Self-reported dietary restraint is associated with elevated levels of salivary cortisol

Previous studies have found inconsistent relationships between restrained eating, dieting, and cortisol. The present study was designed to clarify the relationship between self-reported restrained eating and cortisol using multiple measures of dietary restraint. Eighty-five college-age women completed the Restraint Scale (RS) and the Cognitive Restraint Scale of the Three Factor Eating Questionnaire (TFEQ-R) and provided a saliva sample for analysis of cortisol. Both measures of restraint were positively associated with elevated levels of salivary cortisol, although the TFEQ-R was more strongly associated than the RS. Restrained eating, characterized by largely unsuccessful efforts to control eating, may lead to elevated cortisol levels.     

Phase I study of eniluracil and oral 5-fluorouracil in combination with docetaxel in the treatment of patients with metastatic breast carcinoma

PURPOSE: The authors conducted a single-institution Phase I clinical trial to determine the maximum tolerated doses and to define the toxic effects of oral eniluracil and oral 5-fluorouracil (5-FU) combined with docetaxel in patients with metastatic breast carcinoma. PATIENTS AND METHODS: Patients with metastatic breast carcinoma were eligible if they had disease progression after anthracycline-based therapy and had never been exposed to taxanes. The starting doses of oral eniluracil and oral 5-FU were 11.5 mg/m(2) and 1.15 mg/m(2), respectively, twice daily on Days 1-14. Docetaxel was given intravenously at a starting dose of 50 mg/m(2) on Day 1 only. The dose of docetaxel was escalated among cohorts until a maximum tolerated dose was reached. Courses were repeated every 21 days. RESULTS: The authors treated 19 patients with Stage IV breast carcinoma, of whom 5 had received prior chemotherapy for their metastatic disease. Fifty-three percent had a performance status of 1, and 53% had bone or soft tissue involvement as the dominant site of disease. All patients had received prior therapy with doxorubicin. The dose-limiting toxicity was neutropenic fever. No episodes of sepsis were observed. Significant antitumor activity was observed with a total of two complete and nine partial responses. The recommended doses for Phase II studies are 72 mg/m(2) docetaxel on Day 1 and 10.0/1.0 mg/m(2) oral eniluracil/5-FU twice daily for a total of 14 days, with courses being repeated every 21 days. CONCLUSIONS: The combination of oral eniluracil/5-FU and intravenous docetaxel is a safe and well tolerated regimen. Significant antitumor activity is associated with this combination.     

Phase I study of vinorelbine and docetaxel with granulocyte colony-stimulating factor support in the treatment of metastatic breast cancer

Purpose: Vinorelbine and docetaxel are two active agents in the treatment of metastatic breast cancer. When given together, these drugs exhibit synergistic antitumor activity without significant pharmacokinetic interaction. The dose-limiting toxicities of this combination are neutropenic fever and mucositis. Adding granulocyte colony-stimulating factor (G-CSF) might lessen the toxicity and increase the maximum tolerated dose (MTD) of this combination. The aim of this study was to determine the MTD of vinorelbine and docetaxel given in combination with G-CSF. Patients and methods: Between August 1997 and December 1998, 14 patients with metastatic breast cancer were enrolled in this study. All patients had received doxorubicin-based therapy, and 46% had received paclitaxel in the adjuvant or neoadjuvant setting. Patients were treated with vinorelbine at a starting dose of 20 mg/m ² intravenously over 10 min on days 1 and 5 and docetaxel at a starting dose of 85 mg/m ² intravenously over 1 hr on day 1, following the vinorelbine. Treatments were repeated every 21 days. Prophylactic G-CSF 5 mcg/kg was given subcutaneously on days 3-10. Toxicity was graded according to the National Cancer Institute's grading system. Results: A total of 65 cycles was administered at dose levels 0, -1, -2, and -3. The median absolute granulocyte count nadir for all courses was 200 mm^{- 3} (range, 0.1-7700 mm^{- 3}), and the median time to this nadir was 9 days (range, 7-30). The median platelet nadir was 163 (range, 27-401k), and the median time to this nadir was 8 days (range, 7-30). The most common grade 3 nonhematologic toxicities for all courses were fatigue and myalgia, which occurred in 32 and 10 cycles, respectively. Neutropenic fever was encountered in 11 cycles. Three patients developed colitis-like pictures, two of whom died as a result. Consequently, the protocol was closed to accrual before a MTD was reached. Conclusion: The combination of vinorelbine, docetaxel, and G-CSF in our hands has proven to be a toxic regimen, even when relatively low doses of vinorelbine and docetaxel are given. Meticulous observation of patients receiving this combination is warranted since the combination resulted in two deaths in this study.     

