Elena Tragni

Low density lipoprotein oxidation, antioxidants, and atherosclerosis.

Oxidized low density lipoproteins (LDLs) are believed to be the most atherogenic form of LDL. However, although a number of experimental data support this concept, the protective role of antioxidants that may prevent LDL oxidation in atherosclerosis is only partially confirmed by studies in humans. Observational and epidemiologic data as well as randomized trials failed to provide clear-cut indications because of mixed results on the protective role of antioxidants against cardiovascular diseases. In spite of the lack of a general consensus, recent data reinforce the concept that a regular intake of antioxidants present in food blocks the progression of atherosclerosis and that the reduced oxidisability of LDL may represent a good marker to follow the action of antioxidants. When it becomes possible to monitor the efficacy of any antioxidant therapy with validated markers of oxidation, the potential influence of vitamins and antioxidants on coronary artery disease will eventually be resolved.

Statins and the Risk of Diabetes: Evidence From a Large Population-Based Cohort Study

OBJECTIVE To investigate the relationship between adherence with statin therapy and the risk of developing diabetes. RESEARCH DESIGN AND METHODS The cohort comprised 115,709 residents of the Italian Lombardy region who were newly treated with statins during 2003 and 2004. Patients were followed from the index prescription until 2010. During this period, patients who began therapy with an antidiabetic agent or were hospitalized for a main diagnosis of type 2 diabetes were identified (outcome). Adherence was measured by the proportion of days covered (PDC) with statins (exposure). A proportional hazards model was fitted to estimate hazard ratios (HRs) and 95% CIs for the exposure-outcome association, after adjusting for several covariates. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS During follow-up, 11,154 cohort members experienced the outcome. Compared with patients with very-low adherence (PDC <25%), those with low (26–50%), intermediate (51–75%), and high (≥75%) adherence to statin therapy had HRs (95% CIs) of 1.12 (1.06–1.18), 1.22 (1.14–1.27), and 1.32 (1.26–1.39), respectively. CONCLUSIONS In a real-world setting, the risk of new-onset diabetes rises as adherence with statin therapy increases. Benefits of statins in reducing cardiovascular events clearly overwhelm the diabetes risk.

Telomere shortening over 6 years is associated with increased subclinical carotid vascular damage and worse cardiovascular prognosis in the general population

Leucocyte telomere length (LTL) is an important determinant of telomere function and cellular replicative capacity. The aim of the present study was to examine prospectively the associations between telomere shortening (TS) and both the progression of atherosclerosis and the incidence of cardiovascular events (CVEs).

Adherence to lipid-lowering treatment: the patient perspective

Despite the widespread prescription of highly effective lipid-lowering medications, such as the HMG-CoA reductase inhibitors (statins), a large portion of the population has lipid levels higher than the recommended goals. Treatment failures have been attributed to a variety of causes but the most important is likely to be poor adherence to therapy in the form of irregular or interrupted intake and the high frequency of discontinuation or lack of persistence. Adherence is a multidimensional phenomenon determined by the interplay of patient factors, physician factors, and health care system factors. Patients’ knowledge and beliefs about their illness, motivation to manage it, confidence in their ability to engage in illness-management behaviors, and expectations regarding the outcome of treatment and the consequences of poor adherence interact to influence adherence behavior. Patient-related factors account for the largest incremental explanatory power in predicting adherence. This article provides an overview of this critical issue, focusing on patient role in determining adherence level to lipid-lowering therapy.

