Mechanistic Study of Belinostat Oral Absorption From Spray-Dried Dispersions.

Spray-dried dispersions (SDDs) are an important technology for enhancing the oral bioavailability of poorly water-soluble drugs. To design an effective oral SDD formulation, the key rate-determining step(s) for oral drug absorption must be understood. This work combined in vivo and in vitro tests with in silico modeling to identify the rate-determining steps for oral absorption of belinostat SDDs made with 3 different polymers (PVP K30, PVP VA64, and HPMCAS-M). The goal was developing a belinostat SDD formulation that maximizes oral bioavailability (ideally matching the performance of a belinostat oral solution) and defining critical performance attributes for formulation optimization. The in vivo pharmacokinetic study with beagle dogs demonstrated that 1 of the 3 SDDs (PVP K30 SDD) matched the performance of the oral solution. In vitro data coupled with in silico modeling elucidated differences among the SDDs and supported the hypothesis that absorption of belinostat in the small intestine from the other 2 SDDs (PVP VA64 and HPMCAS-M) may be limited by dissolution rate or reduced drug activity (maximum concentration) in the presence of polymer. It was concluded that drug concentration in the stomach before emptying into the proximal intestine is a key factor for maximizing in vivo performance.

What do older Australians want?

OBJECTIVE: The objective of this study was to report older Australians' views about what they want from aged care reforms expressed in submissions to the Productivity Commission's 'Inquiry into Caring for Older Australians' and the 'Conversations on Ageing' (Conversations). METHOD: Consumer responses to the 'Inquiry into Caring for Older Australians' (n = 59) and findings from the Conversations (n = 31) conducted by the Honourable MarkButler with the Council on the Ageing were summarised. RESULTS: Older people wanted to be included as full citizens in community life with their contributions acknowledged, including as carers. They wanted high quality, accessible and respectful services that supported their independence and over which they had control. They wanted fair and transparent funding arrangements and care that caters for diversity in Australia's older people. They wanted reform to be soon and to have bipartisan support. CONCLUSION: This paper provides consumer perspectives to inform aged care policy, practice and research in Australia.

Utility of in situ sodium alginate/karaya gum gels to facilitate gastric retention in rodents.

Target validation or demonstration of efficacy requires adequate in vivo exposure of tool molecules to determine their activity in order to validate the model or show the potential usefulness of the pharmacophore. Early discovery work is often carried out with compounds which possess undesirable PK properties in small rodents where the discovery formulation scientist is often forced to dose 2-4 times per day. Gastric retentive formulations in small rodents (rats/mice) could enable increased duration of exposure for compounds with narrow absorption windows or increased residence time for compounds with targets located in the GI tract. The aim of this work is to establish an easily administered gastric retentive gel for rodents in situ using a mixture of sodium alginate and karaya gum. Feasibility studies were conducted in Sprague-Dawley rats using barium sulfate as a radio-opaque tracer. The results show that gastric retention of barium was achieved for rats dosed with the gel formulation relative to a barium suspension. The gastric residence time of the gel varied from 1h to >8h (n=3). The data suggest that sodium alginate/karaya gum gels may be a useful tool to achieve gastric retention in rodent studies.

Recovery, place and community mental health services.

BACKGROUND: While some studies have examined recovery in relation to specific contexts (e.g. housing and work), few have looked in detail at the social and environmental conditions in which recovery occurs. AIMS: To explore the relationship between the recovery of people receiving community mental health services and the places in which they live; to generate knowledge concerning aspects of locality which impact on recovery. METHOD: Grounded theory methodology was employed as a framework for collecting and analysing qualitative data. The study incorporated aspects of Photovoice ( Lopez et al., 2005 ) and ethnography. RESULTS: Four overlapping theoretical accounts are presented. These are: housing, space and agency; representations of social identity; natural environments; and replacement communities. CONCLUSIONS: Recovery can be understood as a variety of interacting ecological processes occurring in the context of the social, economic and physical environment. This offers new ways of thinking about recovery-orientated services.

An analysis of practice activities and instructional behaviours used by youth soccer coaches during practice: exploring the link between science and application.

We examined the practice activities and instructional behaviours employed by 25 youth soccer coaches during 70 different practice sessions. We evaluated the extent to which these activities and behaviours differ from those shown in contemporary research to best facilitate skill acquisition. Nine coaches worked with the under-9 years age group and eight coaches each with the under-13 and under-16 years age groups; nine of those coaches were employed at the elite level, nine at the sub-elite level, and seven at the non-elite level. Coaches had players spend more time in activities that were deemed less relevant to soccer match performance, termed "training form" (e.g. physical training, technique and skills practices), than activities deemed more relevant, termed "playing form" (e.g. small-sided/conditioned games and phase of play activities). Coaches provided high levels of instruction, feedback, and management, irrespective of the activity in which players engaged. Few differences in practice activities and instructional behaviours were reported across skill and age groups, implying the absence of any notable age- or skill-related progression. Findings are discussed with reference to recent research in the areas of skill acquisition, motor learning, and expert performance.

Influence of buffer species on the thermodynamics of short DNA duplex melting: sodium phosphate versus sodium cacodylate.

Thermodynamic parameters of the melting transitions of 53 short duplex DNAs were experimentally evaluated by differential scanning calorimetry melting curve analysis. Solvents for the DNA solutions contained approximately 1 M Na+ and either 10 mM cacodylate or phosphate buffer. Thermodynamic parameters obtained in the two solvent environments were compared and quantitatively assessed. Thermodynamic stabilities (deltaG(o) (25 degrees C)) of the duplexes studied ranged from quite stable perfect match duplexes (approximately -30 kcal/mol) to relatively unstable mismatch duplexes (approximately -9 kcal/mol) and ranged in length from 18 to 22 basepairs. A significant difference in stability (average free energy difference of approximately 3 kcal/mol) was found for all duplexes melted in phosphate (greater stability) versus cacodylate buffers. Measured effects of buffer species appear to be relatively unaffected by duplex length or sequence content. The popular sets of published nearest-neighbor (n-n) stability parameters for Watson-Crick (w/c) and single-base mismatches were evaluated from melting studies performed in cacodylate buffer (SantaLucia and Hicks, Annu. Rev. Biophys. Biomol. Struct. 2004, 33, 415). Thus, when using these parameters to make predictions of sequence dependent stability of DNA oligomers in buffers other than cacodylate (e.g., phosphate) one should be mindful that in addition to sodium ion concentration, the type of buffer species also provides a minor but significant contribution to duplex stability. Such considerations could potentially influence results of sequence dependent analysis using published n-n parameters and impact results of thermodynamic calculations. Such calculations and analyses are typically employed in the design and interpretation of DNA multiplex hybridization experiments.