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Biomedical subjects

John A Farmer

Publications and source records attributed to John A Farmer.

At least 19 recordsLinked to original sources
PubMed2006

Optimal low-density lipoprotein levels: evidence from epidemiology and clinical trials.

Aggressive lipid lowering was initially controversial due to evidence from epidemiologic studies that implied an increase in total mortality with low cholesterol levels combined with equivocal results from early trials utilizing bile acid resins or fibric acid derivatives. The advent of statin therapy allowed significant reductions of circulating lipid levels and clearly reduced cardiovascular morbidity and mortality. Additionally, in adequately powered trials, total mortality was also reduced. The optimal level of circulating low-density lipoprotein (LDL) has not been definitely established. However, recent clinical trials with aggressive lipid goals have established that LDL cholesterol can be significantly lowered below 100 mg/dL with improvement in both surrogate measurements and hard clinical endpoints. Ongoing clinical trials have been initiated that will determine the optimal level of LDL cholesterol that will insure cardiovascular benefits and establish the risk-benefit relationship of aggressive pharmacologic lowering of circulating lipid levels.

Cardiovascular Diseases↗
PubMed2006

Drug insight: the role of statins in combination with ezetimibe to lower LDL cholesterol.

The cardiovascular benefits of therapy with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are well documented. Undertreatment of dyslipidemia remains pervasive, however, and the introduction of more-aggressive optional LDL-cholesterol targets in US guidelines only heightens the challenges of reaching the target values. Combination therapy with a statin and the cholesterol absorption inhibitor ezetimibe could help in the management of patients who have an inadequate reduction in cholesterol after making changes to lifestyle or taking statins alone. The effects of the combination on cardiovascular risk remain speculative, however, and clinical trials are in development. In this Review we consider the rationale for combination therapy in the context of achieving LDL-cholesterol goals.

Anticholesteremic Agents↗
PubMed2005

Raising high-density lipoprotein cholesterol: innovative strategies against an old adversary.

The lipid hypothesis, which was proposed over 100 years ago, is based on the premise that dyslipidemia is central to the process of atherosclerosis. Low-density lipoprotein and lipoprotein(a) are clearly atherogenic, whereas the role of very low-density lipoprotein as an independent factor is controversial. The only lipoprotein that is clearly antiatherogenic is high-density lipoprotein (HDL), which is thought to reduce coronary risk by mediating cholesterol efflux from the periphery by way of transportation to the liver for excretion. Traditionally, fibric acid derivatives and nicotinic acid were the major pharmacologic agents used to raise circulating levels of HDL. Recent therapeutic advances have been made in the ability to increase HDL. Apolipoprotein A-I Milano and cholesterol ester transfer protein represent novel approaches to the pharmacologic therapy of individuals with low HDL levels. The mechanisms and clinical implications of these interventions are discussed here.

Animals↗
PubMed2005

Simvastatin decreases myocardial tumor necrosis factor alpha content in heart transplant recipients.

BACKGROUND: Statins improve patient survival and decrease rejection episodes in heart transplant recipients. We studied the effects of simvastatin treatment on myocardial tumor necrosis factor alpha (TNF-alpha) expression; TNF-alpha is a potent pro-inflammatory cytokine associated with hypertrophy and fibrosis in heart transplant recipients. METHODS: We randomized 10 consecutive heart transplant recipients to receive either 20 mg/day simvastatin (n = 5) or placebo (n = 5) for 6 months after cardiac transplantation. Routine surveillance endomyocardial biopsy specimens were obtained from all patients. We analyzed tissues for myocardial TNF-alpha content, total collagen content, and myocyte size using semiquantitative immunohistochemistry. RESULTS: Myocyte size and total collagen content of placebo and simvastatin groups did not show a statistically significant difference at any biopsy time point. Myocardium TNF-alpha content (% tissue area stained) at 1 week after transplantation was similar in the simvastatin and placebo groups. At the 24(th) week after transplantation, when compared with Week 1 values, we found a significant decrease in myocardium TNF-alpha content in the simvastatin group (15.0% +/- 2.3% vs 5.8% +/- 2.4%, p = 0.02) that was not observed in the placebo group (15.0% +/- 1.5% vs 12.0% +/- 2.6%, p = not significant). CONCLUSION: Simvastatin treatment in heart transplant recipients decreased myocardium TNF-alpha expression. This decrease did not translate into a difference in the markers of hypertrophy. However, decreased myocardial TNF-alpha may be a marker of a general statin-mediated decrease in inflammation in the transplanted heart that leads to improved graft and patient survival.

Aged↗
PubMed2004

Hypolipidemic therapy and cholesterol absorption.

