The effectiveness of once-daily dosing of inhaled flunisolide in maintaining asthma control.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of switching to once-daily (qd) administration of flunisolide in patients with asthma that was controlled by twice-daily (bid) dosing of this inhaled steroid. METHODS: Three hundred sixty-six adults and children with bronchial asthma that was controlled with inhaled steroids were recruited for this prospective, double-blind, parallel-group study. After a 4-week, stable baseline period of flunisolide administration, 2 inhalations (500 microg) twice daily, each patient was randomized into one of four 12-week flunisolide treatment groups: group 1, 2 inhalations (500 microg) bid; group 2, 4 inhalations (1000 microg) qd in the morning; group 3, 4 inhalations (1000 microg) qd in the evening; or group 4, 2 inhalations (500 microg) qd in the morning. Outcome measures included morning and evening asthma symptoms (scale of 0 to 3), daytime and nighttime albuterol use, morning and evening peak expiratory flow rate (PEFR), FEV1, and methacholine PC20. In addition, a subset of patients in each group had 24-hour urinary cortisol levels measured before and after randomization. RESULTS: Outcome measures in the four groups were not significantly different at baseline before randomization. The three groups that received maintenance therapy with flunisolide, 1000 microg daily, did not show significant changes from baseline values and remained comparable in all outcome areas. Asthma control in the group randomized to flunisolide 500 microg qd, however, deteriorated significantly: morning symptoms increased by 0.21 units (48%), evening symptoms increased by 0.15 units (31%), daytime albuterol use increased by 0.42 inhalations per day (37%), nighttime albuterol use increased by 0.48 inhalations per night (91%), morning PEFR decreased by 17.1 L/min (4%), and evening PEFR decreased by 12.6 L/min (3%). There were no significant changes in PC20 or 24-hour urinary cortisol levels in any group. CONCLUSIONS: For patients with asthma that was stabilized by 2 inhalations of flunisolide (500 microg) bid, switching to 4 inhalations (1000 microg) qd in either the morning or evening is effective in maintaining asthma control. Reducing the dose to 2 inhalations (500 microg) qd in the morning, however, leads to a deterioration in asthma control.

A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Physostigmine Study Group.

OBJECTIVE: A multicenter trial to evaluate the efficacy of controlled-release physostigmine salicylate, a cholinesterase inhibitor, was conducted in 1,111 mild-to-moderate Alzheimer's disease (AD) subjects. DESIGN: During dose titration, subjects received 18, 24, or 30 mg of physostigmine or placebo daily. After a 2-week washout period, 366 subjects with putative improvement were randomized to receive either placebo or their best dose of physostigmine in a 6-week double-blind trial. Nonresponding patients (439) were randomized to receive in a separate double-blind trial either placebo or their highest tolerated dose of physostigmine. The primary efficacy measures included the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS) and a Clinical Global Impression of Change (CGIC). Secondary measures included the Mini-Mental State Examination and two activities-of-daily-living scales. RESULTS: At the end of the 6-week double-blind phase, physostigmine-treated patients scored 1.75 points higher than placebo-treated patients on the ADAS (p = 0.003) and 0.26 points higher on the CGIC (p = 0.012) in the intent-to-treat analysis. There was no significant improvement on the secondary outcome measures. Patients failing to respond to physostigmine during the dose titration phase failed to respond on any of the outcome measures during the double-blind period of re-exposure. Common adverse events included nausea, vomiting, diarrhea, and anorexia. There were no significant changes in liver function tests. CONCLUSION: This study demonstrated statistically significant differences between physostigmine and placebo on both a performance-based cognitive functioning instrument and a clinician's global evaluation. The magnitude of the effect size was small and occurred only in the subset of patients who responded in the initial dose titration study period. Nevertheless, the results suggest that in a subset of patients, physostigmine can induce a degree of cognitive improvement over 6 weeks of treatment.

Oral physostigmine in Alzheimer's disease: effects on norepinephrine and vasopressin in cerebrospinal fluid and plasma.

