Quetiapine to treat agitation in dementia: a randomized, double-blind, placebo-controlled study.

In this 10-week, double-blind, fixed-dose study, elderly institutionalized patients with dementia and agitation were randomized (3:3:2) to quetiapine 200mg/day, 100mg/day, or placebo. The primary endpoint was change in Positive and Negative Syndrome Scale (PANSS)-Excitement Component (EC) scores at endpoint, analysed using last observation carried forward (LOCF) and observed cases (OC) approaches. Other efficacy measures were the Clinical Global Impression of Change (CGI-C), and response rates (percentage with > or =40% reduction [PANSS-EC]; "much" or "very much improved" [CGI-C]), Neuropsychiatric Inventory-Nursing Home version (NPI-NH), and Cohen-Mansfield Agitation Inventory (CMAI). The key safety measure was incidence of adverse events; change in Mini-Mental State Examination (MMSE) was also assessed. Baseline characteristics of 333 participants (quetiapine 200mg/day, n=117; quetiapine 100mg/day, n=124; placebo, n=92) and completion rates (63-65%) were comparable among groups. Compared with placebo, quetiapine 200mg/day was associated with clinically greater improvements in PANSS-EC (LOCF, p=0.065; OC, p=0.014 [ANCOVA]), CGI-C (LOCF, p=0.017; OC, p=0.002 [ANOVA]), and CGI-C response rates (LOCF, p=0.002; OC, p<0.001 [Chi-square test]). Quetiapine 100mg/day did not differentiate from placebo on these measures. There were no between-group differences in NPI-NH or CMAI. Incidences of cerebrovascular adverse events, postural hypotension, and falls were similar among groups. MMSE did not change in any group. Mortality was numerically higher in the quetiapine groups; rates were not statistically different from placebo. The results of this study suggest that quetiapine 200mg/day was effective and well-tolerated for treating agitation associated with dementia. However, caution should be exercised given the concerns regarding increased mortality with atypical antipsychotics in this vulnerable patient population.

Effect of age on response to zafirlukast in patients with asthma in the Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT).

BACKGROUND: The Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT), evaluated zafirlukast in a wide spectrum of patients from a variety of clinical practices. OBJECTIVE: To determine the effect of age on the response to zafirlukast 20 mg twice daily in 3759 patients with mild, moderate, or severe asthma. METHODS: Patients received open-label administration of zafirlukast 20 mg twice daily (bid) for 4 weeks. Pulmonary function was measured twice daily, and overall asthma symptom scores, number of nighttime awakenings, severity of morning asthma symptoms, and beta2-agonist use were recorded daily. Trial results were analyzed to compare the efficacy of zafirlukast in 263 adolescent (12 to 17 years old), 2602 adult (18 to 65 years old), and 321 elderly (66 years old and older) patients (the evaluable population). RESULTS: After 4 weeks of zafirlukast therapy, improvements in pulmonary function decreased with age and were significant for all measures in adolescents and adults and for morning peak expiratory flow in elderly patients. Improvements in symptom response were statistically significant across age groups. Reduction in beta2-agonist rescue was similar in adolescents and adults but significantly less in elderly patients. CONCLUSIONS: Zafirlukast is an effective treatment for asthma in all patients, regardless of age. In elderly patients, improvement in asthma symptoms rather than pulmonary function may represent a primary marker for efficacy with zafirlukast.

Two first-line therapies in the treatment of mild asthma: use of peak flow variability as a predictor of effectiveness.

