Cilostazol and atherogenic dyslipidemia: a clinically relevant effect?

Introduction: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia.

Areas covered: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material.

Expert opinion: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro-atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients.     

Cilostazol and atherogenic dyslipidemia: a clinically relevant effect?

INTRODUCTION: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia. AREAS COVERED: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material. EXPERT OPINION: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro-atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients.     

The generic alternative in schizophrenia: opportunity or threat?

Pharmacological treatment of schizophrenia often requires careful dosage titration to achieve satisfactory symptom control whilst minimising the risk of adverse effects. Relapses requiring hospitalisation are an important potential source of additional cost for the health service and any inadequate symptom control increases the indirect costs of schizophrenia relating to, for example, the need for sheltered accommodation or intensive social services support. The availability of generic drugs is widely regarded as an opportunity to reduce expenditure on drug costs and deploy limited resources more widely and effectively. However, generic drugs may differ from branded drugs in their formulation and may not show precise bioequivalence with the branded product. This may have consequences for the pharmacokinetic profile of the generic drug. A higher maximum plasma concentration (C(max)) could lead to increased or emergent adverse effects, whereas a decreased absorption or minimum plasma concentration (C(min)) may result in a reduced therapeutic effect. For example, plasma levels of clozapine are critical to therapeutic response. Symptom aggravation occurred in approximately 10% of patients switched from branded to generic clozapine in a small, randomised, crossover study. Patients with schizophrenia may also show suspicion and hostility regarding their treatment. This may result in unwillingness to take an unfamiliar medication and decreased compliance, thus increasing the risk of a relapse. Thus, great care should be taken by psychiatrists when switching patients with schizophrenia from branded to generic antipsychotic drugs; this entails monitoring clinical outcome closely and adjusting the treatment in case of symptom aggravation or emergence of adverse effects.     

PET imaging of beta-adrenoceptors in human brain: a realistic goal or a mirage?

Beta-adrenoceptors are predominantly located in the cerebral cortex, nucleus accumbens and striatum. At lower densities, they are also present in amygdala, hippocampus and cerebellum. Beta-2 sites regulate glial proliferation during ontogenic development, after trauma and in neurodegenerative diseases. The densities of beta-1 adrenoceptors are changed by stress, in several mood disorders (depression, excessive hostility, schizophrenia) and during treatment of patients with antidepressants. A technique for beta-adrenoceptor imaging in the human brain is not yet available. Although 24 (ant)agonists have been labeled with either (11)C or (18)F and some of these are successful myocardial imaging agents, only two (S-1'-(18)F-fluorocarazolol and S-1'-(18)F-fluoroethylcarazolol) could actually visualize beta-adrenoceptors within the central nervous system. Unfortunately, these radiopharmaceuticals showed a positive Ames test. They may be mutagenic and cannot be employed for human studies. Screening of more than 150 beta-blockers described in the literature yields only two compounds (exaprolol and L643,717) which can still be radiolabeled and evaluated for beta-adenoceptor imaging. However, other imaging techniques could be examined. Cerebral beta-adrenoceptors might be labeled after temporary opening of the blood-brain barrier (BBB) and simultaneous administration of a hydrophilic ligand such as S-(11)C-CGP12388. Another approach to target beta-adrenoceptor ligands to the CNS is esterification of a myocardial imaging agent (such as (11)C-CGP12177), resulting in a lipophilic prodrug which can cross the BBB and is split by tissue esterases. BBB opening is not feasible in healthy subjects, but the prodrug approach may be successful and deserves to be explored.     

Complementary or alternative? Patterns of complementary and alternative medicine (CAM) use among Finnish children

Purpose

The aim of this study was to measure patterns of complementary and alternative medicine (CAM) use among Finnish children and to explore whether CAM use among children is mainly complementary or alternative.

Methods

We carried out a cross-sectional population-based survey in spring 2007. The study population consisted of a representative sample (n?=?6,000) of Finnish children under 12?years of age. A questionnaire was sent to their parents, and 4,032 questionnaires were returned (response rate 67?%). Pearson’s chi-square test and logistic regression analysis were conducted to measure factors associated with CAM use.

Results

The prevalence of CAM use among children was 11?%. Fish oils and fatty acids (6?%) followed by probiotics (4?%) were the most commonly reported CAMs used. Being the first born, using vitamins and having at least one symptom predicted the use of CAMs. Parental use of vitamins and CAMs were also associated with CAM use among children. In the preceding 2 days, 3 % of children in the study had used only CAMs, and 7?% had used a CAM concomitantly with prescribed and/or over-the-counter medicines.

