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

Application of Suction-cup-attached VHF Transmitters to the Study of Beluga, Delphinapterus leucas, Surfacing Behavior in Cook Inlet, Alaska

Suction-cup-attached VHF radio transmittes were deployed on belugas, Delphinapterus leucas, in Cook Inlet, Alaska, in 1994 and 1995 to characterize the whales' surfacing behavior. Data from video recordings were also used to characterize behavior of undisturbed whales and whales actively pursued for tagging. Statistics for dive intervals (time between the midpoints of contiguous surfacings) and surfacing intevals (time at the surface per surfacing) were estimated. Operations took place on the tidal delta of the Susitna and Little Susitna Rivers. During the 2-yr study, eight whales were successfully tagged, five tags remained attached for >60 min, and data from these were used in the analyses. Mean dive interval was 24.1 sec (interwhale SD=6.4 sec, n=5). The mean surfacing interval, as determined from the duration of signals received from the radio transmitters, was 1.8 sec (SD=0.3 sec, n=125) for one of the whales. Videotaped behaviors were categorized as "head-lifts" or "slow-rolls." Belugas were more likely to head-lift than to slow-roll during vessel approaches and tagging attempts when compared to undisturbed whales. In undisturbed groups, surfacing intervals determined from video records were significantly different between head-lifting (average = 1.02 sect, SD=0.38 sed, n=28) and slow-rolling whales (average = 2.45 sec, SD=0.37 sec, n=106). Undisturbed juveniles exhibited shorter slow-roll surfacing intervals (average = 2.25 sec, SD=0.32 sec, n=36) than adults (average = 2.55 sec, SD=0.36 sec, n=70). We did not observe strong reactions by the belugas to the suction-cup tags. This tagging method shows promise for obtaining surfacing data for durations of several days

Mapping current range with respect to abiotic site factors of selected southern oaks (Quercus spp) in Mississippi

Physical characteristics of a site that plant species inhabit may be useful in deriving the range of the species. Current range maps for tree species of the United States were originally developed by Elbert Little. These range maps were based primarily on observations. The purpose of this study was to update Little’s (Little, 1971) range maps of select southern oak species in Mississippi by calculating the topological, soil, and climatic features of sites using a Geographic Information System (GIS) to analyze environmental variables associated with species distributions. Data collected from databases were input into ArcMap and site data extracted using Hawth’s Analyst Tools. Stepwise logistic regression performed with site variables yielded the parameters used in predictive models to generate probability maps for each species across Mississippi. These probability maps demonstrate the potential to efficiently manage forests by giving a more encompassing view of species occurrence

Moonlight drives ocean-scale mass vertical migration of zooplankton during the Arctic winter

The creation of the pan-Arctic archive of ADCP data was supported by the UK Natural Environment Research Council (NERC) (Panarchive: NE/H012524/1 and SOFI: NE/F012381/1) as was mooring work in Svalbard (Oceans 2025 and Northern Sea Program). Moorings were also supported by the Research Council of Norway (NFR) projects: Circa (214271), Cleopatra (178766), Cleopatra II (216537), and Marine Night (226471).In extreme high-latitude marine environments that are without solar illumination in winter, light-mediated patterns of biological migration have historically been considered non-existent [1]. However, diel vertical migration (DVM) of zooplankton has been shown to occur even during the darkest part of the polar night, when illumination levels are exceptionally low [2 and 3]. This paradox is, as yet, unexplained. Here, we present evidence of an unexpected uniform behavior across the entire Arctic, in fjord, shelf, slope and open sea, where vertical migrations of zooplankton are driven by lunar illumination. A shift from solar-day (24-hr period) to lunar-day (24.8-hr period) vertical migration takes place in winter when the moon rises above the horizon. Further, mass sinking of zooplankton from the surface waters and accumulation at a depth of ∼50 m occurs every 29.5 days in winter, coincident with the periods of full moon. Moonlight may enable predation of zooplankton by carnivorous zooplankters, fish, and birds now known to feed during the polar night [4]. Although primary production is almost nil at this time, lunar vertical migration (LVM) may facilitate monthly pulses of carbon remineralization, as they occur continuously in illuminated mesopelagic systems [5], due to community respiration of carnivorous and detritivorous zooplankton. The extent of LVM during the winter suggests that the behavior is highly conserved and adaptive and therefore needs to be considered as “baseline” zooplankton activity in a changing Arctic ocean [6, 7, 8 and 9].Publisher PDFPeer reviewe

