Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients

Purpose: The objective of the study was to assess the bioequivalence of two tablet formulations of capecitabine and to explore the effect of age, gender, body surface area and creatinine clearance on the systemic exposure to capecitabine and its metabolites. Methods: The study was designed as an open, randomized two-way crossover trial. A single oral dose of 2000 mg capecitabine was administered on two separate days to 25 patients with solid tumors. On one day, the patients received four 500-mg tablets of formulation B (test formulation) and on the other day, four 500-mg tablets of formulation A (reference formulation). The washout period between the two administrations was between 2 and 8 days. After each administration, serial blood and urine samples were collected for up to 12 and 24 h, respectively. Unchanged capecitabine and its metabolites were determined in plasma using LC/MS-MS and in urine by NMRS. Results: Based on the primary pharmacokinetic parameter, AUC(0-∞) of 5'-DFUR, equivalence was concluded for the two formulations, since the 90% confidence interval of the estimate of formulation B relative to formulation A of 97% to 107% was within the acceptance region 80% to 125%. There was no clinically significant difference between the t(max) for the two formulations (median 2.1 versus 2.0 h). The estimate for C(max) was 111% for formulation B compared to formulation A and the 90% confidence interval of 95% to 136% was within the reference region 70% to 143%. Overall, these results suggest no relevant difference between the two formulations regarding the extent to which 5'-DFUR reached the systemic circulation and the rate at which 5'-DFUR appeared in the systemic circulation. The overall urinary excretions were 86.0% and 86.5% of the dose, respectively, and the proportion recovered as each metabolite was similar for the two formulations. The majority of the dose was excreted as FBAL (61.5% and 60.3%), all other chemical species making a minor contribution. Univariate and multivariate regression analysis to explore the influence of age, gender, body surface area and creatinine clearance on the log-transformed pharmacokinetic parameters AUC(0-∞) and C(max) of capecitabine and its metabolites revealed no clinically significant effects. The only statistically significant results were obtained for AUC(0-∞) and C(max) of intact drug and for C(max) of FBAL, which were higher in females than in males. Conclusion: The bioavailability of 5'-DFUR in the systemic circulation was practically identical after administration of the two tablet formulations. Therefore, the two formulations can be regarded as bioequivalent. The variables investigated (age, gender, body surface area, and creatinine clearance) had no clinically significant effect on the pharmacokinetics of capecitabine or its metabolites.

Generic substitution and prescription drug prices : economic effects of state drug product selection laws /

Item 535.

Assessing health risk associated with airborne polycyclic aromatic hydrocarbons by chemometrics and toxic equivalency factors

Some polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in air and have been implicated as carcinogenic materials. Therefore, literature is replete with studies that are focused on their occurrence and profiles in indoor and outdoor air samples. However, because the relative potency of individual PAHs vary widely, health risks associated with the presence of PAHs in a particular environment cannot be extrapolated directly from the concentrations of individual PAHs in that environment. In addition, database on the potency of PAH mixtures is currently limited. In this paper, we have utilized multi-criteria decision making methods (MCDMs) to simultaneously correlate PAH-related health risk in some microenvironments to the concentration levels, ethoxyresorufin-O-deethylase (EROD) activity induction equivalency factors and toxic equivalency factors (TEFs) of PAHs found in those microenvironments. The results showed that the relative risk associated with PAHs in different air samples depends on the index used. Nevertheless, this approach offers a promising tool that could help identify microenvironments of concern and assist the prioritisation of control strategies.

Creating a therapeutic environment : a non-randomised controlled trial of a quiet time intervention for patients in acute care

Background: Noise is a significant barrier to sleep for acute care hospital patients, and sleep has been shown to be therapeutic for health, healing and recovery. Scheduled quiet time interventions to promote inpatient rest and sleep have been successfully trialled in critical care but not in acute care settings. Objectives: The study aim was to evaluate as cheduled quiet time intervention in an acute care setting. The study measured the effect of a scheduled quiet time on noise levels, inpatients’ rest and sleep behaviour, and wellbeing. The study also examined the impact of the intervention on patients’, visitors’ and health professionals’ satisfaction, and organisational functioning. Design: The study was a multi-centred non-randomised parallel group trial. Settings: The research was conducted in the acute orthopaedic wards of two major urban public hospitals in Brisbane, Australia. Participants: All patientsadmitted to the two wards in the5-month period of the study were invited to participate, withafinalsample of 299 participants recruited. This sample produced an effect size of 0.89 for an increase in the number of patients asleep during the quiet time. Methods: Demographic data were collected to enable comparison between groups. Data for noise level, sleep status, sleepiness and well being were collected using previously validated instruments: a Castle Model 824 digital sound level indicator; a three point sleep status scale; the Epworth Sleepiness Scale; and the SF12 V2 questionnaire. The staff, patient and visitor surveys on the experimental ward were adapted from published instruments. Results: Significant differences were found between the two groups in mean decibel level and numbers of patients awake and asleep. The difference in mean measured noise levels between the two environments corresponded to a ‘perceived’ difference of 2 to 1. There were significant correlations between average decibel level and number of patients awake and asleep in the experimental group, and between average decibel level and number of patients awake in the control group. Overall, patients, visitors and health professionals were satisfied with the quiet time intervention. Conclusions: The findings show that a quiet time intervention on an acute care hospital ward can affect noise level and patient sleep/wake patterns during the intervention period. The overall strongly positive response from surveys suggests that scheduled quiet time would be a positively perceived intervention with therapeutic benefit.

Therapeutic relationships in specialist palliative care nursing practice.

