Cost and effectiveness of laser with phlebectomies compared with foam sclerotherapy in superficial venous insufficiency. Early results of a randomised controlled trial.

OBJECTIVES: Quantify endovenous laser ablation (EVLA) with concurrent phlebectomies and ultrasound-guided foam sclerotherapy (UGFS) in cost and effectiveness at 3 weeks and 3 months. DESIGN: Single-centre, prospective, randomised controlled trial. PATIENTS: One hundred patients (100 legs), C(2-6), age 21-78, M:F 42:58, with primary varicose veins received either EVLA under local anaesthetic or UGFS. METHODS: Assessments included duplex, Aberdeen varicose vein questionnaire (AVVQ), venous clinical severity score (VCSS), venous filling index (VFI), visual analogue 7-day pain score and analgesia requirements. Additional treatments with UGFS were performed, if required. Micro-costing, using individually timed treatments, was based on consumables, staff pay and overheads. RESULTS: Changes in AVVQ, VCSS and VFI values (3 months) did not demonstrate any significant difference between groups. At 3 months, the above-knee GSV occlusion rate (without co-existing reflux) was not significantly different between the groups (74% vs 69%; EVLA vs UGFS; P = .596). Of the 9 haemodynamic failures in each group, 7 EVLA patients and 4 UGFS patients had co-existing cross-sectional above-knee GSV occlusion at some point. However, UGFS significantly outperformed EVLA in cost, treatment duration, pain, analgesia requirements and recovery. CONCLUSIONS: UGFS is 3.15 times less expensive than EVLA (£230.24 vs £724.72) with comparable effectiveness but 56% (versus 6%) required additional foam (ISRCTN:03080206).

Cost-effectiveness of single-use negative-pressure therapy compared with standard care for prevention of reconstruction failure in prepectoral breast reconstruction.

BACKGROUND: Single-use negative-pressure wound therapy (sNPWT) has been reported to reduce the incidence of reconstruction failure in prepectoral breast reconstruction compared with standard surgical dressings. The aim of this economic evaluation was to investigate the cost-effectiveness of sNPWT compared with standard care for the prevention of reconstruction failure in prepectoral breast reconstruction in the UK. METHOD: A decision tree model was used to estimate the expected cost and effectiveness per patient. Effectiveness was measured both by the number of reconstruction failures avoided and the gain in quality-adjusted life-years (QALYs). The baseline incidence of reconstruction failure (8.6 per cent) was taken from a recently published study of 2655 mastectomies in the UK. The effectiveness of sNPWT used results from a clinical study comparing sNPWT with standard dressings. Previously published utility weights were applied. The cost of reconstruction failure was estimated from detailed resource data from patients with reconstruction failure, applying National Health Service reference costs. One-way, probabilistic, scenario and threshold analyses were conducted. RESULTS: The undiscounted cost per patient associated with reconstruction failure was estimated to be £23 628 (£22 431 discounted). The use of sNPWT was associated with an expected cost saving of £1706 per patient, an expected increase in QALYs of 0.0187 and an expected 0.0834 reconstruction failures avoided. Cost-effectiveness acceptability analysis demonstrated that, at a threshold of £20 000 per QALY, 99.94 per cent of the simulations showed sNPWT to be more cost-effective than standard care. CONCLUSION: Among patients undergoing immediate prepectoral breast reconstruction, the use of sNPWT is more cost-effective than standard dressings.

Single-use negative-pressure wound therapy versus conventional dressings for closed surgical incisions: systematic literature review and meta-analysis.

