Improvement in Solubility and Molecular Assembly of Cyclopentadithiophene–Benzothiadiazole Polymer

Using linear side chains for conjugated polymers is hindered by their limited solubility in common organic solvents, creating problems during purification and processing, whereas branched alkyl chains generally preclude interchain interdigitation because their bulkiness usually hinders interchain interactions. To compensate the adverse effects from each side chain, it is shown that replacing commonly employed 2‐ethylhexyl (2EH) solubilizing groups with branched 5‐ethylnonyl (5EN) chains not only improves solution processability to PCDT‐BT polymer, but also induces an advantageous change in polymer self‐assembly and backbone orientation in thin films that correlates with an increase in transistor performance.

     

Mid-infrared spectroscopy and microscopy of subcellular structures in eukaryotic cells with atomic force microscopy – infrared spectroscopy

Atomic force microscopy – infrared (AFM-IR) spectroscopy allows spectroscopic studies in the mid-infrared (mid-IR) spectral region with a spatial resolution better than is allowed by the diffraction limit. We show that the high spatial resolution can be used to perform spectroscopic and imaging studies at the subcellular level in fixed eukaryotic cells. We collect AFM-IR images of subcellular structures that include lipid droplets, vesicles and cytoskeletal filaments, by relying on the intrinsic contrast from IR light absorption. We also obtain AFM-IR absorption spectra of individual subcellular structures. Most spectra show features that are recognizable in the IR absorption spectra of cells and tissue obtained with FTIR technology, including absorption bands characteristic of phospholipids and polypeptides. The quality of the spectra and of the images opens the way to structure and composition studies at the subcellular level using mid-IR absorption spectroscopy.

Atomic force microscopy – infrared (AFM-IR) spectroscopy allows spectroscopic studies in the mid-infrared (mid-IR) spectral region with a spatial resolution better than is allowed by the diffraction limit.     

Electrochemical and optoelectronic properties of terthiophene- and bithiophene-based polybenzofulvene derivatives

The electrochemical behavior of some polybenzofulvene derivatives bearing bithiophene (BT) or terthiophene (TT) side chains was investigated by cyclic voltammetry. Very interestingly, the presence of unsubstituted terminal thiophene moieties allowed poly-6-BT-BF3k and poly-6-TT-BF3k to be cross-linked by electrochemical procedures. Conductive films were obtained by electrodeposition from solutions of these polymers onto electrode surfaces through the formation of covalent cross-linking due to dimerization (i.e. electrochemical oxidation) of the BT or TT side chains. The films showed electrochromic features and switched from yellow-orange (neutral) to green (positively charged) by switching the potential, and were stable to tenths of cycles, without degradation in the wet state in the electrolyte solution. Finally, the thin film obtained by electrodeposition of poly-6-TT-BF3k on a indium tin oxide (ITO) glass substrate showed in the neutral state a significantly red-shifted photoluminescence (PL) emission (∼40 nm red-shifted with respect to that of the corresponding film obtained by casting procedures), which was consistent with the presence of more conjugated moieties produced by the oxidative dimerization of the TT side chains. The innovative architecture and the easy preparation could lead to a broad range of applications in optoelectronics and bioelectronics for these cross-linked hybrid materials based on π-stacked polybenzofulvene backbones bearing oligothiophene side chains.

The electrochemical behavior of some polybenzofulvene derivatives bearing bithiophene (BT) or terthiophene (TT) side chains was investigated by cyclic voltammetry and cross-linked materials were obtained by dimerization of the BT or TT side chains.     

Oral Prolonged‐Release Oxycodone/Naloxone for Managing Pain and Opioid‐Induced Constipation: A Review of the Evidence

Background

Opioids provide effective relief from moderate‐to‐severe pain and should be prescribed as part of a multifaceted approach to pain management when other treatments have failed. Fixed‐dose oxycodone/naloxone prolonged‐release tablets (OXN PR) were designed to address the opioid class effect of opioid‐induced constipation (OIC) by combining the analgesic efficacy of oxycodone with the opioid receptor antagonist, naloxone, which has negligible systemic availability when administered orally. This formulation has abuse‐deterrent properties, since systemic exposure to naloxone by parenteral administration would antagonize the euphoric effects of oxycodone.

