Preparation and characterization of a powder manufactured by spray drying milk based formulations for the delivery of theophylline for pediatric use

The study considered different fat content cow milks to deliver theophylline orally. Powders were obtained by spray drying theophylline dispersed in fresh milk according to a full factorial design of experiments. The correlation of the independent (milk fat content, skimmed to whole milk, theophylline fraction, and drying temperature) with the dependent (yield of the process and residual moisture content of the powder, particle size and distribution, density, surface polarity and theophylline content) variables enabled the construction of a mathematical model and a desirability function to predict the optimized levels of the variables. Good predictability was achieved for density, fairly good for yield, moisture content, surface polarity and yield whereas theophylline content and particle size were poorly predicted. Powders with up to 60% theophylline presented spherical (3.7 \ub5m) and narrow sized distribution particles, with high density (1.6 g/cm 123) in high yields (>70%), stable for 6 month (25 \ub0C/65%RH) in a closed container and for no longer than 2 day, after reconstitution in water due to bacteria growth (no pathogens) without signs of crystallinity. Preparations obtained with low fat milk were less stable than high fat content milk. Therefore, fresh milk can be transformed into stable powder compositions to prepare oral solid/liquid dosage forms to deliver individualized doses of theophylline

Medicinal powders made of fresh milk for pediatric use

Communication presented at the 1st International Congress of CiiEM - From Basic Sciences to Clinical Research. 27-28 November 2015, Egas Moniz, Caparica, Portugal"Nowadays, the need to formulate medicines specifically designed for children is imperative [1] and solid dosage forms are the first choice for providing the required drug stability and dose accuracy. Milk, as a worldwide accepted food, is proposed in this study as a platform to deliver drugs orally in pediatrics. Therefore, the main goals of this project are: (a) to assess the properties of spray-dried milk powders, (b) to evaluate drug-milk interactions and (c) to ascertain the stability of the spray-dried milk powders."Fundação para a Ciência e a Tecnologi

Milk as a drug delivery platform in paediatrics

Communication presented at the PSSRC − 9th Annual Symposium. 16-18 September 2015, Ghent, Belgium"Purpose: to assess the physical properties of spray dried milk powders and evaluate drug-milk interactions.

Spray-dried fresh milk powders for oral drug delivery in pediatrics

Poster presented at the 10th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology. 4-7 April 2016, Glasgow, UKN/

Mechanism for APOBEC3G catalytic exclusion of RNA and non-substrate DNA

The potent antiretroviral protein APOBEC3G (A3G) specifically targets and deaminates deoxycytidine nucleotides, generating deoxyuridine, in single stranded DNA (ssDNA) intermediates produced during HIV replication. A non-catalytic domain in A3G binds strongly to RNA, an interaction crucial for recruitment of A3G to the virion; yet, A3G displays no deamination activity for cytidines in viral RNA. Here, we report NMR and molecular dynamics (MD) simulation analysis for interactions between A3Gctd and multiple substrate or non-substrate DNA and RNA, in combination with deamination assays. NMR ssDNA-binding experiments revealed that the interaction with residues in helix1 and loop1 (T201-L220) distinguishes the binding mode of substrate ssDNA from non-substrate. Using 2\u27-deoxy-2\u27-fluorine substituted cytidines, we show that a 2\u27-endo sugar conformation of the target deoxycytidine is favored for substrate binding and deamination. Trajectories of the MD simulation indicate that a ribose 2\u27-hydroxyl group destabilizes the pi-pi stacking of the target cytosine and H257, resulting in dislocation of the target cytosine base from the catalytic position. Interestingly, APOBEC3A, which can deaminate ribocytidines, retains the ribocytidine in the catalytic position throughout the MD simulation. Our results indicate that A3Gctd catalytic selectivity against RNA is dictated by both the sugar conformation and 2\u27-hydroxyl group

Not Separate but Not Equal: Improving Equity in Discipline in Racially and Ethnically Diverse School Settings

Educational inequities leading to deleterious outcomes and related to discipline continue within racially and ethnically diverse schools for myriad of reasons. Districts and schools require deliberate planning and systems change prioritized by educational administrators to address both interpersonal and structural racism and biases. This article outlines a blueprint that leverages the positive behavioral interventions and supports framework in completion of the following: (a) code of conduct revisions; (b) data analysis; (c) cultural and implicit bias awareness; and (d) culturally responsive hiring, training, and teaching.Institute of Education Sciences, U.S. Department of Education, Grant R305A18000

Examining the Social Validity of a Universal Intervention for Reducing Exclusionary Discipline through Stakeholder Voice

