Oxidative stress and chronic subclinical inflammation are implicated in the pathology of type 2 diabetes (T2D). Consumption of vitamins and nutrients may dampen the harmful oxidative stress, which normally perpetuates inflammation. Reduction of inflammation may delay or reduce the risk of type 2 diabetes. However current research has not been able to confirm the nutrient-inflammation inverse association. Further, postmenopausal women have a different T2D risk and average C-reactive protein (CRP) concentrations than premenopausal women or men of a similar age. Moderate alcohol consumption is another dietary factor which has been associated with a reduced type 2 diabetes risk. Limited evidence also suggests alcohol consumption maybe associated with some sex hormones. Additionally, sex hormones have been associated with type 2 diabetes risk. However, sex hormones as mediators of the alcohol-type 2 diabetes association have not been established. The overall objectives of this dissertation were to examine the role of certain dietary factors (vitamins, nutrients, and alcohol) and inflammation or sex hormones in the pathology of type 2 diabetes in postmenopausal women. Three separate study designs, using 3 distinct datasets, were selected to evaluate the objectives of this dissertation. A cross-sectional study was employed to assess vitamins, nutrients, inflammation and T2D risk with data from the NHANES survey, a stratified, multistage probability sample of the civilian noninstitutionalized U.S. population in 2003-2006. Cross-sectional data from a nested, matched case-control study within the Women's Health Initiative-Observational Study (WHI-OS) were used to examine the separate relations of dietary or supplemental nutrients to biomarkers of inflammation. Prospective data from a matched, nested case-control study within the Women's Health Study (WHS) were used to examine whether circulating concentrations of sex hormones were associated with alcohol intake or mediated the alcohol-T2D association. Nutrient concentrations measured in NHANES were different in postmenopausal women than in premenopausal women, but were similar to men. The nutrients were not associated with reduced inflammation and T2D risk in postmenopausal women. WHI-OS data results indicate that dietary vitamin C, beta-carotene, and alpha-carotene as well as supplemental vitamin E and beta-carotene are modestly inversely associated with concentrations of systemic inflammatory biomarkers among postmenopausal women. The WHS cross-sectional analysis showed positive associations between alcohol intake and endogenous estradiol concentrations. Prospective WHS data suggested that baseline concentrations of estradiol and SHBG might influence the alcohol-T2D association in postmenopausal women.
Abstract (+)-1,2-Di(3,5-dioxopiperazin-1-yl)propane (ICRF-187), the d-enantiomer of the racemic antitumor agent (±)-1,2-di(3,5-dioxopiperazin-1-yl)propane, displays schedule-dependent toxicity in humans and animals. Pharmacokinetic factors which might produce schedule-dependent toxicity were studied in patients during a Phase I trial. The intact drug was assayed by high-performance liquid chromatography in simple aqueous solutions by direct injection or in urine, bile, pleural fluid, or serum after extraction and concentration. Ultraviolet absorbance was monitored at 208 nm. ICRF-187 and an internal standard of ICRF-192 were eluted as separate peaks. Peak height and peak area ratios of ICRF-187 to ICRF-192 were linear over serum ICRF-187 concentrations from 0.05 to 100 µg/ml. The detection limit for ICRF-187 was 2 ng by direct injection, and the quantitation limit in serum was 0.05 µg/ml. Using equilibrium dialysis, there was no evidence for significant protein binding of ICRF-187. Urine and serum specimens were collected during and following i.v. infusions of 1.0 g/sq m ICRF-187 by three different schedules (30-min, 8-hr, and 48-hr infusions) to five adult patients. Total urinary drug recovery was schedule independent, averaging 48%. Serum drug kinetics followed a two-compartment open model ( r 2 > 0.98 for all infusions). Mean peak serum levels for the three schedules were 75.3, 22.8, and 2.9 µg/ml, respectively. Mean central compartment volume of distribution was 0.193 liter/kg, or slightly greater than the expected inulin space. Mean t 1/2 α values were not significantly different among the schedules (9.9, 10.6, and 19.5 min, respectively), nor were mean t 1/2 β values (121.4, 143.6, and 173.0 min, respectively). Integrals of the concentration-time curves did not differ with schedule. Intact ICRF-187 distributed into pleural effusions and was cleared at rates reflecting rapid equilibration with serum in one patient and slower equilibration in a second patient. Biliary drug concentration equaled serum drug concentration in the terminal phase in one patient. Infusion of ICRF-187 over periods >8 hr was necessary for achievement of true steady-state conditions. The greater biological effect of prolonged infusions is probably based upon drug action rather than upon pharmacokinetic factors and thus might be associated with improved antitumor activity.
Future studies could examine other programs to help people with cancer manage symptoms at home.Researchers could also look at ways to make the COPE program more helpful for patients. How can people use the results?Cancer treatment centers can use these results when looking at ways to help patients manage symptoms at home.
Cerebral control of foot movements has received limited study. Functional MRI compared slow with rapid foot movement, and right (dominant) with left foot movement. Brain activation during right, as compared with left, foot movement was larger, with higher amplitude task-related motor cortex signal change, and higher laterality index. Brain activation during fast, as compared with slow, foot movement was larger in cortical and cerebellar areas but smaller in deep gray areas. Some principles of cerebral control of hand movement extend to foot, but exceptions found include that dominant foot movement showed greater activation than did nondominant, and faster foot movements activated bilateral deep gray matter structures less than did slower. Results might have utility in trials of restorative therapies.
Panitumumab is a fully human monoclonal antibody targeted to the extracellular domain of human epidermal growth factor receptor (EGFR). A comprehensive population pharmacokinetic model of panitumumab was developed using nonlinear mixed-effects modeling of 1200 patients with advanced solid tumors in 14 clinical studies. The disposition of panitumumab was best described with a 2-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination pathways. For a typical male patient with colorectal cancer (80 kg, 60 years old), the estimates for the linear clearance (CL), the maximum nonlinear clearance (V(max)/K(m)), the central volume of distribution (V(1)), the peripheral volume of distribution (V(2)), and the Michaelis-Menten constant (K(m)) are 0.273 L/d, 28.4 L/d, 3.95 L, 2.59 L, and 0.426 mcg/mL, respectively. Baseline covariates such as body weight, cancer type, age, sex, and race were studied for their influence on panitumumab pharmacokinetics. Body weight was found to be the most influential covariate on panitumumab exposure, affecting CL, V(max), and V(1). The administration of concomitant chemotherapy (IFL, FOLFIRI, or paclitaxel/carboplatin) or intensity of baseline tumor EGFR expression did not alter the pharmacokinetics of panitumumab. The presence of antipanitumumab antibodies in patients (immunogenicity rate 3.4%) did not appear to affect panitumumab exposure substantially (AUC difference 8%). In support of a new drug application in Japan, the model was used to assess panitumumab pharmacokinetics in Japanese patients compared to other racial groups; there were no significant differences in model-predicted steady-state panitumumab AUC, C(max), or C(min) after accounting for the effect of body weight.
