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Biomedical subjects

Janice B Schwartz

Publications and source records attributed to Janice B Schwartz.

15 recordsLinked to original sources
PubMed2006

Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: results from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) initiative.

BACKGROUND: Glycoprotein (GP) IIb/IIIa inhibitors are beneficial in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS); their safe use in women, however, remains a concern. The contribution of dosing to the observed sex-related differences in bleeding is unknown. METHODS AND RESULTS: We explored the relationship between patient sex, GP IIb/IIIa inhibitor use, dose, and bleeding in 32 601 patients with NSTE ACS across 400 CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) hospitals, of whom 18 436 were treated. GP IIb/IIIa inhibitor dose was defined as excessive if not reduced when creatinine clearance was < 50 mL/min for eptifibatide or < 30 mL/min for tirofiban. Major bleeding was defined as a hematocrit drop > or = 0.12, need for transfusion, or intracranial bleeding. Major bleeding was adjusted for clinical factors and antithrombotic dose. The risk for bleeding attributable to excess GP IIb/IIIa dose was determined by sex using prevalence and adjusted odds ratios (ORs). Women had higher rates of major bleeding than men among those treated with GP IIb/IIIa inhibitors (15.7% versus 7.3%, P<0.0001) and among those not treated (8.5% versus 5.4%, P<0.0001). Despite similar serum creatinine levels, creatinine clearance averaged 20 points lower among treated women than men. Treated women were also more likely to receive excess GP IIb/IIIa doses than men (46.4% versus 17.2%, P<0.0001; adjusted OR 3.81, 95% confidence interval [CI] 3.39 to 4.27). Excess dosing was associated with increased risk of bleeding in women (OR 1.72, 95% CI 1.30 to 2.28) and men (OR 1.27, 95% CI 0.97 to 1.66); however, bleeding risk attributable to dosing was much higher in women (25.0% versus 4.4%). CONCLUSIONS: Women experience more bleeding than men whether or not they are treated with GP IIb/IIIa inhibitors; however, because of frequent excessive dosing in women, up to one fourth of this sex-related risk difference in bleeding is avoidable. Appropriate dosing will improve care of all patients with NSTE ACS, with a particular benefit for women.

Acute Disease↗
PubMed2006

Erythromycin breath test results in elderly, very elderly, and frail elderly persons.

BACKGROUND AND OBJECTIVE: Although increasing age is often thought to be associated with slower oxidative drug clearance, limited data from old, very old, and frail patients exist. Our objective was to determine the effects of very old age and frailty on erythromycin breath test (ERBT) results in patients and, secondarily, to determine the effects of sex and comedications on ERBT results. METHODS: ERBTs were performed in 60 individuals aged 65 to 101 years, 27 of whom were classified as frail (mean age [+/-SD], 86 +/- 6 years; mean weight, 66 +/- 17.4 kg; 8 men and 19 women; 24 living in a nursing home and 3 living in the community) and 33 of whom were classified as nonfrail (mean age, 79 +/- 8 years; mean weight, 78.5 +/- 14.5 kg; 16 men and 17 women; 17 living in a nursing home and 16 living in the community). RESULTS: ERBT results were faster in women versus men (3.53% +/- 1.15% carbon 14 [14C] excreted/h versus 2.59% +/- 0.99% 14C excreted/h, respectively; ANOVA, P < .002), faster in frail versus nonfrail patients (3.58% +/- 1.2% 14C excreted/h versus 2.81% +/- 1.06% (14)C excreted/h, respectively; ANOVA, P = .01), and faster in those receiving cytochrome P450 (CYP) 3A inducers versus those without inducers (5.02% +/- 0.89% 14C excreted/h versus 3.02% +/- 1.08% 14C excreted/h, respectively; ANOVA, P = .0007). When subjects receiving CYP inducers were excluded, sex affected ERBT results (ANOVA, P < .007) but frailty effects were not detected (P = .09). Age from 65 to 101 years did not affect ERBT results (r2 = 0.001). CONCLUSIONS: Old and very old patients in the clinical setting, especially women and those receiving enzyme inducers, may have preserved medication clearance. Frail elderly persons do not have slower ERBT results compared with nonfrail elderly persons.

Aged↗
PubMed2006

Population analyses of amlodipine in patients living in the community and patients living in nursing homes.