Conclusions

Our results indicate that the use of CAMs among Finnish children is mainly for improving health and alleviating symptoms, especially in families where at least one parent also uses these modalities. CAMs were mainly used as complementary rather than as an alternative to conventional care. Healthcare professionals should be aware of this complementary use of CAMs and medicines in patients to avoid risks of potential interactions.     

Personalized medicine: is it a pharmacogenetic mirage?

The notion of personalized medicine has developed from the application of the discipline of pharmacogenetics to clinical medicine. Although the clinical relevance of genetically-determined inter-individual differences in pharmacokinetics is poorly understood, and the genotype-phenotype association data on clinical outcomes often inconsistent, officially approved drug labels frequently include pharmacogenetic information concerning the safety and/or efficacy of a number of drugs and refer to the availability of the pharmacogenetic test concerned. Regulatory authorities differ in their approach to these issues. Evidence emerging subsequently has generally revealed the pharmacogenetic information included in the label to be premature. Revised drugs labels, together with a flurry of other collateral activities, have raised public expectations of personalized medicine, promoted as 'the right drug at the right dose the first time.' These expectations place the prescribing physician in a dilemma and at risk of litigation, especially when evidence-based information on genotype-related dosing schedules is to all intent and purposes non-existent and guidelines, intended to improve the clinical utility of available pharmacogenetic information or tests, distance themselves from any responsibility. Lack of efficacy or an adverse drug reaction is frequently related to non-genetic factors. Phenoconversion, arising from drug interactions, poses another often neglected challenge to any potential success of personalized medicine by mimicking genetically-determined enzyme deficiency. A more realistic promotion of personalized medicine should acknowledge current limitations and emphasize that pharmacogenetic testing can only improve the likelihood of diminishing a specific toxic effect or increasing the likelihood of a beneficial effect and that application of pharmacogenetics to clinical medicine cannot adequately predict drug response in individual patients.     

Angiotensin AT-1 receptor antagonism: complementary or alternative to ACE inhibition in cardiovascular and renal disease?

Both angiotensin-converting enzyme (ACE) inhibitors and AT-1 receptor antagonists reduce the effects of angiotensin II, however they may have different clinical effects. This is because the ACE inhibitors, but not the AT-1 receptor antagonists, increase the levels of substance P, bradykinin and tissue plasminogen activator. The AT-1 receptor antagonists, but not the ACE inhibitors, are capable of inhibiting the effects of angiotensin II produced by enzymes other than ACE. On the basis of the present clinical trial evidence, AT-1 receptor antagonists, rather than the ACE inhibitors, should be used to treat hypertension associated with left ventricular (LV) hypertrophy. Both groups of drugs are useful when hypertension is not complicated by LV hypertrophy, and in diabetes. In the treatment of diabetes with or without hypertension, there is good clinical support for the use of either an ACE inhibitor or an AT-1 receptor antagonist. ACE inhibitors are recommended in the treatment of renal disease that is not associated with diabetes, after myocardial infarction when left ventricular dysfunction is present, and in heart failure. As the incidence of cough is much lower with the AT-1 receptor antagonists, these can be substituted for ACE inhibitors in patients with hypertension or heart failure who have persistent cough. Preliminary studies suggest that combining an AT-1 receptor antagonist with an ACE inhibitor may be more effective than an ACE inhibitor alone in the treatment of hypertension, diabetes with hypertension, renal disease without diabetes and heart failure. However, further trials are required before combination therapy can be recommended in these conditions.     

Sphingolipid signalling in the cardiovascular system: good, bad or both?

Sphingolipids are biologically active lipids that play important roles in various cellular processes and the sphingomyelin metabolites ceramide, sphingosine and sphingosine-1-phosphate can act as signalling molecules in most cell types. With the recent development of the immunosuppressant drug FTY720 (Fingolimod) which after phosphorylation in vivo acts as a sphingosine-1-phosphate receptor agonist, research on the role of sphingolipids in the immune and other organ systems was triggered enormously. Since it was reported that FTY720 induced a modest, but significant transient decrease in heart rate in animals and humans, the question was raised which pharmacological properties of drugs targeting sphingolipid signalling will affect cardiovascular function in vivo. The answer to this question will most likely also indicate what type of drug could be used to treat cardiovascular disease. The latter is becoming increasingly important because of the increasing population carrying characteristics of the metabolic syndrome. This syndrome is, amongst others, characterized by obesity, hypertension, atherosclerosis and diabetes. As such, individuals with this syndrome are at increased risk of heart disease. Now numerous studies have investigated sphingolipid effects in the cardiovascular system, can we speculate whether certain sphingolipids under specific conditions are good, bad or maybe both? In this review we will give a brief overview of the pathophysiological role of sphingolipids in cardiovascular disease. In addition, we will try to answer how drugs that target sphingolipid signalling will potentially influence cardiovascular function and whether these drugs would be useful to treat cardiovascular disease.     

