Hepatic metabolism of MK-0457, a potent aurora kinase inhibitor: interspecies comparison and role of human cytochrome P450 and flavin-containing monooxygenase.

MK-0457 (N-[4([4-(4-methylpiperazin-1-yl)-6-[(3-methyl-1H-pyrazol-5 -yl)amino]pyrimidin-2-yl]thio)phenyl]cyclopropanecarboxamide), an Aurora kinase inhibitor in development for the treatment of cancer, was evaluated for its in vitro metabolism in different species. This compound primarily underwent N-oxidation and N-demethylation in human, monkey, dog, and rat liver preparations. However, N-demethylation was less significant in dogs. The formation of minor metabolites varied with species, but all metabolites generated in human hepatocytes were observed in animals. Results of immunoinhibition, selective chemical inhibition, thermal inactivation, and metabolism by recombinant cytochromes P450 and flavin-containing monoogygenases (FMOs) strongly suggest that CYP3A4 and FMO3 comparably contributed to MK-0457 N-oxidation in human liver microsomes, where the reaction conformed to Michaelis-Menten kinetics. These studies indicate a major role of CYP2C8 in the N-demethylation reaction, whereas CYP3A4 only made a minor contribution. However, significant substrate inhibition was observed with MK-0457 N-demethylation at high substrate concentrations (>10 microM) in human liver microsomes relative to the anticipated therapeutic exposure. A multienzyme metabolic pathway such as this may mitigate the potential of drug interactions in clinical treatment with MK-0457.

Assessing influenza immunization rates in Medicare managed care plans: a comparison of three methods.

BACKGROUND: In an effort to improve care delivered to Medicare beneficiaries, the Health Care Financing Administration (HCFA) has encouraged competitive Medicare risk plans to collaborate on quality improvement projects. PRO-West, a private, nonprofit quality improvement organization, fostered a collaboration of all Medicare risk plans in Washington State in order to assess and improve influenza immunization rates among seniors enrolled in managed care. METHODOLOGY: After the 1994-1995 influenza immunization season, immunization rates were determined for each participating plan from administrative data and medical record review. In the 1995-1996 season, these methods were supplemented with a telephone survey. The survey was used to identify perceived barriers to immunization and to estimate immunization rates. RESULTS: Immunization rates, as estimated by administrative data and medical record review, were similar for both years. The average immunization rate using administrative data for the 1995-1996 flu season was 60.6% (range, 42.8% to 72.3%). The estimated rate increased to 77.8% (95% confidence interval, 75.3% to 80.3%) when the telephone survey data were added. Medical record review contributed little additional information. CONCLUSIONS: Influenza immunization rates for seniors enrolled in Medicare risk plans in Washington State exceed those reported for fee-for-service Medicare beneficiaries. Telephone surveys resulted in higher and probably more valid estimates of influenza immunization rates than did analysis of administrative data and medical records. Plans with lower rates can emulate "benchmark" plans that are explicit about the methods they use to achieve high coverage rates. Medicare risk health plans competing in the same markets can collaborate in quality assessment activities in an effective manner.

Expanding use of thrombolytic therapy in the treatment of acute myocardial infarction in rural Alaskan hospitals.

This paper focuses on clinical quality improvement comparing the results of two studies done approximately one year apart on treatment of acute myocardial infarction in four rural hospitals. The purpose of both studies was to determine how often eligible, elderly Medicare patients with acute myocardial infarction received thrombolytic treatment and aspirin. The studies were done by abstracting medical records for the calendar year 1993 and again in the year between October 1, 1994 and September 30, 1995. The results show that the use of thrombolytic therapy in these hospitals for the Medicare population increased by 40% between 1993 and 1995, a statistically significant increase (95% confidence intervals (CI) 20.1% to 60.0%). The rate of thrombolytic therapy among eligible Medicare patients went from 25.5% in 1993 to 65.7% in 1995. The use of aspirin also increased by 12.5% which was borderline significant (95% CI, 0.0% to 34%). The results were not as dramatic because the baseline for aspirin use with acute myocardial infarction was already 67.5% in 1993. These results indicate that the treatment of acute myocardial infarction is evolving closely in line with the American Heart Association/American College of Cardiology 1996 guidelines. Studies of clinical quality improvement such as this are now requirements for hospital certification.

PRESS-related statistics: regression tools for cross-validation and case diagnostics.

In the health science literature, a common approach of validating a regression equation is data-splitting, where a portion of the data fits the model (fitting sample) and the remainder (validation sample) estimates future performance. The R2 and SEE obtained by predicting the validation sample with the fitting sample equation is a proper estimate of future performance, tending to correct for the natural upward bias of the R2 and SEE obtained from fitting sample alone. Data-splitting has several disadvantages, however. These include: 1) difficulty, arbitrariness, and inconvenience of matching samples; 2) the need to report two sets of statistics to determine homogeneity; and 3) the lack of equation stability due to diluted sample size. The PRESS statistic and associated residuals do not require the data to be split, yield alternative unbiased estimates of R2 and SEE, and provide useful case diagnostics. This procedure is easy to use, is widely available in modern statistical packages, but is rarely utilized. The two methods are contrasted here using a simulation from original data for predicting body density from anthropometric measurements of a group of 117 women. The PRESS approach is particularly appropriate for smaller datasets; methods of reporting these statistics are recommended.

Descriptive epidemiology of unintentional residential fire injuries in King County, WA, 1984 and 1985.

