A Pilot Stability Study of Dehydroepiandrosterone Rapid-dissolving Tablets Prepared by Extemporaneous Compounding

Dehydroepiandrosterone supplementation is used to treat a variety of conditions. Rapid-dissolving tablets are a relatively novel choice for compounded dehydroepiandrosterone dosage forms. While rapid-dissolving tablets offer ease of administration, there are uncertainties about the physical and chemical stability of the drug and dosage form during preparation and over long-term storage. This study was designed to evaluate the stability of dehydroepiandrosterone rapid-dissolving tablets just after preparation and over six months of storage. The Professional Compounding Centers of America rapid-dissolving tablet mold and base formula were used to prepare 10-mg strength dehydroepiandrosterone rapid-dissolving tablets. The formulation was heated at 100°C to 110°C for 30 minutes, released from the mold, and cooled at room temperature for 30 minutes. The resulting rapid-dissolving tablets were individually packaged in amber blister packs and stored in a stability chamber maintained at 25°C and 60% relative humidity. The stability samples were pulled at pre-determined time points for evaluation, which included visual inspection, tablet weight check, United States Pharmacopeia disintegration test, and stability-indicating high-performance liquid chromatography. The freshly prepared dehydroepiandrosterone rapiddissolving tablets exhibited satisfactory chemical and physical stability. Time 0 samples disintegrated within 40 seconds in water kept at 37°C. The highperformance liquid chromatographic results confirmed that the initial potency was 101.9% of label claim and that there was no chemical degradation from the heating procedure. Over six months of storage, there were no significant changes in visual appearance, physical integrity, or disintegration time for any of the stability samples. The high-performance liquid chromatographic results also indicated that dehydroepiandrosterone rapid-dissolving tablets retained \u3e95% label claim with no detectable degradation products. The dehydroepiandrosterone rapid-dissolving tablets investigated in this pilot study were physically and chemically stable during preparation and over six months of storage at 25°C and 60% relative humidity

Stability of Glutamate-Aspartate Cardioplegia Additive Solution in Polyolefin IV Bags

Objective: Glutamate-aspartate cardioplegia additive solution (GACAS) is used to enhance myocardial preservation and left ventricular function during some cardiac surgeries. This study was designed to evaluate the stability of compounded GACAS stored in sterile polyolefin intravenous (IV) bags. The goal is to extend the default USP beyond-use date (BUD) and reduce unnecessary inventory waste. Methods: GACAS was compounded and packaged in sterile polyolefin 250 mL IV bags. The concentration was 232 mM for each amino acid. The samples were stored under refrigeration (2°C-8°C) and analyzed at 0, 1, and 2 months. At each time point, the samples were evaluated by pH measurement and visual inspection for color, clarity, and particulates. The samples were also analyzed by high-performance liquid chromatography (HPLC) for potency and degradation products. Due to the lack of ultraviolet (UV) chromophores of glutamate and aspartate, the samples were derivatized by ortho-phthalaldehyde prior to HPLC analysis. Results: The time zero samples of GACAS passed the physical, chemical, and microbiological tests. Over 2 months of storage, there was no significant change in pH or visual appearance for any of the stability samples. The HPLC results also indicated that the samples retained 101% to 103% of the label claim strengths for both amino acids. Conclusion: The physical and chemical stability of extemporaneously prepared GACAS has been confirmed for up to 2 months in polyolefin IV bags stored under refrigeration. With proper sterile compounding practice and microbiology testing, the BUD of this product can be extended to 2 months

Nonlinear power flow control for networked AC/DC microgrids

A method for designing feedforward and feedback controllers for integration of stochastic sources and loads into a nonlinear networked AC/DC microgrid system is provided. A reduced order model for general networked AC/DC microgrid systems is suitable for HSSPFC control design. A simple feedforward steady state solution is utilized for the feedforward controls block. Feedback control laws are provided for the energy storage systems. A HSSPFC controller design is implemented that incorporates energy storage systems that provides static and dynamic stability conditions for both the DC random stochastic input side and the AC random stochastic load side. Transient performance was investigated for the feedforward/feedback control case. Numerical simulations were performed and provided power and energy storage profile requirements for the networked AC/DC microgrid system overall performance. The HSSPFC design can be implemented in the Matlab/Simulink environment that is compatible with real time simulation/controllers.https://digitalcommons.mtu.edu/patents/1150/thumbnail.jp

Method to provide meta-stable operation of DC microgrid comprising a pulsed load

A Hamiltonian surface shaping power flow control (HSSPFC) method is used to analyze the meta-stability and adjust pulsed power loads on a DC electric power distribution network. Pulsed power loads are nonlinear, time-variant systems that cause nonlinear limit-cycles. During the on periods of a pulsed load, the system can be in an unstable state and is damped back to stability during the off state of the load. Therefore, over the entire period of the pulse the system may only be assessed as meta-stable. As shown through simulation, HIL and hardware results, the HSSPFC method is more accurate than the other small-signal approaches, such as Eigenvalues, Nyquist, and Floquet theory, and can reveal important details about the transient responses and performance.https://digitalcommons.mtu.edu/patents/1141/thumbnail.jp

Effect of short-term lycopene supplementation and postprandial dyslipidemia on plasma antioxidants and biomarkers of endothelial health in young, healthy individuals