Methods

A literature search was conducted to assess the evidence base for OXN PR to treat moderate‐to‐severe pain and its impact on bowel function, based on published clinical trials and observational studies.

Results

Extensive data demonstrate that OXN PR provides effective analgesia and clinically relevant improvements in bowel function in patients with OIC and moderate‐to‐severe cancer‐related pain and noncancer pain types such as low back pain, neuropathic pain, and musculoskeletal pain. OXN PR has also been found to improve bowel function in patients with OIC refractory to multiple types of laxatives, and improve Parkinson's disease–related pain. No unanticipated safety concerns have been reported in elderly patients.

Conclusions

Evidence from clinical trials and observational studies confirms that for selected patients OXN PR significantly improves moderate‐to‐severe chronic pain and provides relief from OIC. Treatment should be tailored to individual patients to establish the lowest effective dose. An absence of analgesic ceiling effect was seen across the clinically relevant dose range investigated (≤ 160/80 mg/day).     

The influence of substituent field and resonance effects on the ease of N-heterocyclic carbene formation from imidazolium rings

Using a set of twelve selected substituents, the influence of substituent properties on the ease of deprotonation of imidazolium cations and mesoionic imidazolium-4-olates measured by the CREF index has been investigated. Significant correlations between CREF values and the Swain and Lupton field (F) and resonance (R) substituent constants have been found. In all cases the field effect has the greatest influence but resonance effects are also significant.

The influence of substituents on the relative acidity of C–H bonds.     

Troglitazone amplifies counterregulatory responses to hypoglycemia in nondiabetic subjects

As insulin sensitizers, thiazolidinediones could affect the hormonal counterregulatory response to hypoglycemia via the modulatory effect of insulin on counterregulation. In addition, recent studies suggest that thiazolidinediones may influence key steps in glucose sensing and glucoregulatory hormone secretion. We therefore evaluated the effects of a short course of troglitazone on counterregulatory hormones in response to mild hypoglycemia in eight lean nondiabetic subjects. Subjects received either troglitazone (400 mg/day) or placebo for 7 days before stepped hypoglycemia clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/L target plasma glucose steps, 50 min each). The glycemic thresholds for secretion of epinephrine (3.77 +/- 0.05 mmol/L) and glucagon (3.83 +/- 0.11 mmol/L) were reset to a higher plasma glucose concentration after troglitazone [4.05 +/- 0.05 mmol/L (P = 0.003) and 4.10 +/- 0.05 mmol/L (P = 0.03), respectively]. In addition, the magnitude of the rise in epinephrine and glucagon concentrations was higher with troglitazone (28% and 11%, respectively; P < 0.05 for both), whereas plasma norepinephrine, GH, and cortisol were comparable in both sets of studies. Endogenous glucose production, measured with [3-(3)H]glucose, rose by 33% (P < 0.05) in the troglitazone studies compared with 17% (P = NS) after placebo. We conclude that thiazolidinediones may induce an amplification of the counterregulatory response to hypoglycemia characterized by a shift in the glycemic threshold for and an increase in the magnitude of glucagon and epinephrine secretion, and subsequent activation of glucose production.     

Investigating the effect of sotalol on the repolarization intervals in healthy young individuals

Background

The dissociation between a drug-induced increase of the QT interval prolongation and an increased risk for ventricular arrhythmias has been suggested by academic investigators and regulatory agencies. Yet, there are no alternative or complimentary electrocardiographic (ECG) techniques available for assessing the cardiotoxicity of novel compounds. In this study, we investigated a set of novel ECG parameters quantifying the morphology of the T-loop. In a group of healthy individuals exposed to sotalol, we compared their drug-induced changes to the drug-induced prolongations of the QTc, QTc apex and T-peak to T-end intervals.