Are generic and brand-name statins clinically equivalent? Evidence from a real data-base

BACKGROUND Use of generic drugs can help contain drug spending. However, there is concern among patients and physicians that generic drugs may be clinically inferior to brand-name ones. This study aimed to compare patients treated with generic and brand-name statins in terms of therapeutic interruption and cardiovascular (CV) outcomes. METHODS 13,799 beneficiaries of the health care system of Lombardy, Italy, aged 40 years or older who were newly treated with generic or brand-name simvastatin during 2008, were followed until 2011 for the occurrence of two outcomes: 1) therapeutic discontinuation and 2) hospitalization for CV events. Hazard ratios (HR) associated with use of generic or brand-name at starting therapy (intention-to-treat analysis) and during follow-up (as-treated analysis) were estimated by fitting proportional hazard Cox models. A Monte-Carlo sensitivity analysis was performed to account for unmeasured confounders. RESULTS Patients who started on generic did not experience a different risk of discontinuation (HR: 0.98; 95% CI 0.94 to 1.02) nor of CV outcomes (HR: 0.98; 95% CI 0.79 to 1.22) from those starting on brand-name. Patients who spent >75% of time of follow-up with statin available on generics did not experience a different risk of discontinuation (HR: 0.94; 95% CI 0.87 to 1.01), nor of CV outcomes (HR: 1.06; 95% CI 0.83 to 1.34), compared with those who mainly or only used brand-name statin. CONCLUSIONS Our findings do not support the notion that in the real world clinical practice brand-name statins are superior to generics for keeping therapy and preventing CV outcomes.

Quantification of In Vitro Cytotoxicity of Surfactants: Correlation with their Eye Irritation Potential

AbstractA number of surfactants, including representatives of the cationic, anionic, nonionic, and amphoteric groups, were studied for their effects on lactate dehydrogenase (LDH), protein content, and de novo synthesis, at concentrations ranging from 1 to 500 µg/d medium, in a murine epidermal cell line (HEL/30). Protein synthesis, evaluated as [3H]leucine incorporation into cell proteins, was a more sensitive endpoint of toxicity than LDH leakage or protein content. Comparative surfactant toxicity followed the general order of cationic > anionic > nonionic > amphoteric. A good rank correlation was observed between their relative toxicity produced in vitro and the eye irritation produced in vivo in the Drake test. This sensitive and reproducible in vitro method may offer a means for screening potentially imtating water-soluble chemicals such as surfactants to quantify their toxicity.

Prevalence of the Prescription of Potentially Interacting Drugs

The use of multiple medications is becoming more common, with a correspondingly increased risk of untoward effects and drug-related morbidity and mortality. We aimed at estimating the prevalence of prescription of relevant potentially interacting drugs and at evaluating possible predictors of potentially interacting drug exposure. We retrospectively analyzed data on prescriptions dispensed from January 2004 to August 2005 to individuals of two Italian regions with a population of almost 2.1 million individuals. We identified 27 pairs of potentially interacting drugs by examining clinical relevance, documentation, and volume of use in Italy. Subjects who received at least one prescription of both drugs were selected. Co-prescribing denotes “two prescriptions in the same day”, and concomitant medication “the prescription of two drugs with overlapping coverage”. A logistic regression analysis was conducted to examine the predictors of potential Drug-Drug Interaction (pDDIs). 957,553 subjects (45.3% of study population) were exposed to at least one of the drugs/classes of the 27 pairs. Overall, pDDIs occurred 2,465,819 times. The highest rates of concomitant prescription and of co-prescription were for ACE inhibitors+NSAIDs (6,253 and 4,621/100,000 plan participants). Considering concomitance, the male/female ratio was <1 in 17/27 pairs (from 0.31 for NSAIDs-ASA+SSRI to 0.74 for omeprazole+clopidogrel). The mean age was lowest for methotrexate pairs (+omeprazole, 59.9 years; +NSAIDs-ASA, 59.1 years) and highest for digoxin+verapamil (75.4 years). In 13/27 pairs, the mean ages were ≥70 years. On average, subjects involved in pDDIs received ≥10 drugs. The odds of exposure were more frequently higher for age ≥65 years, males, and those taking a large number of drugs. A substantial number of clinically important pDDIs were observed, particularly among warfarin users. Awareness of the most prevalent pDDIs could help practitioners in preventing concomitant use, resulting in a better quality of drug prescription and potentially avoiding unwanted side effects.

