Effect of varying deep stop times and shallow stop times on precordial bubbles after dives to 25 msw (82 fsw).

In our previous research, a deep 5-min stop at 15 msw (50 fsw), in addition to the typical 3-5 min shallow stop, significantly reduced precordial Doppler detectable bubbles (PDDB) and "fast" tissue compartment gas tensions during decompression from a 25 msw (82 fsw) dive; the optimal ascent rate was 10 msw (30 fsw/min). Since publication of these results, several recreational diving agencies have recommended empirical stop times shorter than the 5 min stops that we used, stops of as little as 1 min (deep) and 2 min (shallow). In our present study, we clarified the optimal time for stops by measuring PDDB with several combinations of deep and shallow stop times following single and repetitive open-water dives to 25 msw (82 fsw) for 25 mins and 20 minutes respectively; ascent rate was 10 msw/min (33 fsw). Among 15 profiles, stop time ranged from 1 to 10 min for both the deep stops (15 msw/50 fsw) and the shallow stops (6 msw/20 fsw). Dives with 2 1/2 min deep stops yielded the lowest PDDB scores--shorter or longer deep stops were less effective in reducing PDDB. The results confirm that a deep stop of 1 min is too short--it produced the highest PDDB scores of all the dives. We also evaluated shallow stop times of 5, 4, 3, 2 and 1 min while keeping a fixed time of 2.5 min for the deep stop; increased times up to 10 min at the shallow stop did not further reduce PDDB. While our findings cannot be extrapolated beyond these dive profiles without further study, we recommend a deep stop of at least 2 1/2 mins at 15 msw (50 fsw) in addition to the customary 6 msw (20 fsw) for 3-5 mins for 25 meter dives of 20 to 25 minutes to reduce PDDB.

A deep stop during decompression from 82 fsw (25 m) significantly reduces bubbles and fast tissue gas tensions.

In spite of many modifications to decompression algorithms, the incidence of decompression sickness (DCS) in scuba divers has changed very little. The success of stage, compared to linear ascents, is well described yet theoretical changes in decompression ratios have diminished the importance of fast tissue gas tensions as critical for bubble generation. The most serious signs and symptoms of DCS involve the spinal cord, with a tissue half time of only 12.5 minutes. It is proposed that present decompression schedules do not permit sufficient gas elimination from such fast tissues, resulting in bubble formation. Further, it is hypothesized that introduction of a deep stop will significantly reduce fast tissue bubble formation and neurological DCS risk. A total of 181 dives were made to 82 fsw (25 m) by 22 volunteers. Two dives of 25 min and 20 min were made, with a 3 hr 30 min surface interval and according to 8 different ascent protocols. Ascent rates of 10, 33 or 60 fsw/min (3, 10, 18 m/min) were combined with no stops or a shallow stop at 20 fsw (6 m) or a deep stop at 50 fsw (15 m) and a shallow at 20 fsw (6 m). The highest bubbles scores (8.78/9.97), using the Spencer Scale (SS) and Extended Spencer Scale (ESS) respectively, were with the slowest ascent rate. This also showed the highest 5 min and 10 min tissue loads of 48% and 75%. The lowest bubble scores (1.79/2.50) were with an ascent rate of 33 fsw (10 m/min) and stops for 5 min at 50 fsw (15 m) and 20 fsw (6 m). This also showed the lowest 5 and 10 min tissue loads at 25% and 52% respectively. Thus, introduction of a deep stop significantly reduced Doppler detected bubbles together with tissue gas tensions in the 5 and 10 min tissues, which has implications for reducing the incidence of neurological DCS in divers.

Effectiveness and tolerability of zafirlukast for the treatment of asthma in children.

OBJECTIVE: This study was undertaken to examine the dose-response relationship of zafirlukast (5 to 40 mg BID) and to assess the efficacy and tolerability of the 10-mg BID dose in school-aged children with mild to moderate asthma. BACKGROUND: The efficacy and tolerability of zafirlukast, an oral leukotriene-receptor antagonist, has been demonstrated in adolescents and adults aged > or = 12 years. METHODS: Data from 2 placebo-controlled, parallel-group, multicenter trials (trial 1, 4-week double-blind; trial 2, 6-week double-blind) were integrated. Children aged 5 to 11 years were randomly assigned to receive zafirlukast 5 mg BID (n = 99), 10 mg BID (n = 205), 20 mg BID (n = 105), 40 mg BID (n = 99), or placebo (n = 206). The primary outcome was change from baseline in forced expiratory volume in 1 second (FEV1) expressed as percent of predicted normal. Secondary outcomes were FEV1 (L), morning and evening peak expiratory flow, peak flow variability, short-acting beta2-agonist use, asthma episode score, and nights awakened by asthma. RESULTS: Mean baseline FEV1 was 76.5% of predicted. The greatest improvements were generally seen with zafirlukast 5 mg BID or 10 mg BID, with no additional clinically significant benefits seen at higher doses. The pooled data analysis showed that 10 mg BID compared with placebo significantly improved (P < 0.045) all efficacy outcomes except asthma-episode score and nights awakened with asthma. However, in the subset of children who had > or = 1 night awakened per week at baseline (zafirlukast 10 mg BID = 78; placebo = 86), 10 mg BID significantly reduced nights awakened (P = 0.009) (mean difference from placebo at end point = -0.81 night/wk). All zafirlukast doses were well tolerated and had tolerability profiles that were clinically indistinguishable from placebo. CONCLUSION: These results support the effectiveness and tolerability of the 10-mg BID dose of zafirlukast for the prophylaxis and chronic treatment of mild to moderate asthma in children.

