Cardiac safety concerns for domperidone, an antiemetic and prokinetic, and galactogogue medicine

Introduction: Domperidone is a dopamine D2-receptor antagonist developed as an antiemetic and prokinetic agents. Oral domperidone is not approved in the US, but is used in many countries to treat nausea and vomiting, gastroparesis, and as a galactogogue (to promote lactation). The US Food and Drug Administration (FDA) have issued a warning about the cardiac safety of domperidone. Areas covered: The authors undertook a review of the cardiac safety of oral domperidone. Expert opinion: The data from preclinical studies are unambiguous in identifying domperidone as able to produce marked hERG channel inhibition and action potential prolongation at clinically relevant concentrations. The compound’s propensity to augment instability of action potential duration and action potential triangulation are also indicative of proarrhythmic potential. Domperidone should not be administered to subjects with pre-existing QT prolongation/LQTS, subjects receiving drugs that inhibit CYP3A4, subjects with electrolyte abnormalities or with other risk factors for QT-prolongation. With these provisos, it is possible that domperidone may be used as a galactogogue without direct risk to healthy breast feeding women but more safety information should be sought in this situation. Also, more safety information is required regarding risk to breast feeding infants or before domperidone is routinely used in gastroparesis or gastroesphageal reflux in children.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Phase II trial of Oxaliplatin and 5-Fluorouracil/Leucovorin combination in epithelial ovarian carcinoma relapsing within 2 years of platinum-based therapy

Objective To evaluate the efficacy and toxicity of Oxaliplatin and 5-Fluorouracil (5-FU)/Leucovorin (LV) combination in ovarian cancer relapsing within 2 years of prior platinum-based chemotherapy in a phase II trial. Methods Eligible patients had at least one prior platinum-based chemotherapy regimen, elevated CA-125 ≥ 60 IU/l, radiological evidence of disease progression and adequate hepatic, renal and bone marrow function. Patients with raised CA-125 levels alone as marker of disease relapse were not eligible. Oxaliplatin (85 mg/m 2) was given on day 1, and 5-Fluorouracil (370 mg/m 2) and Leucovorin (30 mg) was given on days 1 and 8 of a 14-day cycle. Results Twenty-seven patients were enrolled. The median age was 57 years (range 42-74 years). The median platinum-free interval (PFI) was 5 months (range 0-17 months) with only 30% of patients being platinum sensitive (PFI > 6 months). Six patients (22%) had two prior regimens of chemotherapy. A total of 191 cycles were administered (median 7; range 2-12). All patients were evaluable for toxicity. The following grade 3/4 toxicities were noted: anemia 4%; neutropenia 15%; thrombocytopenia 11%; neurotoxicity 8%; lethargy 4%; diarrhea 4%; hypokalemia 11%; hypomagnesemia 11%. Among 27 enrolled patients, 20 patients were evaluable for response by WHO criteria and 25 patients were evaluable by Rustin's CA-125 criteria. The overall response rate (RR) by WHO criteria was 30% (95% CI: 15- 52) [three complete responses (CRs) and three partial responses (PRs)]. The CA-125 response rate was 56% (95% CI: 37-73). Significantly, a 25% (95% CI: 9-53) radiological and a 50% (95% CI: 28-72) CA-125 response rate were noted in platinum resistant patients (PFI < 6 months). The median response duration was 4 months (range 3-12) and the median overall survival was 10 months. Conclusion Oxaliplatin and 5-Fluorouracil/ Leucovorin combination has a good safety profile and is active in platinum-pretreated advanced epithelial ovarian cancer. © 2004 Elsevier Inc. All rights reserved.

