Bioavailability of inhaled fluticasone propionate via chambers/masks in young children.

We determined lung bioavailability of a fluticasone propionate (FP) pressurised metred-dose inhaler (Flovent HFA; GlaxoSmithKline, Research Triangle Park, NC, USA) administered via AeroChamber Plus (Monaghan Medical, Plattsburgh, NY, USA) with Facemask and Babyhaler (GlaxoSmithKline) valved holding chambers (VHCs) using a population pharmacokinetic approach. Children from 1 to <4 yrs of age with stable asthma but a clinical need for inhaled corticosteroid therapy were administered 88 µg FP hydrofluoroalkane (2 × 44 µg) twice daily delivered through the two devices in an open-label, randomised crossover manner for 8 days each. Patients were randomised to one of three sparse sampling schedules for blood collection throughout the 12-h dosing interval on the 8th day of each treatment for pharmacokinetic analysis. The area under the FP plasma concentration-time curve (AUC) was determined for each regimen. 17 children completed the study. The population mean AUC following FP with AeroChamber Plus with Facemask was 97.45 pg·h·mL(-1) (95% CI 85.49-113.32 pg·h·mL(-1)) and with Babyhaler was 51.55 pg·h·mL(-1) (95% CI 34.45-64.46 pg·h·mL(-1)). The relative bioavailability (Babyhaler/AeroChamber Plus) was 0.53 (95% CI 0.30-0.75). Clinically significant differences in lung bioavailability were observed between the devices. VHCs are not interchangeable, as differences in drug delivery to the lung may occur. A population pharmacokinetic approach can be used to determine lung bioavailability of FP.

Intervention strategies for children poorly adherent with asthma medications; one center's experience.

Poor adherence to medications and other aspects of the treatment plan is common in pediatric patients with asthma, and is a common reason for inadequate asthma control. In selected patients we have used electronic monitoring of pulmonary function, behavior contracts, home nursing visits, and medical neglect reports in an attempt to improve adherence and asthma control. Improved outcomes were seen with the most aggressive intervention, home nursing, and medical neglect referral, but not with less aggressive measures.

Pulmonary function response to EDTA, an additive in nebulized bronchodilators.

BACKGROUND: Some nebulized bronchodilator solutions contain additives, such as EDTA, benzalkonium chloride (BAC), or both. OBJECTIVE: Although BAC-induced bronchoconstriction has been well documented in patients with asthma, there is no information on the effects of EDTA on FEV(1) when inhaled in the amounts that would be administered during emergency department treatment of asthma. METHODS: Eighteen subjects with stable asthma and airway responsiveness to methacholine were randomly assigned to inhale up to four 600-microg nebulized doses of EDTA, BAC (positive control), and normal saline (placebo) in a double-blind crossover manner on separate days. FEV(1) was measured 15 minutes after each dose. Treatments were repeated every 20 minutes until FEV(1) decreased by 20% or greater or a maximum of 4 doses were administered. RESULTS: Mean +/- SD maximum percent decrease in FEV(1) was 1.8% +/- 5.8% after EDTA, 16.6% +/- 13.9% after BAC, and 3.6% +/- 8.2% after placebo (P <.001); there was no significant difference between EDTA and placebo. CONCLUSION: The amount of EDTA contained in maximum recommended doses of nebulized bronchodilators does not induce bronchospasm. In contrast, BAC induces clinically important bronchospasm, which could decrease the efficacy of a bronchodilator during an emergency.

Adherence to oral montelukast and inhaled fluticasone in children with persistent asthma.

