Prostaglandins in health and disease: an overview

OBJECTIVES: Prostaglandins are a group of biologically active compounds that play major roles in human physiology in both health and disease. They function in many different ways and in all major organs. This article reviews the basic physiology of prostaglandins and their application to specific effects on these systems in normal and abnormal clinical states. The critical therapeutic implications of the use of nonsteroidal antiinflammatory drugs in altering organ homeostasis are also examined. METHODS: References were taken from Medline, Embase, and Index Medicus from 1966 to September 2005. A search was done with keywords, including prostaglandins, nonsteroidal antiinflammatory drugs, inflammation, arachidonic acid, Cox-1 (cyclooxygenase-1), and Cox-2 (cyclooxygenase-2). RESULTS: There was a close correlation and predictability between basic prostaglandin physiology and the anticipated effects of these compounds on the heart, lungs, kidneys, gastrointestinal tract, bones and joints, brain, and male and female reproductive systems. These effects are organ and tissue specific. Despite these findings, unexplained and sometimes paradoxical physiologic responses were identified. A prime example of this is the role of prostaglandins in bone metabolism demonstrating both stimulatory and inhibitory effects. In addition all NSAIDs have the potential to impair the normal physiologic effects of prostaglandins depending primarily on the specific organ and the clinical setting. CONCLUSIONS: Prostaglandins are regulatory compounds that play important roles in many physiologic processes in the human body. An understanding of the basic science of prostaglandins is valuable in anticipating the organ-specific biologic effects of these unique compounds in health and disease. However, at selected sites and under different physiologic conditions, unexplained and sometimes paradoxical effects are generated. Impairment of their regulatory functions can lead to significant short- or long-term organ dysfunction.     

Chronic pediatric inflammatory diseases: Effects on bone

In children, chronic inflammatory diseases present a significant challenge to long-term skeletal health. These conditions are often associated with poor appetite and suboptimal overall nutrition, altered nutrient utilization, delayed puberty, inactivity, and reduced muscle mass, all of which can alter bone metabolism. In addition, bone cell activity is susceptible to the effects of the immune response that characterizes these diseases. Moreover, drugs used to treat these maladies, notably glucocorticoids, may have negative effects on bone formation and on linear growth in developing children. As a result, predicted peak bone mass may not be achieved, and fracture risk may be increased in the short term or in the future. Studies using primarily dual energy X-ray absorptiometry have documented that deficits in bone mass are common in these diseases. However, there are wide variations in the prevalence of low bone mass, largely due to differences in the characteristics of each study population. Recent studies provide insight into the pathogenesis of decreased bone mass in these conditions. In this paper we will provide an overview of the effects of chronic inflammatory conditions on bone mass in children. We will also present relevant data from adult patients, when pediatric data are scant or not available.     

Diadenosine polyphosphates: postulated mechanisms mediating the cardiac effects

Diadenosine polyphosphates (Ap(n)A) are naturally occurring molecules which have been identified in human and guinea-pig cardiac tissue and whose physiological role is being established. They are stored in platelet dense granules in a metabolically inactive form. Ap(n)A form a class of dinucleotides, including diadenosine triphosphate (Ap3A), diadenosine tetraphosphate (Ap4A), diadenosine pentaphosphate (Ap5A) and diadenosine hexaphosphate (Ap6A) which have vasopressor actions in some tissues and vasodilator actions in others. Ap(n)A have been reported to interact with receptors distinct from P1 and P2-purinoceptors, and the presence of a unique Ap4A receptor has been demonstrated in isolated ventricular myocytes. Despite the identification of this receptor, other studies suggest that some of the cardiovascular effects are mediated by purinoceptors. Ap(n)A are released from platelet dense granules into the circulation during the platelet release reaction where they can reduce heart rate. The existence of Ap(n)A in myocardial tissue and platelet granules as well as their effects on coronary artery tone and myocardial function suggests a regulatory role for these compounds in the heart. This review describes the effects of Ap(n)A in terms of their coronary vasomotor and cardiac electrophysiological effects. The mechanism responsible for these effects is reviewed; including the involvement of purinergic receptors, the effects of alterations in extracellular pH and the contribution of nitric oxide and prostanoids. Potential pro-arrhythmogenic effects of diadenosine polyphosphates during myocardial ischaemia are also discussed as these compounds could contribute to inhomogeneities of repolarization in ischaemic myocardium.     