Evaluation of brief dietary questions to estimate vegetable and fruit consumption – using serum carotenoids and red-cell folate

Objective: To evaluate responses to self-administered brief questions regarding consumption of vegetables and fruit by comparison with blood levels of serum carotenoids and red-cell folate. Design: A cross-sectional study in which participants reported their usual intake of fruit and vegetables in servings per day, and serum levels of five carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin and lycopene) and red-cell folate were measured. Serum carotenoid levels were determined by high-performance liquid chromatography, and red-cell folate by an automated immunoassay system. Settings and subjects: Between October and December 2000, a sample of 1598 adults aged 25 years and over, from six randomly selected urban centres in Queensland, Australia, were examined as part of a national study conducted to determine the prevalence of diabetes and associated cardiovascular risk factors. Results: Statistically significant (P<0.01) associations with vegetable and fruit intake (categorised into groups: ≤1 serving, 2–3 servings and ≥4 servings per day) were observed for α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin and red-cell folate. The mean level of these carotenoids and of red-cell folate increased with increasing frequency of reported servings of vegetables and fruit, both before and after adjusting for potential confounding factors. A significant association with lycopene was observed only for vegetable intake before adjusting for confounders. Conclusions: These data indicate that brief questions may be a simple and valuable tool for monitoring vegetable and fruit intake in this population.

The effect of retail store managers on aboriginal diet in remote communities

Key nutrient densities of the diet of two remote northern coastal Aboriginal communities were measured using the store-turnover method during the periods that three store managers were responsible for each store respectively. Individual store managers were a greater determinant of nutrient density than the community itself. Furthermore, nutrient densities tended to be highest in both communities when their stores were administered by one particular store manager. The results support the notion that store managers wield considerable power over the food supply of remote Aboriginal communities, and raise questions concerning the ability of Aboriginal community members to influence their own food supplies in retail stores. However, the study also confirms that store managers can be important allies in efforts to improve Aboriginal dietary intake.

Supportive and palliative care for lung cancer patients

Lung cancer patients face poor survival and experience co-occurring chronic physical and psychological symptoms. These symptoms can result in significant burden, impaired physical and social function and poor quality of life. This paper provides a review of evidence based interventions that support best practice supportive and palliative care for patients with lung cancer. Specifically, interventions to manage dyspnoea, one of the most common symptoms experienced by this group, are discussed to illustrate the emerging evidence base in the field. The evidence base for the pharmacological management of dyspnoea report systemic opioids have the best available evidence to support their use. In particular, the evidence strongly supports systemic morphine preferably initiated and continued as a once daily sustained release preparation. Evidence supporting the use of a range of other adjunctive non-pharmacological interventions in managing the symptom is also emerging. Interventions to improve breathing efficiency that have been reported to be effective include pursed lip breathing, diaphragmatic breathing, positioning and pacing techniques. Psychosocial interventions seeking to reduce anxiety and distress can also improve the management of breathlessness although further studies are needed. In addition, evidence reviews have concluded that case management approaches and nurse led follow-up programs are effective in reducing breathlessness and psychological distress, providing a useful model for supporting implementation of evidence based symptom management strategies. Optimal outcomes from supportive and palliative care interventions thus require a multilevel approach, involving interventions at the patient, health professional and health service level.

Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer : report of a phase I/II dose-escalating study

The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis. (C) 2000 Elsevier Science Ltd.

Pharmacist, general practitioner, and nurse perceptions, experiences, and knowledge of medication dosage form modification

Background: People often modify oral solid dosage forms when they experience difficulty swallowing them. Modifying dosage forms may cause adverse effects to the patient, and the person undertaking the modification. Pharmacists are often the first point of contact for people in the general community seeking advice regarding medications. Nurses are at the forefront of administering medications to patients and are likely to be most directly affected by a patient’s swallowing ability, while general practitioners (GPs) are expected to consider swallowing abilities when prescribing medications. Objective: To compare the perspectives and experiences of GPs, pharmacists, and nurses regarding medication dosage form modification and their knowledge of medication modification. Method: Questionnaires tailored to each profession were posted to 630 GPs, and links to an online version were distributed to 2,090 pharmacists and 505 nurses. Results: When compared to pharmacists and GPs, nurses perceived that a greater proportion of the general community modified solid dosage forms. Pharmacists and GPs were most likely to consider allergies and medical history when deciding whether to prescribe or dispense a medicine, while nurses’ priorities were allergies and swallowing problems when administering medications. While nurses were more likely to ask their patients about their ability to swallow medications, most health professionals reported that patients “rarely” or “never” volunteered information about swallowing difficulties. The majority of health professionals would advise a patient to crush or split noncoated non-sustained-release tablets, and would consult colleagues or reference sources for sustained-release or coated tablets. Health professionals appeared to rely heavily upon the suffix attached to medication names (which suggest modified release properties) to identify potential problems associated with modifying medications. Conclusion: The different professional roles and responsibilities of GPs, pharmacists, and nurses are associated with different perspectives of, and experiences with, people modifying medications in the general community and knowledge about consequences of medication modification.