STUDY OBJECTIVE: To evaluate adherence to oral montelukast and inhaled fluticasone in children with persistent asthma and to determine if age, monotherapy, and duration of therapy affect adherence. DESIGN: Retrospective analysis. SETTING: Pediatric pulmonary clinic. PATIENTS: One hundred seventy-one children with asthma who required continuous treatment with a controller agent year-round and in whom montelukast and/or fluticasone had been prescribed for at least 90 days. INTERVENTION: Montelukast monotherapy had been prescribed for 54 patients, fluticasone monotherapy for 48 patients, and combination therapy for 69 patients. MEASUREMENTS AND MAIN RESULTS: Prescription refill histories were obtained from pharmacies identified by the parents or from Medicaid pharmacy reimbursement records. The maximum possible adherence was calculated as [(no. of doses refilled)/(no. of doses prescribed)] x 100, for a mean observation period of 203 days (range 84-365 days) for montelukast and 314 days (range 97-365 days) for fluticasone. Median adherence rates were 59% (95% confidence interval [CI] 48-65%) for montelukast and 44% (90% CI 35-50%) for fluticasone. Adherence did not significantly correlate with age, length of observation period, or whether the patient was receiving monotherapy or combination therapy. The odds ratio for very poor adherence (< 50%) was 2.0 (95% CI 1.3-3.2) for fluticasone relative to montelukast. CONCLUSIONS: Adherence to both drugs was suboptimal. However, these data indicate that our patients were likely to take montelukast more consistently than fluticasone. Whether this translates into better asthma control requires further study.

Levalbuterol nebulizer solution: is it worth five times the cost of albuterol?

Albuterol is a 50:50 mixture of R-albuterol, the active enantiomer, and S-albuterol, which appears to be inactive in humans. The Food and Drug Administration recently approved levalbuterol, the pure R-isomer, as a preservative-free nebulizer solution. Published studies indicate that it is neither safer nor more effective than an equimolar dose of racemic albuterol (levalbuterol 1.25 mg = albuterol 2.5 mg). However, these studies were conducted in patients with stable asthma (at the top of the dose-response curve), whereas a nebulized bronchodilator most likely would be used by patients with an acute exacerbation. Because such patients, in the hospital setting, often require higher doses of albuterol, the manufacturer's recommended dose of levalbuterol is likely to be too low for rescue therapy. Levalbuterol may cost as much as 5 times more than racemic albuterol, depending on purchase method. We conclude that levalbuterol offers no advantage over albuterol but is likely to be more costly.

Telephoning the patient's pharmacy to assess adherence with asthma medications by measuring refill rate for prescriptions.

OBJECTIVE: To determine whether a prescription refill history obtained by telephoning patients' pharmacies identifies poor adherence with asthma medications more frequently than physician assessment. METHODS: The study population consisted of 116 children with persistent asthma who were Medicaid recipients; patients who received medication samples were excluded. During a clinic visit pulmonologists interviewed patients, caretakers, or both and estimated adherence on a checklist. A nurse asked the caretakers where they obtained medications and telephoned 66 identified pharmacies for refill histories. The maximum possible adherence was calculated as the number of doses refilled/number of doses prescribed x 100 for a mean duration of 163 days (range, 63 to 365 days). The accuracy of the refill information was determined from Medicaid reimbursement records. RESULTS: Information provided by pharmacies was 92% accurate. The mean (95% CI) of maximum potential adherence was 72% (65%,77%) for theophylline, 61% (55%,68%) for inhaled corticosteroids, and 38% (23%,53%) for cromolyn; only cromolyn and theophylline were significantly different. Physicians were able to identify 21 (49%) of 43 patients who refilled

Dose selection and dosing interval determination for LTRA use in asthma.

The dose and dosing interval for leukotriene receptor antagonists montelukast and zafirlukast in adult asthmatic patients were determined by bronchoprovocation with exercise or leukotriene D4 inhalation. Subsequent dose-ranging studies confirmed that once-daily ingestion of a 10-mg dose of montelukast was effective and safe; higher doses did not improve efficacy or increase the risk of adverse effects. In contrast, zafirlukast doses that exceeded the approved dose of 20 mg ingested twice daily during fasting improved efficacy but increased the risk of elevated liver enzymes. Pharmacokinetic studies showed that montelukast bioavailability is not affected by food and did not interact with other drugs. Zafirlukast inhibited warfarin metabolism while food intake and concurrent therapy with theophylline or aspirin decreased zafirlukast levels. Pharmacokinetic and subsequent efficacy or safety studies revealed that a 5-mg and a 4-mg chewable tablet of montelukast ingested once daily were effective in and well tolerated by patients in the 6- to 14-year and 2- to 5-year age-groups, respectively. Both pediatric montelukast doses produced the same magnitude of tissue exposure as did the 10-mg adult dose. The Food and Drug Administration approved a 10-mg film-coated tablet of zafirlukast for children 7 to 11 years of age. It must be administered twice daily fasting.