45 pagesExclusionary disciplinary practices are utilized in schools despite limited benefits and associated negative student outcomes. Alternative strategies, such as Positive Behavioral Interventions and Supports, reduce exclusionary discipline practices, though research is limited in secondary settings. This study examines how student and school staff input was utilized throughout the iterative refinement of the Inclusive Skill-building Learning Approach (ISLA), an intervention to reduce exclusionary discipline practices in middle school through instructional and restorative practices. Intentional stakeholder involvement was hypothesized to impact acceptability and fidelity of implementation, critical for achieving intervention outcomes. Data across a two-year mixed methods approach indicate that engaging stakeholders throughout implementation enhanced fidelity. Quantitative findings demonstrate better understanding of stakeholder experiences. Implications for practice, limitations, and suggestions for future research are discussed.Grant R305A180006, Institute of Education Sciences, U.S. Department of Educatio

The very low-dose dexamethasone suppression test in the general population: A cross-sectional study

Determinants of the hypothalamic-pituitary-adrenal (HPA) axis functioning are increasingly explored in population-based studies. However, functional tests measuring the negative feedback of the HPA axis cannot easily be implemented into large observational studies. Furthermore, high doses of dexamethasone often completely suppress the HPA axis in healthy persons. This study aimed to detect the effects of the health, lifestyle and sociodemographic factors, psychiatric problems and cognitive functions on the negative feedback of the HPA axis using a very low-dose (0.25 mg) dexamethasone suppression test (DST). We evaluated the associations of several determinants with the saliva cortisol concentrations after dexamethasone intake in a confounder-adjusted model also corrected for baseline saliva cortisol concentrations in the Rotterdam Study, a large population-based study (N = 1822). We found that female sex, low income, lack of exercise, instrumental disability and smoking were all independently associated with stronger suppression of the HPA axis. Even though there were no linear associations between psychiatric measures and cortisol suppression, we found that depressive symptoms and anxiety disorders were more common in persons with non-suppression of cortisol. Conversely, psychotropic medication use was related to enhanced suppression of cortisol after DST. In this large study, we found that female gender, low socioeconomic status and poor health were all related to suppression of the HPA axis. Non-linear associations were detected between the suppression of the HPA axis and common psychiatric disorders in community-dwelling persons

Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188

Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The current viral pandemic caused by SARS-CoV-2 is in dire need of DAAs. The Main protease (M(pro)) is the focus of extensive structure-based drug design efforts which are mostly covalent inhibitors targeting the catalytic cysteine. ML188 is a non-covalent inhibitor designed to target SARS-CoV-1 M(pro), and provides an initial scaffold for the creation of effective pan-coronavirus inhibitors. In the current study, we found that ML188 inhibits SARS-CoV-2 M(pro) at 2.5 microM, which is more potent than against SAR-CoV-1 M(pro). We determined the crystal structure of ML188 in complex with SARS-CoV-2 M(pro) to 2.39 A resolution. Sharing 96% sequence identity, structural comparison of the two complexes only shows subtle differences. Non-covalent protease inhibitors complement the design of covalent inhibitors against SARS-CoV-2 main protease and are critical initial steps in the design of DAAs to treat CoVID 19

Anti-Arrhenius cleavage of covalent bonds in bottlebrush macromolecules on substrate

Spontaneous degradation of bottlebrush macromolecules on aqueous substrates was monitored by atomic force microscopy. Scission of C─C covalent bonds in the brush backbone occurred due to steric repulsion between the adsorbed side chains, which generated bond tension on the order of several nano-Newtons. Unlike conventional chemical reactions, the rate of bond scission was shown to decrease with temperature. This apparent anti-Arrhenius behavior was caused by a decrease in the surface energy of the underlying substrate upon heating, which results in a corresponding decrease of bond tension in the adsorbed macromolecules. Even though the tension dropped minimally from 2.16 to 1.89 nN, this was sufficient to overpower the increase in the thermal energy (kBT) in the Arrhenius equation. The rate constant of the bond-scission reaction was measured as a function of temperature and surface energy. Fitting the experimental data by a perturbed Morse potential V = V0(1 - e-βx)2 - fx, we determined the depth and width of the potential to be V0 = 141 ± 19 kJ/mol and β-1 = 0.18 ± 0.03 Å, respectively. Whereas the V0 value is in reasonable agreement with the activation energy Ea = 80–220 kJ/mol of mechanical and thermal degradation of organic polymers, it is significantly lower than the dissociation energy of a C─C bond De = 350 kJ/mol. Moreover, the force constant Kx = 2β2V0 = 1.45 ± 0.36 kN/m of a strained bottlebrush along its backbone is markedly larger than the force constant of a C─C bond Kl = 0.44 kN/m, which is attributed to additional stiffness due to deformation of the side chains