From Aussiewood Movies to Guerrilla Filmmaking: Independent Filmmaking and Contemporary Australian Cinema

Independent filmmaking within the context of Australian cinema is a multifaceted subject. In comparison to the United States, where production can be characterised as bifurcated between major studio production and so-called “indie” or independent production without the backing of the majors, since the 1970s and until recently the vast majority of Australian feature film production has been independent filmmaking. Like most so-called national cinemas, most Australian movies are supported by both direct and indirect public subvention administered by state and federal government funding bodies, and it could be argued that filmmakers are, to a certain degree, “dependent” on official mandates. As this chapter demonstrates national production slates are subjected to budget restraints and cut-backs, official cultural policies (for example pursuing international co-productions and local content quotas) and shifts in policy directions among others. Therefore, within the context of Australian cinema, feature film production operating outside the public funding system could be understood as “independent”. However, as is the case for most English-language national cinemas, independence has long been defined in terms of autonomy from Hollywood, and – as alluded to above – as Australia becomes more dependent upon international inputs into production, higher budget movies are becoming less independent from Hollywood. As such, this chapter argues that independence in Australian cinema can be viewed as having two poles: independence from direct government funding and independence from Hollywood studios. With a specific focus on industry and policy contexts, this chapter explores key issues that constitute independence for Australian cinema. In so doing it examines the production characteristics of four primary domains of contemporary independent filmmaking in Australia, namely: “Aussiewood” production; government-backed low-to-mid budget production; co-productions; and guerrilla filmmaking.

Visually impaired drivers who use bioptic telescopes : self-assessed driving skills and agreement with on-road driving evaluation

Purpose. To compare self-assessed driving habits and skills of licensed drivers with central visual loss who use bioptic telescopes to those of age-matched normally sighted drivers, and to examine the association between bioptic drivers' impressions of the quality of their driving and ratings by a “backseat” evaluator. Methods. Participants were licensed bioptic drivers (n = 23) and age-matched normally sighted drivers (n = 23). A questionnaire was administered addressing driving difficulty, space, quality, exposure, and, for bioptic drivers, whether the telescope was helpful in on-road situations. Visual acuity and contrast sensitivity were assessed. Information on ocular diagnosis, telescope characteristics, and bioptic driving experience was collected from the medical record or in interview. On-road driving performance in regular traffic conditions was rated independently by two evaluators. Results. Like normally sighted drivers, bioptic drivers reported no or little difficulty in many driving situations (e.g., left turns, rush hour), but reported more difficulty under poor visibility conditions and in unfamiliar areas (P < 0.05). Driving exposure was reduced in bioptic drivers (driving 250 miles per week on average vs. 410 miles per week for normally sighted drivers, P = 0.02), but driving space was similar to that of normally sighted drivers (P = 0.29). All but one bioptic driver used the telescope in at least one driving task, and 56% used the telescope in three or more tasks. Bioptic drivers' judgments about the quality of their driving were very similar to backseat evaluators' ratings. Conclusions. Bioptic drivers show insight into the overall quality of their driving and areas in which they experience driving difficulty. They report using the bioptic telescope while driving, contrary to previous claims that it is primarily used to pass the vision screening test at licensure.

Useful field of view test

A test of the useful field of view was introduced more than two decades ago and was designed to reflect the visual difficulties that older adults experience with everyday tasks. Importantly, the useful field of view is one of the most extensively researched and promising predictor tests for a range of driving outcomes measures, including driving ability and crash risk, as well as other everyday tasks. Currently available commercial versions of the test can be administered using personal computers and measure speed of visual processing speed for rapid detection and localization of targets under conditions of divided visual attention and in the presence and absence of visual clutter. The test is believed to assess higher order cognitive abilities, but performance also relies on visual sensory function since targets must be visible in order to be attended to. The format of the useful field of view test has been modified over the years; the original version estimated the spatial extent of useful field of view, while the latest versions measures visual processing speed. While deficits in the useful field of view are associated with functional impairments in everyday activities in older adults, there is also emerging evidence from several research groups that improvements in visual processing speed can be achieved through training. These improvements have been shown to reduce crash risk, and have a positive impact on health and functional well being, with the potential to increase the mobility and hence independence of older adults.