Lower incidence of macrovascular complications in patients on insulin glargine versus those on basal human insulins: A population-based cohort study in Italy

BACKGROUND AND AIM The aim of this study was to compare the use of insulin glargine and intermediate/long-acting human insulin (HI) in relation to the incidence of complications in diabetic patients. METHODS AND RESULTS A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients without macrovascular diseases and treated with either intermediate/long-acting HI or glargine were followed for 3-years; the incidence of diabetic (macrovascular, microvascular and metabolic) complications was ascertained by hospital discharge claims and estimated using Cox proportional hazard models. Propensity score (PS) matching was also used to adjust for significant differences in the baseline characteristics between the two groups. RESULTS Overall, 1921 diabetic patients were included: 744 intermediate/long-acting HI and 1177 glargine users. During the 3-year follow-up, 209 (28.1%) incident events of any diabetic complication occurred in the intermediate/long-acting HI and 159 (13.5%) in the glargine group. After adjustment for covariates, glargine users had an HR (95% CI) of 0.57 (0.44-0.74) for any diabetic complication and HRs of 0.61 (0.44-0.84), 0.58 (0.33-1.04) and 0.35 (0.18-0.70) for macrovascular, microvascular and metabolic complications, respectively, compared to intermediate/long-acting HI users. PS analyses supported these findings. CONCLUSIONS The use of glargine is associated with a lower risk of macrovascular complications compared with traditional basal insulins. However, limitations inherent to the study design including the short length of observation and the lack of data on metabolic control or diabetes duration, do not allow us to consider this association as a proof of causality.

Blood pressure and antihypertensive therapy according to the global cardiovascular risk level in Italy: the CHECK Study

Background Elevated blood pressure (BP) is one of the most important modifiable risk factors for cardiovascular diseases. In this study we assessed the excess of cardiovascular risk attributable to high BP and antihypertensive treatment in a sample of Italian patients enrolled by the ‘Cholesterol and Health: Education, Control and Knowledge’ (CHECK) study. Methods CHECK is a large, cross-sectional epidemiological study, which randomly enrolled patients aged 40–79 years from 425 Italian General Practices from March 2002 to April 2004. Among 5731 patients enrolled in the study [49.6% men, mean age (standard deviation) 57.7 (10.3) years], 723 (12.6%) had ‘optimal’ BP, 1496 (26.1%) had ‘high normal’ BP, and 1942 (33.9%) were hypertensive. Results According to the European Guidelines stratification of the cardiovascular risk-excess attributable to high BP, 34.7% of the sample had a low added risk and 53.2% had a moderate-to-very high added risk. The pharmacological therapy was prescribed in 22.3, 43.9, 61.4, and 76.9% of the patients with low, moderate, high, and very high added risk, respectively. Conclusion Overall dietary and drug therapies are under prescribed, as most of the treated patients would require two additional antihypertensive drugs to meet the recommended BP target. This effort could provide significant individual benefit to moderate/high-risk patients.

Arachidonic acid metabolism in HEL/30 murine epidermal Cell Line

SummaryThe established mouse epidermis-derived cell line HEL/30 was incubated in the presence of 3H arachidonic acid (AA) for 1 h. After medium removal, cells were reincubated with fresh medium in the presence or absence of the calcium ionophore A23187 and tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The AA metabolites formed were extracted from cell-free medium and analyzed using TLC and HPLC. The distribution of the recovered radioactivity showed PGE2, 15-hydroxy-eicosatetraenoic acid (15-HETE), and leukotriene B4 (LTB4), as major products of AA metabolism. The presence of calcium ionophore A23187 increased the release of radioactivity, without affecting the profile of metabolites present in the medium. TPA elicited a preferential increase of cycloxygenase metabolism, this effect being reversed by indomethacin. 5,8,11,14-eicosatetraynoic acid (ETYA) almost completely inhibited LT and HETE formation in A23187 and TPA-treated cells. The results show that HEL/30 cells are able to metabolize AA via both cyclo-and lipoxygenase pathways and that these activities can be modified by chemical means. This cell line might be a suitable tool for studying the involvement of arachidonic acid cascade in cell response to exogenous stimuli.