OBJECTIVE: Our objective was to determine the effects of age, sex, and morbidity on the apparent oral clearance (CL/F) of amlodipine. METHODS: Population pharmacokinetic analyses were performed on data from 211 patients receiving oral racemic amlodipine (dose of 7.2 +/- 3.6 mg/d [mean +/- SD]) on a long-term basis. Of the patients, 105 were men, with a mean age of 72 +/- 13 years and lean body weight (LBW) of 60.7 +/- 7.6 kg, and 106 were women, with a mean age of 79 +/- 11 years and LBW of 44.2 +/- 6.0 kg; 119 lived in the community, 20 in assisted living facilities, and 72 in nursing homes. Amlodipine was measured by liquid chromatography-tandem mass spectrometry. Population analyses were performed by use of NONMEM with sex, age, race, living site, alcohol intake, and concomitant medications considered as covariates. The significance of covariates was determined by likelihood ratio tests. RESULTS: Female sex and living in a nursing home were associated with a faster CL/F compared with men and community-dwelling patients, respectively. The mean CL/F was 7.83 +/- 0.50 mL.min(-1).kg(-1) (LBW) in women compared with 6.31 +/- 1.01 in men and 8.68 +/- 1.00 mL.min(-1).kg(-1) in nursing home residents compared with 6.32 +/- 1.17 in community-dwelling patients. Increasing age was associated with decreasing CL/F only in community-dwelling patients and residents of assisted living facilities. CONCLUSIONS: In middle-aged and very old (>80 years) patients, amlodipine CL/F was faster in women compared with men and was faster in nursing home residents compared with community-dwelling patients, with increasing age decreasing CL/F only in community-dwelling patients and residents of assisted-living facilities.

Aged↗
PubMed2005

Sample size computations for PK/PD population models.

We describe an accurate, yet simple and fast sample size computation method for hypothesis testing in population PK/PD studies. We use a first order approximation to the nonlinear mixed effects model and chi-square distributed Wald statistic to compute the minimum sample size to achieve given degree of power in rejecting a null hypothesis in population PK/PD studies. The method is an extension of Rochon's sample size computation method for repeated measurement experiments. We compute sample sizes for PK and PK/PD models with different conditions, and use Monte Carlo simulation to show that the computed sample size retrieves the required power. We also show the effect of different sampling strategies, such as minimal, i.e., as many observations per individual as parameters in the model, and intensive on sample size. The proposed sample size computation method can produce estimates of minimum sample size to achieve the desired power in hypothesis testing in a greatly reduced time than currently available simulation-based methods. The method is rapid and efficient for sample size computation in population PK/PD study using nonlinear mixed effect models. The method is general and can accommodate any type of hierarchical models. Simulation results suggest that intensive sampling allows the reduction of the number of patients enrolled in a clinical study.

Algorithms↗
PubMed2004

A sample size computation method for non-linear mixed effects models with applications to pharmacokinetics models.

We propose a simple method to compute sample size for an arbitrary test hypothesis in population pharmacokinetics (PK) studies analysed with non-linear mixed effects models. Sample size procedures exist for linear mixed effects model, and have been recently extended by Rochon using the generalized estimating equation of Liang and Zeger. Thus, full model based inference in sample size computation has been possible. The method we propose extends the approach using a first-order linearization of the non-linear mixed effects model and use of the Wald chi(2) test statistic. The proposed method is general. It allows an arbitrary non-linear model as well as arbitrary distribution of random effects characterizing both inter- and intra-individual variability of the mixed effects model. To illustrate possible uses of the method we present tables of minimum sample sizes, in particular, with an illustration of the effect of sampling design on sample size. We demonstrate how (D-)optimal or frequent sampling requires fewer subjects in comparison to a sparse sampling design. We also present results from Monte Carlo simulations showing that the computed sample size can produce the desired power. The proposed method greatly reduces computing times compared with simulation-based methods of estimating sample sizes for population PK studies.

Black People↗
PubMed2004

Estrogen and progestin use and the QT interval in postmenopausal women.