The impact of the built environment on health across the life course : design of a cross-sectional data linkage study

Introduction: The built environment is increasingly recognised as being associated with health outcomes. Relationships between the built environment and health differ among age groups, especially between children and adults, but also between younger, mid-age and older adults. Yet few address differences across life stage groups within a single population study. Moreover, existing research mostly focuses on physical activity behaviours, with few studying objective clinical and mental health outcomes. The Life Course Built Environment and Health (LCBEH) project explores the impact of the built environment on self-reported and objectively measured health outcomes in a random sample of people across the life course. Methods and analysis: This cross-sectional data linkage study involves 15 954 children (0–15 years), young adults (16–24 years), adults (25–64 years) and older adults (65+years) from the Perth metropolitan region who completed the Health and Wellbeing Surveillance System survey administered by the Department of Health of Western Australia from 2003 to 2009. Survey data were linked to Western Australia's (WA) Hospital Morbidity Database System (hospital admission) and Mental Health Information System (mental health system outpatient) data. Participants’ residential address was geocoded and features of their ‘neighbourhood’ were measured using Geographic Information Systems software. Associations between the built environment and self-reported and clinical health outcomes will be explored across varying geographic scales and life stages. Ethics and dissemination: The University of Western Australia's Human Research Ethics Committee and the Department of Health of Western Australia approved the study protocol (#2010/1). Findings will be published in peer-reviewed journals and presented at local, national and international conferences, thus contributing to the evidence base informing the design of healthy neighbourhoods for all residents.

Denial predicts outcome in anxiety following group cognitive behavioral therapy

This study aimed to explore whether participants' pretherapy coping strategies predicted the outcome of group cognitive behavioral therapy (CBT) for anxiety and depression. It was hypothesized that adaptive coping strategies such as the use of active planning and acceptance would be associated with higher reductions, whereas maladaptive coping strategies such as denial and disengagement would be associated with lower reductions in anxious and depressed symptoms following psychotherapy. There were 144 participants who completed group CBT for anxiety and depression. Measures of coping strategies were administered prior to therapy, whereas measures of depression and anxiety were completed both prior to and following therapy. The results showed that higher levels of denial were associated with a poorer outcome, in terms of change in anxiety but not depression, following therapy. These findings suggest the usefulness of using the Denial subscale from the revised Coping Orientation to Problems Experienced (COPE) as a predictor of outcome in group CBT for anxiety.

Prevention of Alcohol-Related Crime and Trauma (PACT) : brief interventions in routine care pathway – a study protocol

Background Globally, alcohol-related injuries cause millions of deaths and huge economic loss each year . The incidence of facial (jawbone) fractures in the Northern Territory of Australia is second only to Greenland, due to a strong involvement of alcohol in its aetiology, and high levels of alcohol consumption. The highest incidences of alcohol-related trauma in the Territory are observed amongst patients in the Maxillofacial Surgery Unit of the Royal Darwin Hospital. Accordingly, this project aims to introduce screening and brief interventions into this unit, with the aims of changing health service provider practice, improving access to care, and improving patient outcomes. Methods Establishment of Project Governance: The project governance team includes a project manager, project leader, an Indigenous Reference Group (IRG) and an Expert Reference Group (ERG). Development of a best practice pathway: PACT project researchers collaborate with clinical staff to develop a best practice pathway suited to the setting of the surgical unit. The pathway provides clear guidelines for screening, assessment, intervention and referral. Implementation: The developed pathway is introduced to the unit through staff training workshops and associate resources and adapted in response to staff feedback. Evaluation: File audits, post workshop questionnaires and semi-structured interviews are administered. Discussion This project allows direct transfer of research findings into clinical practice and can inform future hospital-based injury prevention strategies.