Influence of Formulation Factors on PpIX Production and Photodynamic Action of Novel ALA-loaded Microparticles

A novel 5-aminolevulinic acid (ALA)-containing microparticulate system was produced recently, based on incorporation of ALA into particles prepared from a suppository base that maintains drug stability during storage and melts at skin temperature to release its drug payload. The novel particulate system was applied to the skin of living animals, followed by study of protoporphyrin IX (PpIX) production. The effect of formulating the microparticles in different vehicles was investigated and also the phototoxicity of the PpIX produced using a model tumour. Particles formulated in propylene glycol gels (10% w/w ALA loading) generated the highest peak PpIX fluorescence levels in normal mouse skin. Peak PpIX levels induced in skin overlying subcutaneously implanted WiDr tumours were significantly lower than in normal skin for both the 10% w/w ALA microparticles alone and the 10% w/w ALA microparticles in propylene glycol gels during continuous 12 h applications. Tumours not treated with photodynamic therapy continued to grow over the 17 days of the anti-tumour study. However, those treated with 12 h applications of either the 10% w/w ALA microparticles alone or the 10% w/w ALA microparticles in propylene glycol gel followed by a single laser irradiation showed no growth. The gel formulation performed slightly better once again, reducing the tumour growth rate by approximately 105%, compared with the 89% reduction achieved using particles alone. Following the promising results obtained in this study, work is now going on to prepare particle-loaded gels under GMP conditions with the aim of initiating an exploratory clinical trial.

A two compartment in vitro release model for the testing of HIV microbicide formulations

BACKGROUND: In vitro release testing of vaginal formulations is usually performed in a one-compartment model (OCM) where the release medium, usually comprising pH-adjusted water, an aqueous surfactant solution or a solvent-water solution, provides sink conditions throughout the release experiment. Although this model is useful in evaluating the effect of formulation parameters upon release, it rarely reflects in vivo conditions. Here we report use of a two-compartment diffusion cell model (TCM, comprising a small volume donor, a large volume receptor, and separated by a model epithelial membrane) to more closely mimic in vivo vaginal release and tissue absorption following administration of a UC781 vaginal ring.

METHODS: Macaque-sized matrix silicone elastomer vaginal rings containing 100mg UC781 were prepared by injection molding, and in vitro release testing performed using both OCM (20mL simulated vaginal fluid, SVF) and TCM (5mL SVF in donor cell and variable quantities of Tween 80; silicone elastomer membrane; 100mL 3:2 ethanol/water in receptor cell). In the TCM, drug levels were measured by HPLC in both donor and receptor cells, representing fluid and tissue levels respectively. Rings containing 100mg UC781 and 10% w/w Tween 80 were also manufactured and tested.

RESULTS: The amount of UC781 released from rings was significantly influenced by the choice of release model. Greatest release (56mg/14 days) was measured in the ethanol/water OCM, compared with no measurable release into SVF only. Increasing the concentration of Tween 80 in the SVF medium (1, 3 and 5% w/w) led to increased UC781 release (11, 16 and 18mg, respectively), demonstrating that vaginal fluid solubility of UC781 may be rate-determining in vivo. In the TCM, UC781 accumulates in the receptor cell medium over time, despite not being measured in the donor medium containing the ring device. Incorporation of Tween 80 directly into the ring provided enhanced release in both donor and receptor cells.

CONCLUSIONS: Release of UC781 was influenced by the choice of release medium and the inclusion of Tween 80 in the ring. Although use of SVF-only in the OCM indicated no measurable UC781 release from rings, data from the TCM confirms that UC781 is not only released but is also capable of penetrating across the model epithelial membrane. The TCM may therefore provide a more representative in vitro release model for mimicking in vivo absorption.

No evidence of morphine analgesia to noxious shock in the shore crab, Carcinus maenas

A number of criteria have been suggested for testing if pain occurs in animals, and these include an analgesic effect of opiates (Bateson, 1991). Morphine reduces responses to noxious stimuli in crustaceans but also reduces responsiveness in a non-pain context. Here we use a paradigm in which shore crabs receive a shock in a preferred dark shelter but not if they remain in an unpreferred light area. Analgesia should thus enhance movement to the preferred dark area because they should not experience 'pain'. However, morphine inhibits rather than enhances this movement even when no shock is given. Morphine produces a general effect of non-responsiveness rather than a specific analgesic effect and this could also explain previous studies claiming analgesia. However, we question the utility of this criterion of pain and suggest instead that behavioural criteria be employed. (C) 2011 Published by Elsevier B.V.

