Local injury information,community participation and injury reduction

Abstract: Better injury prevention is now a national health priority in Australia. Applying the health promotion strategies of the Ottawa Charter to injury prevention forms the basis of the World Health Organization's worldwide Safe Communities program. Taking such a community-focused approach has led to quantifiable reductions in injuries in several overseas countries, particularly in Scandinavia where falls of up to 30 per cent in particular injuries have been reported over a three-year period. In the Illawarra area of New South Wales, data from local hospital emergency departments have been used as the basis for a ‘community information’ strategy, in an attempt to replicate this overseas experience in an Australian setting. Reductions of 17 per cent in attendances by children for injuries (P < 0.001) and a 14 per cent fall in accident-related hospital admissions of children (not statistically significant) have been observed over the course of the four-year intervention. Problems of community definition and external confounding influences outside the control of the project make it difficult to confirm a causal relationship. However, community information forms one important component in a comprehensive local injury-reduction strategy.     

Population pharmacokinetics of adjuvant cyclophosphamide,methotrexate and 5-fluorouracil (CMF)

Despite the success of adjuvant cyclophosphamide, methotrexate (MTX), 5-fluouracil (5-FU) (CMF) treatment for early stage breast cancer, more than 35% of patients die within 5 years of diagnosis. Optimisation of the dose of each component drug may improve survival and reduce toxicity. In this study, the pharmacokinetics of intravenous (i.v.) cyclophosphamide (600 mg/m(2)), MTX (40 mg/m(2)) and 5-FU (600 mg/m(2)) were determined in 46 women, with data on two consecutive courses available for 41 patients. A population analysis using NONMEM was performed to investigate the effect of patient covariates on pharmacokinetics (PK), and to estimate the relative magnitude of interindividual and interoccasion variability. Patient weight had a significant influence on the clearance of cyclophosphamide and on the volume of central compartment for MTX, whose clearance was dependent on renal function. For all three drugs, interoccasion variability was of the same order (20-40%) as that between individuals, suggesting a limited potential for dose-optimisation of this regimen.     

Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types.

PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for >or= 3 months; seven of these patients remained on study drug for >or= 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.     

An introduction to patient-reported outcome measures in ophthalmic research

Clinical outcomes, such as quantifying the extent of visual field loss by automated perimetry, are valued highly by health professionals, but such measures do not capture the impact of the condition on a patient''s life. Patient-reported outcomes describe any report or measure of health reported by the patient, without external interpretation by a clinician or researcher. In this review, we discuss the value of the measures that capture this information (patient-reported outcome measures; PROMs), and why they are important to both the clinician and the researcher. We also consider issues around developing or selecting a PROM for ophthalmic research, the emerging challenges around conducting and reporting PROMs in clinical trials and highlight best practice for their use. Search terms for this review comprised: (1) (patient-reported outcomes OR patient-reported outcome measures) AND (2) randomised controlled trials AND (3) limited to ophthalmic conditions. These terms were expanded as follows: (((‘patients''(MeSH Terms) OR ‘patients''(All Fields) OR ‘patient''(All Fields)) AND (‘research report''(MeSH Terms) OR (‘research''(All Fields) AND ‘report''(All Fields)) OR ‘research report''(All Fields) OR ‘reported''(All Fields)) AND outcomes(All Fields)) OR ((‘patients''(MeSH Terms) OR ‘patients''(All Fields) OR ‘patient''(All Fields)) AND (‘research report''(MeSH Terms) OR (‘research''(All Fields) AND ‘report''(All Fields)) OR ‘research report''(All Fields) OR ‘reported''(All Fields) AND (‘outcome assessment (health care)''(MeSH Terms) OR (‘outcome''(All Fields) AND ‘assessment''(All Fields) AND ‘(health''(All Fields) AND ‘care)''(All Fields)) OR ‘outcome assessment (health care)''(All Fields) OR (‘outcome''(All Fields) AND ‘measures''(All Fields)) OR ‘outcome measures''(All Fields)))) AND (‘randomized controlled trial''(Publication Type) OR ‘randomized controlled trials as topic''(MeSH Terms) OR ‘randomised controlled trials''(All Fields) OR ‘randomized controlled trials''(All Fields)) AND (ophth*(All Fields)). The authors also utilised the extensive non-ophthalmic literature and online resources relating to PROs and PROMs to inform this review.     

Lack of p53 and ras mutations in Helicobacter hepaticus-induced liver tumors in A/JCr mice

Helicobacter hepaticus is a recently discovered bacterium that invades mouse liver causing chronic active hepatitis followed by development of preneoplastic hepatocellular foci, hepatocellular adenomas and carcinomas. This establishes a unique animal model for study of the mechanisms of cancer development due to a chronic bacterial infection. A possible mechanism of bacteria-associated tumorigenesis is mutation of oncogenes or tumor suppressor genes. Since mutations in ras oncogenes have been widely detected in a variety of chemically induced and spontaneous mouse liver tumors and specific mutations in the p53 tumor suppressor gene have been associated with human bladder cancers attributed to chronic schistosomal infection, we studied exons 1 and 2 of the N-, K- and H-ras genes and exons 5-8 of the p53 gene for the presence of point mutations in 25 liver tumors from 10 naturally infected A/JCr mice, ranging in age from 16 to 24 months. The 20 adenomas and five carcinomas varied in size from 0.1 to 2.3 cm and arose in livers characterized by a wide assortment of pathological profiles, including hepatitis, inflammation, hyperplasia, hypertrophy, leukocyte infiltration, necrosis and focal phenotypic alteration. DNA samples extracted from formalin-fixed paraffin-embedded tissues were screened by PCR/SSCP analysis and showed no mutations in the analyzed genes. Complete absence of mutations in ras genes in 25 mouse liver tumors is unusual. Other genes may be targeted or H. hepaticus infection causes liver cancer through other pathways than direct damage to DNA.      

Anti-adherent and antifungal activities of surfactant-coated poly(ethylcyanoacrylate) nanoparticles

Application of non-drug-loaded poly(ethylcyanoacrylate) nanoparticles (NP) to buccal epithelial cells (BEC) imparted both anti-adherent and antifungal effects. NP prepared using emulsion polymerisation and stabilised using cationic, anionic and non-ionic surfactants decreased Candida albicans blastospore adhesion, an effect attributable to the peripheral coating of surfactant. Cetrimide and Pluronic^® P123 were shown to be most effective, producing mean percentage reductions in blastospore adherence of 52.7 and 37.0, respectively. Resultant zeta potential matched the polarity of the surfactant, with those stabilised using cetrimide being especially positive (+31.3 mV). Preparation using anionic surfactants was shown to be problematic, with low yield and wide particle size distribution. Evaluation of the antifungal effect of the peripheral coat was evaluated using zones of inhibition and viable counts assays. The former test revealed poor surfactant diffusion through agar, but did show evidence of limited kill. However, the latter method showed that cationic surfactants associated with NP produced high levels of kill, in contrast to those coated with anionic surfactants, where kill was not evident. Non-ionic surfactant-coated NP produced intermediate kill rates. Results demonstrate that surfactant-coated NP, particularly the cationic types, form the possible basis of a prophylactic formulation that primes the candidal target (BEC) against fungal adhesion and infection.     

Ventilatory function after exposure to various respirable hazards in a population of former coal miners

The ventilatory function of 406 male former coal miners who had presented at the Cook County Hospital occupational medicine clinic between January 1976 and April 1987 was studied to determine whether subsequent exposure to respiratory hazards after leaving the coal mines adversely affected lung function. The miners were divided into five exposure groups based on their exposure to respirable hazards. These were coal dust only, coal dust plus asbestos dust, coal dust plus silica dust, coal dust plus another respirable hazard and coal dust plus two other respirable dust exposures. Duration of employment in coal mines, race, smoking history, and mean age were not significantly different between the various exposure groups. No significant difference was found in the per cent of predicted forced expiratory volume in one second (FEV1), per cent of predicted forced vital capacity (FVC), and FEV1/FVC when the coal dust only group was compared with each of the other four exposure groups using ANOVA. Among former coal miners who present for a respiratory disability determination, therefore, exposure to respirable hazards subsequent to employment in coal mines is not associated with a statistically significant deterioration in ventilatory function.     

Ventilatory function after exposure to various respirable hazards in a population of former coal miners.

The ventilatory function of 406 male former coal miners who had presented at the Cook County Hospital occupational medicine clinic between January 1976 and April 1987 was studied to determine whether subsequent exposure to respiratory hazards after leaving the coal mines adversely affected lung function. The miners were divided into five exposure groups based on their exposure to respirable hazards. These were coal dust only, coal dust plus asbestos dust, coal dust plus silica dust, coal dust plus another respirable hazard and coal dust plus two other respirable dust exposures. Duration of employment in coal mines, race, smoking history, and mean age were not significantly different between the various exposure groups. No significant difference was found in the per cent of predicted forced expiratory volume in one second (FEV1), per cent of predicted forced vital capacity (FVC), and FEV1/FVC when the coal dust only group was compared with each of the other four exposure groups using ANOVA. Among former coal miners who present for a respiratory disability determination, therefore, exposure to respirable hazards subsequent to employment in coal mines is not associated with a statistically significant deterioration in ventilatory function.     

Phase I trial with pharmacokinetics of CB10-277 given by 24 hours continuous infusion.

The dose limiting toxicities of the short infusion trial of the dacarbazine analog, CB10-277, were nausea and vomiting which appeared to be related to the peak plasma level of the parent drug. In addition, based on mouse studies, these dose limiting toxicities occurred at a less than optimal level of the monomethyl metabolite, the presumed species required for antitumour activity. An alternative schedule that would avoid the parent drug peak plasma levels of short infusion, while possibly allowing an increase in the amount of monomethyl metabolite produced was considered. Thus, a 24 h continuous infusion schedule, repeated every 21 days was explored. Twenty-two patients received 42 courses with a dose range of 4,700-15,000 mg m-2. The dose limiting toxicity was myelosuppression (leucopenia and thrombocytopenia). Although nausea and vomiting also occurred, it was manageable with routine antiemetic therapy. Other toxicities included diarrhoea, hallucinations, malaise, muscle ache, headache and flushing and all were < or = WHO grade 2. Pharmacokinetic studies were performed with 13 courses which included all dose levels. The mean t1/2 of the parent drug was 178 min. Area under the concentration x time curve (AUC) at the highest dose for the parent drug and the monomethyl metabolite were 2,350 and 9 mM x minutes, respectively. This monomethyl metabolite AUC and the associated myelosuppression showed a more favourable comparison to the preclinical data determined in mice than the results from the short infusion trial of CB10-277. Therefore, the recommended Phase II dose and schedule of this drug was 12,000 mg m-2 given by 24 h continuous infusion.     

Preclinical, phase I and pharmacokinetic studies with the dimethyl phenyltriazene CB10-277.

Decarbazine is an imidazole dimethyltriazene with reproducible activity in patients with metastatic melanoma. CB10-277 is a phenyl dimethyltriazene which, like dacarbazine, requires metabolic activation to its corresponding monomethyl species for antitumour activity. In preclinical models (human melanoma xenografts and transplantable rodent tumours) CB10-277 showed a similar spectrum and level of activity when compared to dacarbazine. Pharmacokinetic studies were performed with CB10-277 in mice treated i.v. at the LD10 (750 mg m-2) and plasma analysed by HPLC. The parent drug area under the plasma concentration vs time curve (AUC) was 142 mM x minutes. Drug metabolism occurred as evidenced by the HPLC identification of the monomethyl species (AUC = 8 mM x minutes) as well as other metabolites. A Phase I trial using a short infusion with doses repeated every 21 days has been performed. Thirty-six patients received 80 courses over a dose range of 80-6,000 mg m-2. The dose limiting toxicity was nausea and vomiting which occurred in 80% of the evaluable courses > or = 900 mg m-2. The only other common side effect was a flushing or warm sensation, which occurred in over 75% of courses at > or = 1,350 mg m-2. There were no hemodynamic consequences. Responses occurred in patients with melanoma (one complete, two partial, one mixed/11), sarcoma (one mixed/6) and carcinoid (one partial/l). Pharmacokinetics were performed in 46 courses. The CB10-277 AUC increased linearly with dose (r = 0.9203, P < 0.001) up to 700 mM x minutes at 6,000 mg m-2). Evidence of CB10-277 metabolism was observed, as in mice, by detection of the monomethyl species and other metabolites. However, the plasma levels of the monomethyl species in patients (1.8 and 3.7 mM x minutes at 6,000 mg m-2) were less than those predicted from studies in mice. Despite this, antitumour activity in dacarbazine sensitive histologies was observed and additional studies with CB10-277 are recommended.