The objective of this study was to test the hypothesis that the effect of a high-fat meal (HFm) on plasma lipid-soluble antioxidants and biomarkers of vascular oxidative stress and inflammation would be attenuated by short-term lycopene supplementation in young healthy subjects. Following restriction of lycopene-containing foods for 1-wk (LYr), blood was collected in a fasting state and 3 h after a HFm and a low-fat meal (LFm) in N = 18 men aged 23 ± 2 years, and after a HFm only in N = 9 women aged 23 ± 1 years. Blood was also sampled pre- and post-meals following 1-wk of 80 mg/day lycopene supplementation (LYs) under continued dietary LYr. In the fasting state, LYs compared with LYr not only evoked a >2-fold increase in plasma lycopene but also increased plasma β-carotene and α-tocopherol (p < 0.01), though LYs did not affect plasma nitrate/nitrite (biomarker of nitric oxide), malondialdehyde (biomarker of lipid oxidative stress), vascular- and intercellular-adhesion molecules or C-reactive protein (biomarkers of inflammation). Contrary to the hypothesis, the HFm-induced dyslipidemic state did not affect plasma malondialdehyde, C-reactive protein, or adhesion molecules in either LYr or LYs. Both the HFm and LFm were associated with decreases in the nitric oxide metabolites nitrate/nitrite and lipid-soluble antioxidants (p < 0.05). The data revealed that 1-wk of LYs increased plasma lycopene, β-carotene, and α-tocopherol yet despite these marked changes to the plasma lipid-soluble antioxidant pool, biomarkers of vascular oxidative stress and inflammation were unaffected in the fasted state as well as during dyslipidemia induced by a HFm in young healthy subjects

The Role of Patient Activation in Preferences for Shared Decision Making: Results From a National Survey of US Adults

Financial support for this study was provided by a contract with UnitedHealthcare, Optum Institute. The funding agreement ensured our independence in designing the study, interpreting the data, and writing and publishing the report. Samuel G. Smith is supported by a Cancer Research UK Postdoctoral Fellowship (C42785=A17965). Carol J. Simon and Steven R. Rush are employed by the sponsor

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Stimulant Reduction Intervention using Dosed Exercise (STRIDE) - CTN 0037: Study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>There is a need for novel approaches to the treatment of stimulant abuse and dependence. Clinical data examining the use of exercise as a treatment for the abuse of nicotine, alcohol, and other substances suggest that exercise may be a beneficial treatment for stimulant abuse, with direct effects on decreased use and craving. In addition, exercise has the potential to improve other health domains that may be adversely affected by stimulant use or its treatment, such as sleep disturbance, cognitive function, mood, weight gain, quality of life, and anhedonia, since it has been shown to improve many of these domains in a number of other clinical disorders. Furthermore, neurobiological evidence provides plausible mechanisms by which exercise could positively affect treatment outcomes. The current manuscript presents the rationale, design considerations, and study design of the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) CTN-0037 Stimulant Reduction Intervention using Dosed Exercise (STRIDE) study.</p> <p>Methods/Design</p> <p>STRIDE is a multisite randomized clinical trial that compares exercise to health education as potential treatments for stimulant abuse or dependence. This study will evaluate individuals diagnosed with stimulant abuse or dependence who are receiving treatment in a residential setting. Three hundred and thirty eligible and interested participants who provide informed consent will be randomized to one of two treatment arms: Vigorous Intensity High Dose Exercise Augmentation (DEI) or Health Education Intervention Augmentation (HEI). Both groups will receive TAU (i.e., usual care). The treatment arms are structured such that the quantity of visits is similar to allow for equivalent contact between groups. In both arms, participants will begin with supervised sessions 3 times per week during the 12-week acute phase of the study. Supervised sessions will be conducted as one-on-one (i.e., individual) sessions, although other participants may be exercising at the same time. Following the 12-week acute phase, participants will begin a 6-month continuation phase during which time they will attend one weekly supervised DEI or HEI session.</p> <p>Clinical Trials Registry</p> <p>ClinicalTrials.gov, <a href="http://www.clinicaltrials.gov/ct2/show/NCT01141608">NCT01141608</a></p> <p><url>http://clinicaltrials.gov/ct2/show/NCT01141608?term=Stimulant+Reduction+Intervention+using+Dosed+Exercise&rank=1</url></p

Survey of Activated FLT3 Signaling in Leukemia

Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 is therefore an attractive drug target. However, the molecular mechanisms by which FLT3 mutations lead to cell transformation in AML remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream effectors, we performed detailed phosphoproteomic analysis of FLT3 signaling in human leukemia cells. We identified over 1000 tyrosine phosphorylation sites from about 750 proteins in both AML (wild type and mutant FLT3) and B cell acute lymphoblastic leukemia (normal and amplification of FLT3) cell lines. Furthermore, using stable isotope labeling by amino acids in cell culture (SILAC), we were able to quantified over 400 phosphorylation sites (pTyr, pSer, and pThr) that were responsive to FLT3 inhibition in FLT3 driven human leukemia cell lines. We also extended this phosphoproteomic analysis on bone marrow from primary AML patient samples, and identify over 200 tyrosine and 800 serine/threonine phosphorylation sites in vivo. This study showed that oncogenic FLT3 regulates proteins involving diverse cellular processes and affects multiple signaling pathways in human leukemia that we previously appreciated, such as Fc epsilon RI-mediated signaling, BCR, and CD40 signaling pathways. It provides a valuable resource for investigation of oncogenic FLT3 signaling in human leukemia