Clinical review 145: Pleiotropic effects of statins: lipid reduction and beyond

There is accumulating evidence that statins have beneficial effects that are independent of their classical actions on lipoproteins. These effects include reductions in inflammation in the vasculature, kidney, and bone. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. These agents appear to reduce bone fractures and may improve insulin sensitivity and reduce the likelihood of persons progressing from impaired glucose tolerance to type II diabetes. Potential beneficial pleiotropic effects of statins are covered in this review.     

Hyponatremia in cirrhosis: clinical features and management

The presence of dilutional hyponatremia has a poor prognosis for survival in patients with cirrhosis and ascites. Effective and safe treatments are needed to improve prognosis in patients with cirrhosis and dilutional hyponatremia. The initial approach to management includes fluid restriction, low sodium diet, and minimizing the use of diuretics. In addition, the use of hypertonic saline should be avoided in patients with cirrhosis and dilutional hyponatremia. Furthermore, patients should be placed on the top of the list for liver transplantation if they are appropriate candidates. Although V2 arginine vasopressin receptor antagonists that selectively enhance solute-free water excretion in patients with cirrhosis seem very promising, two points must be considered in relation to the available data. First, although the results of phase-2 studies are encouraging, the efficacy and safety of these compounds should be further evaluated. Second, the clinical utility of these agents in cirrhosis has only been assessed in short-term studies. The long-term effects of these drugs remain unknown. Future research with these compounds should not only focus on the effects on serum sodium, but also on treatment and prevention of recurrence of ascites. In addition, the possible beneficial effects of these drugs in the prevention of hepatic encephalopathy would be worth studying.     

Chapter 3: choosing the important outcomes for a systematic review of a medical test

In this chapter of the Evidence-based Practice Centers Methods Guide for Medical Tests, we describe how the decision to use a medical test generates a broad range of outcomes and that each of these outcomes should be considered for inclusion in a systematic review. Awareness of these varied outcomes affects how a decision maker balances the benefits and risks of the test; therefore, a systematic review should present the evidence on these diverse outcomes. The key outcome categories include clinical management outcomes and direct health effects; emotional, social, cognitive, and behavioral responses to testing; legal and ethical outcomes, and costs. We describe the challenges of incorporating these outcomes in a systematic review, suggest a framework for generating potential outcomes for inclusion, and describe the role of stakeholders in choosing the outcomes for study. Finally, we give examples of systematic reviews that either included a range of outcomes or that might have done so. The following are the key messages in this chapter: Consider both the outcomes that are relevant to the process of testing and those that are relevant to the results of the test. Consider inclusion of outcomes in all five domains: clinical management effects, direct test effects; emotional, social, cognitive and behavioral effects; legal and ethical effects, and costs. Consider to which group the outcomes of testing are most relevant. Given resource limitations, prioritize which outcomes to include. This decision depends on the needs of the stakeholder(s), who should be assisted in prioritizing the outcomes for inclusion.     

Minireview: aldosterone and the cardiovascular system: genomic and nongenomic effects

There is clear evidence for rapid nongenomic effects of aldosterone in the cardiovascular system in addition to its well characterized effects of unidirectional transepithelial sodium transport. Many of these effects are mediated by the classical mineralocorticoid receptors, although others may be exerted independently. Given that mineralocorticoid receptors are largely constitutively occupied but not activated by physiological glucocorticoids, effects of aldosterone administered in vitro or in vivo may or may not equate with true physiological mineralocorticoid roles. In many systems (e.g. blood pressure regulation and cardiac fibrosis), the time course of effects is such that it is not possible, and perhaps not important, to distinguish between rapid nongenomic and classical genomic effects in the context of homeostatic physiology.     