Enhanced Antitumor Activity of the Photosensitizer meso-Tetra(N-methyl-4-pyridyl) Porphine Tetra Tosylate through Encapsulation in Antibody-Targeted Chitosan/Alginate Nanoparticles

meso-Tetra(N-methyl-4-pyridyl) porphine tetra tosylate (TMP) is a photosensitizer that can be used in photodynamic therapy (PDT) to induce cell death through generation of reactive oxygen species in targeted tumor cells. However, TMP is highly hydrophilic, and therefore, its ability to accumulate intracellularly is limited. In this study, a strategy to improve TMP uptake into cells has been investigated by encapsulating the compound in a hydrogel-based chitosan/alginate nanoparticle formulation. Nanoparticles of 560 nm in diameter entrapping 9.1 µg of TMP per mg of formulation were produced and examined in cell-based assays. These particles were endocytosed into human colorectal carcinoma HCT116 cells and elicited a more potent photocytotoxic effect than free drug. Antibodies targeting death receptor 5 (DR5), a cell surface apoptosis-inducing receptor up-regulated in various types of cancer and found on HCT116 cells, were then conjugated onto the particles. The conjugated antibodies further enhanced uptake and cytotoxic potency of the nanoparticle. Taken together, these results show that antibody-conjugated chitosan/alginate nanoparticles significantly enhanced the therapeutic effectiveness of entrapped TMP. This novel approach provides a strategy for providing targeted site-specific delivery of TMP and other photosensitizer drugs to treat colorectal tumors using PDT.

A device to investigate the axial strain dependence of the critical current density in superconductors

We have developed an instrument to study the behavior of the critical current density (J(c)) in superconducting wires and tapes as a function of field (mu(0)H), temperature (T), and axial applied strain (epsilon(a)). The apparatus is an improvement of similar devices that have been successfully used in our institute for over a decade. It encompasses specific advantages such as a simple sample layout, a well defined and homogeneous strain application, the possibility of investigating large compressive strains and the option of simple temperature variation, while improving the main drawback in our previous systems by increasing the investigated sample length by approximately a factor of 10. The increase in length is achieved via a design change from a straight beam section to an initially curved beam, placed perpendicular to the applied field axis in the limited diameter of a high field magnet bore. This article describes in detail the mechanical design of the device and its calibrations. Additionally initial J(c)(epsilon(a)) data, measured at liquid helium temperature, are presented for a bronze processed and for a powder-in-tube Nb3Sn superconducting wire. Comparisons are made with earlier characterizations, indicating consistent behavior of the instrument. The improved voltage resolution, resulting from the increased sample length, enables J(c) determinations at an electric field criterion E-c=10 muV/m, which is substantially lower than a criterion of E-c=100 muV/m which was possible in our previous systems. (C) 2004 American Institute of Physics.

Community pharmacists and people with dementia: a cross-sectional survey exploring experiences, attitudes, and knowledge of pain and its management

Objectives
To explore community pharmacists' experiences with and attitudes towards people with dementia, and to determine the knowledge they have about pain and its management in this patient population. 

Methods
A questionnaire comprising five sections, including the Approaches to Dementia Questionnaire, was mailed, on two occasions, during February and March 2011, to all community pharmacies in Northern Ireland (n=530). 

Results
The response rate was 34.3%. A greater proportion of pharmacists provided pharmaceutical care to people with dementia living at home (91.2%) than those living in care homes (40.1%). Respondents most frequently encountered queries relating to starting and stopping medications, compliance with medication, and availability of formulation types. The mean total score for the Approaches to Dementia Questionnaire measure was 72.8, indicating a positive attitude towards people with dementia, and respondents demonstrated a strong person-centred approach towards this patient population. The majority of respondents recognised the difficulty of assessing pain in people with dementia; however, younger pharmacists (p=0.041) and pharmacists who provided pharmaceutical care to people with dementia (p=0.012) were more likely to be aware of the pain assessment tools for use in people with dementia. Pharmacists appeared uncertain about how to appropriately manage pain in people with dementia.

Conclusions
The study has revealed that community pharmacists often encounter people with dementia, especially those living in their own homes, and they have positive attitudes towards the patient population. However, training in the assessment and management of pain in people with dementia must be developed to further improve their knowledge in this area. 

An Observational Study of Blood Concentrations and Kinetics of Methyl- and Propyl-Parabens in Neonates

Purpose: Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients.

