Delivery and Biodistribution of Traceable Polymeric Micellar Diclofenac in the Rat

The nonsteroidal anti-inflammatory drugs elevate cardiovascular risk, perhaps, due to their accumulation in the heart and kidneys. We designed nanodelivery systems for cardiotoxic diclofenac to reduce its presence in these organs. Diclofenac ethyl ester (DFEE) was encapsulated in traceable micelles based on poly(ethylene oxide)-b-poly(ε-caprolactone) (DFEE-PCL-TM) or poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (DFEE-PBCL-TM). Diclofenac pharmacokinetics and tissue distribution were studied after intravenous (iv) and intraperitoneal administration of the nanoformulations and compared with those after iv doses of free diclofenac (n = 3-6/group). The average diameters for DFEE-PBCL-TM and DFEE-PCL-TM were 37.2 ± 0.06 and 45.1 ± 0.06 nm, respectively. Drug concentration dropped below the assay sensitivity after free drug administration in 6 h, but persisted for 24 h following DFEE-PBCL-TM (2.3 ± 1.4 μg/mL) and DFEE-PCL-TM (1.9 ± 0.6 μg/mL) iv administration. The diclofenac heart:blood and kidney:blood ratios were 5- to 12-fold lower with the nanoformulations than with free diclofenac. Near-infrared fluorescence measurements in tissues suggested exposure patterns to nanocarriers parallel with those achieved for delivered diclofenac by nanoformulations. Administration of DFEE-PCL-TM by iv or intraperitoneal injection, resulted in comparable pharmacokinetics and 6 h postdose near-infrared fluorescence in the heart, kidneys, liver, and spleen. When compared to each other, DFEE-PBCL-TM showed significantly lower diclofenac levels in the heart compared to DFEE-PCL-TM (0.3 ± 0.03 vs. 0.5 ± 0.1 μg/g). Developed nanoformulations of diclofenac prolonged diclofenac circulation and reduced its presence in the heart and kidneys, strongly suggesting cardiac-safe delivery vehicles for diclofenac.     

Antibiotic‐induced Cardiac Arrhythmias

This review aims to clarify the underlying risk of arrhythmia associated with the use of macrolides and fluoroquinolones antibiotics. Torsades de pointes (TdP) is a rare potential side effect of fluoroquinolones and macrolide antibiotics. However, the widespread use of these antibiotics compounds the problem. These antibiotics prolong the phase 3 of the action potential and cause early after depolarization and dispersion of repolarization that precipitate TdP. The potency of these drugs, as potassium channel blockers, is very low, and differences between them are minimal. Underlying impaired cardiac repolarization is a prerequisite for arrhythmia induction. Impaired cardiac repolarization can be congenital in the young or acquired in adults. The most important risk factors are a prolonged baseline QTc interval or a combination with class III antiarrhythmic drugs. Modifiable risk factors, including hypokalemia, hypomagnesemia, drug interactions, and bradycardia, should be corrected. In the absence of a major risk factor, the incidence of TdP is very low. The use of these drugs in the appropriate settings of infection should not be altered because of the rare risk of TdP, except among cases with high‐risk factors.     

Diabetes mellitus, myocardial reperfusion, and outcome in patients with acute ST-elevation myocardial infarction treated with primary angioplasty (from HORIZONS AMI)

Diabetes mellitus (DM) increases mortality in acute ST-segment elevation myocardial infarction (STEMI) but the responsible mechanism is not fully elucidated. We compared the rate of successful myocardial reperfusion measured by tissue myocardial perfusion grade (TMPG) and outcomes in patients with and without DM undergoing primary percutaneous coronary intervention (PCI) for STEMI. Patients enrolled in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS AMI) trial were analyzed according to presence of DM with respect to TMPG after PCI and outcomes at 30 days and 3 years. Multivariable logistic regression was performed to identify the independent contribution to mortality of DM and TMPG and the interaction between the 2 was assessed. Complete data were available for 3,265 patients, of whom 533 (16.3%) had DM. Diabetic patients were significantly older and heavier and had more risk factors for coronary disease and more previous MI, revascularization, and heart failure. There were no differences in rates of Thrombolysis In Myocardial Infarction grade 3 flow after PCI in the infarct artery or TMPG 2/3 between patients with and without DM. Compared to nondiabetics, mortality was significantly higher at 30 days and at 3 years in the DM group (1.8% vs 4.5%, p = 0.0002 and 5.4% vs 11.0%, p <0.0001, respectively). DM and TMPG were significantly associated with 3-year mortality, but there was no statistical interaction between DM and TMPG (p = 0.70). In conclusion, DM is associated with a significantly higher risk of death but this association is not mediated by impaired epicardial or myocardial reperfusion.     

