Development of a novel rate-modulated fixed dose analgesic combination for the treatment of mild to moderate pain

MSc (Med),Dept of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the WitwatersrandPain is the net effect of multidimensional mechanisms that engage most parts of the central nervous system (CNS) and the treatment of pain is one of the key challenges in clinical medicine (Le Bars et al., 2001; Miranda et al., 2008). Polypharmacy is seen as a barrier to analgesic treatment compliance, signifying the necessity for the development of fixed dose combinations (FDCs), which allow the number of tablets administered to be reduced, with no associated loss in efficacy or increase in the prevalence of side effects (Torres Morera, 2004). FDCs of analgesic drugs with differing mechanisms of nociceptive modulation offer benefits including synergistic analgesic effects, where the individual agents act in a greater than additive manner, and a reduced occurrence of side-effects (Raffa, 2001; Camu, 2002). This study aimed at producing a novel, rate-modulated, fixed-dose analgesic formulation for the treatment of mild to moderate pain. The fixed-dose combination (FDC) rationale of paracetamol (PC), tramadol hydrochloride (TM) and diclofenac potassium (DC) takes advantage of previously reported analgesic synergy of PC and TM as well as extending the analgesic paradigm with the addition of the anti-inflammatory component, DC. The study involved the development of a triple-layered tablet delivery system with the desired release characteristics of approximately 60% of the PC and TM being made available within 2 hours to provide an initial pain relief effect and then sustained zero-order release of DC over a period of 24 hours to combat the on-going effects of any underlying inflammatory conditions. The triple-layered tablet delivery system would thus provide both rapid onset of pain relief as well as potentially address an underlying inflammatory cause. The design of a novel triple-layered tablet allowed for the desired release characteristics to be attained. During initial development work on the polymeric matrix it was discovered that only when combined with the optimized ratio of the release retarding polymer polyethylene oxide (PEO) in combination with electrolytic-crosslinking activity, provided by the biopolymer sodium alginate and zinc gluconate, could the 24 hour zero-order release of DC be attained. It was also necessary for this polymeric matrix to be bordered on both sides by the cellulosic polymers containing PC and TM. Thus the application of multi-layered tableting technology in the form of a triple-layered tablet were capable of attaining the rate-modulated release objectives set out in the study. The induced barriers provided by the three layers also served to physically separate TM and DC, reducing the likelihood of the bioavailability-diminishing interaction noted in United States Patent 6,558,701 and detected in the DSC analysis performed as part of this study. The designed system provided significant flexibility in modulation of release kinetics for drugs of varying solubility. The suitability of the designed triple-layered tablet delivery system was confirmed by a Design of Experiments (DoE) statistical evaluation, which revealed that Formulation F4 related closest to the desired more immediate release for PC and TM and the zero-order kinetics for DC. The results were confirmed by comparing Formulation F4 to typical release kinetic mechanisms described by Noyes-Whitney, Higuchi, Power Law, Pappas-Sahlin and Hopfenberg. Using f1 and f2 fit factors Formulation F4 compared favourably to each of the criteria defined for these kinetic models. The Ultra Performance Liquid Chromatographic (UPLC) assay method developed displayed superior resolution of the active pharmaceutical ingredient (API) combinations and the linearity plots produced indicated that the method was sufficiently sensitive to detect the concentrations of each API over the concentration ranges studied. The method was successfully validated and hence appropriate to simultaneously detect the three APIs as well as 4-aminophenol, the degradation product related to PC. Textural profile analysis in the form of swelling as well as matrix hardness analysis revealed that an increase in the penetration distance was associated with an increase in hydration time of the tablet and also an increase in gel layer thickness. The swelling complexities observed in the delivery system in terms of both the PEO, crosslinking sodium alginate and both cellulose polymers as well as the actuality of the three layers of the tablet swelling simultaneously suggests further intricacies involved in the release kinetics of the three drugs from this tablet configuration. Modified release dosage forms, such as the one developed in this study, have gained widespread importance in recent years and offer many advantages including flexible release kinetics and improved therapy and patient compliance