Enhancing effects of estrogen on inhibitory avoidance performance may be in part independent of intracellular estrogen receptors in the hippocampus

Estradiol (E(2)) can have classical actions via intracellular estrogen receptors (ERs) in the dorsal hippocampus, as well as effects independent of ERs ('non-genomic' mechanisms). These experiments investigated whether E(2)'s cognitive enhancing effects in the inhibitory avoidance task require actions at ERs in the dorsal hippocampus. Ovariectomized (ovx) rats were administered E(2) (s.c. or to the dorsal hippocampus), an E(2) conjugate (E(2):BSA), or vehicle and/or an ER antagonist, tamoxifen (10 mg/kg s.c.) or ICI 182,780 (10 microg intrahippocampally), or vehicle for 2 days prior to training (Day 3) and testing (Day 4) in the inhibitory avoidance task. Exp 1: crossover latencies in the inhibitory avoidance task were significantly increased in ovx rats with s.c. E(2) silastic capsules or s.c. injections of 1000 or 10 microg E(2) compared to vehicle-administered rats. Exp 2: bilateral inserts of E(2) to the dorsal hippocampus significantly increased crossover latencies compared to vehicle. Exp 3: s.c. tamoxifen, the ER antagonist, did not block the increased crossover latencies produced by 10 microg E(2) s.c. (compared to vehicle). Exp 4: s.c. tamoxifen did not block the increased crossover latencies produced by intrahippocampal E(2) (compared to vehicle). Exp 5: ICI 182,780 was unable to attenuate the increased crossover latencies produced by intrahippocampal E(2). Exp 6: E(2):BSA administered to the dorsal hippocampus significantly enhanced performance on the inhibitory avoidance task compared to control implants to the hippocampus. The ability of systemic and intrahippocampal E(2) to similarly enhance inhibitory avoidance performance suggests that actions of E(2) in the dorsal hippocampus are sufficient to enhance cognitive performance. Further, that neither tamoxifen nor ICI 182,780 blocked E(2)'s enhancing effects on inhibitory avoidance and that E(2):BSA was able to enhance performance suggest that non-genomic mechanisms may in part mediate E(2)'s cognitive enhancing performance in this task.     

Subsyndromal depression is associated with functional impairment in patients with bipolar disorder

BACKGROUND: The purpose of this study was to assess whether a relationship exists between mild depressive symptoms and overall functioning in subjects with bipolar disorder. METHOD: Twenty-five male subjects with bipolar I disorder (DSM-III-R criteria), who had not experienced a DSM-III-R episode of mania, hypomania, or major depression for 3 months as determined using the Structured Clinical Interview for DSM-III-R, were evaluated for degree of depressive symptoms using the Hamilton Rating Scale for Depression (HAM-D) and for overall functional status using the Global Assessment of Functioning (GAF, DSM-IV Axis V). RESULTS: GAF scores were significantly negatively correlated with HAM-D scores (r = -0.61, df = 23, p = .001), despite the fact that no patient had a HAM-D score high enough to be considered clinically depressed. CONCLUSION: The results of this study support a relationship between subsyndromal depressive symptoms and functional impairment in bipolar subjects, despite their not meeting threshold criteria for a major depressive episode. These findings raise the possibility that in some patients with bipolar disorder subsyndromal depressive symptoms might contribute to ongoing functional impairment.     

Plasma levels of TNF-alpha and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure

BACKGROUND: Cytochrome P450 (CYP) enzymes are important mediators of drug metabolism, and activity of these enzymes is a major determinant of the duration and intensity of drug effect. Circulating plasma concentrations of pro-inflammatory cytokines (e.g., tumor necrosis factor [TNF]-alpha and interleukin [IL]-6) are elevated in patients with heart failure and these cytokines have been shown to down-regulate CYP enzyme activity. The purpose of this study was to evaluate the relationship between plasma cytokine concentrations and CYP enzyme activities in patients with heart failure. METHODS AND RESULTS: Sixteen patients with congestive heart failure (New York Heart Association classes II-IV) received a metabolic probe cocktail consisting of caffeine, mephenytoin, dextromethorphan, and chlorzoxazone to assess the activities of the CYP enzymes 1A2, 2C19, 2D6, and 2E1. Blood and urine samples were collected for drug and metabolite determinations by high-performance liquid chromatography (HPLC); cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA). We found a striking inverse relationship between both TNF-alpha and IL-6 plasma concentrations and the activity of CYP2C19; metabolism of caffeine (CYP1A2) also had a negative association with IL-6 plasma concentrations. CONCLUSIONS: Cytokine-mediated decreases in drug metabolism may contribute to observed variability in drug response and augment the risk of adverse drug effects in CHF patients.     