BACKGROUND: Surgical-site complications (SSCs) remain a significant cause of morbidity and mortality, particularly in high-risk patients. The aim of this study was to determine whether prophylactic use of a specific single-use negative-pressure wound therapy (sNPWT) device reduced the incidence of SSCs after closed surgical incisions compared with conventional dressings. METHODS: A systematic literature review was performed using MEDLINE, Embase and the Cochrane Library to identify articles published from January 2011 to August 2018. RCTs and observational studies comparing PICO™ sNPWT with conventional dressings, with at least 10 patients in each treatment arm, were included. Meta-analyses were performed to determine odds ratios (ORs) or mean differences (MDs), as appropriate. PRISMA guidelines were followed. The primary outcome was surgical-site infection (SSI). Secondary outcomes were other SSCs and hospital efficiencies. Risk of bias was assessed. RESULTS: Of 6197 citations screened, 29 studies enrolling 5614 patients were included in the review; all studies included patients with risk factors for SSCs. sNPWT reduced the number of SSIs (OR 0.37, 95 per cent c.i. 0.28 to 0.50; number needed to treat (NNT) 20). sNPWT reduced the odds of wound dehiscence (OR 0.70, 0.53 to 0.92; NNT 26), seroma (OR 0.23, 0.11 to 0.45; NNT 13) and necrosis (OR 0.11, 0.03 to 0.39; NNT 12). Mean length of hospital stay was shorter in patients who underwent sNPWT (MD -1.75, 95 per cent c.i. -2.69 to -0.81). CONCLUSION: Use of the sNPWT device in patients with risk factors reduced the incidence of SSCs and the mean length of hospital stay.

Long-term cost-effectiveness of weight management in primary care.

BACKGROUND: As obesity prevalence and health-care costs increase, Health Care providers must prevent and manage obesity cost-effectively. METHODS: Using the 2006 NICE obesity health economic model, a primary care weight management programme (Counterweight) was analysed, evaluating costs and outcomes associated with weight gain for three obesity-related conditions (type 2 diabetes, coronary heart disease, colon cancer). Sensitivity analyses examined different scenarios of weight loss and background (untreated) weight gain. RESULTS: Mean weight changes in Counterweight attenders was -3 kg and -2.3 kg at 12 and 24 months, both 4 kg below the expected 1 kg/year background weight gain. Counterweight delivery cost was pound59.83 per patient entered. Even assuming drop-outs/non-attenders at 12 months (55%) lost no weight and gained at the background rate, Counterweight was 'dominant' (cost-saving) under 'base-case scenario', where 12-month achieved weight loss was entirely regained over the next 2 years, returning to the expected background weight gain of 1 kg/year. Quality-adjusted Life-Year cost was pound2017 where background weight gain was limited to 0.5 kg/year, and pound2651 at 0.3 kg/year. Under a 'best-case scenario', where weights of 12-month-attenders were assumed thereafter to rise at the background rate, 4 kg below non-intervention trajectory (very close to the observed weight change), Counterweight remained 'dominant' with background weight gains 1 kg, 0.5 kg or 0.3 kg/year. CONCLUSION: Weight management for obesity in primary care is highly cost-effective even considering only three clinical consequences. Reduced healthcare resources use could offset the total cost of providing the Counterweight Programme, as well as bringing multiple health and Quality of Life benefits.

Prophylactic G-CSF in patients with early-stage breast cancer: a health economic review.

Although the use of prophylactic granulocyte colony-stimulating factor (G-CSF) in conjunction with myelosuppressive chemotherapy is supported by clinical research evidence and advocated by international clinical guidelines when the consequent risk of febrile neutropenia exceeds 20%, there remains doubt as to the cost-effectiveness of the practice. There are limited economic data, and the data that are available are not necessarily applicable to the management of breast cancer in a European setting. Much of the available evidence on G-CSF in the management of febrile neutropenia is partial, focusing primarily on direct costs to the health service - that is, those related to hospitalisation and drug treatment. A full assessment of the cost effectiveness of G-CSF prophylaxis needs to take account of both costs and outcomes, including mortality, quality of life and patient functioning. As febrile neutropenia has been shown to affect productivity, consideration should also be given to quantifying the indirect costs of neutropenia.

An economic evaluation of VAC therapy compared with wound dressings in the treatment of diabetic foot ulcers.

