Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group

BACKGROUND: This report presents the results of a survival update based on the combined data from two studies that compared the efficacy and tolerability of anastrozole (1 or 10 mg once daily), a selective, nonsteroidal aromatase inhibitor administered orally, and megestrol acetate (40 mg 4 times daily) in the treatment of postmenopausal women with advanced breast carcinoma whose disease had progressed after treatment with tamoxifen. METHODS: Two randomized, parallel-group, multicenter trials were conducted, involving a total of 764 patients. The two trials were identical in design; both were double blind for anastrozole and open label for megestrol acetate. Overview analyses were conducted with the intent of strengthening the interpretation of results from each trial. The median follow-up duration for this survival update was 31 months. RESULTS: At the clinical dose of 1 mg daily, anastrozole demonstrated a statistically significant survival advantage over megestrol acetate, with a hazard ratio of 0.78 (P < 0.025)(0.60 < 97.5% confidence interval [CI] <1.0). The 1 mg anastrozole group also had a longer median time to death (26.7 months) compared with 22.5 months for the megestrol acetate group. The 10 mg anastrozole group also had a survival benefit over the megestrol acetate group, with a hazard ratio of 0.83 (P=0.09, not significant)(0.64 < 97.5% CI < 1.1). Higher 2-year survival rates were observed for both anastrozole treatment groups than for the megestrol acetate group (56.1%, 54.6%, and 46.3% for the groups given 1 mg anastrozole, 10 mg anastrozole, and megestrol acetate, respectively). CONCLUSIONS: This combined analysis of two trials of postmenopausal patients with advanced breast carcinoma has clearly demonstrated that, after disease progression with tamoxifen, treatment with anastrozole 1 mg once daily results in a statistically and clinically significant advantage over a standard treatment, megestrol acetate. This important benefit, in addition to the good tolerability profile of anastrozole, supports the use of this drug as a valuable new treatment option for this patient population.     

Differences in fine control of forces generated by the tongue, lips and fingers in humans

This study compared the fine control of forces generated by the tongue, lips and fingers in middle-aged adults. The aims were to determine whether (1) the articulatory organs (tongue, lips) and fingers differed in the manner of motor control, (2) force control of the various articulatory organs was similar, and (3) control of forces generated by males was different from that of forces generated by females. The relation among several variables of the ramp-and-hold force contraction and target force level was quantified for the articulatory organs and the fingers in 14 normal individuals (7 males and 7 females). Using visual feedback, participants produced ramp-and-hold compression forces as rapidly and accurately as possible to targets ranging from 0.25 to 2 N. The results showed differences in the profiles of forces generated by the articulatory organs and fingers. In particular, the forefingers were characterized by a greater accuracy of force control and precision of movement, a greater stability of the hold phase, but by slower velocities than the articulatory organs. Motor control of the lower lip differed from that of the upper lip and tongue. Mostly, the lower lip was characterized by a greater precision of contraction, faster development of the force, and greater stability of the hold phase than the upper lip and tongue. Gender was a distinguishing factor in the force task; males were able to produce forces with higher velocities and greater precision than females.     

Arachidonic acid activates a proton current in the rat glutamate transporter EAAT4

The excitatory amino acid transporter EAAT4 is expressed predominantly in Purkinje neurons in the rat cerebellum (1-3), and it participates in postsynaptic reuptake of glutamate released at the climbing fiber synapse (4). Transporter-mediated currents in Purkinje neurons are increased more than 3-fold by arachidonic acid, a second messenger that is liberated following depolarization-induced Ca2+ activation of phospholipase A2 (5). In this study we demonstrate that application of arachidonic acid to oocytes expressing rat EAAT4 increased glutamate-induced currents to a similar extent. However, arachidonic acid did not cause an increase in the rate of glutamate transport or in the chloride current associated with glutamate transport but rather activated a proton-selective conductance. These data reveal a novel action of arachidonate on a glutamate transporter and suggest a mechanism by which synaptic activity may decrease intracellular pH in neurons where this transporter is localized.     

Renal stone analysis: is there any clinical value?

OBJECTIVE: To provide national-level data concerning the percentage of pharmacies selling tobacco products, examine relationships between selling practices and pharmacy characteristic variables, and explore perceptions of conflicts between tobacco-selling activity and professional and personal values and the potential effects of such conflicts. DESIGN, SETTING, PARTICIPANTS: Data were collected from a geographically stratified systematic random sample of 899 pharmacies. Multiple mailings were sent to the attention of the pharmacy manager. A random sample of nonrespondents was also contacted by telephone, urging participation. MAIN OUTCOME MEASURES: Whether the pharmacy currently sold cigarettes and/or smokeless tobacco products, and if so, whether these practices differed from what respondents' personal or professional values tell them to do. Scales designed to measure job satisfaction, job-induced tension, and propensity to leave were also included. RESULTS: Slightly more than half (50.5%) of the pharmacies sold cigarettes and 35.4% sold smokeless tobacco products. Independents were less likely than chain pharmacies to sell tobacco products. For those respondents working in pharmacies where tobacco products were sold, 47.6% responded that this practice differs from what their personal values tell them to do and 63.9% replied that this practice differs from what their professional values tell them to do. Even when controlling for pharmacy type, respondents working in pharmacies that sold tobacco products had significantly lower levels of global job satisfaction, higher levels of job-induced tension, and a higher propensity to leave than did respondents working in pharmacies that did not. CONCLUSION: Decision makers in pharmacies where tobacco products are still sold should take a serious look at the justification for the continued availability of tobacco products in an environment that has a goal of promoting health.     