Neuroleptic exposure in bipolar outpatients in a research setting

The study purpose was to determine the extent of neuroleptic exposure in bipolar outpatients maintained on mood-stabilizing medications and any clinical correlates associated with this exposure. Data on medication and severity of illness were gathered from the records (prospective and retrospective) of 70 bipolar patients involved in outpatient research studies at the National Institute of Mental Health (NIMH). The percentage of patients requiring neuroleptic treatment, percentage of time on neuroleptics during the period of observation, total dose of neuroleptics in chlorpromazine (CPZ) equivalency, and number of neuroleptic trials were among the variables calculated. Regression analyses and analyses of variance (ANOVAs) were performed to assess the relationships between neuroleptic exposure and clinical course. Forty-five patients (64.3%) had a neuroleptic trial during the prospective study. Subjects exposed to neuroleptics spent, on average, 15.4% (median, 6.0%) of the time in study on neuroleptic treatment, and were administered, on average, a total of 11,770.5 mg (median, 1,621.9 mg) of neuroleptics (in CPZ equivalency) per year in the prospective study. As expected, bipolar I compared with bipolar II patients had significantly higher neuroleptic exposure by a number of measures. The number of hospitalizations for mania prior to study entry was associated with greater prospective neuroleptic use during the study. Despite maintenance treatment with one or more moodstabilizing agents, we found a relatively high need for adjunctive neuroleptic medication even in this sample of high-functioning bipolar outpatients. These results highlight the need for the study of alternatives, as well as more effective primary mood-stabilizing agents.     

New treatment strategies for malignant gliomas

Malignant gliomas are the most prevalent type of primary brain tumor in adults. Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal. The median survival of patients with glioblastoma muhiforme, the most common grade of malignant glioma, is 10-12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Essentially, tumor recurrence is inevitable. Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit. Therapies targeting the underlying molecular pathogenesis of brain tumors are urgently required. Common genetic abnormalities in malignant glioma specimens are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy.     

Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast cancer: preliminary data of a prospective randomized trial.

PURPOSE: Paclitaxel has significant antitumor activity in patients with metastaticbreast cancer who have been previously treated with or exposed to anthracycline-containing chemotherapy. In this prospective randomized trial, the role of paclitaxel was evaluated in an adjuvant setting to determine its impact on reducing the risk of recurrence in patients with operable breast cancer. EXPERIMENTAL DESIGN: Five hundred twenty-four patients were randomized to be treated either with 4 cycles of paclitaxel followed by 4 cycles of combination therapy with 5-fluorouracil, Adriamycin, and cyclophosphamide (Pac/FAC) or with 8 cycles of FAC alone. Patients with intact primary breast cancer received the initial 4 cycles of paclitaxel or 4 cycles of FAC in a neoadjuvant setting. Planned duration of therapy was the same in all patients. After completion of 8 cycles of chemotherapy, those patients who were > or =50 years and whose tumors were positive for estrogen receptors received tamoxifen for 5 years. RESULTS: Ninety-two patients have had a recurrence after a median follow-up of 60 months with a range of 5-89 months. Estimated disease-free survival at 48 months was 0.83 for FAC and 0.86 for Pac/FAC group. The difference between the two groups was not statistically significant (P = 0.09). The overall estimated hazard ratio for Pac/FAC compared with FAC derived by fitting the Cox regression model and incorporating terms for prognostic factors was 0.66. CONCLUSION: Preliminary results suggest that the addition of paclitaxel to a FAC regimen of adjuvant or neoadjuvant therapy may further reduce the risk of disease recurrence; however, differences were not statistically significant. At the time of this analysis, there have been 47 deaths. The survival data are too preliminary to permit meaningful evaluation of the impact of paclitaxel on mortality.