OBJECTIVE: To determine the cost-effectiveness ofVacuum Assisted Closure (VAC) therapy (KCI Medical), based on a comparison with both traditional and advanced wound dressings, for the treatment of diabetic foot ulcers in the US. METHOD: A Markov model was designed to estimate the cost per amputation avoided and the cost per quality-adjusted life year (QALY) of VAC therapy, compared with both traditional and advanced dressings. Over a one-year period the Markov model simulated 1000 patients using transition probabilities obtained from the literature. The health states used in the model were: uninfected ulcer; infected ulcer; infected ulcer post-amputation; healed; healed post-amputation; amputation; and death. Patients initially treated with VAC switched to the advanced dressing after three months of treatment if their wound remained unhealed. Patients treated with traditional or advanced dressings were assumed to continue with their treatment for the full 12 months if they remained unhealed. RESULTS: The model results demonstrate improved healing rates (61% versus 59%), more QALYs (0.54 versus 0.53) and an overall lower cost of care ($52,830 versus $61,757 per person) for patients treated with VAC therapy compared with advanced dressings. Vacuum Assisted Closure was also shown to be a dominant intervention when compared with traditional dressings. CONCLUSION: The model results indicate thatVAC therapy is less costly and more effective than both traditional and advanced dressings. The results are robust to changes in key parameters, including the transition probabilities, the cost ofVAC therapy and the utility weights applied to health states.

Potential economic impacts from improving breastfeeding rates in the UK.

RATIONALE: Studies suggest that increased breastfeeding rates can provide substantial financial savings, but the scale of such savings in the UK is not known. OBJECTIVE: To calculate potential cost savings attributable to increases in breastfeeding rates from the National Health Service perspective. DESIGN AND SETTINGS: Cost savings focussed on where evidence of health benefit is strongest: reductions in gastrointestinal and lower respiratory tract infections, acute otitis media in infants, necrotising enterocolitis in preterm babies and breast cancer (BC) in women. Savings were estimated using a seven-step framework in which an incidence-based disease model determined the number of cases that could have been avoided if breastfeeding rates were increased. Point estimates of cost savings were subject to a deterministic sensitivity analysis. RESULTS: Treating the four acute diseases in children costs the UK at least £89 million annually. The 2009-2010 value of lifetime costs of treating maternal BC is estimated at £959 million. Supporting mothers who are exclusively breast feeding at 1 week to continue breast feeding until 4 months can be expected to reduce the incidence of three childhood infectious diseases and save at least £11 million annually. Doubling the proportion of mothers currently breast feeding for 7-18 months in their lifetime is likely to reduce the incidence of maternal BC and save at least £31 million at 2009-2010 value. CONCLUSIONS: The economic impact of low breastfeeding rates is substantial. Investing in services that support women who want to breast feed for longer is potentially cost saving.

The cost-effectiveness of triple nucleoside analogue therapy antiretroviral regimens in the treatment of HIV in the United Kingdom.

PURPOSE: Treatment of HIV infection has improved markedly in recent years due to the use of combination antiretroviral therapies. However, the cost of these treatments remains a concern for those who fund health services. This article reports the results of an economic evaluation to determine the incremental cost-effectiveness of triple combination nucleoside analogue (NA) therapy compared with dual NA therapy. METHOD: A Markov model was developed to assess the incremental cost effectiveness of triple therapy treatment versus dual therapy treatment. Clinical data was derived from published clinical trials and large observational cohorts whilst cost data was derived from a prospective database that monitors health care resource use in the UK HIV population. RESULTS: The model predicted that triple NA combination treatment extended life expectancy by an additional 1.2 years compared with dual therapy NA treatment with an incremental cost-effectiveness ratio of 8,419 pounds per life-year saved. The incremental cost per quality-adjusted life-year (QALY) was estimated to be between 10,072-16,168 pounds per QALY gained depending on the assumptions. CONCLUSION: The results show triple nucleoside analogue therapy to be a cost effective means of delaying HIV progression and extending life expectancy. However, further research into this issue is warranted.

