Development of magnetically aligned phospholipid bilayers in mixtures of palmitoylstearoylphosphatidylcholine and dihexanoylphosphatidylcholine by solid-state NMR spectroscopy

AbstractThis study reports the solid-state NMR spectroscopic characterization of a long chain phospholipid bilayer system which spontaneously aligns in a static magnetic field. Magnetically aligned phospholipid bilayers or bicelles are model systems which mimic biological membranes for magnetic resonance studies. The oriented membrane system is composed of a mixture of the bilayer forming phospholipid palmitoylstearoylphosphatidylcholine (PSPC) and the short chain phospholipid dihexanoylphosphatidylcholine (DHPC) that breaks up the extended bilayers into bilayered micelles or bicelles that are highly hydrated (approx. 75% aqueous). Traditionally, the shorter 14 carbon chain phospholipid dimyristoylphosphatidylcholine (DMPC) has been utilized as the bilayer forming phospholipid in bicelle studies. Alignment (perpendicular) was observed with a PSPC/DHPC q ratio between 1.6 and 2.0 slightly above Tm at 50°C with 2H and 31P NMR spectroscopy. Paramagnetic lanthanide ions (Yb3+) were added to flip the bilayer discs such that the bilayer normal was parallel with the static magnetic field. The approx. 1.8 (PSPC/DHPC) molar ratio yields a thicker membrane due to the differences in the chain lengths of the DMPC and PSPC phospholipids. The phosphate-to-phosphate thickness of magnetically aligned PSPC/DHPC phospholipid bilayers in the Lα phase may enhance the activity and/or incorporation of different types of integral membrane proteins for solid-state NMR spectroscopic studies

Pharmacodynamic differentiation of lorazepam sleepiness and dizziness using an ordered categorical measure

Categorical measures of lorazepam sleepiness and dizziness were modeled to identify differences in pharmacodynamic (PD) parameters between these adverse events (AEs). Differences in data-derived PD parameters were compared with relative incidence rates in the drug label (15.7% and 6.9%, respectively). Healthy volunteers ( n  = 20) received single oral doses of 2 mg lorazepam or placebo in a randomized, double-blind, cross-over fashion. A seven-point categorical scale measuring the intensity of AEs was serially administered over 24 h. The maximum score (MaxS), and area under the effect curve (AUEC) were determined by noncompartmental methods and compared using a paired t -test. Individual scores were modeled using a logistic function implemented in NONMEM. AUEC and MaxS for sleepiness were significantly higher than dizziness (20.35 vs. 9.76, p  < 0.01) and (2.35 vs. 1.45, p  < 0.01). Model slope estimates were similar for sleepiness and dizziness (0.21 logits × mL/ng vs. 0.19 logits × mL/ng), but baseline logits were significantly higher for sleepiness (−2.81 vs. −4.34 logits). Data-derived PD parameters were in concordance with label incidence rates. The higher intensity of sleepiness may be directly related to baseline (no drug present) while the increase in intensity as a result of drug was relatively similar for both AEs. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3628–3641, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77428/1/22093_ftp.pd

Sexual Hookups via Dating Apps: A Qualitative Study Exploring the Experiences of Black Men Who Have Sex with Men in Florida

Background: Sexual hookups via social media dating apps have been understudied among Black men who have sex with men (BMSM). Purpose: The objective of this qualitative study was to explore the role of dating apps on hookup culture and to describe the sexual experiences among BMSM in Florida. Specifically, this research delves into various sexual hookup themes. Methods: Seventeen semi-structured interviews were conducted with BMSM participants aged 18 to 25 in Florida who self-identified as frequent dating app users. A grounded theory approach was applied to thematically analyze the hookup encounters and the factors that drive these perceptions and experiences among BMSM. QSR NVIVO 12 was used to code, categorize, and collect emergent themes. Results: Three major themes emerged depicting the complexities of hookup culture using social media dating applications among BMSM. 1. Positive hookup experiences were linked to feelings of “no strings attached” to some participants, while others associated this positive experience to the use of alcohol and drugs; 2. Negative hookup experiences revolved around miscommunication on sexual roles, catfishing, and disclosure of HIV status; 3. Psychological aspects of hookups were centered on feelings of regret, disbelief, and disgust after a sexual hookup encounter. Discussion: Understanding BMSM hookup culture could aid in the development of prioritized evidence-based interventions for behavioral change to improve safer sexual health encounters among this vulnerable populatio

Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children.