The effect of Cys LT1 receptor blockade on airway responses to allergen.

STUDY OBJECTIVE: To evaluate the effect of a potent experimental leukotriene receptor antagonist, MK-571, on airway responses to inhaled allergen. DESIGN: Randomized, double-blind, placebo-controlled, crossover trial. SETTING: Clinical research center. SUBJECTS: Eight male volunteers with allergic asthma. INTERVENTIONS: An intravenous loading dose was followed by an 8-hour infusion of MK-571 or placebo, with a 7- to 14-day washout between treatments. Allergen challenge was performed after the loading dose and a histamine challenge was performed before and 24 hours after allergen. MEASUREMENTS AND MAIN RESULTS: Forced expiratory volume in 1 second was measured serially. MK-571 provided about 50% protection during maximum early and late responses compared with placebo (p=0.005), but airway obstruction persisted 8-24 hours after allergen on both treatment days. Airway responsiveness to histamine was not significantly attenuated at 24 hours. CONCLUSION: Blocking Cys LT1 receptors for 8 hours attenuated the early and late responses but did not interrupt the cascade of events leading to subsequent allergen-induced airway obstruction and hyperreactivity.

Therapeutic equivalence of Spiros dry powder inhaler and Ventolin metered dose inhaler. A bioassay using methacholine.

Because chlorofluorocarbons (CFCs) contribute to depletion of stratospheric ozone, CFC-containing metered-dose inhalers (MDIs) such as Ventolin and Proventil are being phased out of production. In terms of delivery of albuterol to the lungs, we compared an alternative delivery system, the Spiros dry-powder inhaler (DPI), with Ventolin, using a methacholine challenge-based clinical bioassay. Twenty-four adults and adolescents with asthma completed this double-blind, four-period crossover study. Doses evaluated were one and three actuations each of Spiros and Ventolin (90- and 270-microgram albuterol base). A methacholine challenge (Cockcroft method) was initiated 3 h before and 0.25 h after albuterol. Predose PC(20)FEV(1) values were not significantly different between study days. Postdose PC(20)FEV(1) results met standard bioassay study validity criteria: i.e., a significant dose-response relationship was present (p = 0.0002); tests for deviation from parallelism and overlap of dose-response curves were nonsignificant (p = 0.08, 0.69). By using Finney 2-by-2 bioassay analysis, we estimate that each Spiros actuation delivers 1.12 times as much albuterol to the airways as one Ventolin actuation (90% confidence interval, 0.68 to 1.94). There were no significant differences in markers of systemic effects (vital signs, potassium, and blood glucose concentrations). We conclude that Spiros and Ventolin inhalers deliver comparable quantities of albuterol to the airways.

Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial.

Leukotrienes are pro-inflammatory mediators which may contribute to tissue, sputum, and blood eosinophilia seen in allergic and inflammatory diseases, including asthma. Montelukast is a cysteinyl leukotriene1 (CysLT1) receptor antagonist which improves asthma control; the aim of this study was to investigate its effect on induced sputum eosinophils. Montelukast 10 mg (n=19) or placebo (n=21) were administered orally once in the evening for 4 weeks to 40 chronic adult asthmatic patients, aged 19-64 yrs, in a double-blind, randomized, parallel group study. Patients were included if, at prestudy, they had >5% sputum eosinophils, symptomatic asthma with a forced expiratory volume in one second > or =65% of the predicted value and were being treated only with "as needed" inhaled beta2-agonists. In addition to sputum eosinophils, blood eosinophils and clinical endpoints were also assessed. Four weeks of montelukast treatment decreased sputum eosinophils from 7.5% to 3.9% (3.6% decrease, 95% confidence interval (CI) -16.6-0.4). In contrast, placebo treatment was associated with an increase in sputum eosinophils from 14.5% to 17.9% (3.4% increase, 95% CI -3.5-9.8). The least squares mean difference between groups (-11.3%, 95% CI -21.1-(-1.4)) was significant (p=0.026). Compared with placebo, montelukast significantly reduced blood eosinophils (p=0.009), asthma symptoms (p=0.001) and beta2-agonist use (p<0.001) while significantly increasing morning peak expiratory flow (p=0.001). Montelukast was generally well tolerated in this study, with a safety profile similar to the placebo. These results demonstrate that montelukast decreases airway eosinophilic inflammation in addition to improving clinical parameters. Its efficacy in the treatment of chronic asthma may be due, in part, to the effect on airway inflammation.