A nanofabricated, monolithic, path-separated electron interferometer

We report a self-aligned, monolithic electron interferometer, consisting of two 45 nm thick silicon layers separated by 20 $\mu$m. This interferometer was fabricated from a single crystal silicon cantilever on a transmission electron microscope grid by gallium focused ion-beam milling. Using this interferometer, we demonstrate beam path-separation, and obtain interference fringes in a Mach-Zehnder geometry, in an unmodified 200 kV transmission electron microscope. The fringes have a period of 0.32 nm, which corresponds to the $\left[\bar{1}\bar{1}1\right]$ lattice planes of silicon, and a maximum contrast of 15 %. This design can potentially be scaled to millimeter-scale, and used in electron holography. It can also be applied to perform fundamental physics experiments, such as interaction-free measurement with electrons.Comment: 21 pages (including supplementary info), 8 figures; Corrected typos, added references for introduction and conclusion, changed ordering of paragraphs of Discussion, results unchange

Social Work Interventions in Cancer Care: Final Report

This report presents the findings of an intervention study investigating the reasons for referral to oncology social workers and the types of interventions undertaken by them. The study was an academic and practitioner collaboration between the University of Sydney and practitioners from six cancer care settings in metropolitan, regional and rural centres in New South Wales, Victoria and Queensland. Clinical data mining methodology was used, with a cross analysis of key variables mapped to existing social work classification systems. The findings indicated that high-level relationship-based skills were required to deliver social work services. Key domains of social work practice were linked to health inequalities. Areas for further research were identified including greater engagement with Aboriginal and Torres Strait Islander patients, the need for improved health literacy about the role of social work in their cancer treatment and the need for increased access to social workers and cancer services in rural and regional centres. This preprint is related to a published article: Rosalie Pockett, Kim Hobbs, Raymond Araullo & Kashmira Dave (2020) Social Work Interventions in Cancer Care, Australian Social Work, DOI: 10.1080/0312407X.2020.174867

Drop Impact on Liquid Surfaces: Formation of Lens and Spherical Drops at the Air-Liquid Interface

Droplets at the air-liquid interface of immiscible liquids usually form partially-submerged lens shapes (e.g. water on oil). In addition to this structure, we showed that droplets released from critical heights above the target liquid can sustain the impact and at the end maintain a spherical ball-shape configuration above the surface, despite undergoing large deformation. Spherical drops are unstable and will transform into the lens mode due to slight disturbances. Precision dispensing needles with various tip diameter sizes were used to release pendant drops of deionized water onto the surface of fluorocarbon liquid (FC-43, 3M). A cubic relationship was found between the nozzle tip diameter and the released droplet diameter. Drop impact was recorded by a high speed camera at a rate of 2000 frames per second. In order for the water drops to sustain the impact and retain a spherical configuration at the surface of the target liquid pool, it is required that they be of a critical size and be released from a certain height; otherwise the commonly observed lens shape droplets will form at the surface

Investigating the Goban Spur rifted continental margin, offshore Ireland, through integration of new seismic reflection and potential field data

