failure following acute myocardial infarction in addition to neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and β-blockers. This strategy can be expected to benefit both mortality and morbidity. Due to the fact that eplerenone is a selective aldosterone receptor antagonist, it does not cause troublesome hormonal side effects. This is an important feature of the drug that is likely to help maintain compliance.     

Therapeutic role of vasopressin receptor antagonism in patients with liver cirrhosis

Vasopressin, or antidiuretic hormone, is a peptide hormone that is released from the posterior pituitary gland in response to changes in blood pressure and plasma osmolality. The main pathophysiological states associated with high plasma vasopressin concentrations are cirrhosis, cardiac failure and syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Pharmacological treatments for disorders of excess vasopressin secretion have been limited. However, oral bio-available selective and non-selective V(1) and V(2) receptor antagonists have recently become available for clinical use. Water retention in cirrhosis is a common problem, leading to ascites, peripheral oedema and hyponatraemia. Raised plasma vasopressin concentrations and decreased delivery of glomerular filtrate are believed to be the most important factors in the development of water retention. V(2) receptor antagonists are aquaretic agents that promote water excretion and improve hyponatraemia. Their potential role in cirrhosis has been examined in a number of recent studies that have shown increased free water clearance and serum sodium concentrations with few adverse effects. V(2) receptor antagonists represent a novel and promising new class of agent that may have major clinical utility in the treatment of patients with liver cirrhosis.     

Newer therapeutic agents for asthma

The past decade has seen significant advances in the available treatments for asthma. These include longer-acting bronchodilating agents, high topical potency inhaled corticosteroids, and agents that interfere with leukotriene production or action. Table 3 summarizes the clinical effects of the newer therapeutic agents reviewed. Experimental therapies for the steroid-dependent patient have also been discussed. Although clinical trials to date have established many of these as effective in asthma, the results of ongoing, large, multicenter studies investigating the relative merits of these therapies, alone and in combination, will further clarify how to maximize the utility of these agents in the treatment of asthma.     

Rebound platelet activation after termination of prasugrel and aspirin therapy due to confirmed non-compliance in patient enrolled in the JUMBO Trial

Therapy with aspirin and/or adenosine diphosphate (ADP) receptor blockers is associated with better outcomes via inhibition of platelet activity, and subsequent reduction of ischemic vascular events. Non-compliance (NC) is a well-recognised hazard limiting the clinical utility of antiplatelet agents, and, probably worsening outcomes. However, comprehensive platelet characteristics of a confirmed NC patient after acute vascular event have never been reported within a major randomised trial with ADP-receptor antagonists. A 48-year-old male patient, well-educated, was among patients enrolled in the platelet sub-study for the JUMBO trial. He received 325 mg of aspirin daily for 9 months, presented with unstable angina for urgent coronary intervention, and was successfully reperfused with two intracoronary stents. The patient was randomised to a 60 mg prasugrel loading dose, and 10 mg of prasugrel daily for 30 days. Platelets were assessed at baseline, 4 and 24 h, and at 30 days after acute coronary event utilising ADP-, and collagen-induced conventional aggregometry, rapid cartridge-based analyser and flow cytometry. Loading with prasugrel resulted in significant inhibition of platelet activity during and after stenting. However, after assessing platelet biomarkers at 30 days, voluntary withdrawal from the antiplatelet agents was suspected. Based on the platelet activity characteristics, NC was later confirmed, and the patient admitted that he stopped taking both prasugrel and aspirin shortly after discharge due to minor bleeding episodes after shaving. Major platelet activity biomarkers of the index NC patient were compared with those from compliant prasugrel-, clopidogrel-treated patients, and healthy controls. The platelet tests uniformly revealed rebound activation by all platelet measures (at least twofold increase) while being especially high for ADP-, and collagen-induced aggregation, platelet/endothelial cell adhesion molecule-1 (PECAM-1), glycoprotein (GP)Ib, GPIIb/IIIa activity, P-selectin, protease activated receptor (PAR)-1 thrombin receptor (activated and intact epitopes), and thrombospondin expression. The clinical benefits of antiplatelet agents are not only denied in NC outpatients, but may put them at additional risk for worsened vascular outcomes due to the rebound platelet activation. Proclaimed 'resistance' to antiplatelet agents may at least in part be a result of NC, especially in the chronic uncontrolled setting. Enforcing compliance will improve outcomes in the clinical trials, and save lives of patients really receiving antiplatelet therapy.     

醛固酮与转化生长因子-β1在心肌纤维化中的作用机制

目的探讨醛固酮与转化生长因子-β1（TGF-β1）在心肌纤维化的作用机制。方法将体外培养的心肌成纤维细胞（CFs）分为对照组、醛固酮组、醛固酮＋依普利酮组、依普利酮组及SB431542预处理组。给予相应处理后,ELISA检测TGF-β1水平,RT-PCR检测Smad2、Ⅰ型胶原、Ⅲ型胶原表达。结果与对照组比较,醛固酮处理后,能显著促进TGF-β1分泌,促进Smad2、Ⅰ型胶原、Ⅲ型胶原表达（P〈0.01）;与醛固酮组比较,醛固酮＋依普利酮组TGF-β1分泌、Smad2、Ⅰ型胶原、Ⅲ型胶原表达均明显下降（P〈0.01）;与醛固酮组比较,SB43l542预处理组抑制Smad2、Ⅰ型胶原和Ⅲ型胶原表达的差异有统计学意义（P〈0.01）。结论醛固酮通过激活MR促进CFs细胞TGF-β1分泌,激活Smad2,使Ⅰ型胶原、Ⅲ型胶原表达增加,诱导心肌纤维化。     

The quinolones: decades of development and use

The discovery of nalidixic acid in 1962, and its introduction for clinical use in 1967, marks the beginning of five decades of quinolone development and use. It was not until the discovery and licensing of the fluoroquinolones in the 1970s and 1980s that these drugs began to establish their place in the armamentarium of clinically useful antimicrobials. At the beginning of the 21st century, in their fifth decade of discovery and use, our understanding of structure-function relationships has improved, and better compounds, in terms of both spectrum of antimicrobial cover and pharmacokinetics, have been developed. The clinical utility of this expanding class of antimicrobial agents, and the lower propensity for the development of resistance with the "newer" fluoroquinolones will need to be continually monitored in the changing therapeutic environment. Antibiotic drug choice will remain difficult in the presence of increasing resistance, but the introduction of the new fluoroquinolones has created a new and exciting era in antimicrobial treatment. The role of these agents has already been acknowledged in a number of clinical guidelines, and appropriate use of these agents may help to preserve their clinical utility, enabling them to realize their full therapeutic potential.