BACKGROUND: New drug evaluations in patients with mild asthma are sometimes complicated by enrollment of patients whose disease is too mild to show improvement with therapy. A peak expiratory flow (PEF) variability criterion may help to more clearly define a mild asthmatic population. OBJECTIVE: To evaluate the effectiveness of zafirlukast (20 mg twice daily) and cromolyn sodium (1600 microg four times daily) compared with placebo as first-line therapy for mild asthma using a retrospective analysis, which stratified patients by PEF variability (<10% or > or =10%). STUDY DESIGN: Symptomatic patients (daytime asthma symptoms score > or =8) were randomized to 13 weeks of treatment in a double-blind, double-dummy, placebo-controlled, parallel-group, multicenter trial. PATIENTS AND METHODS: Patients (n = 287) were nonsmokers (age > or =12 years) with reversible airway disease, a forced expiratory volume in one second (FEV1) of > or = 55% of predicted, and previous treatment with beta2-agonist or theophylline only. Assessments included changes from baseline to endpoint in daytime and nocturnal asthma symptoms, beta2-agonist use, PEF, and FEV1. Response to treatment was assessed by predetermined diary card and FEV1 criteria. Safety was determined from adverse events and laboratory test results. RESULTS: No significant treatment effects were seen across efficacy measures for patients with PEF variability < 10%. For patients with PEF variability > or = 10%, both active treatments significantly (P < .05) decreased the daytime asthma symptoms score, nighttime awakenings, and beta2-agonist use, and increased morning PEF and FEV1 compared with placebo. Response to diary card criteria was 70% and 75% for zafirlukast and cromolyn, respectively; response to FEV1 criteria was 47% for both treatments. All treatments were tolerated well by patients. CONCLUSIONS: Zafirlukast and cromolyn are effective first-line therapies for mild asthma, with both therapies producing greater benefits in patients whose PEF variability was > or = 10%. In prospective trials to evaluate therapies in patients with mild asthma, it may be worthwhile to include PEF variability with a 10% cutoff either as an inclusion criteria or as a tool for subset analysis.

An evaluation of zafirlukast in the treatment of asthma with exploratory subset analyses.

BACKGROUND: Consensus asthma guidelines recommend antileukotriene agents as alternative therapy to existing anti-inflammatory medications; however, the full therapeutic potential of these medications has not yet been determined. OBJECTIVE: The purpose of this study was to assess the efficacy and safety of the oral leukotriene receptor antagonist zafirlukast (20 mg twice daily) in subgroups of patients who have asthma with the use of integrated data from four 13-week trials. METHODS: The trials had comparable designs, entry criteria, and clinical assessments. Patient subgroups were characterized by demographic and baseline asthma characteristics. Analysis of covariance models were tested for overall treatment effect and for interactions between treatment and subgroup characteristics. RESULTS: Patients with mild-to-moderate asthma (12 to 76 years old) who were treated with albuterol alone were randomized (nZ = 879; nP = 605) and included in subset analyses. Significant overall treatment effects, favoring zafirlukast, were noted for measures of daytime and nighttime symptoms, beta2 -agonist use, and pulmonary function (P <.05). A significant, quantitative, treatment-by-age interaction was noted for beta2 -agonist use (P <. 03), suggesting greater reductions in rescue medication use with increasing patient age. Compared with placebo, similar size and/or direction of response was noted with zafirlukast in the various subgroups, indicating a benefit with zafirlukast regardless of subgroup. Significant treatment-by-strata interactions (P <.05), favoring zafirlukast, were noted for various outcome measures in subgroups with the greatest amount of baseline beta2 -agonist use (>8 puffs/day) and with greater baseline peak flow variability (>/=20%) and baseline airflow obstruction (FEV1 /forced vital capacity ratio, <0.70). The overall treatment failure rate was significantly lower in the zafirlukast group compared with the placebo group (P <.003). No associations were observed between any adverse events and subgroups defined by demographic characteristics. CONCLUSIONS: Exploratory subset analyses showed that zafirlukast is similarly efficacious in patients with asthma who have differing demographic characteristics and degrees of subjective symptoms. Additionally, zafirlukast appears to be incrementally beneficial in patients with more moderate disease, defined by a greater requirement for as-needed rescue medication and more abnormal pulmonary function at baseline. Over 13 weeks, zafirlukast was well tolerated and demonstrated a safety profile clinically indistinguishable from placebo.

Therapeutic effect of zafirlukast as monotherapy in steroid-naive patients with severe persistent asthma.