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.

The leukotriene D4-receptor antagonist zafirlukast attenuates exercise-induced bronchoconstriction in children.

OBJECTIVE: To determine the effects of zafirlukast on exercise-induced bronchoconstriction in children. STUDY DESIGN: Exercise challenges were done 4 hours after single oral doses of zafirlukast or placebo were administered in asthmatic children (6 to 14 years) treated with beta 2-agonists alone. Subjects randomized to treatment had a >/=20% decrease in forced expiratory volume in 1 second (FEV1 ) after a screening challenge. In a randomized, double-blind, 3-way, crossover design, group 1 (n = 20) received placebo and 5 and 20 mg zafirlukast, and group 2 (n = 19) received placebo and 10 and 40 mg zafirlukast. Maximal percentage fall in FEV1, area under the curve, and time to recovery of FEV1 to within 5% of baseline after the challenge were compared with analysis of variance. RESULTS: Mean values for maximal fall in FEV1 ranged from -8.7% +/- 1.7% to -11.1% +/- 1.9% after zafirlukast compared with -17.1% +/- 1.8% and -16.3% +/- 1.9% after placebo. Differences from placebo for fall in FEV1 and area under the curve were significant (P

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.

Zafirlukast improves asthma symptoms and quality of life in patients with moderate reversible airflow obstruction.

BACKGROUND: Previous trials demonstrated the effectiveness of the leukotriene receptor antagonist zafirlukast in patients with mild-to-moderate asthma. OBJECTIVES: We sought to assess the efficacy and safety of zafirlukast and its effect on patients' quality of life (QOL) during a 13-week, double-blind, placebo-controlled, multicenter trial in adults and adolescents with moderate reversible airflow obstruction. METHODS: Patients (age range, 12 to 68 years) with total daytime asthma symptoms scores of 10 or greater over 7 consecutive days (maximum, 21/wk), FEV1 45% or greater but less than or equal to 80% of predicted value (>/=6 hours after beta2 -agonist), and reversible airway disease were randomized to 20 mg zafirlukast twice daily (nZ = 231) or placebo twice daily (nP = 223). Efficacy was assessed from changes in daytime and nocturnal symptoms, beta2 -agonist use, nasal congestion score, and pulmonary function. QOL was evaluated with a disease-specific Asthma Quality of Life Questionnaire. Safety was determined from adverse event information and clinical laboratory test results. RESULTS: Zafirlukast was significantly (P <.001) more effective than placebo, with reductions from baseline in the daytime asthma symptoms score (-23%), nighttime awakenings with asthma (-19%), and beta2 -agonist use (-24%) and improvements from baseline in morning (+25 L/min) and evening (+18 L/min) peak expiratory flow rates. Compared with placebo, zafirlukast significantly (P /=0.5-unit change from baseline; P

Effect of trifluoromethyl ketone-based elastase inhibitors on neutrophil function in vitro.

Neutrophils release elastase, which is known secondarily to cause tissue damage. However, it is rapidly inactivated by the endogenous alpha1-proteinase inhibitor (alpha1Pi). Nevertheless, under pathological conditions, alpha1i is inactivated by oxidants released from neutrophils, resulting in an excess of elastase at the site of inflammation. This elastase/alpha1Pi imbalance has been implicated as a pathogenic factor in cystic fibrosis, acute respiratory distress syndrome, and emphysema. Elastase inhibitors, which do not interfere with the microbicidal activity of neutrophils and are resistant to neutrophil-released oxidants, would undoubtedly represent an important advance in the management of neutrophil-mediated tissue injury. We report that a new family of elastase inhibitors ICI200355 and ZD0892 was found to be resistant toward superoxide, hypochlorous acid, hydrogen peroxide, hydroxyl radical, and peroxynitrite mediated degradation as well as having no effect on the formation of these oxidants by activated neutrophils. More importantly, we found that these inhibitors did not interfere with the ability of human neutrophils to phagocytose and to kill Staphylococcus aureus. In conclusion, a new potent class of elastase inhibitors, while blocking the effects of neutrophil elastase, was found not to impede various physiological functions of human neutrophils, in particular the ability of these phagocytic cells to phagocytose and kill bacteria.

Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. The Zafirlukast Trialists Group.

The efficacy of the oral leukotriene-receptor antagonist zafirlukast was assessed as maintenance therapy for patients with mild-to-moderate asthma. A total of 762 patients aged 12 to 76 years were enrolled in a 13-week, multicenter, double-masked, placebo-controlled, parallel-group trial and randomly assigned to receive either zafirlukast (20 mg twice daily) or placebo. Patients were maintained on as-needed beta-agonist therapy throughout the study and had to have a cumulative daytime asthma symptoms score > or = 8 (on a daily scale of 0 to 3) over 7 consecutive days before randomization. Efficacy was assessed by changes in symptoms, beta-agonist use, and pulmonary function. Safety was assessed by adverse experiences, laboratory test results, physical examination, and electrocardiography. Zafirlukast significantly decreased daytime asthma symptoms scores (-26.5%), nighttime awakenings (-19.8%), mornings with asthma (-29.0%), and beta-agonist use (-22.3%) and significantly increased morning peak expiratory flow rate (6.9%) and forced expiratory volume in 1 second (6.3%) compared with placebo. Changes in symptoms, beta-agonist use, and pulmonary function occurred within 2 days of zafirlukast treatment and continued throughout the trial. Zafirlukast was well tolerated. Pharyngitis and headache were the most common adverse events, occurring with similar frequency in both the zafirlukast and placebo groups. No clinically significant changes were observed in laboratory test results, findings on physical examination, or electrocardiographic findings. We conclude that zafirlukast produces early and sustained effects in the treatment of mild-to-moderate asthma.

Developmental differences in catalase activity and hypoxic-hyperoxic effects on fluid balance in isolated lamb lungs.

The effects of hypoxia (95% N2/5% CO2) followed by hyperoxia (95% O2/5% CO2) were determined in isolated lungs of premature (gestational age 128 to 135 d) and full-term (postnatal age 0 to 5 d) lambs perfused with autologous blood (100 mL.min-1.kg body weight-1). In full-term lungs, hypoxia-hyperoxia compared with hypoxia alone decreased pulmonary artery pressure and increased weight gain and extravascular lung water. In premature lungs, the increase in weight gain was greater and was associated with hemorrhage and increased pulmonary arterial and peak airway pressures. Papaverine eliminated reoxygenation-induced differences in pulmonary artery pressure, peak airway pressure, and weight gain in both age groups. Osmotic reflection coefficients for total protein and albumin, measured by a modification of the filtered volume technique, averaged 0.591 +/- 0.054 (SEM) and 0.465 +/- 0.054 (SEM), respectively, and were not altered by reoxygenation or age. Catalase activity in lung tissue and erythrocytes was lower in premature lambs, but there were no age-related differences in superoxide dismutase or glutathione peroxidase activities. These results demonstrate that hypoxia-hyperoxia in isolated lamb lungs increased lung weight due to edema formation in full-term lamb lungs and hemorrhage in premature lamb lungs and that this increase was greater in premature lamb lungs. We speculate that the weight gain caused by reoxygenation was due to a vasodilation-induced increase in surface area in full-term lamb lungs and a vasoconstriction-induced increase in vascular pressure in premature lamb lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of an antihistamine-decongestant combination for young children with the common cold: a randomized, controlled clinical trial.

We tested the hypothesis that antihistamine-decongestant combinations cause no clinically significant relief of the symptoms of upper respiratory tract infections in young children by randomly assigning 96 children to one of three treatment groups: antihistamine-decongestant, placebo, and no treatment. There were no differences among the three study groups in the proportion of children considered "better" overall by the parent 48 hours after the initial assessment (drug, 67%; placebo, 71%; no treatment, 57%; p = 0.53). There were no differences among groups in individual or composite symptom score changes. Two thirds of parents whose children were eligible for the drug trial believed that their child needed medicine for cold symptoms. In the proportion of parents believing that their child needed medicine, there was no difference between those who consented to participate and those who refused. Parents who wanted medicine at the initial visit reported more improvement at follow-up, regardless of whether the child received drug, placebo, or no treatment. We conclude that there is no clinically significant improvement in symptoms of upper respiratory tract infection, including no significant placebo effect, in young children for whom an antihistamine-decongestant is prescribed.