Although most studies have concentrated on fatal residential fire injuries, which are a leading cause of fatal injuries in the United States, few investigators have examined in detail nonfatal injuries as a consequence of residential fires. This population-based study used the Washington State Fire Incident Reporting System to assess the incidence and descriptive epidemiology of fatal and nonfatal burns or respiratory tract damage resulting from unintentional residential fires. For the 2-year period 1984-85 in King County, WA, the mortality rate due to injury in a residential fire was 0.7 per 100,000 per year, and the incidence of nonfatal injuries was 5.6 per 100,000 per year. Of 17 fatalities, 59 percent of the deaths occurred at the scene of the fire. Of 128 persons with nonfatal injuries, 19 percent were hospitalized; although the 55 percent seen as outpatients and the 26 percent treated by the fire department or paramedics at the fire scene usually had minor injuries, they would not have been captured if only traditional data sources had been employed. Those injured averaged 2.8 days of restricted activity, but the range was from less than 1 day to 1 year. Injuries were more common in the households with a low socioeconomic status and among nonwhites, especially American Indians. Variation in incidence by age, sex, and source of ignition for deaths and nonfatal injuries suggests appropriate targets for future fire injury prevention programs.

Association of smoking and alcohol drinking with residential fire injuries.

To investigate whether tobacco, alcohol, and their combined use are important risk factors for fire injuries, the authors analyzed data from a population-based case-control study in King County, Washington, between 1986 and 1987. Cases (n = 116) were households with at least one fatal or nonfatal unintentional residential fire injury reported to the Washington State Fire Incident Reporting System from 1984 through 1985. Controls were selected by random digit dialing (n = 256). After adjustment for household size, number of male household members, total household income, and education of the head of the household, the odds ratio for fire injury in households whose members collectively smoked 1-9 cigarettes per day was 1.5 (95% confidence interval (CI) 0.6-4.2) relative to households with no smokers; for 10-19 cigarettes per day, the odds ratio was 6.6 (95% CI 2.5-17.5), and for 20 or more cigarettes per day, it was 3.6 (95% CI 1.9-7.2). Although households with alcohol drinkers who consumed five or more drinks per occasion were found to be at increased risk in the crude analysis, multivariate analysis suggested that this was partly because drinkers tended to live in households with higher smoking levels. Thus, even though households with alcohol drinkers who consume five or more drinks per occasion may be at increased risk of residential fire injury, smoking appears to be the more important underlying risk factor.

Body composition alterations consequent to an exercise program for pre and postmenopausal women.

The purposes of this study were: (a) to evaluate the effects of an exercise program upon the body composition of premenopausal (no. 43) and postmenopausal (no. 66) women, aged 35-70 years, and (b) to compare exercise Ss with age matched control Ss. Body composition was assessed by skinfold measurement and hydrostatic weighing. Exercise Ss walked or jogged and performed light resistive exercise for 60 minutes per day three times per week for 24 weeks. Control Ss remained sedentary. ANOVAs revealed: (a) no significant (p greater than or equal to .05) differences in exercise training effects between premenopausal and postmenopausal Ss, and (b) exercise Ss exhibited less body fatness while control Ss possessed more body fat as represented by significant changes (p less than or equal to .05) for the exercise and control Ss, respectively in: body density (+.002 g/cc, -.001 g/cc); % fat (-1.2%, +.6%); fat weight (-.4 kg, +1.1 kg); suprailiac skinfold (-.3 mm, +7 mm); and abdominal skinfold (-.3 mm, +1.5 mm). It was concluded that: (a) menopausal status did not alter the effects of exercise in this study, and (b) exercise training produced a positive effect in the exercise Ss by reversing body composition trends associated with a sedentary lifestyle.

The effect of high level physical activity (8.5 METs or greater) and estrogen replacement therapy upon bone mass in postmenopausal females, aged 50-68 years.

The purpose of this study was to assess the effect of physical activity (PA) and estrogen therapy (ET) upon bone mass at the 1/3 and 4 mm distal radial sites in 50 postmenopausal females. The Ss (means age = 57.4 +/- 5.4 yrs) completed: 1) activity and gynecological surveys, 2) Balke treadmill tests (85% of age determined HR), and 3) single photon absorptiometry measurements of the radius. The activity surveys and treadmill tests were used to categorize Ss into high (8.5 METs or greater, n = 27) and low (6.0 METs or less, n = 23) physical activity groups (HPA/LPA), and the gynecological surveys were used to distinguish Ss who were on estrogen therapy (n = 17) and those who had never been on estrogen therapy (n = 33). Data revealed the HPA group had significantly higher BMC (g/cm) and BMC/BW (g/cm2) at the 1/3 distal radial site than the LPA group (.834 g/cm to .721 g/cm, p less than .01; and .698 g/cm2 to .653 g/cm2, p less than .06, respectively) but were not significantly different at the 4 mm distal site. The ET group had a significantly higher bone mass than the never on ET group for BMC/BW at the 4 mm site (.907 g/cm to .809 g/cm p less than .027). It was concluded that high level physical activity (8.5 METs or greater) or estrogen therapy was helpful in reducing the risk of bone loss in postmenopausal women.

Cardiovascular responses of hyperactive children to methylphenidate.

Heart rate, blood pressure, and oxygen consumption were measured in 27 hyperactive children during rest, exercise, and recovery, once taking placebo and again taking methylphenidate hydrochloride. Half were measured first taking the drug and half first taking the placebo. Twenty-three matched controls were also measured twice to test for reproducibility of results. Drug and placebo ECGs were recorded on 12 of the subjects. Oxygen consumption did not change (P = .40), but heart rate (P = .001) and blood pressure (P = .003) increased significantly with methylphenidate therapy. There was a significant correlation between size of dose in milligrams per kilogram and increase in heart rate (.38, P less than .05) and blood pressure (.50, P less than .05 systolic) (.46, P less than .05 diastolic). No evidence of the development of tolerance to these drug effects was found in children who had been taking methylphenidate from two months to more than a year. No ECG changes other than tachycardia were seen.