STUDY OBJECTIVES: We evaluated the efficacy of the leukotriene receptor antagonist zafirlukast (Accolate), 20 mg twice daily, as monotherapy in patients with severe persistent asthma (defined by an FEV1 < 60% of predicted before treatment and frequent night-time symptoms). DESIGN: Data were analyzed from a subgroup of 261 steroid-naive patients (zafirlukast, n = 149; placebo, n = 112) from four randomized, double-blind, placebo-controlled, 13-week trials with similar experimental designs, entry criteria, and clinical assessments. PATIENTS: These patients were mostly men (57%) older than 30 years (56%) with pulmonary obstruction, ie, FEV1/FVC ratio < 0.7 (79%), and reversible airway disease demonstrated by a 15% increase in FEV1 after inhaled bronchodilator use. RESULTS: At end point, patients who received zafirlukast monotherapy had significant (p < 0.05) improvements from baseline, and compared with placebo, in FEV1, morning and evening peak expiratory flow (PEF), daytime asthma symptoms, nighttime awakenings, and beta2-agonist use. A stratified analysis based on the FEV1/FVC ratio showed an interaction between treatment and the amount of airflow obstruction for nighttime awakenings and mornings with asthma. Moreover, 37% of patients in both treatment groups had PEF variability > or = 20% (an indirect measure of airway inflammation). Zafirlukast patients with PEF variability > or = 20% had increases from baseline in the morning and evening PEF of approximately 40 and 11 L/min, respectively. For patients who take zafirlukast and who have a PEF variability of < 20%, the morning and evening PEF increased by 25 and 30 L/min, respectively. Regardless of the degree of PEF variability, zafirlukast significantly (p < 0.05) increased morning and evening PEF compared with placebo. CONCLUSION: Patients with severe persistent asthma who received zafirlukast as monotherapy had clinically significant improvements across all efficacy measures compared with placebo and significant reductions in PEF variability.

Effect of zafirlukast (Accolate) on cellular mediators of inflammation: bronchoalveolar lavage fluid findings after segmental antigen challenge.

The effect of zafirlukast (Z) to alter the inflammatory response to segmental antigen challenge (SAC) was assessed by bronchoalveolar lavage (BAL) in this double-blind, placebo-controlled, two-period, crossover trial in 11 allergic asthmatic patients. Patients with asthma and positive skin tests to antigen received 7 d of treatment with Z (20 mg twice daily) or placebo (P) during two trial periods 14 to 21 d apart. At steady state (Day 5), patients underwent SAC followed by BAL immediately after challenge and 48 h later. Purified alveolar macrophages were analyzed ex vivo for phorbol myristate acetate (PMA)-driven superoxide release. Results were analyzed by analysis of variance (ANOVA). Forty-eight hours after SAC, Z therapy was associated with significantly reduced BAL lymphocytes and alcian blue-positive cells (presumably basophils) compared with P (p < 0.01), with a trend toward reduced numbers of alveolar macrophages (p = 0.06). PMA-driven superoxide release by purified alveolar macrophages was significantly reduced 48 h after SAC in the Z versus P arms (p < 0.05). Reduction of basophil influx, mediator release, and cellular activation may be important in attenuating the late phase of asthma. Collectively, the data suggest that zafirlukast therapy alters cellular infiltration and activation associated with antigen challenge.

The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma.

Inhalation of sulfur dioxide (SO2) causes bronchoconstriction in most people with asthma. To examine the role of leukotrienes in this response, the antagonism of SO2-induced bronchoconstriction by a single oral dose of the leukotriene receptor antagonist zafirlukast was assessed in a double-blind, placebo-controlled, two-period crossover trial in 12 subjects with mild-to-moderate asthma. Subjects had bronchial hyperresponsiveness, an FEV1 < or = 70% of predicted, and a positive response to inhaled SO2 (an 8-unit increase in specific airway resistance on inhaling an SO2 concentration of < or = 4 ppm (PC8SRaw). Subjects were treated with zafirlukast (20 mg) or placebo on two treatment days 5 to 14 d apart. Two and 10 hours after treatment, subjects inhaled SO2 (0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 ppm) during eucapnic hyperventilation at 20 L/min. PC8SRaw was determined after each challenge. Blood samples were collected to assess zafirlukast plasma concentrations versus effect. PC8SRaw was significantly higher 2 h after zafirlukast compared with placebo (3.1 versus 1.5 ppm; p = 0.02) and remained higher 10 h after treatment with zafirlukast (2.7 versus 1.9 ppm; p = 0.09). An association was found between zafirlukast plasma concentrations and increases in PC8SRaw 10 h after treatment (p = 0.001). The safety profile of zafirlukast was not clinically different from placebo. A single 20-mg dose of zafirlukast attenuated SO2-induced bronchoconstriction. We conclude that S02-induced bronchoconstriction involves release of leukotrienes and that treatment with zafirlukast attenuates the bronchoconstrictor response.

