Double-blind, placebo-controlled evaluation of extended-release bupropion in elderly patients with major depressive disorder.

Major depressive disorder in the elderly is associated with increased morbidity and reduced quality of life. This 10 week, placebo-controlled study investigated the efficacy and tolerability of extended-release bupropion (150-300 mg once daily) in depressed patients aged 65 years or older. The statistical assumptions necessary for the validity of the protocol-specified analysis of covariance were not met for the analysis of the primary outcome variable (Montgomery-Asberg Depression Rating Scale total score at Week 10, last observation carried forward). Alternative statistical methods used for the analysis of this variable demonstrated statistical significance. Statistically significant improvements were observed on the majority of secondary end points when compared with placebo, including the health outcome measures for motivation and energy, and life satisfaction and contentment. Adverse events were generally mild to moderate and similar between treatment groups. This study demonstrated that the extended-release bupropion is an effective, well-tolerated treatment for major depression in the elderly.

Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR.

The efficacy, safety and tolerability of bupropion XR and venlafaxine XR was assessed and compared with placebo in adult outpatients with major depressive disorder (MDD). Adults meeting DSM-IV criteria for MDD with a minimum Hamilton Depression Rating Scale (HAMD) 17-Item total score of > or =18 were randomized to eight weeks of double-blind treatment with either bupropion XR (150 mg/day), venlafaxine XR (75 mg/day) or placebo. At the end of the fourth week of treatment, a dosage increase to bupropion XR 300 mg/day or venlafaxine XR 150 mg/day was allowed if, in the opinion of the investigator, response was inadequate. The primary efficacy endpoint was mean change from baseline at week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score last observation carried forward (LOCF). Mean changes from baseline at week 8 (LOCF) in MADRS total score were statistically significant for bupropion XR and venlafaxine XR patients compared to the placebo group: -16.0 for bupropion XR (P = 0.006 vs placebo), -17.1 for venlafaxine XR (P < 0.001 vs placebo) and -13.5 for placebo. Secondary outcomes (including CGI-S, HAM-A, MEI, Q-LES-Q-SF, responder and remitter analyses) also improved significantly for both active treatment groups compared with placebo. The most frequently reported adverse events were dry mouth and insomnia for bupropion XR, and nausea, hyperhidrosis, fatigue, and insomnia for venlafaxine XR. In this double-blind, placebo-controlled trial, bupropion XR at doses up to 300 mg/day and venlafaxine XR at doses up to 150 mg/day demonstrated comparable antidepressant efficacy.

The direct effects of protamine sulfate on myocyte contractile processes.

The use of protamine sulfate in patients has been associated with circulatory collapse and is suspected to directly depress left ventricular function. However, the cellular basis for these changes that occur after protamine administration are unknown. Accordingly, the first objective of this study was to determine the direct effects of protamine on isolated myocyte contractile function. Myocytes were isolated from porcine hearts and contractile function was examined at baseline and then after the administration of protamine in concentrations of 20, 40, or 80 micrograms/ml. These concentrations were chosen because they reflect the serum concentrations of protamine commonly obtained in patients. The presence of protamine resulted in a dose-dependent decline in myocyte contractile function. For example, in the presence of a 20 microgram/ml concentration of protamine myocyte contractile function did not change significantly from baseline values, whereas an 80 microgram/ml protamine concentration caused myocyte percent and velocity of shortening to fall by more than 35% from baseline values. In light of the fact that protamine directly depressed myocyte contractile function, a second objective of this study was to examine potential cellular mechanisms responsible for this effect. Accordingly, in the next series of experiments, the effects of protamine on the myocyte sarcolemmal beta-adrenergic receptor system were examined by measuring myocyte contractile function with the beta-adrenergic agonist isoproterenol (25 nmol/L), as well as with the concomitant addition of protamine and isoproterenol. In the presence of protamine, myocyte beta-adrenergic responsiveness was significantly reduced. For example, in the presence of an 80 microgram/ml dose of protamine, both myocyte percent and velocity of shortening fell by greater than 50% when compared with isoproterenol alone values (p < 0.05). To determine the reversibility of these protamine effects, we performed additional experiments in the presence of heparin. Incubation with heparin before protamine addition prevented the negative effects of protamine on myocyte function. However, the addition of heparin after protamine incubation failed to reverse the negative effects of protamine on myocyte function. In a final set of experiments, the effects of protamine on isolated myocyte electrophysiologic properties were examined using microelectrode techniques at baseline and with either 40 or 80 micrograms/ml doses of protamine. Myocyte resting membrane potential changed from baseline with the addition of a 40 micrograms/ml dose of protamine (-79.2 +/- 0.5 versus -75.2 +/- 0.8 mV (p < 0.05), with no further change at an 80 micrograms/ml dose of protamine (-73.0 +/- 1.3 mV).(ABSTRACT TRUNCATED AT 400 WORDS)

Educational, occupational, and insurance status of childhood cancer survivors in their fourth and fifth decades of life.