Health economics in HIV disease. A review of the European literature.

The costs of providing healthcare resources for patients with HIV disease have continued to rise during the last 2 decades since the first outbreak of AIDS. Although new and effective therapies have become available during this time, and are increasingly being used, outcome measures for, and the economic consequences of, differing models of care are poorly documented or understood. Most available economic and clinical data, especially data documenting post-therapy outcomes, are from small, short term studies. This has led to the use of modelling to estimate which determinants can improve the quality and cost effectiveness of HIV care in the future. Although the attempt to provide what is currently perceived to be the standard of care is stretching many healthcare budgets, it is an anachronism that there are few studies of health economics in HIV disease. Most published data relate only to North America, and there remains a paucity of European studies. This paper provides a review of the available data from Europe and attempts to highlight the trends that have taken place to date.

Developing guidance for budget impact analysis.

The role of economic evaluation in the efficient allocation of healthcare resources has been widely debated. Whilst economic evidence is undoubtedly useful to purchasers, it does not address the issue of affordability which is an increasing concern. Healthcare purchasers are concerned not just with maximising efficiency but also with the more simplistic goal of remaining within their annual budgets. These two objectives are not necessarily consistent. This paper examines the issue of affordability, the relationship between affordability and efficiency and builds the case for why there is a growing need for budget impact models to complement economic evaluation. Guidance currently available for such models is also examined and it is concluded that this guidance is currently insufficient. Some of these insufficiencies are addressed and some thoughts on what constitutes best practice in budget impact modelling are suggested. These suggestions include consideration of transparency, clarity of perspective, reliability of data sources, the relationship between intermediate and final end-points and rates of adoption of new therapies. They also include the impact of intervention by population subgroups or indications, reporting of results, probability of re-deploying resources, the time horizon, exploring uncertainty and sensitivity analysis, and decision-maker access to the model. Due to the nature of budget impact models, the paper does not deliver stringent methodological guidance on modelling. The intention was to provide some suggestions of best practice in addition to some foundations upon which future research can build.

A prospective evaluation of the cost effectiveness of adding lamivudine to zidovudine-containing antiretroviral treatment regimens in HIV infection. European perspective.

BACKGROUND: A prospective cost-effectiveness analysis undertaken as part of the CAESAR (Canada, Australia, Europe, South Africa) placebo-controlled clinical trial showed that adding lamivudine to zidovudine-containing regimens for 1 year reduced progression to AIDS or death and, in addition, significantly reduced the number of hospitalisations, unscheduled outpatient visits and the requirement for medications for HIV-related illness. Data from all 1840 patients included in the intent-to-treat population of the CAESAR trial were used in the analysis reported in this paper. Because a third-party payer perspective was adopted, possible savings associated with increased productivity (indirect costs) were not taken into account. All costs were adjusted to 1997 prices. RESULTS: The savings associated with reduced healthcare resource use in the CAESAR study were estimated to be 3045 Deutschmarks (DM) [German analysis] or 432 pounds sterling (Pound) [UK analysis] per patient for the 1-year time period. These savings partly offset the cost of lamivudine in the 2 countries. The German analysis showed that the addition of lamivudine to zidovudine-containing regimens resulted in an incremental cost-effectiveness ratio of DM22,405 [95% confidence interval (CI): -DM2199 to DM59,154] for progression to AIDS/death avoided and of DM8869 (95% CI: -DM1047 to DM23,365) for HIV-related illness avoided. The corresponding ratios for the UK analysis were 12,030 Pounds (95% CI: 6752 Pounds to 21,888 Pounds) for progressions avoided and 4762 Pounds (95% CI: 2796 Pounds to 9484 Pounds) for new and recurrent HIV-related illness avoided. CONCLUSIONS: Our findings indicate that treatments that slow the progression of HIV infection to AIDS or death have the potential to facilitate healthcare savings during the period that the treatment is effective. The results also demonstrate that it is possible to undertake economic evaluations in parallel with a major clinical end-point study.