OBJECTIVE: To determine whether menopausal hormone therapy alters the QT interval in primarily healthy postmenopausal women. BACKGROUND: Despite well-known gender differences in myocardial repolarization that include a longer heart-rate-corrected QT interval (QT(C)) in women compared to men, the effects of menopausal hormone therapy on myocardial repolarization in women have not been well characterized. METHODS: We studied 34,378 postmenopausal women participating in the dietary intervention component of the Women's Health Initiative. Cross-sectional associations were examined to assess possible effects of estrogen + progesterone on myocardial repolarization. Women who reported that they were never treated with menopausal hormone therapy (n = 12,451) were compared to women with a past use of menopausal hormone therapy (n = 3891), currently taking unopposed estrogen therapy (n = 9987), or combined current estrogen and progesterone therapy (n = 8049). RESULTS: Using analysis of covariance, the mean (+/-SEM) QT(C) interval was 423.1 +/- 0.2 milliseconds (ms) in those never treated with menopausal hormone therapy, 423.9 +/- 0.3 ms in past menopausal hormone therapy users, 425.6 +/- 0.2 ms in those currently on estrogen alone, and 424.0 +/- 0.2 ms in women currently on combined estrogen-progesterone therapy. Differences in mean QT(C) between those on estrogen alone and the other three groups were statistically significant. Comparisons of JT intervals, QT intervals, and linear corrected QT intervals among the groups yielded similar results. CONCLUSION: These results suggest that unopposed estrogen in menopausal women mildly prolongs myocardial repolarization, and the effect is reversed by progesterone. Whether these findings have clinical significance requires further study.

Analysis of Variance↗
PubMed2003

Population analyses of sustained-release verapamil in patients: effects of sex, race, and smoking.

OBJECTIVE: Our objective was to determine the effects of age, sex, and sustained-release formulation on apparent oral clearance of sustained-release racemic verapamil in patient populations. METHODS: Population pharmacokinetic analyses were performed on data from 186 patients with hypertension, coronary artery disease, or supraventricular arrhythmias who were receiving long-term sustained-release oral racemic verapamil (Covera SR in 105 patients, Calan SR in 67 patients, and other formulations in 14 patients; mean +/- SD dose, 280 +/- 139 mg) for clinical care or as a part of phase III efficacy studies. Of those 186 patients, 135 were men (age, 63 +/- 12 years; ideal body weight, 70.7 +/- 6.6 kg) and 51 were women (age, 60 +/- 17 years; ideal body weight, 53.7 +/- 7.2 kg). Verapamil was measured by HPLC, and population analyses were performed by use of NONMEM software. Sex, age, and formulation were the covariates considered in the population model building. Subgroup analyses of race, smoking, and alcohol consumption were also performed. Significance of covariates was determined by likelihood ratio tests. RESULTS: Sex significantly affected steady-state clearance of oral sustained-release racemic verapamil. Apparent oral clearance of sustained-release verapamil was 23.8 +/- 2.3 mL/min per kilogram in women compared with 18.6 +/- 3.4 mL/min per kilogram in men. Clearance estimates were faster in black subjects compared with white subjects, as well as in smokers compared with nonsmokers. Effects of age, formulation, and alcohol consumption were not detected. CONCLUSIONS: In middle-aged and older patients, apparent oral clearance of sustained-release racemic verapamil was affected by sex (faster in women compared with men), race (faster in black subjects compared with white subjects), and smoking (faster in smokers compared with nonsmokers) but not by age, alcohol, or formulation.

Administration, Oral↗
PubMed2003

The influence of sex on pharmacokinetics.

Biologic differences exist between men and women that can result in differences in responses to drugs. Both pharmacokinetic and pharmacodynamic differences between the sexes exist, with more data on pharmacokinetic differences. On average, men are larger than women. Body size differences results in larger distribution volumes and faster total clearance of most medications in men compared to women. Greater body fat in women (until older ages) may increase distribution volumes for lipophilic drugs in women. Total drug absorption does not appear to be significantly affected by sex although absorption rates may be slightly slower in women. Bioavailability after oral drug dosing, for CYP3A substrates in particular, may be somewhat higher in women compared to men. Bioavailability after transdermal drug administration does not appear to be significantly affected by gender; nor does protein binding. Renal processes of glomerular filtration, tubular secretion, and tubular reabsorption appear to be faster in men compared to women whether considered on a mg/kg basis or total body weight basis. Algorithms to estimate glomerular filtration rate incorporate sex as a factor; some also include weight. For hepatic processes, drugs metabolized by Phase I metabolism (oxidation, reduction, and hydrolysis via cytochrome P450's 1A, 2D6, 2E1), Phase II conjugative metabolism (glucuronidation, conjugation, glucuronyltransferases, methyltransferases, dehydrogenases) and by combined oxidative and conjugation processes are usually cleared faster in men compared to women (mg/kg basis). Metabolism by CYP2C9, CYP2C19, and N-acetyltransferase, appear to be similar in men and women (mg/kg). Clearance of p-glycoprotein substrates appear to be similar in men and women. In contrast, total clearance of a number of CYP3A substrates appear to be mildly or moderately faster (mg/kg) in women compared to men. The clinical significance of reported differences warrants consideration. Clearance reported on a per kg basis directly addresses organ or enzyme clearance. The difference in size between men and women means translating these results to clinical dosage rates should include an adjustment for body size. Unfortunately, this is not standard. Reports of sex differences that persist after considering weight may warrant further dosage adjustments. In addition, investigations are often performed in healthy fasting individuals yet medications are prescribed to patients with confounding influences of disease, co-medications, diet, and social habits. The relative role of sex on pharmacokinetics as compared to genetics, age, disease, social habits and their potential interactions in the clinical setting is not yet fully known but should be routinely considered and further studied.

