Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the mopioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be instrumental to the development of new opioid therapeutics

Fish, Fish-Derived n-3 Fatty Acids, and Risk of Incident Atrial Fibrillation in the Atherosclerosis Risk in Communities (ARIC) Study

Results of observational and experimental studies investigating the association between intake of long-chain n-3 polyunsaturated fatty acids (PUFAs) and risk of atrial fibrillation (AF) have been inconsistent.We studied the association of fish and the fish-derived n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with the risk of incident AF in individuals aged 45-64 from the Atherosclerosis Risk in Communities (ARIC) cohort (n = 14,222, 27% African Americans). Intake of fish and of DHA and EPA were measured via food frequency questionnaire. Plasma levels of DHA and EPA were measured in phospholipids in a subset of participants (n = 3,757). Incident AF was identified through the end of 2008 using ECGs, hospital discharge codes and death certificates. Cox proportional hazards regression was used to estimate hazard ratios of AF by quartiles of n-3 PUFAs or by fish intake.During the average follow-up of 17.6 years, 1,604 AF events were identified. In multivariable analyses, total fish intake and dietary DHA and EPA were not associated with AF risk. Higher intake of oily fish and canned tuna was associated with a nonsignificant lower risk of AF (p for trend = 0.09). Phospholipid levels of DHA+EPA were not related to incident AF. However, DHA and EPA showed differential associations with AF risk when analyzed separately, with lower risk of AF in those with higher levels of DHA but no association between EPA levels and AF risk.In this racially diverse sample, dietary intake of fish and fish-derived n-3 fatty acids, as well as plasma biomarkers of fish intake, were not associated with AF risk

Noise Cancellation using Selectable Adaptive Algorithm for Speech in Variable Noise Environment

Some of the teething problems associated in the use of two-sensor noise cancellation systems are the nature of the noise signals—a problem that imposes the use of highly complex algorithms in reducing the noise. The usage of such methods can be impractical for many real time applications, where speed of convergence and processing time are critical. At the same time, the existing approaches are based on using a single, often complex adaptive filter to minimize noise, which has been determined to be inadequate and ineffective. In this paper, a new mechanism is proposed to reduce background noise from speech communications. The procedure is based on a two-sensor adaptive noise canceller that is capable of assigning an appropriate filter adapting to properties of the noise. The criterion to achieve this is based on measuring the eigenvalue spread based on the autocorrelation of the input noise. The proposed noise canceller (INC) applies an adaptive algorithm according to the characteristics of the input signal. Various experiments based on this technique using real-world signals are conducted to gauge the effectiveness of the approach. Initial results illustrated the system capabilities in executing noise cancellation under different types of environmental noise. The results based on the INC technique indicate fast convergence rates; improvements up to 30 dB in signal-to-noise ratio and at the same time shows 65% reduction of computational power compared to conventional method

Awareness of physicians and pharmacists of aldosterone antagonists in heart failure and myocardial infarction in Jordan

Objective: to evaluate physicians and clinical pharmacists' awareness and practices regarding use of aldosterone antagonists in heart failure (HF) and post-myocardial infarction (MI). Methods: First, we reviewed the prescription of aldosterone antagonists among 408 patients presenting to the cardiology clinic at a major hospital in Jordan. Second, physicians and pharmacists working in cardiovascular departments completed a questionnaire related to use of aldosterone antagonists in HF and post-MI. Results: Thirty patients (7.59%) were eligible for aldosterone antagonist; only 4 received them at discharge (13.3%). The survey was completed by 153 professionals (response rate 76.12%). About 72.1% of participants were aware of studies regarding use of aldosterone antagonists post-MI and in HF. Moreover, 10.45%/53.6% of participants strongly agreed/agreed that these agents are useful in normotensive post-MI and HF patients. Spironolactone was the most prescribed drug by 92.1% of participants. About 41.8% of participants reported use of spironolactone in post-MI and HF. With respect to guidelines, only 39.2% of participants agreed that adding spironolactone to standard therapy in HF is recommended, and 48.3% agreed on adding it directly post-MI. Clinical pharmacists and cardiologists were generally more aware of guidelines than pharmacists, cardiac surgeons and residents/fellows. Conclusions: there is an under-use of aldosterone antagonists in HF and post-MI patients, and a lack of detailed awareness of current guidelines among health care providers. Dissemination of evidence-based guidelines and usage protocols may improve management of post-MI and HF