A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility

OBJECTIVE: To determine the effectiveness of the in vivo administration of vitamin E as treatment for reactive oxygen species-associated male infertility. SETTING: University-based center for reproductive medicine. DESIGN: Double-blind randomized placebo cross-over controlled trial. PATIENTS, PARTICIPANTS: Thirty healthy men with high levels of reactive oxygen species generation in semen and a normal female partner. INTERVENTIONS: Patients were allocated to two groups according to the blinded randomization. Each patient received either 600 mg/d of vitamin E (Ephynal, 300 mg tablets; F. Hoffman-La Roche Ltd., Basle, Switzerland) (order A) or identical placebo tablets (order B) for 3 months. Then after a 1-month wash-out period the patients were crossed-over to the other treatment. MAIN OUTCOME MEASURES: Improvement in the in vitro function of the spermatozoa measured by conventional semen analysis, computerized motility assessment, determination of reactive oxygen species generation, binding to the zona pellucida of the unfertilized human oocyte in a competitive zona binding assay, development of hyperactivated motility (both spontaneous and in the presence of 20% of the natural agonist, human follicular fluid) and pregnancy. RESULTS: Rise in the blood serum vitamin E levels after treatment accompanied by improvement in one of the sperm function tests: the zona binding assay. The zona binding ratio for order A improved from 0.2 (range 0 to 0.5) before treatment to 0.5 (range 0.1 to 1.0) after treatment, the corresponding values for order B were 0.2 (range 0 to 1.0) before treatment and 0.3 (range 0.1 to 0.7) after treatment. CONCLUSION: Oral administration of vitamin E significantly improves the in vitro function of human spermatozoa as assessed by the zona binding test.     

Synthesis and dopamine transporter affinity of 2-(methoxycarbonyl)-9-methyl-3-phenyl-9-azabicyclo[3.3.1]nonane derivatives

A series of 9-methyl-3 beta-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were synthesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT). The conformation of the bicyclic structures and the stereochemistry of the substituents were determined by NMR and X-ray crystallography. The in vitro binding affinity (Ki) of the 9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they were found to be 100-fold (Ki = 2-14 microM) less potent than cocaine and other tropane analogs. From these results it is evident that the cocaine-binding site at the DAT is very sensitive to structural modifications of the unsubstituted methylene bridge [C(6)-C(7)] of cocaine and cocaine-like compounds.     

Economic analyses in clinical trials for cooperative groups: operational considerations

The objective of this prospective, cohort study was to compare the nutritional status of full-term infants who were fed human milk (BF, n = 29), formula (FF, n = 30) or evaporated milk formulae (EM, n = 30) for at least 3 months. Infants were seen at enrollment, 3 and 6 months, at which times a blood sample, diet record and anthropometric data were collected. Infants in the EM group received solids earlier (12 +/- 5 weeks) than did FF infants (15 +/- 4 weeks), and both were earlier than BF infants (19 +/- 4 weeks). Only 26% of the EM fed group received iron supplements as ferrous sulphate drops. Seven BF, 12 FF and 20 EM had abnormal ferritin values (< 10 ng ml-1) at 6 months. Copper intake was lower in the EM infants at 3 and 6 months. However, plasma copper and erythrocyte copper zinc superoxide dismutase (ZnCuSOD) levels did not differ between groups. Selenium intake was lower in the EM group (5 +/- 1 and 10 +/- 5 micrograms d-1; 3 and 6 months) than in the FF infants (13 +/- 4 and 19 +/- 7 micrograms d-1; 3 and 6 months). Erythrocyte SeGHSPx levels in EM infants were lower at 6 months (EM, 33.2 +/- 3.4; FF. 35.2 +/- 3.9: BF, 36.1 +/- 3.8 mU mg Hb-1). Thiamin intake (0.99 +/- 0.08 and 1.24 +/- 0.32; 3 and 6 months, mg 1000 kcal-1) was higher in the FF group than in EM infants (0.38 +/- 0.39 and 0.66 +/- 0.38; 3 and 6 months). There were more (13%) abnormal thiamin assays in the EM group at 6 months than in the BF and FF infants (0%). In conclusion, infants fed evaporated milk formula receive adequate copper but may not receive enough thiamin or selenium. Unless supplemented from birth with medicinal iron, intakes of iron will be inadequate.