Animals↗
PubMedDate not supplied

Gender-specific implications for cardiovascular medication use in the elderly optimizing therapy for older women.

Sex should be considered during the selection of cardiovascular medications and dosages of cardiovascular medications. There is mounting evidence that clinically important differences between the sexes exist in the pharmacokinetic processes that determine drug concentrations and in the pharmacodynamic processes that determine physiologic responses to pharmacologic agents. Although aging also affects these processes, aging does not eliminate the sex-related differences. The major pharmacokinetic differences between the sexes, on average, are lower weight and distribution volumes in women compared with men and lower renal drug clearance in women compared with men. Sex-related differences in hepatic drug clearance are less predictable. Pharmacodynamic responses that differ between the sexes include increased adverse cardiovascular drug effects in women compared with men (torsade de pointes arrhythmias, increased risk of hemorrhagic consequences of anticoagulation or thrombolytic therapy, electrolyte abnormalities with diuretics, myopathy with HMG Co-A reductase inhibitors, cough with ACE inhibitors, and increased incidence of thrombosis). Recommendations for optimizing cardiovascular drug therapy for the older women include individualization of drug selection to minimize the number of medications and side effects; dosage adjustment based on age, size, and sex; close monitoring for side effects; and consideration of cost and access to medications. Optimal care for the older woman with cardiovascular disease will also require investigation of cardiovascular medications in older women and of therapies for cardiovascular diseases that are more common in women than men.

Aged↗
PubMedDate not supplied

What does the Medicare prescription drug legislation mean for the American cardiologist?

The Medicare Modernization Act of 2003 authorized the most sweeping changes to the Medicare and Medicaid programs since their inception in 1965. One key feature, a prescription drug benefit, will begin enrolling seniors in November 2005, and the benefit will begin in January 2006. This benefit will have complex and largely unknown effects on medication adherence in the elderly. It has a complex system of copayments and deductibles and subsidy eligibility requirements, as well as a "donut hole." Drug coverage for people dually eligible for Medicare and Medicaid will change greatly. Medicare beneficiaries will have to choose from a large, bewildering choice of prescription plans and many will turn to their physicians for advice. This article details the background, benefits, and expected impact of all of these aspects of the new Medicare Part D prescription drug benefit.

Aged↗
PubMedDate not supplied

Pharmacogenetics: has it reached the clinic?

Genetic variation in drug-metabolizing enzymes contributes to the variability in drug responses seen in humans. Information in the area is expanding rapidly, and the clinical significance of many of the polymorphisms is only now being elucidated. It is clear that polymorphism frequency varies markedly by race and ethnicity, but major differences by sex have not been reported. Screening for genetic variation in most drug-metabolizing enzymes is not recommended; the very important exception is the need to determine the thiopurine transferase activity of patients who may receive thiopurines (e.g., 6-mercaptopurine and azathioprine) because clinically life-threatening complications or decreased efficacy is strongly related to the genetically determined activity of this enzyme.

Animals↗
PubMedDate not supplied

Pharmacologic agents for weight reduction.

Obesity is a major health problem in U.S. adults. Most successful weight loss programs have multiple components, including lifestyle modifications, reduced caloric intake, and exercise. Short-term use of medications for weight loss may be a part of such a plan. Currently, most medications are adrenergic stimulants and can produce adverse CNS and cardiovascular effects. Antiabsorptive agents appear to be safer but have significant GI side effects. An important finding is the potential for adverse life-threatening effects with over-the-counter products and dietary supplements that do not undergo evaluation similar to prescription drugs. The search continues for safe and effective pharmacologic agents to assist in weight loss.

Anti-Obesity Agents↗