Writing about writing: Qualities of metacognitive L2 writing reflections

This case study of two L2 writers in an intermediate English writing class examines each student’s use of in-class opportunities for written, metacognitive reflection as part of a supplemental curriculum that also included the use of inventories, explicit explanation of relevant terms, and teacher modeling of metacognitive activity. Written reflections were completed throughout the course to facilitate metacognitive development and were used as the primary unit of analysis with the aim of gaining a deeper understanding of this development for the purpose of self-regulation. Flavell’s (1979) categories of person, task, and strategic metacognitive knowledge were utilized in the analysis of data as well as Norman and Aron’s (2003) concepts of availability, accessibility, and perceived control, proposed to affect motivation to achieve or avoid a possible future self. These ideas were used in order to examine the relationships between each individual’s expressed writing goals and aspects of their metacognitive activities. One student’s goal was available, accessible, and well-aligned to the course goals; this seemed to allow her to actively strategize to monitor her progress more effectively. Furthermore, she displayed a higher level of self-efficacy than the other student. Degree of self-efficacy seemed to affect the students’ level of perceived control; the other student’s pre-occupation with his negative self-efficacy seemed to hinder the development of strategic knowledge and his ability to monitor his progress, in spite of his stated enjoyment of writing. Additionally, his goals were less available, less accessible, and less aligned to the purpose of the course. Although more research is needed, the results point to a need for L2 writing curricula to include effective L2 writing goal-setting strategies in metacognitive classroom activities because of the potential effect on student motivation as well as metacognitive development

The Effect of Multiple Cooling Channels on the Formation of Dark Compact Objects

A dissipative dark sector can result in the formation of compact objects with masses comparable to stars and planets. In this work, we investigate the formation of such compact objects from a subdominant inelastic dark matter model, and study the resulting distributions of these objects. In particular, we consider cooling from dark Bremsstrahlung and a rapid decay process that occurs after inelastic upscattering. Inelastic transitions introduce an additional radiative processes which can impact the formation of compact objects via multiple cooling channels. We find that having multiple cooling processes changes the mass and abundance of compact objects formed, as compared to a scenario with only one cooling channel. The resulting distribution of these astrophysical compact objects and their properties can be used to further constrain and differentiate between dark sectors.Comment: 20 pages, 4 figure

Different domains of C. elegans PAR-3 are required at different times in development

AbstractPolarity is a fundamental cellular feature that is critical for generating cell diversity and maintaining organ functions during development. In C. elegans, the one-cell embryo is polarized via asymmetric localization of the PAR proteins, which in turn are required to establish the future anterior–posterior axis of the embryo. PAR-3, a conserved PDZ domain-containing protein, acts with PAR-6 and PKC-3 (atypical protein kinase; aPKC) to regulate cell polarity and junction formation in a variety of cell types. To understand how PAR-3 localizes and functions during C. elegans development, we produced targeted mutations and deletions of conserved domains of PAR-3 and examined the localization and function of the GFP-tagged proteins in C. elegans embryos and larvae. We find that CR1, the PAR-3 self-oligomerization domain, is required for PAR-3 cortical distribution and function only during early embryogenesis and that PDZ2 is required for PAR-3 to accumulate stably at the cell periphery in early embryos and at the apical surface in pharyngeal and intestinal epithelial cells. We also show that phosphorylation at S863 by PKC-3 is not essential in early embryogenesis, but is important in later development. Surprisingly neither PDZ1 nor PDZ3 are essential for localization or function. Our results indicate that the different domains and phosphorylated forms of PAR-3 can have different roles during C. elegans development

Reduction of Cesarean Section Surgical Site Infections (SSI): Progression and Implementation of Evidence Based Practice

To improve cesarean section patient experience by reduction of postoperative SSI.https://digitalcommons.centracare.com/nursing_posters/1072/thumbnail.jp

