Metabolic Consequences of Anabolic Steroids, Insulin, and Growth Hormone Abuse in Recreational Bodybuilders: Implications for the World Anti-Doping Agency Passport.

BACKGROUND: Hormonal doping in recreational sports is a public-health concern. The World Anti-Doping Agency (WADA) promoted the creation of the Athlete Biological Passport, aiming to monitor athlete's biological variables over time to facilitate indirect detection of doping. Detection tests for anabolic androgenic steroids (AAS) and growth hormone (GH) are available while insulin abuse cannot be revealed. We have determined in recreational bodybuilders the metabolic effects associated with different patterns of hormone abuse. All analyses were conducted using Statistical Package for Social Sciences (SPSS) 21.0 software (SPSS Chicago, IL). RESULTS: We have assessed plasma concentrations of selected metabolic markers and fatty acid content in erythrocyte membranes of 92 male bodybuilders and in 45 healthy controls. Hormonal abuse was identified by anonymous questionnaires. 43% (%) of recruited bodybuilders regularly abused hormones, i.e., anabolic androgenic steroids (95%) often associated with GH (30%) and/or insulin (38%). HDL-cholesterol was lower in insulin and/or GH abusers. Alanine (ALT) and aspartic (AST) transaminases were greater in hormone abusing bodybuilders than in non-doping bodybuilders and controls. Insulin doping was selectively associated with increased plasma ALT-to-AST ratio. In erythrocyte membranes, elongase activity (i.e., stearic-to-palmitic ratio) was lower in insulin and/or growth hormone doping, whereas increased Δ-9 desaturase activity (i.e., palmitoleic-to-palmitic ratio) was selectively associated with insulin doping. CONCLUSIONS: In conclusion, our study demonstrates that insulin and GH abuse are characterized by multiple alterations of specific metabolic markers. Although further studies are needed to test whether longitudinal monitoring of selected metabolic marker such as muscle contraction time, HDL levels, ALT-AST ratio as well as the activities of selected enzymes (e.g. Δ-9 desaturase and elongase), could contribute to the detection of insulin and GH abuse in sport.

Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives.

Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1-10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25-30%. Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.

[1,2,4]Triazolo[1,5-c]pyrimidines as Tools to Investigate A3 Adenosine Receptors in Cancer Cell Lines.

The A3 adenosine receptor is an interesting target whose role in cancer is controversial. In this work, a structural investigation at the 2-position of the [1,2,4]triazolo[1,5-c]pyrimidine nucleus was performed, finding new potent and selective A3 adenosine receptor antagonists such as the ethyl 2-(4-methoxyphenyl)-5-(methylamino)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxylate (20, DZ123) that showed a Ki value of 0.47 nM and an exceptional selectivity profile over the other adenosine receptor subtypes. Computational studies were performed to rationalize the affinity and the selectivity profile of the tested compounds at the A3 adenosine receptor and the A1 and A2A adenosine receptors. Compound 20 was tested on both A3 adenosine receptor positive cell lines (CHO-A3 AR transfected, THP1 and HCT16) and on A3 negative cancer cell lines, showing no effect in the latter and a pro-proliferative effect at a low concentration in the former. These interesting results pave the way to further investigation on both the mechanism involved and potential therapeutic applications.

Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy.

Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a "gold standard", the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins.