Drug bioactivation, covalent binding to target proteins and toxicity relevance

A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients. Further studies using proteomic and genomic approaches with high throughput capacity are needed to identify the protein targetsof reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.

Colorectal cancer screening in Australia: an economic evaluation of a potential biennial screening program using faecal occult blood tests

Objective: To evaluate whether the introduction of a national, co-ordinated screening program using the faecal occult blood test represents 'value-for-money' from the perspective of the Australian Government as third-party funder.  Methods: The annual equivalent costs and consequences of a   biennial screening program in 'steady-state' operation were estimated for the Australian population using 1996 as the reference year. Disability-adjusted life years (DALYs) and the years of life lost (YLLs) averted, and the health service costs were modelled, based on the epidemiology and the costs of colorectal cancer in Australia together with the mortality reduction achieved in randomised controlled trials. Uncertainty in the model was examined using Monte Carlo simulation methods. Results: We estimate a minimum or 'base program' of screening those aged 55 to 69 years could avert 250 deaths per annum (95% uncertainty interval 99–400), at a gross cost of $A55 million (95% UI $A46 million to $A96 million) and a gross incremental cost-effectiveness ratio of $A17,000/DALY (95% UI $A13,000/DALY to $A52,000/DALY). Extending the program to include 70 to 74-year-olds is a more effective option (cheaper and higher health gain) than including the 50 to 54-year-olds. Conclusions: The findings of this study support the case for a national program directed at the 55 to 69-year-old age group with extension to 70 to 74-year-olds if there are sufficient resources. The pilot tests recently announced in Australia provide an important opportunity to consider the age range for screening and the sources of uncertainty, identified in the modelled evaluation, to assist decisions on implementing a full national program.

Early detection of emotional and behavioural problems in children with diabetes: the validity of the child health questionnaire as a screening instrument

Aims: To assess the validity of the Child Health Questionnaire (CHQ) as a screening tool for detecting 'at risk' emotional and behavioural  maladjustment in children with diabetes, using the Behaviour Assessment System for Children (BASC) as a gold standard measure. Methods: CHQ and BASC were administered to 103 parents of children with Type 1 diabetes, aged 7–12 years. Sub-scales of the two measures were compared using Pearson's bivariate correlations. CHQ sensitivity and specificity cut-points were optimized against the BASC borderline category using receiver operating characteristic curves. Results: The BASC Externalizing Problems scale correlated strongly with CHQ Behaviour, Global Behaviour, Mental Health, Family Activities and Family Cohesion scales (r-values −0.68, −0.54, −0.51, −0.59, and −0.42, respectively). BASC Internalizing Problems scale correlated strongly with CHQ Behaviour, Mental Health and Family Cohesion scales (r-values −0.40, −0.43 and −0.45, respectively). Using receiver operating characteristic curve analysis, the CHQ Mental Health scale most effectively identified children classified as borderline on the BASC Internalizing Problems scale (sensitivity 87%, specificity 78%), while the CHQ Global Behaviour scale most effectively identified children classified as borderline on the BASC Externalizing Problems scale (sensitivity 73%, specificity 82%). Conclusions: Significant correlations were seen between the CHQ Global Behaviour and Mental Health scales and the BASC Externalizing and Internalizing scales, respectively. Sequential use of the CHQ, as a screening tool, followed by an established mental health measure such as the BASC, may help identify children with diabetes 'at risk' for chronic maladjustment and poor health outcomes.

Cost-effectiveness analysis of screening for lung cancer with low dose spiral CT (computed tomography) in the Australian setting

Introduction:
Low dose spiral computed tomography (CT) is a sensitive screening tool for lung cancer that is currently being evaluated in both non-randomised studies and randomised controlled trials.
Methods:
We conducted a quantitative decision analysis using a Markov model to determine whether, in the Australian setting, offering spiral CT screening for lung cancer to high risk individuals would be cost-effective compared with current practice. This exploratory analysis was undertaken predominantly from the perspective of the government as third-party funder. In the base-case analysis, the costs and health outcomes (life-years saved and quality-adjusted life years) were calculated in a hypothetical cohort of 10,000 male current smokers for two alternatives: (1) screen for lung cancer with annual CT for 5 years starting at age 60 year and treat those diagnosed with cancer or (2) no screening and treat only those who present with symptomatic cancer.
Results:
For male smokers aged 60–64 years, with an annual incidence of lung cancer of 552 per 100,000, the incremental cost-effectiveness ratio was $57,325 per life-year saved and $105,090 per QALY saved. For females aged 60–64 years with the same annual incidence of lung cancer, the cost-effectiveness ratio was $51,001 per life-year saved and $88,583 per QALY saved. The model was used to examine the relationship between efficacy in terms of the expected reduction in lung cancer mortality at 7 years and cost-effectiveness. In the base-case analysis lung cancer mortality was reduced by 27% and all cause mortality by 2.1%. Changes in the estimated proportion of stage I cancers detected by screening had the greatest impact on the efficacy of the intervention and the cost-effectiveness. The results were also sensitive to assumptions about the test performance characteristics of CT scanning, the proportion of lung cancer cases overdiagnosed by screening, intervention rates for benign disease, the discount rate, the cost of CT, the quality of life in individuals with early stage screen-detected cancer and disutility associated with false positive diagnoses. Given current knowledge and practice, even under favourable assumptions, reductions in lung cancer mortality of less than 20% are unlikely to be cost-effective, using a value of $50,000 per life-year saved as the threshold to define a “cost-effective” intervention.
Conclusion:
The most feasible scenario under which CT screening for lung cancer could be cost-effective would be if very high-risk individuals are targeted and screening is either highly effective or CT screening costs fall substantially.

Screening Michael Jackson's face : reading Martin Bashir's living with Michael Jackson

The screening of Martin Bashir's Living with Michael Jackson on Australian television elicited a phenomenal amount of interest in the news media, at water coolers and on the Internet. Much of the response in the Australian print media was critical of Bashir's representation of Jackson, as well as denouncing Jackson as sad victim, warped predator and allround freakshow. This article considers these interpretations to argue that the production and consumption of 'wacko Jacko' is underpinned by the increasing instability of the natural in an age of information technologies, as well as the collapse of boundaries between documentary and fictional entertainment forms.

Mathematical thinking: a screening profile for 'operations'

This paper comments on and adapts the screening profile developed from 'ACER Mathematics Profile Series (MAPS): Operations' (1977). A sample screening profile worksheet for 'Operations' is provided. This adaptation of the ACER MAPS Operations test may help teachers identify students who are able to use more advanced levels of mathematical thinking. Survey results may help form ability groups, deliver special needs curriculum materials, and guide students tackling the algebra curriculum.