Methods: A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. ‘Dried Blood Spot’ samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach.

Results: A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL_{PNA<21 days} 0.57 versus CL_PNA>21days 0.88 L/h.

Conclusions: Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Localized structures in complex plasmas in the presence of a magnetic field

In this work, the general framework in which fits our investigation is that of modeling the dynamics of dust grains therein dusty plasma (complex plasma) in the presence of electromagnetic fields. The generalized discrete complex Ginzburg-Landau equation (DCGLE) is thus obtained to model discrete dynamical structure in dusty plasma with Epstein friction. In the collisionless limit, the equation reduces to the modified discrete nonlinear Schrödinger equation (MDNLSE). The modulational instability phenomenon is studied and we present the criterion of instability in both cases and it is shown that high values of damping extend the instability region. Equations thus obtained highlight the presence of soliton-like excitation in dusty plasma. We studied the generation of soliton in a dusty plasma taking in account the effects of interaction between dust grains and theirs neighbours. Numerical simulations are carried out to show the validity of analytical approach.

Validity, trustworthiness and rigour:reasserting realism in qualitative research

Aim The aim of this paper is to challenge recent sceptical approaches to the possibility of validating qualitative research and to underline the benefits of adopting a realist approach to validity. Background In recent discussion about the methodological bases for qualitative research it has been argued that, because different methodologies take different approaches to validity, attempts to develop a common set of validation criteria are futile. On the basis of this sceptical view, a number of strategies for judging qualitative research have been proposed. These include suggestions that: it should be judged according to aesthetic or rhetorical criteria, rather than epistemological validity; responsibility for appraisal should move from researchers to readers; each methodology should be assessed individually according to its own merits. Discussion None of these suggestions provide a viable alternative to validity, defined as the extent to which research reflects accurately that to which it refers. Because the form of research does not determine its content, replacement of epistemology by aesthetics is unsustainable. Because research reports mediate between writer and reader, a one-sided approach to this relationship constitutes a false dichotomy. If we accept the criterion of practitioner confidence as a means of judging methodological approaches, this involves rejection of judgement according to a methodology�s own merits. Conclusion If qualitative research is actually about something, and if it is required to provide beneficial information, then a realist approach to validity holds out greatest promise.

Modulated temperature differential scanning calorimetry and its application to freeze-drying

MTDSC is a software modification of the traditional DSC thermal analysis technique that allows more accurate determination of the glass transition as well as measurement of the endothermic relaxation that often accompanies the transition. The glass transition is an essential parameterboth of the original frozen solution and of the end product. Measurement of endothermic relaxation allows the determination of molecularrelaxation times in the freeze-dried product that may be useful in predicting the effect of formulation variables and storage conditions on physical stability.

Motivational trade-offs and potential pain experience in hermit crabs

One criterion of pain experience is that the emotional response to pain may be traded-off against other motivational requirements. This was tested in hermit crabs, housed in either preferred or unpreferred species of shells, by subjecting their abdomens to electric shocks of gradually increasing intensity. The first observable response was not affected by shell species but those in preferred shells evacuated at a higher shock level than those in poor quality shells. Thus, they seem to trade-off the requirement to retain a high quality shell with that of avoidance of the noxious stimulus. Some crabs returned to their shells and those that got back into the preferred species did so with less probing of the aperture before getting in and subsequently thrust their abdomen in and out less often in further investigation, thus confirming their shell species preference. Not all crabs returned to the vicinity of the shell and some attempted to climb the wall of the experimental chamber. Others engaged in shell rapping as if in a fight and grooming of the abdomen was noted. These findings are consistent with the idea of a pain experience rather than a nociceptive reflex. (C) 2009 Elsevier B.V. All rights reserved.

Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet

We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first-and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.

Buckling mode transition in hat-stiffened composite panels loaded in uniaxial compression

A combined experimental and analytical study of a hat-stiffened carbon-fibre composite panel loaded in uniaxial compression was investigated. A buckling mode transition was observed in the panel's skin bay which was not captured using non-linear finite-element analysis. Good correlation between experimental and numerical strain and displacement results was achieved in the prebuckling and initial postbuckling region of the loading history. A Marguerre-type Rayleigh-Ritz energy method was applied to the skin bay using representative displacement functions of permissible mode shapes to explain the mode transition phenomenon. The central criterion of this method was based on the assumption that a change in mode shape occurred such that the total potential energy of the structure was maintained at a minimum. The ultimate strength of the panel was limited by the column buckling strength of the hat-stiffeners.