Significance of wine and resveratrol in cardiovascular disease: French paradox revisited

Many recent studies have reported promising health benefits from red wine consumption. The present article reviews some of the key studies, and the known mechanisms for these beneficial effects. Evidence from different experimental studies, including from the authors' laboratories, have suggested that these beneficial effects are due to polyphenols found in red wine, especially resveratrol in grape skins. These benefits include a reduction in cardiovascular morbidity and mortality, lung cancer and prostate cancer by approximately 30% to 50%, 57% and 50%, respectively. Polyphenols possess antioxidant, superoxide-scavenging, ischemic-preconditioning and angiogenic properties. Some of these properties of polyphenols may explain their protective effects on the cardiovascular system, as well as other body organs. In fact, results from several epidemiological, case-control and prospective studies have prompted the United States Department of Health and Human Services to recommend moderate alcohol consumption in its national health promotion and disease prevention initiative, Healthy People 2010. Further studies are warranted to describe the precise molecular mechanisms for these potential beneficial effects of red wine on the general health of the population, particularly on cardiovascular morbidity and mortality.     

Insulin: cardiovascular effects and therapeutic applications

Several studies have suggested a beneficial role of insulin and glucose infusions after myocardial infarction and in critically ill diabetic and non-diabetic patients. However, the insulin-glucose infusions are not routinely given to these patients, since no large randomized control trial was carried out, mechanisms involved in the benefits obtained are poorly understood, infusion protocols are complex and finally, health professionals need to change their cultural premises to apply them in their practice. Insulin has beneficial cardiovascular effects, such as the optimization of substrate use by cardiomyocites, coronary vasodilation, anti-inflammatory action and direct anti-apoptotic effects on myocardial cells. In this context, clinical studies of glucose and insulin infusions after myocardial infarction and cardiovascular surgery are reviewed, as well as possible pathophysiologic mechanisms leading to these benefits, and finally, a practical algorithm is proposed for use in intensive care and cardiovascular postoperative care units.     

Low-dose radiation effects: experimental hematology and the changing paradigm

This review looks at the emerging field of nontargeted radiation effects and their impact on low-dose radiation risk assessment and radiotherapy. It identifies the major role of experimental hematologists and cytogeneticists in changing the old view of radiation action on living things. It also considers the history of radiobiology, seeking to explain why it is only now that we are considering indirect or nontargeted effects of low doses even though the evidence was there, though buried, in the old literature. Effects receiving major attention worldwide now include genomic instability and bystander effects. The impact of these effects, both on radiotherapy used to treat cancer and on radiation induction of cancer, still need to be clarified. Techniques developed by experimental hematologists are central to these efforts and have been instrumental in causing radiobiologists to consider that a paradigm shift is necessary. Throughout, we make a plea to think "outside the box" since the very construction of a framework necessarily limits our thinking and our experimental design.     

Drug insight: cyclo-oxygenase-2 inhibitors--a critical appraisal

Following the withdrawal of rofecoxib and valdecoxib, the discussion concerning selective cyclo-oxygenase (COX)-2 inhibitors was often characterized more by emotions than scientific evidence. In fact, the original rationale of these substances is still valid, in that selective COX2 inhibitors cause significantly fewer severe side effects in the gastrointestinal tract than traditional NSAIDs. Off-label long-term use of COX2 inhibitors in patients with a history of colorectal adenomas in well-designed, placebo-controlled trials showed that treatment with these agents is associated with an increased rate of cardiovascular adverse effects. Other studies have shown that both COX2 inhibitors and NSAIDs are associated with a similar cardiovascular risk, suggesting that there is presently no rationale for a further differentiation of these groups of drugs in terms of cardiovascular toxicity. Referring to the current debate, potential mechanisms underlying cardiovascular adverse effects associated with the long-term use of COX2 inhibitors and NSAIDs are discussed. Moreover, this Review summarizes the pharmacology of COX2 inhibitors with emphasis on their different pharmacokinetic characteristics.     