HDL-cholesterol: is it really good? Differences between apoA-I and HDL

Since the very first report showing the regression of established atherosclerotic lesions by means of high-density lipoprotein cholesterol (HDL-C) plasma fraction, much information has been generated about the protective role of HDL-C in atherosclerosis. Nonetheless, this positive point of view about HDL has been nearly surpassed since modern informations concerning torcetrapib have appeared. Disappointment was palpable when its pivotal morbidity-and-mortality clinical trial, ILLUMINATE, was abruptly stopped due to excess mortality amongst the group randomized to receive torcetrapib. In this work we will try to put things in perspective. Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a proven strategy for reducing the cardiovascular disease (CVD) risk. Despite the impressive benefits of statins, there remain a significant proportion of treated patients in which cardiovascular events are not prevented. Low HDL-C levels are an important independent risk factor for CVD. There is a need to develop suitable therapies to reduce this residual risk through HDL-C related mechanisms. Therefore, we will first review HDL-C pathways and we will subsequently state the new pharmacological approaches to HDL-C metabolism.     

Beyond anorexia -cachexia. Nutrition and modulation of cancer patients' metabolism: supplementary, complementary or alternative anti-neoplastic therapy?

Anorexia and muscle wasting are frequently observed in cancer patients and influence their clinical outcome. The better understanding of the mechanisms underlying behavioral changes and altered metabolism yielded to the development of specialized nutritional support, which enhances utilization of provided calories and proteins by counteracting some of the metabolic derangements occurring during tumor growth. Inflammation appears to be a key factor determining the cancer-associated biochemical abnormalities eventually leading to anorexia and cachexia. Interestingly, inflammation is also involved in carcinogenesis, cancer progression and metastasis by impairing immune surveillance, among other mechanisms. Therefore, nutritional interventions aiming at modulating inflammation to restore nutritional status may also result in improved response to pharmacological anti-cancer therapies. Recent clinical data show that supplementation with nutrients targeting inflammation and immune system increases response rate and survival in cancer patients. This suggests that nutrition therapy should be considered as an important adjuvant strategy in the multidimensional approach to cancer patients.     

COX-2 expression in atherosclerosis: the good, the bad or the ugly?

Cyclooxygenase (COX) is the rate limiting enzyme catalyzing the conversion of arachidonic acid into prostanoids, lipid mediators critically implicated in a variety of physiological and pathophysiological processes, including inflammation, vascular and renal homeostasis, and immune responses. Since the early 1990s it has been appreciated that two isoforms of COX exist, referred to as COX-1 and COX-2. Although structurally homologous, COX-1 and COX-2 are regulated by two independent and quite different systems and have different functional roles. In the setting of acute ischemic syndromes it has been recognized that COX pathway plays an important role; however, whereas the function of platelet COX-1 in acute ischemic diseases is firmly established, the role of COX-2 in atherothrombosis remains controversial. The complex role of COX-2 in this setting is also confirmed by the unexpected cardiovascular side effects of long-term treatment with COX-2 inhibitors. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, the effects of the variable expression of upstream and downstream enzymes in the prostanoid biosynthesis on COX-2 expression and inhibition.     

Use of anabolic-androgenic steroids in adolescence: winning, looking good or being bad?

OBJECTIVE: To investigate the prevalence of anabolic-androgenic steroid (AAS) use among Norwegian adolescents and to contrast three perspectives on AAS use: performance enhancement in sports competition, body image and eating concerns, and AAS-use as belonging to a cluster of problem behaviors. METHOD: A nationally representative sample of 8,877 (53.8% female) Norwegian youths (15-22 years of age) were surveyed (response rate 78%). Sports participation included measures of participation in strength sports, participation in competitive sports, strength training and perceived athletic competence. Body image and eating concerns included measures of disordered eating, perceived physical appearance and satisfaction with body parts. Problem behavior was measured by three dimensions of conduct problems (overt destruction, overt nondestruction and covert destruction), illicit drug use and sexual involvement. RESULTS: Information about AAS was obtained from 8,508 subjects. Lifetime AAS use was 0.8% (1.2% male and 0.6% female), 12-month prevalence was 0.3% and 5.1% had been offered AAS. AAS use did not vary according to sports involvement and demographics. Logistic regression analyses showed that AAS use was associated with such problem behavior as marijuana (cannabis) involvement and overt nondestruction (e.g., aggressive-type conduct problems) and, to some extent, with involvement in power sports and disordered eating. AAS users differed little from those who had been offered but refrained from using AAS, except that they were more likely to be current marijuana users. CONCLUSIONS: Adolescent AAS use seems primarily to be another type of problem behavior and only secondarily is it associated with strength-sport participation and disordered eating.