The leukotriene D4-receptor antagonist, ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis.

The efficacy and safety of single oral doses of the leukotriene D4-receptor antagonist, ICI 204,219, were tested in subjects with acute seasonal allergic rhinitis. Subjects who were enrolled in the double-blind, placebo-controlled trial spent 8 h/d for two consecutive days in a park at the peak of ragweed season (counts > 1,000 grains/m3). Subjects (n = 164) who had sufficient symptoms during a 3-h baseline period on Day 1 were randomized to treatment with 10 (n = 33), 20 (n = 33), 40 (n = 33), or 100 mg (n = 32) of ICI 204,219 or placebo (n = 33). Rhinitis symptoms (nasal congestion, sneezing, rhinorrhea, itchy nose, throat and palate, and eye symptoms) were recorded hourly in the park and three times each evening at home. Blood samples were collected twice daily to determine plasma levels of ICI 204,219. Nasal congestion improved (p < 0.01) most consistently from the evening of Day 1 through Day 2 after treatment with 20- and 40-mg doses of ICI 204,219 versus placebo. Sneezing and rhinorrhea (p < or = 0.05) also improved on Day 2 for subjects who received 20- and 40-mg doses of ICI 204,219 compared with placebo. Mean symptoms scores for the entire day showed that 20 mg of ICI 204,219 was the minimally effective dose in this trial. The onset of action for all treatment groups, including placebo, was within the first 2 h of dosing. No serious adverse events were reported during the trial. ICI 204,219 was well tolerated and relieved symptoms of acute seasonal allergic rhinitis.

Inhaled ICI 204,219 blocks antigen-induced bronchoconstriction in subjects with bronchial asthma.

Three inhalation formulations of ICI 204,219 were compared for antagonism of antigen-induced bronchoconstriction in 16 subjects with asthma who demonstrated reproducible hypersensitivity to allergen during screening challenges. Each subject received a single 0.2-mg dose of each formulation and was challenged with ragweed 30 min after administration of ICI 204,219 until the forced expiratory volume in 1 s (FEV1) decreased by 20 percent or the maximum allergen concentration (100 micrograms/ml) was reached. The majority of subjects tolerated 100 micrograms/ml of allergen without a 20 percent decrease in FEV1. Inhalation formulations of ICI 204,219 successfully inhibited bronchoconstriction in subjects with reproducible sensitivity to ragweed challenges.

Inhibition of leukotriene D4-induced bronchoconstriction in subjects with asthma: a concentration-effect study of ICI 204,219.

The peptide-leukotriene antagonist, ICI 204,219 [4-(5-cyclopentyloxycarbonylamino-lmethylindol-3-ylmethyl )-3-methoxy-n-o-tolylsulfonyl benzamide], was administered 12 hours before an inhaled leukotriene D4 (LTD4) challenge during a double-blind, placebo-controlled, randomized, two-period crossover trial. Subjects with mild asthma were randomized into five treatment groups (six subjects each) and received single oral doses of placebo and either 5, 10, 20, 40, or 100 mg of ICI 204,219 on day 1 of each treatment period. ICI 204,219 was tolerated well by all subjects. A progressive dose response was observed for doses of ICI 204,219 from 5 mg through 100 mg. Compared with placebo, ICI 204,219 increased the concentration (PC20FEV1) and dose of LTD4 needed to reduce forced expiratory volume in 1 second (FEV1) by 20%. Mean LTD4 PC20FEV1 for groups that received placebo and 10, 40, or 100 mg ICI 204,219 increased by tenfold or more (p < 0.05). An association was found between the plasma concentration and protective effect of ICI 204,219 (p < 0.01). ICI 204,219 is the first leukotriene receptor antagonist for which a relationship has been established between drug plasma levels and its protective effect in subjects with asthma.