Methods

We implemented a set of parameters describing the morphology of the T loop in its preferential plane. These parameters measure the time interval needed for the heart vector amplitude to change from its maximum value to a time when its amplitude has been reduced by 30%, 50%, and 70%. These measurements are called early repolarization duration (ERD) when they are located before the T-wave apex and late repolarization duration (LRD) when measured after the apex. They depend on both the speed of the repolarization process and the morphology of the T loop. Thirty-nine healthy individuals were exposed to sotalol in a crossover-design study. Sixteen ECGs were recorded per day during 3 days. The first day (day 0) was baseline; a single dose of sotalol (160 mg) was given during day 1, and a double dose was given during day 2 (320 mg). The plasma concentration of the drug was measured just before the ECG recordings.

Results

The values of all investigated parameters revealed a dose-dependent effect of sotalol (in average between parameters, ρ = 0.9, P < .001). Our investigations described profound and statistically significant changes in the morphology of the vectorial T loop for day 1 (peak effect of sotalol: ΔERD_50% = 23 ± 6 msec, P < .05; ΔLRD_50% = 8 ± 3 msec, P = .05) and day 2 (peak effect of sotalol: ΔERD_50% = 51 ± 14 msec, P < .05; ΔLRD_50% = 20 ± 12 msec, P = .05). When investigating the timing of peak drug concentration and peak effect of the drug on the various repolarization parameters, we found asynchrony between ERDs/LRDs (≥3.5 hours after dosing) and QTc/QTc apex profiles (<3.5 hours after dosing), suggesting that the time of maximum prolongation on the repolarization process was not synchronized with the time of maximum drug-induced heterogeneity of repolarization.

Conclusion

This study describes the sotalol-induced changes of the T-loop morphology in healthy individuals based on novel vectocardiographic parameters. These observations might help in improving the next generation of ECG markers for the evaluation of drug cardiotoxicity.     

Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of major depressive disorder. A number of studies have shown that this dysregulation is correlated with impaired forebrain glucocorticoid receptor (GR) function. To determine whether a primary, acquired deficit in forebrain GR signaling is an etiologic factor in the pathogenesis of depression, we generated a line of mice with time-dependent, forebrain-specific disruption of GR (FBGRKO). These mice develop a number of both physiological and behavioral abnormalities that mimic major depressive disorder in humans, including hyperactivity of the HPA axis, impaired negative feedback regulation of the HPA axis and, increased depression-like behavior. Importantly, a number of these abnormalities are normalized by chronic treatment with the tricyclic antidepressant, imipramine. Our findings suggest that imipramine's proposed activities on forebrain GR function are not essential for its antidepressant effects, and that alteration in GR expression may play a causative role in disease onset of major depressive disorder.     

Time dependence of defibrillator benefit after coronary revascularization in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II.

OBJECTIVES: The study was designed to assess the effect of elapsed time from coronary revascularization (CR) on the benefit of the implantable cardioverter-defibrillator (ICD) and the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. BACKGROUND: The ICD improves survival in appropriately selected high-risk cardiac patients by 30% to 54%. However, in the Coronary Artery Bypass Graft (CABG)-Patch trial no evidence of improved survival was shown among a similar population of patients in whom an ICD was implanted prophylactically at the time of elective CABG. METHODS: The outcome by time from CR was analyzed in 951 patients in whom a revascularization procedure was performed before enrollment in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. RESULTS: The adjusted hazard ratio (HR) of ICD versus conventional therapy was 0.64 (p = 0.01) among patients enrolled more than six months after CR, whereas no survival benefit with ICD therapy was shown among patients enrolled six months or earlier after CR (HR = 1.19; p = 0.76). In the conventional therapy group, the risk of cardiac death increased significantly with increasing time from CR (p for trend = 0.009), corresponding mainly to a six-fold increase in the risk of SCD among patients enrolled more than six months after CR. CONCLUSIONS: In patients with ischemic left ventricular dysfunction, the efficacy of ICD therapy after CR is time dependent, with a significant life-saving benefit in patients receiving device implantation more than six months after CR. The lack of ICD benefit when implanted early after CR may be related to a relatively low risk of SCD during this time period.