Anomalous radial artery anatomy is relatively common and is a significant cause of procedural failure. Within each specific anomalous pattern there is a differential procedural failure rate. This has implications for clinical practice and suggests a need for imaging of the radial artery after sheath insertion.
Efforts to apply nanotechnology in cancer have focused almost exclusively on the delivery of cytotoxic drugs to improve therapeutic index. There has been little consideration of molecularly targeted agents, in particular kinase inhibitors, which can also present considerable therapeutic index limitations. We describe the development of Accurin polymeric nanoparticles that encapsulate the clinical candidate AZD2811, an Aurora B kinase inhibitor, using an ion pairing approach. Accurins increase biodistribution to tumor sites and provide extended release of encapsulated drug payloads. AZD2811 nanoparticles containing pharmaceutically acceptable organic acids as ion pairing agents displayed continuous drug release for more than 1 week in vitro and a corresponding extended pharmacodynamic reduction of tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration. A specific AZD2811 nanoparticle formulation profile showed accumulation and retention in tumors with minimal impact on bone marrow pathology, and resulted in lower toxicity and increased efficacy in multiple tumor models at half the dose intensity of AZD1152, a water-soluble prodrug of AZD2811. These studies demonstrate that AZD2811 can be formulated in nanoparticles using ion pairing agents to give improved efficacy and tolerability in preclinical models with less frequent dosing. Accurins specifically, and nanotechnology in general, can increase the therapeutic index of molecularly targeted agents, including kinase inhibitors targeting cell cycle and oncogenic signal transduction pathways, which have to date proved toxic in humans.
Background-Therapies for patients with chronic heart failure caused by left ventricular systolic dysfunction have advanced substantially over recent decades. The cumulative effect of these therapies on mortality, mode of death, symptoms, and clinical characteristics has yet to be defined. Methods and Results-This study was a comparison of 2 prospective cohort studies of outpatients with chronic heart failure caused by left ventricular systolic dysfunction performed between 1993 and 1995 (historic cohort: nϭ281) and 2006 and 2009 (contemporary cohort: nϭ357). In the historic cohort, 83% were prescribed angiotensin-converting enzyme inhibitors and 8.5% were prescribed -adrenoceptor antagonists, compared with 89% and 80%, respectively, in the contemporary cohort. Mortality rates over the first year of follow-up declined from 12.5% to 7.8% between eras (Pϭ0.04), and sudden death contributed less to contemporary mortality (33.6% versus 12.7%; PϽ0.001). New York Heart Association class declined between eras (PϽ0.001). QTc dispersion across the chest leads declined from 85 ms (SD, 2) to 34 ms (SD, 1) and left ventricular end-diastolic dimensions declined from 65 mm (SD, 0.6) to 59 mm (SD, 0.5) (both PϽ0.001). Conclusions-Survival has significantly improved in patients with chronic heart failure caused by left ventricular systolic dysfunction over the past 15 years; furthermore, sudden death makes a much smaller contribution to mortality, and noncardiac mortality is a correspondingly greater contribution. This has been accompanied by an improvement in symptoms and some markers of adverse electric and structural left ventricular remodeling. (Circ Heart Fail. 2011;4: 396-403.)
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