Physostigmine is a cholinesterase inhibitor which enhances central and peripheral cholinergic activity. In this study, we explored in persons with Alzheimer's disease (AD) the effects of an acute dose of physostigmine in patients receiving chronic physostigmine treatment on the activity of the cholinergically regulated noradrenergic and arginine vasopressin (AVP) systems. Specifically, we estimated the effects of sustained release oral physostigmine on central and peripheral noradrenergic and AVP systems by measuring norepinephrine (NE) and AVP in cerebrospinal fluid (CSF) and plasma. Lumbar punctures were performed in both physostigmine and no drug treatment conditions. In some subjects the effects of physostigmine on the plasma AVP response to the osmolar stimulus of a hypertonic saline infusion also were measured. NE concentrations in both CSF and plasma were significantly lower in the physostigmine than in the no drug condition. AVP concentrations did not differ between conditions in either compartment, nor did physostigmine affect the AVP response to hypertonic saline. Physostigmine appears to decrease both central and peripheral noradrenergic activity in AD.

Sex differences in platelet adherence to subendothelium: relationship to platelet function tests and hematologic variables.

Men have significantly more atherosclerotic disease than women. Platelet-mediated thrombosis plays a role in the initiation of myocardial infarction and stroke. Citrated whole blood from male and female donors was perfused through an annular system over everted human umbilical artery segments. Comparisons were made between platelet adherence and thrombus formation on subendothelium, platelet aggregation in citrated whole blood, hematologic variables, and the bleeding time. Platelet spreading and adherence were approximately 22% greater with male blood (P < 0.001), whereas thrombus formation on subendothelium and collagen- and arachidonic acid-induced platelet aggregation did not show sex-related differences. Platelet aggregation with adenosine diphosphate was greater in women, related to their lower hematocrit values. By contrast, in women hematocrit values showed a slight but significant positive correlation with platelet adherence on subendothelium. Fibrinogen was significantly correlated with collagen- and adenosine-diphosphate-induced platelet aggregation and with platelet adherence, spreading, and thrombus formation on subendothelium. The mean bleeding time was slightly longer in women than in men (P = 0.118). Platelet aggregation was not associated with the bleeding time except for collagen-induced platelet aggregation in males; the latter was significantly correlated with platelet adherence and spreading in both sexes, while arachidonic acid-induced platelet aggregation predicted platelet adherence and spreading in males. Male blood shows enhanced primary hemostatic activity; this may predispose men to atherosclerosis.

An open study of auranofin in the treatment of steroid-dependent asthma.

To determine the efficacy of oral gold in asthma, 20 patients with steroid-dependent asthma received auranofin at a dose of 3 mg by mouth, twice daily, in a 24-week open clinical trial. Prospective evaluation of bronchial responsiveness to methacholine was determined before and 8 and 16 weeks after initiation of auranofin therapy. Serial spirometry (FEV1 and FVC), lung volumes, and diffusing capacities (single breath carbon monoxide diffusing capacity of the lungs) were measured before and at 10 and 20 weeks after treatment. All subjects were required to record concomitant medications, symptom scores, and morning and evening peak expiratory flow rates. In vitro immunologic studies performed before and after 8 and 20 weeks of auranofin therapy included leukocyte histamine release in response to antihuman IgE, lymphocyte blast transformation in response to concanavalin A and phytohemagglutinin, and leukocyte inhibitory factor activity in response to Candida albicans and tetanus toxoid antigens. In 18 patients evaluated, there were no significant differences between baseline and posttreatment spirometry, single breath carbon monoxide diffusing capacity of the lungs, and lung volumes. At week 16 of treatment, the steroid cumulative dose or the total prednisone dose administered from 7 days before through 10 days after each methacholine test day decreased from a mean of 293 +/- 125 mg at baseline to 192 +/- 115 mg. At week 16, nine of 18 patients (50%) exhibited decreased methacholine responsiveness as defined by a more than one-half log10 increase in the concentration of methacholine causing a 20% decrease in FEV1. A significant correlation (r = 0.60) was observed between the increase in the concentration of methacholine causing a 20% decrease in FEV1 and the decrease in steroid cumulative dose after 16 weeks of treatment. Leukocyte histamine release to anti-IgE exhibited significant reductions from baseline at week 20 to 10(-2) (p less than 0.002) and at 10(-3) (p less than 0.005) dilutions. At week 20, leukocyte inhibitory factor activity in response to Candida increased from baseline at the 0.1 mg per well (p = 0.025) and 1 mg per well (p = 0.05) concentrations; similarly, the responses to tetanus toxoid increased at the 1 mg per well (p less than 0.05) and 0.1 mg per well (p less than 0.01) concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)