Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

The relationship between research and service development: an illustrative example of a pilot study introducing complementary therapies into primary care

In this paper the commissioners of an evaluation and the researchers jointly review the relationship between research and service development at a local level in an evaluated health authority pilot project to introduce complementary therapies into primary care. The article discusses the importance of organisational arrangements between the research and the service development, focusing on the close working relationship between researchers and stakeholders in the research and corresponding service development. The relationship between the research and service development was not linear and the benefits were not based solely on outcomes of the treatment but also on the ways the evaluation gave insight into how the pilot service was delivered. Factors such as personal commitment to the project and close working relationships by all concerned are important. These elements are rarely emphasised but have to be taken into account if evidence-based health care is to achieve its potential.     

Low Prenatal Weight Gain Among Adult WIC Participants Delivering Term Singleton Infants: Variation by Maternal and Program Participation Characteristics

Objective: To determine the association of maternal and prenatal WIC program participation characteristics with low prenatal weight gain among adult women delivering liveborn, singleton infants at term. Methods: WIC program data for 19,017 Black and White Alabama women delivering in 1994 were linked with birth certificate files to examine the association of anthropometric, demographic, reproductive, hematologic, behavioral and program participation characteristics with low prenatal weight gain. Results: One third (31.0%) had low prenatal weight gain as defined by the Institute of Medicine. The incidence of low weight gain was increased among women who had < 12 years of education, were single, Black, anemic, had low or normal pre-pregnancy body mass index (BMI), increased parity, interpregnancy intervals 24 months, used tobacco or alcohol, or entered prenatal care or WIC programs after the first trimester. After adjusting for selected maternal characteristics, the adjusted odds ratios (AOR) for low weight gain were increased with short interpregnancy intervals (AOR 1.21 to 2.20); tobacco use (AOR 1.16 to 1.40), anemia (AOR 1.20 to 1.25), and second trimester entry into prenatal care (AOR 1.14 to 1.20); the size of the AORs and 95% confidence intervals varied by BMI and racial subgroup. Conclusions: The results of this study suggest that WIC interventions targeting low prenatal weight gain be focused on risk factors present not only during pregnancy, but during the pre- and interconceptional periods as well. Interventions should target low BMI, tobacco use, and anemia, and include attention to nutrition screening and risk reduction among women in postpartum and family planning clinic settings.     

Reliability and validity of measures of cardiac output during incremental to maximal aerobic exercise. Part I: Conventional techniques

The assessment of cardiac function, particularly cardiac output (Q) during heavy exercise is essential for the evaluation of cardiovascular factors that might limit oxygen transport. A series of invasive and noninvasive techniques has been developed for the assessment and monitoring of Q during resting and submaximal exercise conditions. However, very few techniques have been found to give accurate and reliable determinations of Q during vigorous to maximum exercise. For exercise physiologists and sport cardiologists, maximal exercise data are of primary importance. The 'gold standard' measures of cardiac function are considered to be the direct Fick and dye-dilution methods. These have been widely shown to give accurate and reliable determinations of Q during resting and submaximal exercise conditions; however, their use during maximal exercise conditions is debatable due to the inherent risks involved with each and their increasing inaccuracy during the later stages of vigorous exercise. Thermodilution has also been considered to be a relatively good method for the determination of Q during rest and exercise conditions, but recent authors have questioned its use due to the nature of the measure and its inaccuracy during strenuous exercise. Various noninvasive measures of cardiac function have been developed to overcome the problems associated with the 'gold standard' measures. The first part of this article discusses conventional techniques used in exercise physiology settings. The majority of these provide accurate and reliable determinations of Q during rest and submaximal exercise. However, very few techniques are suitable for maximal exercise conditions. Perhaps only the foreign gas rebreathe using acetylene (C2H2) meets all the criteria of being noninvasive, simple to use, reliable over repeated measurements, accurate and useful during maximal exercise.     

Core competencies for preventive medicine residents: Version 2.0

During the early 1990s, the American College of Preventive Medicine (ACPM), with support from the Health Resources and Services Administration (HRSA), identified core competencies and performance indicators (measures to assess their achievement) for all preventive medicine residents. After the competencies were approved, distributed by the ACPM and HRSA, and published in the American Journal of Preventive Medicine, they were integrated in various ways into the operation of individual residency programs. Changes in the health care system during the decade, however, necessitated an update of the original competencies to better equip preventive medicine educators to prepare residents for new roles those in preventive medicine can play in a restructured health care system. HRSA funded an effort to produce Version 2.0 of the preventive medicine competencies based on review and refinement of the original competencies through a consensus process. This article includes these revised core competencies and performance indicators.