Serum adenosine deaminase may predict disease activity in rheumatoid arthritis

To determine the relationship between serum adenosine deaminase (ADA) and disease activity, and to develop a new disease activity index based on serum ADA in rheumatoid arthritis (RA). Seventy RA patients were included. Disease activity based on Disease Activity Score 28-ESR (DAS28-ESR) and Disease Activity Score 28-CRP (DAS28-CRP) and serum ADA were measured. There were correlations when serum ADA compared with DAS28-ESR and DAS28-CRP. (R ²?=?0.014, 0.175, respectively, P values?<?0.00). New disease activity index was developed by replacing ADA with ESR and CRP in DAS28-ESR and DAS28-CRP. There were strong correlations when new model compared with DAS28-ESR and DAS28-CRP. (R ²?=?0.94 and 0.95, respectively, P values?<?0.00) The best new model values corresponding to DAS28-ESR values of 2.6, 3.2, and 5.1 were 2.79, 3.4, and 4.82, respectively; and new model values corresponding to DAS28-CRP values of 2.3, 2.7, and 4.1 were 2.1, 2.9, and 4, respectively. There were agreements when the new model compared with DAS28-ESR and DAS28-CRP for determination of patients in different disease activity categories. (Kappa?=?0.81 and 0.71, respectively, P values?<?0.00). The new disease activity index that applies serum ADA may help in predicting disease activity in RA.     

Contemporary approaches to treatment of beta-thalassemia intermedia

Beta-thalassemia intermedia (TI) is associated with a variety of serious clinical complications that require proactive and comprehensive management. These include skeletal deformities and osteopenia, compensatory extramedullary hematopoiesis and tumor formation, progressive splenomegaly, a hypercoagulable state resulting in thromboembolic events and pulmonary hypertension, and increased gastrointestinal iron absorption that often results in nontransfusional iron overload and liver damage. Although TI is generally considered a non-transfusion-dependent thalassemia, transfusion therapy may be an important part of the comprehensive management of this disease. This review describes the current state of the art for medical management of TI, with particular focus on the roles of splenectomy, transfusion, and iron chelation therapy.     

Brain Inconspicuous Effect by Local Sinusoidal Extremely Low Frequency Magnetic Exposure Based on Wavelet Packet Analysis: Innovation in Online Passive Neurofeedback Therapy by the Neuro-LSELF System

Neurofeedback (NF) is a training approach that aims to reinforce brain activity by using the information of human electroencephalogram (EEG) rhythms as a feedback. In addition, some studies have reported Extremely Low Frequency (0–300 Hz, intensity < 500 µT) Magnetic Field (ELF MF) effects upon the EEG and its rhythms. The purpose of this study is to determine if an approach that combines the effects of Local Sinusoidal Extremely Low Frequency Magnetic Fields (LSELF MF) with NF yields higher performance on desired NF goals. The NF protocol used in this study consisted of enhancement of the beta rhythm and inhibition of theta and high beta rhythms in exposed and sham groups for the purpose of improving attention. Twenty-four healthy subjects of at least average intelligence attended 10 sessions of NF training. Sixteen of them were exposed to 45 Hz sinusoidal ELF (360 µT) at F3 to lead to the desired LSELF MF effects on Cz. Wavelet packet analysis was used for the detection of changes in EEG rhythms. Results suggest that, compared to sham exposure, LSELF magnetic waves can significantly affect and modulate brainwaves according to this new neurofeedback approach. In comparison to sham exposure, improved ability to attend (as measured by a decrease in the theta-to-beta ratio) was observed when LSELF MF was combined with NF (p < .05). The hypothesis that LSELF MF can affect the theta-to-beta ratio was confirmed. These effects occurred after approximately 10 min of each NF procedure. This study aimed to pilot a new NF system known as the Neuro-ELF system, a method that may allow for more effective control of brainwave activity. However, we suggest that the effects of LSELF-NF require further research.     

A Sensitivity Analysis to the Role of the Fronto‐Parietal Suture in Lacerta Bilineata: A Preliminary Finite Element Study

Cranial sutures are sites of bone growth and development but micromovements at these sites may distribute the load across the skull more evenly. Computational studies have incorporated sutures into finite element (FE) models to assess various hypotheses related to their function. However, less attention has been paid to the sensitivity of the FE results to the shape, size, and stiffness of the modeled sutures. Here, we assessed the sensitivity of the strain predictions to the aforementioned parameters in several models of fronto‐parietal (FP) suture in Lacerta bilineata. For the purpose of this study, simplifications were made in relation to modeling the bone properties and the skull loading. Results highlighted that modeling the FP as either an interdigitated suture or a simplified butt suture, did not reduce the strain distribution in the FP region. Sensitivity tests showed that similar patterns of strain distribution can be obtained regardless of the size of the suture, or assigned stiffness, yet the exact magnitudes of strains are highly sensitive to these parameters. This study raises the question whether the morphogenesis of epidermic scales in the FP region in the Lacertidae is related to high strain fields in this region, because of micromovement in the FP suture. Anat Rec, 2013. © 2012 Wiley Periodicals, Inc.