Bronchoconstrictor additives in bronchodilator solutions.

Nebulized bronchodilator solutions are available in the United States as both nonsterile and sterile-filled products. Sulfites, benzalkonium chloride (BAC), or chlorobutanol are added to nonsterile products to prevent bacterial growth, but there have been reports of contaminated solutions containing preservatives. Ethylenediamine tetraacetic acid (EDTA) is added to some products to prevent discoloration of the solution. With the exception of chlorobutanol, all of these additives are capable of inducing bronchospasm in a concentration-dependent manner. However, it is rarely apparent to the patient or health care provider that the additive diminishes the bronchodilator effects. Older products (eg, isoproterenol and isoetharine) contain enough sulfites to produce bronchospasm in most patients with asthma, even in those without a prior history of sulfite sensitivity. Bronchoconstriction from inhaled BAC is cumulative, prolonged, and correlates directly with basal airway responsiveness. The multidose dropper bottle of albuterol contains 50 microg BAC/dose, which is below the threshold for bronchoconstriction whereas the screwcap unit-dose vial contains 300 microg/dose, which is above the threshold for many patients. If the screwcap product is used in the emergency department, a patient could receive as much as 1800 microg of BAC in the first hour. Three sterile-filled unit dose albuterol products contain no additives, whereas a fourth, (manufactured by Dey Laboratories) contains 300 microg of EDTA, which is also below the threshold dose for bronchoconstriction. Only additive-free sterile solutions should be used for hourly or continuous nebulization of albuterol. The multidose dropper bottle or the Dey product can be used when the interval between doses is longer, whereas the screwcap product should not be used for acute therapy. Ipratropium is available only as a sterile, additive-free unit-dose vial, as is levalbuterol.

Degradation of histamine solutions used for bronchoprovocation.

STUDY OBJECTIVES: To determine optimal storage conditions for histamine diphosphate (HDP) solutions used for bronchoprovocation. DESIGN: HDP was dissolved in buffered saline solution to concentrations of 0.125 to 16 mg/mL and stored in 3-mL unit dose syringes at different temperatures for varying lengths of time, with and without protection from fluorescent light. SETTING: Dark freezer (-20 degrees C), dark refrigerator (4 degrees C), and laboratory counter top (20 degrees C) illuminated by fluorescent light (375 foot-candles). MEASUREMENTS: HDP concentrations were measured after the solutions were prepared and during storage by a high-performance liquid chromatographic assay that differentiates histamine from its break down products. RESULTS: All dilutions were sterile after preparation and contained 97 to 110% of the labeled amount of HDP. Solutions constantly exposed to fluorescent light (375 foot-candles) and room temperature (20 degrees C) contained only 20 to 37% of the initial concentrations after 7 days. The same dilutions stored at room temperature, but protected from light, contained 83 to 94% of the initial concentrations. Dilutions stored in the dark in a refrigerator (4 degrees C) retained 97% of the initial concentrations after 8 weeks, while dilutions stored in the dark freezer (-20 degrees C) were stable for 12 months. CONCLUSIONS: Exposure to fluorescent light at room temperature results in degradation of histamine solutions used for bronchoprovocation. Dilutions stored in unit dose syringes and protected from light are stable for at least 8 weeks in the refrigerator and up to 12 months frozen. Once removed from the refrigerator or freezer, the solutions should be used within 6 h or discarded.

Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction.