Research into the use of health economics in decision making in the United Kingdom--Phase II. Is health economics 'for good or evil'?

The purpose of this phased research project is to better understand the role of health economic arguments in the decision making process of healthcare providers and purchasers in the United Kingdom. Phase I of the research was directed at General Practitioners (GPs); in phase II we broadened the scope of the research to include different agents who influence resource allocation and the wider health care environment. The objective of phase II was to determine the relevance and appeal of diverse health economic measures to different decision makers. This phase of qualitative research involved 34 decision makers in 17 duo interviews. The study has provided a rich source of qualitative evidence on the role of health economics in decision making. The main conclusions to emerge are; different individuals seek different outcomes; health economic studies should report actionable conclusions; and any cost savings must be applicable. To succeed, economists need to demonstrate a better understanding of the contracting and budgetary processes of the National Health Service. Opinions of the value of health economic evaluations varied widely, however most respondents believed it would become increasingly influential in the prioritisation process in the National Health Service of the future.

Health economics. Perfect combination.

The assumption by some HAs that a shift from mono to combination drug therapies for HIV results in a proportional increase in drug expenditure, regardless of health gains, is misguided. Methods of calculating anti-HIV drug expenditure have failed to keep up with changing treatment regimes. There is an urgent need to change the way data on antiretroviral use is collected and presented to establish the true cost-effectiveness of new drug regimes.

Effect of exercise referral schemes in primary care on physical activity and improving health outcomes: systematic review and meta-analysis.

OBJECTIVE: To assess the impact of exercise referral schemes on physical activity and health outcomes. Design Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, PsycINFO, Cochrane Library, ISI Web of Science, SPORTDiscus, and ongoing trial registries up to October 2009. We also checked study references. Study selection Design: randomised controlled trials or non-randomised controlled (cluster or individual) studies published in peer review journals. POPULATION: sedentary individuals with or without medical diagnosis. Exercise referral schemes defined as: clear referrals by primary care professionals to third party service providers to increase physical activity or exercise, physical activity or exercise programmes tailored to individuals, and initial assessment and monitoring throughout programmes. Comparators: usual care, no intervention, or alternative exercise referral schemes. RESULTS: Eight randomised controlled trials met the inclusion criteria, comparing exercise referral schemes with usual care (six trials), alternative physical activity intervention (two), and an exercise referral scheme plus a self determination theory intervention (one). Compared with usual care, follow-up data for exercise referral schemes showed an increased number of participants who achieved 90-150 minutes of physical activity of at least moderate intensity per week (pooled relative risk 1.16, 95% confidence intervals 1.03 to 1.30) and a reduced level of depression (pooled standardised mean difference -0.82, -1.28 to -0.35). Evidence of a between group difference in physical activity of moderate or vigorous intensity or in other health outcomes was inconsistent at follow-up. We did not find any difference in outcomes between exercise referral schemes and the other two comparator groups. None of the included trials separately reported outcomes in individuals with specific medical diagnoses. Substantial heterogeneity in the quality and nature of the exercise referral schemes across studies might have contributed to the inconsistency in outcome findings. Conclusions Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.

The clinical effectiveness and cost-effectiveness of exercise referral schemes: a systematic review and economic evaluation.