Smoking and Neuroimaging: A Review

Cigarette smoking is a significant public health concern, often resulting in nicotine dependence, a chronic-relapsing psychiatric diagnosis that is responsible for up to 10% of the global cardiovascular disease burden. Due to its significantly deleterious effects on health, much research has been dedicated to elucidating the underlying neurobiology of smoking. This brief article is intended to provide a digestible synopsis of the considerable research being conducted on the underlying neural bases of cigarette smoking and nicotine dependence, especially for cardiologists who are often at the front lines of treating nicotine dependence. To this end, we first review some of the most common neuroimaging methodologies used in the study of smoking, as well as the most recent findings from this exciting area of research. Then, we focus on several fundamental topics including the acute pharmacologic effects, acute neurocognitive effects, and the long-term neurobiological effects associated with smoking. Lastly, we review recent findings regarding the neuropsychological processes associated with smoking cessation, including cue-induced craving and regulation of craving. Research in this field is beginning to uncover how some of these neuropsychological processes are similar across clinical disorders that cardiologists also encounter frequently, such as craving for food resulting in overeating. We conclude with recommendations for future neuroimaging work on these topics.     

Effects of statins beyond lipid lowering: potential for clinical benefits

BACKGROUND: The role of statin drugs in the reduction of serum lipids has been well documented. More recently, evidence suggesting that statins may positively impact many organ systems and disease states independent of lipid reduction has emerged. The term "pleiotropic effects" has been used to refer to these properties. We reviewed the evidence exploring such potential effects. METHODS: A search of the MEDLINE database was conducted for articles published between 1985 to 2005 on the pleiotropic and the lipid-lowering independent effects of statin drugs. The search terms "statin", "HMG-CoA reductase inhibitor", "pleiotropic effects", and "inflammation" were used. English language articles were selected for inclusion along with selected cross-references. RESULTS: Numerous animal and clinical studies support the presence of a spectrum of beneficial effects for statins that are independent of their lipid-lowering properties. These effects are mediated by a variety of mechanisms and they suggest that the therapeutic role of statins may expand. CONCLUSION: Statins have shown great promise beyond their lipid-lowering effects. Ongoing and future studies will help to further clarify the potential clinical impact of these "pleiotropic effects".     

Understanding how the brain perceives alcohol: neurobiological basis of ethanol discrimination

Understanding the neurobiological mechanisms that regulate how the brain perceives the intoxicating effects of alcohol is highly relevant to understanding the development and maintenance of alcohol addiction. The basis for the subjective effects of intoxication can be studied in drug discrimination procedures in which animals are trained to differentiate the presence of internal stimulus effects of a given dose of ethanol (EtOH) from its absence. Research on the discriminative stimulus effects of psychoactive drugs has shown that these effects are mediated by specific receptor systems. In the case of alcohol, action mediated through ionotropic glutamate, gamma-aminobutyric acid, and serotonergic receptors concurrently produce complex, or multiple, basis for the discriminative stimulus effects of EtOH. These receptor systems may contribute differentially to the discriminative stimulus effects of EtOH based on the EtOH dose, species differences, physiological states, and genetic composition of the individual. An understanding of the receptor mechanisms that mediate the discriminative stimulus effects of EtOH can be used to develop medications aimed at decreasing the subjective effects associated with repeated intoxication. The goal of this symposium was to present an overview of recent findings that highlight the neurobiological mechanisms of EtOH's subjective effects and to suggest the relevance of these discoveries to both basic and clinical alcohol research.     