PURPOSE: Survivors of childhood cancer who are now greater than or equal to 30 years of age are available for study in significant numbers for the first time. An evaluation of their educational achievement, current employment status, frequency of problems in the work-place, and ability to obtain affordable health and life insurance was the aim of this study. PATIENTS AND METHODS: This was a case-control study of 219 childhood cancer survivors with individually matched controls from two tertiary-care pediatric centers. Telephone interviews were used and drew on a 356-item basic instrument for both subjects and controls. Medical (including intensity of therapy), marital, and psychosocial areas were included in the survey, but statistical comparisons concentrated on educational and economic issues. RESULTS: The overall current status of survivors and controls in the relevant areas, ie, education, employment, and insurance, was similar. A history of employment discrimination for entry into the uniformed services and in other special situations, and life insurance discrimination during the initial years after the completion of therapy was noted. Survivors experienced few problems in the work-place. Survivors of CNS tumors were unique, with problems in many of the areas studied, although there were notable individual exceptions. CONCLUSION: With the exception of those individuals with CNS tumor histories, survivors who were treated in the era of 1945 to 1975 had few economic sequelae of cancer or its therapy that extended beyond the first decades after treatment.

Ventricular failure and cellular remodeling with chronic supraventricular tachycardia.

Chronic supraventricular tachycardia has been associated with ventricular dysfunction in human beings and in animals. The changes in ventricular size and shape and the myocyte remodeling that may occur with chronic supraventricular tachycardia are unknown. Left and right ventricular remodeling and myocyte changes were examined in 12 pigs after 3 weeks of atrial pacing (supraventricular tachycardia at 240 beats/min and in 10 control pigs (105 +/- 3 beats/min). Chronic supraventricular tachycardia resulted in decreased left ventricular and right ventricular ejection fractions compared with control values (left ventricle, 26% +/- 4% versus 60% +/- 1%; right ventricle, 19% +/- 3% versus 53% +/- 3%; p less than 0.05 for both), decreased wall thickness (left ventricle, 8.3 +/- 0.1 mm versus 10.5 +/- 0.2 mm; right ventricle, 2.8 +/- 0.3 mm versus 4.2 +/- 0.2 mm; p less than 0.05 for both), and increased end-diastolic volumes (left ventricle, 66 +/- 10 ml versus 54 +/- 4 ml; right ventricle, 78 +/- 8 ml versus 56 +/- 4 ml; p less than 0.05 for both). Myocardial water content was significantly higher with supraventricular tachycardia than in control pigs (left ventricle, 82% +/- 4% versus 76% +/- 4%; right ventricle, 83% +/- 4% versus 78% +/- 2%; p less than 0.05 for both). According to computer-aided stereological studies, the percent volume of myocytes in the subendocardial layer of the hearts that underwent supraventricular tachycardia was smaller than that of the control hearts (left ventricle, 62% +/- 2% versus 79% +/- 1%; right ventricle, 55% +/- 4% versus 77% +/- 1%; p less than 0.05 for both) and myocyte diameter was reduced (left ventricle, 16 +/- 1 microns versus 23 +/- 2 microns; right ventricle, 13 +/- 1 microns versus 22 +/- 2 microns; p less than 0.05 for both). Further, myocytes isolated from the left ventricles of the group with supraventricular tachycardia were significantly longer than were control myocytes (190 +/- 25 microns versus 145 +/- 30 microns, p less than 0.05 for both). In summary, chronic supraventricular tachycardia caused significant right and left ventricular failure, with a reduction in wall thickness and chamber dilatation. This was accompanied by a reduction in the percent volume of myocytes occupying the subendocardial layer, with reduced myocyte diameter and increased myocyte length and water content. These changes are likely to be important in understanding supraventricular tachycardia-induced ventricular dysfunction.

Social adjustment of children successfully treated for cancer.

Compared 56 children between the ages of 5 and 12 years to a sample of healthy controls. All cancer patients had been treated between the ages of 2 and 5 years. Children completed the Self-Perception Profile for children and questionnaires assessing social adjustment. Parent and teacher ratings were also obtained. The cancer patients reported greater feelings of isolation than the controls but otherwise few differences were noted. There were few differences between cancer patients and controls in the teacher and parent report. Results are discussed in terms of the need to investigate behavioral sequelae of childhood illness and directions for future research.