BACKGROUND: Exercise referral schemes (ERS) aim to identify inactive adults in the primary-care setting. The GP or health-care professional then refers the patient to a third-party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the individual. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of ERS for people with a diagnosed medical condition known to benefit from physical activity (PA). The scope of this report was broadened to consider individuals without a diagnosed condition who are sedentary. DATA SOURCES: MEDLINE; EMBASE; PsycINFO; The Cochrane Library, ISI Web of Science; SPORTDiscus and ongoing trial registries were searched (from 1990 to October 2009) and included study references were checked. METHODS: Systematic reviews: the effectiveness of ERS, predictors of ERS uptake and adherence, and the cost-effectiveness of ERS; and the development of a decision-analytic economic model to assess cost-effectiveness of ERS. RESULTS: Seven randomised controlled trials (UK, n = 5; non-UK, n = 2) met the effectiveness inclusion criteria, five comparing ERS with usual care, two compared ERS with an alternative PA intervention, and one to an ERS plus a self-determination theory (SDT) intervention. In intention-to-treat analysis, compared with usual care, there was weak evidence of an increase in the number of ERS participants who achieved a self-reported 90-150 minutes of at least moderate-intensity PA per week at 6-12 months' follow-up [pooled relative risk (RR) 1.11, 95% confidence interval 0.99 to 1.25]. There was no consistent evidence of a difference between ERS and usual care in the duration of moderate/vigorous intensity and total PA or other outcomes, for example physical fitness, serum lipids, health-related quality of life (HRQoL). There was no between-group difference in outcomes between ERS and alternative PA interventions or ERS plus a SDT intervention. None of the included trials separately reported outcomes in individuals with medical diagnoses. Fourteen observational studies and five randomised controlled trials provided a numerical assessment of ERS uptake and adherence (UK, n = 16; non-UK, n = 3). Women and older people were more likely to take up ERS but women, when compared with men, were less likely to adhere. The four previous economic evaluations identified suggest ERS to be a cost-effective intervention. Indicative incremental cost per quality-adjusted life-year (QALY) estimates for ERS for various scenarios were based on a de novo model-based economic evaluation. Compared with usual care, the mean incremental cost for ERS was £169 and the mean incremental QALY was 0.008, with the base-case incremental cost-effectiveness ratio at £20,876 per QALY in sedentary people without a medical condition and a cost per QALY of £14,618 in sedentary obese individuals, £12,834 in sedentary hypertensive patients, and £8414 for sedentary individuals with depression. Estimates of cost-effectiveness were highly sensitive to plausible variations in the RR for change in PA and cost of ERS. LIMITATIONS: We found very limited evidence of the effectiveness of ERS. The estimates of the cost-effectiveness of ERS are based on a simple analytical framework. The economic evaluation reports small differences in costs and effects, and findings highlight the wide range of uncertainty associated with the estimates of effectiveness and the impact of effectiveness on HRQoL. No data were identified as part of the effectiveness review to allow for adjustment of the effect of ERS in different populations. CONCLUSIONS: There remains considerable uncertainty as to the effectiveness of ERS for increasing activity, fitness or health indicators or whether they are an efficient use of resources in sedentary people without a medical diagnosis. We failed to identify any trial-based evidence of the effectiveness of ERS in those with a medical diagnosis. Future work should include randomised controlled trials assessing the cinical effectiveness and cost-effectivenesss of ERS in disease groups that may benefit from PA. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Can economic evaluation guidelines improve efficiency in resource allocation? The cases of Portugal, The Netherlands, Finland, and the United Kingdom.

The use of economic evaluation in decision making appears to have increased over the past few years and economic evaluation is looked upon as another measure to help contain costs and improve efficiency in an evidence-based decision-making environment. Following the examples of Australia and the Canadian Province of Ontario, four European Union (EU) countries (Finland, the Netherlands, Portugal, and the United Kingdom) have recently introduced economic evaluation guidelines. In addition to the Australian and Canadian guidelines, which constitute a hurdle to reimbursement, the paradigm that seems to be evolving in the four EU countries follows a similar route. Finland and the Netherlands seem to be moving toward the notion of a fourth hurdle to reimbursement, whereas the National Institute for Clinical Excellence in England and Wales was in principle meant to influence practice, although in reality this essentially acts as a hurdle to reimbursement, requiring a different data set to that used by regulatory authorities. Whereas the Portuguese guidelines were developed to assist in preparing economic submissions to support reimbursement decisions, they are unclear about when such evidence will be required and also discuss the dissemination of economic evidence to broader audiences. The introduction of these guidelines poses a number of challenges to policy makers, the implications of which are analyzed in the paper: a) to ensure that economic evaluations are carried out scientifically without industrial or political bias; b) to define an acceptable methodology that would increase their credibility; and c) to address certain practical issues ranging from deciding how to use economic evaluations in policy making to setting up new institutions or improving the coordination and dissemination of evidence. The variation in the use of economic evaluation guidelines in the four EU countries highlights the differences in national pharmaceutical policies and is in line with policy makers' continuous attempts to contain costs. While the paper critically discusses the guidelines, it also points out that a series of methodologic issues need to be addressed if economic criteria are to be introduced in policy making with the aim to improve resource allocation. The paper concludes that economic evaluation as a discipline is beginning to impact on policy, whereas the consistent use of economic evaluation results is, in principle, being adopted by policy makers but needs to go a step further to reach practitioners.