The advent of safe and effective hypolipidemic therapy has revolutionized the ability of the clinician to optimize abnormalities in the lipid profile. The advent of statin therapy has provided a potent option to decrease low-density lipoprotein and frequently allows achievement of National Cholesterol Education Program target lipid levels with monotherapy. However, lipid goals are frequently not achieved due to inadequate response to therapy or side effects. The role of combination therapy in the optimization of the lipid profile provides a means by which the implementation of pharmacologic agents with synergistic mechanisms of action allows further improvement in circulating levels of low-density lipoprotein cholesterol. Statins have been combined with bile acid resins, fibric acid derivatives, and nicotinic acid. However, bile acid resins, although not systemically absorbed, have significant problems with patient compliance and drug interactions. The implementation of therapy with fibric acid derivatives or nicotinic acid increases the risk of significant side effects such as rhabdomyolysis or liver toxicity. Ezetimibe is a prototype of a new class of agents that specifically block the absorption of cholesterol from the gastrointestinal tract. Ezetimibe has minimal systemic absorption and a metabolic pathway involving enterohepatic circulation that allows for once a day administration due to a prolonged half-life. Ezetimibe lacks the drug interactions that are common with the bile acid resins and it may be utilized as either monotherapy or in combination with other pharmacologic agents. Ezetimibe has a relatively flat dose-response curve and titration is not required. This review centers on the role of pharmacologic agents that act predominantly by the reduction of cholesterol absorption, including colesevelam and ezetimibe.

Allylamine↗
PubMed2004

Hypertension and the metabolic syndrome.

The metabolic syndrome is a highly prevalent condition in the United States and it has been estimated from the Third National Health and Nutrition Examination Survey that approximately 40 million individuals fulfill the diagnostic criteria, which include a waist circumference greater than 40 inches in men and 35 inches in women, triglycerides in excess of 150 mg/dL, and a high-density lipoprotein cholesterol under 40 mg/dL in men or under 50 mg/dL in women. Additionally, a blood pressure in excess of 130/85 mm Hg and a fasting plasma glucose above 110 mg/dL is required. The diagnosis of the metabolic syndrome requires at least three of the five major criteria for qualification. Hypertension, dyslipidemia, and diabetes frequently cluster and share common pathogenetic mechanisms, resulting in a complex interplay between these apparently disparate risk factors. This review centers on the common metabolic pathways that are common to the major conditions seen in the metabolic syndrome, and centers on the central role of hypertension and the clinical impact of drug therapy on other metabolic parameters.

Humans↗
PubMed2003

The Heart Protection Study: expanding the boundaries for high-risk coronary disease prevention.

Clinical trial evidence strongly favors aggressive risk factor modification in the prevention of coronary artery disease (CAD). The latest landmark trial of therapy using a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) is the Heart Protection Study (HPS) of simvastatin versus placebo in a cohort of patients at high risk for CAD. The HPS reported a number of highly significant reductions in the risk for major vascular events with treatment. It also provides new insights into the effects of statin therapy in patient subgroups, such as the elderly, women, and those with noncoronary vascular disease. These data are likely to have an important influence on the future of cardiovascular disease prevention.

Clinical Trials as Topic↗
PubMed2003

Statins and myotoxicity.

The significant age-adjusted decline in cardiovascular mortality that has occurred over the past three decades is multifactorial. However, the advent of statin therapy has markedly facilitated the optimization of dyslipidemia in patients at risk for coronary events. Statin therapy has proven to be effective in reducing morbidity and mortality in large-scale primary and secondary prevention trials. As with all therapies, the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co A) reductase inhibitors is not without clinical risks. Myopathy, albeit uncommon, was one of the earliest clinical problems associated with statin therapy. Recent data from the large-scale statin mega-trials have clarified the quantitative clinical risk-benefit relationship of reductase inhibitors relative to the induction of muscle toxicity. Histopathologic studies have clarified the potential role of statins in the syndrome of myalgias and normal creatine kinase levels. However, the precise mechanism of statin-associated muscle toxicity remains unclear and is potentially related to genetically mediated muscle enzyme defects, drug interactions, intracellular depletion of metabolic intermediates, and intrinsic properties of the statins per se.

Clinical Trials as Topic↗
PubMed2002

Atherosclerosis and inflammation.

The pathophysiology of coronary atherosclerosis is complex and multifactorial. The probability of the development of symptomatic coronary heart disease may be predicted by standard risk factor stratification involving hypertension, dyslipidemia, age, positive family history, and diabetes. However, risk factor stratification has been demonstrated to have significant limitations in the individual patient, which has generated a search for more specific and sensitive markers. Evidence is increasing that atherosclerosis is a disease characterized by inflammation, beginning with the earliest identifiable lesion (fatty streak) to the advanced vulnerable plaque. Clinical markers of inflammation, including C-reactive protein, modified low-density lipoprotein, homocysteine, tumor necrosis factor, and thermogenicity, have been identified as emerging risk factors that may add prognostic information in patient management. This review centers on inflammation as a potential pathogenetic factor in atherosclerosis and the role that clinical markers may play in the identification of patients at risk.

C-Reactive Protein↗
PubMed2002

The role of inflammation in the pathogenesis of heart failure.

Heart failure is not a simple defect in the pumping function of cardiac muscle, but rather a complex systemic inflammatory disease affecting many organ systems. Recognition of this fact has led to new therapeutic interventions such as angiotensin-converting enzyme inhibitors and beta-blockers, which have a significant impact on the quality of life and survival of patients with heart failure. During the course of heart failure, the steps involved in the activation of inflammation are now better understood. As a result, new therapies will develop that block, modify, or prevent these inflammatory changes, and supplement our armamentarium for providing better and longer lives for patients.

Adrenergic beta-Antagonists↗