ALBERT

Description: Abstract 4966 Background Doxorubicin (DOX) and related drugs are incompletely cleared from the heart, persist for months to years (Stewart et al Anticancer Res 1993), and slowly transform to longer-lived and more toxic secondary alcohol metabolites (eg, DOXOL) that are associated with an increased lifetime risk of congestive heart failure (Minotti et al J Pharmacol Exp Ther 2010). Anthracycline-related cardiotoxicity can be precipitated by enhanced stress or exposure to drugs that increase DOXOL formation. PIX is a novel aza-anthracenedione that is under development in patients with NHL that relapsed or was refractory after DOX-containing combination therapy. In preclinical models, PIX produced substantially less cardiotoxicity than DOX or MITOX even when animals were pretreated with DOX. Compared to anthracyclines and the anthracenedione analogue, mitoxantrone (MITOX), PIX lacks a hydroquinone moiety that binds iron and facilitates cardiotoxic free radical reactions. To further establish that it is safe in patients with NHL and prior DOX exposure, PIX should also have no effect on or diminish DOXOL formation from the cardiac residues of first-line DOX. Aims To characterize the effects of PIX on DOXOL formation in a translational cardiac model of DOX administration followed by PIX administration. MITOX was used as the comparator. Methods Myocardial samples that were routinely discarded during aorto-coronary bypass grafting were dissected into strips and loaded with 10 μM DOX in plasma. After 30 min the strips were subjected to 2h multiple washouts to simulate post-treatment clearance. The strips were then incubated for 1.5h in fresh anthracycline-free plasma w/wo 1 μM PIX or MITOX. After the experiments, DOX(OL), PIX, and MITOX were extracted from the soluble fractions of the strips and assayed by HPLC. Pharmacometabolic interactions of 10 μM or 50 μM DOX with increasing concentrations of PIX or MITOX were also studied in NADPH-supplemented isolated soluble fractions. Results After sequential DOX loading/clearance and PIX or MITOX administration, PIX:DOX ratios were significantly higher than MITOX:DOX ratios in soluble fractions of human myocardial strips. This correlated with inhibition of DOXOL formation by both PIX and MITOX, but PIX decreased DOXOL levels in a significant manner when compared to MITOX (Table). In isolated soluble fractions, both PIX and MITOX, in a concentration-dependent manner, inhibited the metabolism of 10 μM DOX to DOXOL; however, PIX caused stronger inhibition (Figure). Increasing DOX to 50 μM abated inhibition by MITOX but not by PIX. Discussion PIX inhibited DOXOL formation in a translation model of human heart used to simulate sequential DOX and PIX administration. This finding was obtained under pharmacokinetically relevant conditions that probed DOX and PIX at their clinically documented plasma Cmax values of 10 μM or 1 μM, respectively. Studies with isolated soluble fractions suggest that PIX diminished DOXOL formation by noncompetitive inhibition of NADPH-dependent reductases. MITOX was less effective than PIX at diminishing DOXOL formation, which correlated with the lower MITOX:DOX ratios in treated human myocardial strips and with the competitive mode of action of MITOX. By inhibiting formation of toxic and long-lived DOXOL, PIX potentially is a cardiac tolerable therapeutic agent for patients with NHL that failed or relapsed after DOX treatment. Inhibition of DOXOL formation by PIX and MITOX in isolated soluble fractions of human myocardium incubated with NADPH (0.25 mM) and DOX for 4h. Control DOXOL was 0.15–0.19 nmoles/mg of protein at 10 μM DOX and 0.34–0.84 nmoles/mg of protein at 50 μM DOX. Each inhibition curve is the mean and SE of three experiments. Disclosures: Salvatorelli: Cell Therapeutics, Inc: Research Funding. Gonzalez Paz:Cell Therapeutics, Inc: Research Funding. Singer:Cell Therapeutics, Inc: Employment. Menna:Cell Therapeutics, Inc: Research Funding. Minotti:Cell Therapeutics, Inc: Research Funding.

Description: The use of wearable sensors for health monitoring is rapidly growing. Over the past decade, wearable technology has gained much attention from the tech industry for commercial reasons and the interest of researchers and clinicians for reasons related to its potential benefit on patients’ health. Wearable devices use advanced and specialized sensors able to monitor not only activity parameters, such as heart rate or step count, but also physiological parameters, such as heart electrical activity or blood pressure. Electrocardiogram (ECG) monitoring is becoming one of the most attractive health-related features of modern smartwatches, and, because cardiovascular disease (CVD) is one of the leading causes of death globally, the use of a smartwatch to monitor patients could greatly impact the disease outcomes on health care systems. Commercial wearable devices are able to record just single-lead ECG using a couple of metallic contact dry electrodes. This kind of measurement can be used only for arrhythmia diagnosis. For the diagnosis of other cardiac disorders, additional ECG leads are required. In this study, we characterized an electronic interface to be used with multiple contactless capacitive electrodes in order to develop a wearable ECG device able to perform several lead measurements. We verified the ability of the electronic interface to amplify differential biopotentials and to reject common-mode signals produced by electromagnetic interference (EMI). We developed a portable device based on the studied electronic interface that represents a prototype system for further developments. We evaluated the performances of the developed device. The signal-to-noise ratio of the output signal is favorable, and all the features needed for a clinical evaluation (P waves, QRS complexes and T waves) are clearly readable.

Description: Atherosclerosis-related coronary artery disease (CAD) is one of the leading sources of mortality and morbidity in the world. Primary and secondary prevention appear crucial to reduce CAD-related complications. In this scenario, statin treatment was shown to be clinically effective in the reduction of adverse events, but systemic administration provides suboptimal results. As an attempt to improve bioavailability and effectiveness, polymers and nanoparticles for statin delivery were recently investigated. Polymers and nanoparticles can help statin delivery and their effects by increasing oral bioavailability or enhancing target-specific interaction, leading to reduced vascular endothelial dysfunction, reduced intimal hyperplasia, reduced ischemia-reperfusion injury, increased cardiac regeneration, positive remodeling in the extracellular matrix, reduced neointimal growth and increased re-endothelization. Moreover, some innovative aspects described in other cardiovascular fields could be translated into the CAD scenario. Recent preclinical studies are underlining the effect of statins in the stimulation and differentiation of endogenous cardiac stem cells, as well as in targeting of local adverse conditions implicated in atherosclerosis, and statin delivery through poly-lactic-co-glycolic acid (PLGA) appears the most promising aspect of current research to enhance drug activity. The present review intends to summarize the current evidence about polymers and nanoparticles for statin delivery in the field of cardiovascular disease, trying to shed light on this topic and identify new avenues for future studies.