Biomass scoping study: opportunities for agriculture in Western Australia

This report aims to provide a summary of national and international activity in the use of agricultural by-products for the production of bioenergy and biofuels. The summary is primarily an internal report for the Department of Agriculture and Food, Western Australia (DAFWA), but will hopefully be of some value to industry proponents that are interested in pursuing the opportunities provided by what are currently low value agricultural waste products. We outline three processes for obtaining energy from these by-products that may be appropriate for the farming sector in Western Australia (WA).https://researchlibrary.agric.wa.gov.au/bulletins/1064/thumbnail.jp

Fall Safety Assessment at the New School of Public Health and Health Services Building

Objective: Falls are one of the leading causes of workplace death, lost work time, and costs to industry, particularly in construction. The public health burden of falls is significant, as approximately 25% of nonfatal injuries and 38% of fatalities in the general construction industry are due to falls. The goal of this study is to develop an assessment tool to evaluate fall safety in general construction and to evaluate fall safety among five skilled construction trades (i.e. electricians, painters, carpenters, welders, and roofers) throughout different stages of a new building construction project. The project is the new School of Public Health and Health Services building at The George Washington University at Washington Circle in Foggy Bottom, Washington, DC, being built by the general contractor The Whiting-Turner Contracting Company. Methods: A comprehensive assessment instrument was developed through review of pre-existing assessment tools and modified according to Occupational Safety and Health Administration (OSHA) standards for general construction, validated through inter-rater reliability by a panel of experts (including the on-site safety superintendent), and tested for on-site usability through a two-week pilot study. Data were collected using the GW Audit of Fall Risk (GAFR) instrument by a master\u27s-level researcher through routine observation of the construction site throughout the five construction phases (i.e. concrete pouring, skin, interior rough end, interior finishes, and roofing). Results: Collected data are organized in the GAFR assessment instrument into eight domains: general safety, guardrails, personal fall arrest, safety net system, roof sheathing, scaffolding, aerial lifts, and ladders. Observations are scored dichotomously as to whether or not it was observed, and if observed, whether or not it meets the definition of best safety practice (as noted in OSHA regulations). Though the study is still ongoing, the current collected data presents statistics on the prevalence of fall hazards, and the frequency of fall safety compliances for each of the five trades by construction phase. Conclusions: Fall hazards in skilled trades have been understudied. This unique university-general contractor partnership capitalizes on the opportunity to ensure public health principles are being realized during construction. This presentation will include the application of the GAFR assessment instrument and the current preliminary results, highlighting the importance of observational assessment of worksites. Additionally, the lessons learned from the field assessments will also be discussed

A multifactorial approach for understanding fall risk in older people

OBJECTIVE: To identify the interrelationships and discriminatory value of a broad range of objectively measured explanatory risk factors for falls. DESIGN: Prospective cohort study with 12-month follow-up period. SETTING: Community sample. PARTICIPANTS: Five hundred community-dwelling people aged 70 to 90. MEASUREMENTS: All participants underwent assessments on medical, disability, physical, cognitive, and psychological measures. Fallers were defined as people who had at least one injurious fall or at least two noninjurious falls during a 12-month follow-up period. RESULTS: Univariate regression analyses identified the following fall risk factors: disability, poor performance on physical tests, depressive symptoms, poor executive function, concern about falling, and previous falls. Classification and regression tree analysis revealed that balance-related impairments were critical predictors of falls. In those with good balance, disability and exercise levels influenced future fall risk-people in the lowest and the highest exercise tertiles were at greater risk. In those with impaired balance, different risk factors predicted greater fall risk-poor executive function, poor dynamic balance, and low exercise levels. Absolute risks for falls ranged from 11% in those with no risk factors to 54% in the highest-risk group. CONCLUSIONS: A classification and regression tree approach highlighted interrelationships and discriminatory value of important explanatory fall risk factors. The information may prove useful in clinical settings to assist in tailoring interventions to maximize the potential benefit of falls prevention strategies