Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as ‘legal highs’ in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many ‘legal highs’, little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine

Nitric Oxide Releasing Materials Triggered by Near-Infrared Excitation Through Tissue Filters

Novel materials for the phototherapeutic release of the bioregulator nitric oxide (nitrogen monoxide) are described. Also reported is a method for scanning these materials with a focused NIR beam to induce photouncaging while minimizing damage from local heating. The new materials consist of poly(dimethylsiloxane) composites with near-infrared-to-visible upconverting nanoparticles (UCNPs) that are cast into a biocompatible polymer disk (PD). These PDs are then impregnated with the photochemical nitric oxide precursor Roussin's black salt (RBS) to give UCNP_RBS_PD devices that generate NO when irradiated with 980 nm light. When the UCNP_RBS_PD composites were irradiated with NIR light through filters composed of porcine tissue, physiologically relevant NO concentrations were released, thus demonstrating the potential of such devices for minimally invasive phototherapeutic applications

Narcissistic Features in Young Adolescents: Relations to Aggression and Internalizing Symptoms

Recent research and theory suggest narcissistic features contribute to aggression in adults. The present study examined the association of narcissistic features with aggression and internalizing symptoms in 233 students of 5th–8th grade at three inner-city schools. A factor analysis of the Narcissistic Personality Inventory in this sample revealed three factors: Adaptive Narcissism, Exploitativeness, and Exhibitionism. Regression analyses were used to predict the association of these three narcissistic features with self-, teacher-, and peer-reported aggression and self-reported internalizing symptoms. Results indicate narcissistic exploitativeness positively predicted self-reported proactive aggression, and narcissistic exhibitionism positively predicted internalizing symptoms. Narcissism and self-esteem interacted to predict teacher-reported aggression and self-reported internalizing symptoms. Results are discussed in the context of existing theories of narcissism, threatened egotism, and self-perception bias.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45298/1/10964_2004_Article_485227.pd

Self-Reported Wisdom and Happiness: An Empirical Investigation

Possible tensions between wisdom and happiness have been extensively debated in philosophy. Some regard wisdom as the 'supreme part of happiness', whereas other think that a more accurate and wiser view on reality might reduce happiness. Analyzing a Dutch internet survey of 7037 respondents, we discovered that wisdom and happiness were modestly positively related. Wisdom, measured with the Three-Dimensional Wisdom Scale (3D-WS), explained 9.2% of the variation in hedonic happiness. The correlation with the reflective dimension of wisdom was the strongest. In addition, wisdom was more important for happiness among adults with only an elementary education. Our results suggest that happiness and wisdom do not conflict

A retrospective review of outcomes and flap selection in free tissue transfers for complex lower extremity reconstruction.

PURPOSE: Complex lower extremity wounds present a significant challenge to the reconstructive surgeon. We report a consecutive experience of free tissue transfers for lower extremity reconstruction with a focus on outcomes and flap selection. METHODS: A retrospective review of all free tissue transfers for lower extremity reconstruction between 2006 and 2011 was performed. Minor complications were defined as nonoperative complications (infection, seroma, hematoma, wound breakdown, and partial loss). Major complication required a surgical intervention (total flap loss, thrombosis, nonunion, amputation, and hematoma). RESULTS: A total of 119 free flaps were performed in 114 patients. Reconstructed defects were most commonly derived from acute traumatic (N = 40) or chronic traumatic (N = 34) wounds, oncologic (N = 14), or diabetic (N = 8). Flap loss occurred at a rate of 5.9% and the overall lower extremity salvage rate was 93%. Complications were significantly higher for free tissue transfers to the region of the distal tibia (p = 0.04). Major complications were significantly higher in patients with chronic obstructive pulmonary disease (p = 0.02) and in patients who experienced intraoperative technical difficulties (p = 0.014). Flap loss was significantly higher when the rectus abdominis flap was used (p = 0.02) and when a delayed venous thrombotic event occurred (p = 0.001). CONCLUSION: Patient comorbidities and defect location can be associated with higher rates of complications; flap selection and delayed venous thrombotic events appear to be associated with flap failure.Level of Evidence Prognostic/risk category, level III