OBJECTIVES: The objectives of this study were to investigate the population pharmacokinetics of posaconazole in immunocompromised children, evaluate the influence of patient characteristics on posaconazole exposure and perform simulations to recommend optimal starting doses. METHODS: Posaconazole plasma concentrations from paediatric patients undergoing therapeutic drug monitoring were extracted from a tertiary paediatric hospital database. These were merged with covariates collected from electronic sources and case-note reviews. An allometrically scaled population-pharmacokinetic model was developed to investigate the effect of tablet and suspension relative bioavailability, nonlinear bioavailability of suspension, followed by a step-wise covariate model building exercise to identify other important sources of variability. RESULTS: A total of 338 posaconazole plasma concentrations samples were taken from 117 children aged 5 months to 18 years. A one-compartment model was used, with tablet apparent clearance standardised to a 70-kg individual of 15 L/h. Suspension was found to have decreasing bioavailability with increasing dose; the estimated suspension dose to yield half the tablet bioavailability was 99 mg/m2. Diarrhoea and proton pump inhibitors were also associated with reduced suspension bioavailability. CONCLUSIONS: In the largest population-pharmacokinetic study to date in children, we have found similar covariate effects to those seen in adults, but low bioavailability of suspension in patients with diarrhoea or those taking concurrent proton pump inhibitors, which may in particular limit the use of posaconazole in these patients

The Pain That Love Produced

The Pain that Love Produced examines our obsession with the warrior persona in contemporary society. I am exploring the way this fixation relates to soldiers and athletes, and how their worlds intersect. This is part of a larger conversation about race and privilege in America. My sculpture is a critique of the impact of gladiator sports and war, and the peripheral damage they cause to marginalized groups, particularly young, Black men and their families. I depict the peripheral events of conflict through dioramic arrangements and highly-representational figures which also reflect my own experiences of sports and military engagement. I am interested in the socio-political expression of sculpture from Hellenistic through present times. This propels me to consider who determines what is art and what is war. My efforts are a mesh of allegorical imagery, color, texture and surface contrasts. I employ a method I call Neo-Maché Art. With bits of paper and ordinary glue, I use this time-extensive, laborious process to render the intricate and specific details of human anatomy to make hyper-realistic works that portray scenes from wearying events. I also experiment with assemblage to explore psychological states, deterioration, fragmentation, and the experiences of danger and intimidation. In short, a metaphorical splintering. I am looking at the caste system of games, from players to sports fans. I want the viewer to feel the physical exertion of competition. My depictions of athletes allow others to apprehend a Black man’s state of mind every day when, or if he wakes up. My project is a story of expendability

Pharmacokinetics of a single dose of the antifungal posaconazole as oral suspension in subjects with hepatic impairment

Abstract Objective: To evaluate posaconazole pharmacokinetics in subjects with different degrees of hepatic impairment compared with matched healthy subjects. Research design and methods: A total of 37 subjects were enrolled in this open-label, single-dose, parallel-group study; 19 with hepatic impairment and 18 healthy subjects with matching demographics. Each subject received a single 400-mg oral dose of posaconazole after a high-fat meal. Blood samples for analysis were taken up to 648 h (∼4 weeks) postdose. Results: Compared with maximum plasma concentration (Cmax) values in matched subjects with normal hepatic function, values were higher among subjects with moderate hepatic impairment (517 vs. 724 ng/mL) but lower among subjects with severe hepatic impairment (608 vs. 403 ng/mL). No clear trend toward increased or decreased exposure was observed with increasingly severe hepatic impairment, and extensive overlap occurred between normal and hepatically impaired subjects. Therefore, pharmacokinetic variables Cmax and area under the curve from time 0 to the time of final quantifiable sample (AUCtf) values were pooled for subjects with hepatic impairment. Pooled Cmax values were similar to the pooled normal groups (607 vs. 605 ng/mL), whereas there was an overall 36% increase in exposure (AUCtf) for the pooled hepatic impairment group compared with the pooled normal group. Posaconazole was well-tolerated, with six (33%) healthy subjects and six (32%) hepatically impaired subjects reporting adverse events. Conclusions: The data from this small single-dose study suggest posaconazole is safe. Furthermore, although limited by the small number of subjects enrolled, the authors feel that dose adjustments are probably not necessary in patients with hepatic impairment; however, physicians should continue to monitor posaconazole use in patients with hepatic impairment

A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers

OBJECTIVES: Posaconazole is an extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis. The marketed oral suspension should be taken with food to maximize systemic absorption. A new solid oral tablet has been developed with improved bioavailability that can be administered without regard to food. The aim of this study was to evaluate rising single- and multiple-dose pharmacokinetics, safety and tolerability of the new tablet. METHODS: This was a single-centre, randomized, placebo-controlled, Phase I, rising single- and multiple-dose study of healthy subjects aged 18–65 years who received a posaconazole tablet as 200 mg once daily, 200 mg twice daily or 400 mg once daily. The 24 subjects were studied in two cohorts of 12 subjects each (9 active and 3 placebo). RESULTS: After single or multiple oral dose administration of posaconazole tablets (200 and 400 mg), exposure increased in a dose-related manner. Peak posaconazole concentrations were attained at a median T(max) of 4–5 h. Mean half-life was similar for 200 and 400 mg posaconazole doses (25 and 26 h). The accumulation ratio upon multiple doses over 8 days was ∼3 for 200 and 400 mg once daily and ∼5 for 200 mg twice daily. C(avg) values exceeded 1300 ng/mL. The posaconazole oral tablet was safe and well tolerated, although mild, transient elevations in liver function were reported in some patients. CONCLUSIONS: Posaconazole exposure increased in a dose-related manner. The pharmacokinetics of this new solid oral tablet of posaconazole supports the clinical evaluation of once-daily dosing regimens for fungal infections