Androgen deficiency: effects on body composition

Published data on the effects of androgen deficiency and testosterone administration on body composition in men and women are reviewed. In experimental paradigms, androgen deprivation decreases lean body mass and increases fat mass in men, and physiologic replacement reverses these abnormalities. The anabolic effects of testosterone administration on muscle in men are well-established, and current understanding of the underlying mechanisms are discussed. Randomized, placebo-controlled studies have been performed to investigate the effects of testosterone administration on body composition in a number of male hypogonadal states, including HIV-associated weight loss, supraphysiologic glucocorticoid administration, aging and obesity, with variable outcomes, and the results are reviewed. There are few data investigating the effects of hypoandrogenemia or androgen replacement on body composition in women, in whom endogenous testosterone levels are a fraction of those in men. A recent randomized, placebo-controlled study of physiologic testosterone replacement therapy in women with profound hypoandrogenemia due to hypopituitarism demonstrated an increase in skeletal muscle mass but no change in body fat. Further research is needed to establish the effects of endogenous androgens on the regulation of body composition in women.     

Airways and air pollution in childhood: State of the art

Correlations between ambient pollutants and health effects, such as observed in SIDS, may in reality be to a larger extent the result of indoor sources. These distinctions between indoor and outdoor sources, while important, do not detract from the overall conclusion that pollution affects the airway in children directly and indirectly. Much still needs to be learned about the permanence of these effects, the mechanism by which the effect is mediated, and the conditions under which some of these effects are maximal. Two approaches seem particularly suited to shed further light on these issues. First, identification of biological markers for exposure to pollutants will yield both more accurate measures of exposure to pollutants and information about health consequences [58]. Second, newer modeling techniques promise to predict health outcomes under a variety of environmental conditions. Shumway et al., for instance, describe a promising model predicting an increase in mortality due to ambient pollutants in the Los Angeles Basin with higher levels under extremes of temperature, especially during cold spells [59]. Time series and factor analyses may further our knowledge as well [60]. In the near future, large cohort studies should begin to reveal the cumulative effects of air pollution on the respiratory system, especially in relation to active smoking. Finally, studies on Black children are virtually unavailable. Given their high risk for respiratory illnesses, such studies are sorely needed.     

Simvastatin: two decades in a circle

Simvastatin is an agent of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor group of drugs. It is administrated orally once a day in doses of 5-80 mg. Although its main action is to reduce total and low-density lipoprotein (LDL) cholesterol, it is able to reduce triglycerides and increase high-density lipoprotein cholesterol levels, though at a lower extent. Beyond this action, studies enrolled with simvastatin have shown beneficial effect on endothelial function, smooth muscle cell function, hemostasis, vascular wall function, LDL oxidation, and inflammation. All these actions mentioned above are known as pleiotropic effects. In this review, we will present all these effects, as well as the beneficial effects on atherogenesis and the reduction in cardiovascular morbidity and mortality related to simvastatin.     

The Buzz about Anabolic Androgenic Steroids: Electrophysiological Effects in Excitable Tissues

Anabolic androgenic steroids (AAS) comprise a large and growing class of synthetic androgens used clinically to promote tissue-building in individuals suffering from genetic disorders, injuries, and diseases. Despite these beneficial therapeutic applications, the predominant use of AAS is illicit: these steroids are self-administered to promote athletic performance and body image. Hand in hand with the desired anabolic actions of the AAS are untoward effects on the brain and behavior. While the signaling routes by which the AAS impose both beneficial and harmful actions may be quite diverse, key endpoints are likely to include ligand-gated and voltage-dependent ion channels that govern the activity of electrically excitable tissues. Here, we review the known effects of AAS on molecular targets that play critical roles in controlling electrical activity, with a specific focus on the effects of AAS on neurotransmission mediated by GABA(A) receptors in the central nervous system.     

Leukotrienes: One step in our understanding of asthma

The steps leading to the discovery of leukotrienes and the researchers that played a major part in this long process are presented. The pharmacology of these exquisitely potent compounds shows that they express bronchoconstrictor activity and numerous cellular effects via very specific receptors. Experimental evidence strongly suggests that these mediators play a significant role in asthma physiopathology. Numerous approaches were taken to block their effects on the lungs and this led to the discovery of selected drugs used for asthma treatment. The complexity of this disease and its treatment is emphasized.