The effect of stress on the antioxidative potential of serum: implications for Alzheimer's disease.

There is growing consensus in the literature that oxidation status is increased in Alzheimer's disease (AD), and that antioxidant supplementation as prevention or treatment strategy should be investigated further. In the present study the total antioxidant status (TAS) was found to be highly significantly lower in 22 AD patients (p < 0.0001) than in 22 age- and gender matched non-demented controls. The TAS was also lower than controls in 22 patients with vascular dementia, but not significantly. The increased oxidation status in AD was verified using the benzoate hydroxylation method. The origin of the enhanced oxidation status in AD has not been elucidated. To determine whether a causal effect between stress and oxidative status of serum can be demonstrated, a rat model was used with two different kinds of stressors, swim stress (exercise) and restraint stress (non-exercise stress). Following swim stress the maximum oxidative effect was observed at one hour post stress (p < 0.001). At 24 h the oxidative status had recovered significantly to below control values. Restraint stress, however, showed progressively increased oxidation which attained significance after 24 h (p < 0.005). It is postulated that stress may contribute to the higher oxidation status in AD patients.

Melatonin prevents beta-amyloid-induced lipid peroxidation.

Beta-amyloid is a major constituent of senile plaques that occur in the brains of Alzheimer's disease (AD) patients. Cell culture studies have shown that high concentrations of beta-amyloid are toxic and damage biological macromolecules. A number of experiments have shown that melatonin is a potent antioxidant. Melatonin not only neutralizes oxygen-derived free radicals but can also scavenge species of other types such as carbon-centered free radicals. The present study was designed to determine whether beta-amyloid toxicity would cause lipid peroxidation of human platelet membranes. Since aluminum has been implicated in the etiology of AD, we investigated the effects of aluminum on lipid peroxidation and whether the harmful effects of beta-amyloid are aggravated by aluminum. We also investigated whether melatonin had the ability to protect against beta-amyloid toxicity. Our results indicate that both beta-amyloid and aluminum dose-dependently increased lipid peroxidation in platelet membranes. Aluminum was more potent than beta-amyloid. Incubation of platelet membranes with increasing concentrations of aluminum in the presence of 100 microM beta-amyloid (fragment 25-35) resulted in lipid peroxidation levels of similar magnitude as the two substances, respectively. Prior administration of melatonin dose-dependently inhibited this effect. These results confirm the toxic effects of beta-amyloid to biological membranes. While aluminum itself damages membranes, its presence did not exacerbate the toxic effects of beta-amyloid. Melatonin effectively reduced the lipid peroxidation induced by beta-amyloid and aluminum, suggesting that its supplementation to AD patients may be beneficial.

Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer.

PURPOSE: To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. MATERIALS AND METHODS: Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). RESULTS: The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. CONCLUSION: The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.

Assessment of estrogenic recruitment before chemotherapy in advanced breast cancer: a double-blind randomized study. European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group.

PURPOSE: In the present phase III study, the specific effect of estrogenic recruitment was assessed by comparing two groups of patients with advanced breast cancer receiving either ethinylestradiol (EE2) or placebo (PL) before chemotherapy (CT). PATIENTS AND METHODS: The therapeutic regimen consisted of (1) estrogen suppression by aminoglutethimide (AGL) 1 g/d plus hydrocortisone (HC) 40 mg/d, with surgical castration performed on premenopausal patients; (2) fluorouracil (5-FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide (CPA) 500 mg/m2 (FAC) intravenously (IV) every 3 weeks; (3) following randomization, patients were double-blinded to receive either PL or EE2 50 micrograms exactly 24 hours before receiving FAC. All patients had advanced breast cancer presumably sensitive to endocrine therapy (estrogen receptor-positive [ER+] and/or progesterone receptor-positive [PgR+] status) with measurable lesions; none had received prior systemic antineoplastic therapy for metastatic disease; prior adjuvant hormonal therapy (HT) or CT (without anthracyclines) was allowed if interval since completion was longer than 1 year. RESULTS: Among 154 patients treated according to the protocol, tolerance, response rates, time to progression, and median survival duration were identical in the PL and EE2 groups. Only performance status, dominant metastatic site, and menopausal status seemed to influence response (overall response, 64%), with the highest levels of partial remission (PR) and complete remission (CR) being achieved in premenopausal women (CR plus PR, 26% plus 55%) and in those with dominant soft tissue lesions (CR plus PR, 45% plus 28%). CONCLUSION: We conclude that the validity of the hormonal recruitment concept has not yet been established in clinical practice so that this approach remains experimental. The results achieved by combining (near) complete estrogenic suppression and cyclical FAC chemotherapy are not significantly different from those to be expected with the more conventional use of HT followed by CT in presumably hormone-responsive (ER+) patients.

Comparison of various physiologic and psychomotor parameters in patients sedated with intravenous lorazepam, diazepam, or midazolam during oral surgery.

Intravenously administered lorazepam (0.05 mg/kg), diazepam (0.25 mg/kg), and midazolam (0.1 mg/kg) were compared for sedation during oral surgery under local anesthesia. Sixty patients were randomly allocated into three groups in this double-blind, parallel study. The results from this trial show that all three drugs provide satisfactory sedation. Average mean arterial pressures, however, decreased significantly with midazolam and diazepam. Statistically significantly higher heart rates during the entire procedure were also found for lorazepam when compared with diazepam and midazolam. At the postblock stage, the midazolam group had respiratory rates that were significantly higher than those of the other two drug groups. Patients in the diazepam and midazolam groups took significantly longer to complete the pegboard test at the preblock stage than those in the lorzepam group. At 1, 1.5, and 2 hours after arrival in the recovery room, an inversion of groups took place, with the lorazepam group taking significantly longer for their tests than the other two groups. Significantly more improvement in anxiety levels was found at 10 minutes postdrug for the patients who had received diazepam and this tended to remain so on arrival in the recovery room. When compared with the other two groups, significantly more patients in the lorazepam group reported giddiness/dizziness and significantly more in the diazepam group reported pain on injection.