'Fourth hurdle reviews', NICE, and database applications.

The 'fourth hurdle' is commonly described as what has to be done to gain market access and reimbursement for a pharmaceutical, medical technology, or biotech product. Demonstrating to regulatory agencies just a product's safety, efficacy, and quality (the first three hurdles) is no longer sufficient. Manufacturers must often now demonstrate both clinical effectiveness (Is the new product better than currently available alternatives, including no treatment?) as well as cost-effectiveness (Is the product good value for money?) in order to assure success in the marketplace. In the last few years there have been a number of governmental and non-governmental agencies constituted for fourth hurdle reviews and recommendations to governments and other funding and reimbursement agencies. The National Institute for Clinical Effectiveness (NICE) in the UK, although not the first such group, is arguably the most visible and influential. This paper describes the NICE review process in detail, as well as the expected substantial impact of fourth hurdle reviews on drug development and clinical trials. Potential uses of databases and modelling in fourth hurdle reviews are also explored.

DNA sequence analysis of methylene chloride-induced HPRT mutations in Chinese hamster ovary cells: comparison with the mutation spectrum obtained for 1,2-dibromoethane and formaldehyde.

Glutathione-S-transferase-mediated metabolism of methylene chloride (MC) generates S-chloromethylglutathione, which has the potential to react with DNA, and formaldehyde, which is a known mutagen. MC-induced mutations in the HPRT gene of Chinese hamster ovary cells have been sequenced and compared with the mutations induced by 1, 2-dibromoethane (1,2-DEB), which is known to act through a glutathione conjugate, and formaldehyde. All three compounds induced primarily point mutations, with a small number of insertion and deletion events. The most common point mutations induced by MC were GC-->AT transitions (4/8), with two GC-->CG transversions and two AT-->TA transversions. This pattern of mutations showed greater similarity with 1,2-DBE, where the dominant point mutations were GC-->AT transitions (7/9), than formaldehyde, where all mutations were single base transversions and 5/6 occurred from AT base pairs. The mutation sequence results for MC suggest that S-chloromethylglutathione plays a major role in MC mutagenesis, with only a limited contribution from formaldehyde. The involvement of a glutathione (GSH) conjugate in MC mutagenicity would be analogous to the well-characterized pathway of activation of 1,2-DBE.

Effect of sub-MIC antibiotics on the cell surface and extracellular virulence determinants of Pseudomonas cepacia.

The effects of sub-MICs of ciprofloxacin and tobramycin on the cell surface characteristics and extracellular virulence factors of Pseudomonas cepacia were evaluated. Cells were grown in batch culture under iron-deficient and iron-replete conditions. At sub-MIC levels that did not affect bacterial growth cell surface hydrophobicity decreased under both iron-replete and iron-depleted conditions with ciprofloxacin, but increased with tobramycin under iron-sufficient conditions. Exopolysaccharide synthesis, lipase production and siderophore production were all significantly increased by the presence of ciprofloxacin under both growth conditions. Outer membrane protein and lipopolysaccharide profiles were not affected by exposure to the two antibiotics.