The Goban Spur, offshore Ireland, is a magma-poor rifted continental margin conjugate to the well-studied Newfoundland margin, offshore Canada. Published studies demonstrated that a 70-km-wide zone of exhumed serpentinized mantle lies between oceanic crust and stretched continental crust at the seaward limit of Goban Spur. However, the along-strike extent of this serpentinized zone has, until now, been unknown due to insufficient data coverage. The crustal architecture of the margin is complicated due to its multi-staged tectonic history. Here, six newly acquired multi-channel seismic reflection lines are processed and interpreted, along with vintage seismic profiles, to characterize its structure and evolution. These seismic profiles reveal significant along-strike structural variations along the Goban Spur margin, and allow us to delimit five distinct crustal zones related to different rifting stages and their regional extents. The geometries of each crustal domain are variable along the margin strike, probably suggestive of different extension rates during the evolution of the margin or inherited variations in crustal composition and rheology. The transitional zone between oceanic crust and stretched continental crust consists of both shallow peridotite ridges and deeper exhumed serpentinized mantle, much like the conjugate Iberian and Newfoundland margins. Above the top basement in the exhumed domain, the syn-exhumed sediments show strikingly weak reflectivity, rarely seen at other magma-poor margins. Magmatic events occur coincident with each rifting stage, and the volume of magmatic accretions increases from NW to SE, more than previously interpreted. Plate reconstruction of the Goban Spur and its possible conjugate – the Flemish Cap, shows asymmetry in the crustal architectures, likely due to rift evolution involving more 3-D complexity than can be explained by simple 2-D extensional kinematics

New limits on the population of normal and millisecond pulsars in the Large and Small Magellanic Clouds

We model the potentially observable populations of normal and millisecond radio pulsars in the Large and Small Magellanic Clouds (LMC and SMC) where the known population currently stands at 19 normal radio pulsars. Taking into account the detection thresholds of previous surveys, and assuming optimal period and luminosity distributions based on studies of Galactic pulsars, we estimate there are (1.79 +/- 0.20) x 10^4 and (1.09 +/- 0.16) x 10^4 normal pulsars in the LMC and SMC respectively. When we attempt to correct for beaming effects, and the fraction of high-velocity pulsars which escape the clouds, we estimate birth rates in both the LMC and SMC to be comparable and in the range 0.5--1 pulsar per century. Although higher than estimates for the rate of core-collapse supernovae in the clouds, these pulsar birth rates are consistent with historical supernova observations in the past 300 yr. A substantial population of active radio pulsars (of order a few hundred thousand) have escaped the LMC and SMC and populate the local intergalactic medium. For the millisecond pulsar (MSP) population, the lack of any detections from current surveys leads to respective upper limits (at the 95% confidence level) of 15,000 for the LMC and 23,000 for the SMC. Several MSPs could be detected by a currently ongoing survey of the SMC with improved time and frequency resolution using the Parkes multibeam system. Giant-pulse emitting neutron stars could also be seen by this survey.Comment: 5 pages, 2 figures, accepted for publication in MNRAS Letter

Evaluation of Lancaster County Early Assessment Process

In January 2009, Lancaster County implemented an early screening and assessment process. The goal of this pilot project was to ensure consistent processing of juvenile offenses, especially for very young offenders, and to ensure that youth were matched to the most appropriate early intervention. The Juvenile Justice Institute was invited to evaluate the effectiveness of this early intervention. Little is known about the effect this project has had on official juvenile court processing of youth, so another important question is how this early process has impacted the overall number of youth entering the Lancaster County juvenile justice system. To evaluate the overall effect of the early screening process, we examined: 1) the process itself, 2) data on youth referred to the early screening process, and 3) trends in Lancaster County’s juvenile justice system. We analyzed three aspects of the process itself including: how long it takes a case to progress through the early assessment program, the assessment instrument utilized, and legal aspects related to this intervention. One important finding is that this early intervention is not available to all Lancaster County youth. Another key finding is that often the prosecuting attorney’s decision did not coincide with the Assessment Specialist’s recommendation. Most importantly, we found that this early intervention did not increase the number of youth entering the juvenile justice system in Lancaster County; nor did it increase the number of younger children being brought into the system. Trend data indicate that as Lancaster County becomes more reliant on alternative programs like the early assessment program, the number of youth officially processed through the courts has declined. This trend has not been consistently downward, and has fluctuated from year to year, so Lancaster County should remain vigilant and reexamine this baseline data in a few years