There has been limited research into the scope or standards of specialist palliative care nursing practice in an Australian context. This study sought to develop a competency framework that described the core domains of specialist palliative care nursing. This article explores one key domain of specialist palliative care nursing practice - therapeutic relationships - that was identified as underpinning other domains of practice. A mixed method was used, involving a literature review, a survey including practice exemplars and an interview of specialist palliative care nurses. Seventy-four registered nurses working in designated specialist palliative care nursing roles from each Australian state and mainland territory were involved. The nurses represented metropolitan, regional, rural and remote communities, various inpatient facilities and community practice settings. Five core domains of specialist palliative care nursing practice were identified: complex supportive care, collaborative practice, leadership, improving practice and therapeutic relationships. Therapeutic relationships were identified as the central domain of specialist palliative care nursing practice to which all other domains were inextricably linked.

A naturalistic inquiry of registered nurses' perspectives and expectations of psychodynamic therapeutic care in acute psychiatric inpatient facilities

Within contemporary inpatient mental health nursing practice, the psychodynamic model of care considered previously to be central to the nurse-patient relationship now seems a radical concept. It appears to exist only within primary care facilities and public health care practice settings. This naturalistic inquiry aimed to explicate mental health nurses' perspectives and expectations of providing psychodynamic therapeutic care in acute inpatient psychiatric facilities. Ten registered nurses working in acute inpatient mental health facilities were interviewed. Five themes emerged: a career for life, relating in a psychodynamic manner, swimming against the current, adopting a position of difference, and hopeful expectancy.

Property damage crash equivalency factors to solve crash frequency-severity dilemma: Case study on South Korean rural roads

Safety interventions (e.g., median barriers, photo enforcement) and road features (e.g., median type and width) can influence crash severity, crash frequency, or both. Both dimensions—crash frequency and crash severity—are needed to obtain a full accounting of road safety. Extensive literature and common sense both dictate that crashes are not created equal, with fatalities costing society more than 1,000 times the cost of property damage crashes on average. Despite this glaring disparity, the profession has not unanimously embraced or successfully defended a nonarbitrary severity weighting approach for analyzing safety data and conducting safety analyses. It is argued here that the two dimensions (frequency and severity) are made available by intelligently and reliably weighting crash frequencies and converting all crashes to property-damage-only crash equivalents (PDOEs) by using comprehensive societal unit crash costs. This approach is analogous to calculating axle load equivalents in the prediction of pavement damage: for instance, a 40,000-lb truck causes 4,025 times more stress than does a 4,000-lb car and so simply counting axles is not sufficient. Calculating PDOEs using unit crash costs is the most defensible and nonarbitrary weighting scheme, allows for the simple incorporation of severity and frequency, and leads to crash models that are sensitive to factors that affect crash severity. Moreover, using PDOEs diminishes the errors introduced by underreporting of less severe crashes—an added benefit of the PDOE analysis approach. The method is illustrated with rural road segment data from South Korea (which in practice would develop PDOEs with Korean crash cost data).

Investigation of electrophoretic loading and enhanced mechanical properties of hydrogels for delivery of therapeutic proteins

Hydrogels, which are three-dimensional crosslinked hydrophilic polymers, have been used and studied widely as vehicles for drug delivery due to their good biocompatibility. Traditional methods to load therapeutic proteins into hydrogels have some disadvantages. Biological activity of drugs or proteins can be compromised during polymerization process or the process of loading protein can be really timeconsuming. Therefore, different loading methods have been investigated. Based on the theory of electrophoresis, an electrochemical gradient can be used to transport proteins into hydrogels. Therefore, an electrophoretic method was used to load protein in this study. Chemically and radiation crosslinked polyacrylamide was used to set up the model to load protein electrophoretically into hydrogels. Different methods to prepare the polymers have been studied and have shown the effect of the crosslinker (bisacrylamide) concentration on the protein loading and release behaviour. The mechanism of protein release from the hydrogels was anomalous diffusion (i.e. the process was non-Fickian). The UV-Vis spectra of proteins before and after reduction show that the bioactivities of proteins after release from hydrogel were maintained. Due to the concern of cytotoxicity of residual monomer in polyacrylamide, poly(2-hydroxyethyl- methacrylate) (pHEMA) was used as the second tested material. In order to control the pore size, a polyethylene glycol (PEG) porogen was introduced to the pHEMA. The hydrogel disintegrated after immersion in water indicating that the swelling forces exceeded the strength of the material. In order to understand the cause of the disintegration, several different conditions of crosslinker concentration and preparation method were studied. However, the disintegration of the hydrogel still occurred after immersion in water principally due to osmotic forces. A hydrogel suitable for drug delivery needs to be biocompatible and also robust. Therefore, an approach to improving the mechanical properties of the porogen-containing pHEMA hydrogel by introduction of an inter-penetrating network (IPN) into the hydrogel system has been researched. A double network was formed by the introduction of further HEMA solution into the system by both electrophoresis and slow diffusion. Raman spectroscopy was used to observe the diffusion of HEMA into the hydrogel prior to further crosslinking by ã-irradiation. The protein loading and release behaviour from the hydrogel showing enhanced mechanical property was also studied. Biocompatibility is a very important factor for the biomedical application of hydrogels. Different hydrogels have been studied on both a three-dimensional HSE model and a HSE wound model for their biocompatibilities. They did not show any detrimental effect to the keratinocyte cells. From the results reported above, these hydrogels show good biocompatibility in both models. Due to the advantage of the hydrogels such as the ability to absorb and deliver protein or drugs, they have potential to be used as topical materials for wound healing or other biomedical applications.