BACKGROUND: Patients with mild asthma frequently have only exercise-induced bronchoconstriction, a symptom of inadequate control of asthma. We evaluated the ability of montelukast, a leukotriene-receptor antagonist, to protect such patients against exercise-induced bronchoconstriction. METHODS: We randomly assigned 110 patients (age, 15 to 45 years) with mild asthma and a decrease in the forced expiratory volume in one second (FEV1) of at least 20 percent after exercise on two occasions during a placebo run-in period to receive 10 mg of montelukast (54 patients) or placebo (56 patients) once daily at bedtime for 12 weeks in a double-blind study. Treatment was followed by a two-week, single-blind washout period during which all patients received placebo. Exercise challenges were performed at base line; 20 to 24 hours after dosing at weeks 4, 8, and 12; and at the end of the washout period. The primary end point was the area under the curve for FEV1 (expressed as the percent change from base-line values) in the first 60 minutes after exercise. This measure summarized the extent and duration of bronchoconstriction after exercise. RESULTS: At 12 weeks, montelukast therapy offered significantly greater protection against exercise-induced bronchoconstriction than placebo therapy (expressed as the percentage of inhibition of the end points), as evidenced by the improvement in the area under the FEV1 curve (degree of inhibition, 47.4 percent; P=0.002). Montelukast therapy was also associated with a significant improvement in the maximal decrease in FEV1 after exercise (P=0.003) and the time from the maximal decrease in FEV1 to the return of lung function to within 5 percent of pre-exercise values (P=0.04). The differences between groups in the various measures of lung function were similar at 4, 8, and 12 weeks; there was no evidence of rebound worsening of lung function in the montelukast group after the washout period. After 12 weeks of treatment, patients in the montelukast group were more likely to rate their asthma control as better and less likely to require rescue therapy with a beta-agonist during or after exercise challenge. The rates of adverse events were similar in the two groups. CONCLUSIONS: As compared with placebo, once-daily treatment with montelukast provided significant protection against exercise-induced asthma over a 12-week period. Tolerance to the medication and rebound worsening of lung function after discontinuation of treatment were not seen.

Preservatives in nebulizer solutions: risks without benefit.

Edetate disodium (EDTA) and benzalkonium chloride (BAC) are often present as preservative or stabilizing agents in nebulizer solutions used to treat asthma and chronic obstructive pulmonary disease. Benzalkonium chloride is a potent bronchoconstrictor when inhaled in concentrations similar to those in which it is present in these solutions. Inclusion of BAC (together with EDTA) in the ipratropium bromide (Atrovent) nebulizer solution resulted in paradoxic bronchoconstriction in some asthmatic patients and an overall reduction in bronchodilator efficacy. The presence of BAC in albuterol nebulizer solutions does not affect the short-term bronchodilator response to a single dose, although case reports suggest that its repeated use in patients with severe asthma may result in paradoxic bronchoconstriction. When inhaled by asthmatic subjects, EDTA also causes dose-dependent bronchoconstriction, although it is less potent than BAC. The use of preservative-free bronchodilator nebulizer solutions does not result in clinically significant bacterial contamination if they are dispensed in sterile unit-dose vials, in volumes and concentrations that do not require modification by the user. Despite this evidence, in the United States a number of solutions, including some preparations of albuterol, contain either BAC or EDTA. Current regulations do not require that the concentration of preservatives be documented on the product; however, considerably different doses of BAC are delivered with different products. For example, a standard 2.5-mg dose of albuterol nebulizer solution contains 50 microg of BAC when administered from the multidose dropper bottle and 300 microg from the unit-dose screw-cap product. Furthermore, it is legal for pharmacists to substitute or compound solutions containing high concentrations of BAC when the physician has prescribed a preservative-free product. We recommend that the United States follow the practice of most Western countries and withdraw bronchodilator nebulizer solutions that contain preservatives such as BAC. We further recommend that the solutions should be prepared under sterile conditions, formulated preservative free, and made available in unit-dose vials.

Apparent decrease in population clearance of theophylline: implications for dosage.

BACKGROUND: Having observed in recent years that the theophylline dose requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml infrequently reached previously described mean values, we hypothesized that a downward shift in the range of dose requirements had occurred among patients with asthma. STUDY DESIGN: We examined dosage requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml in all patients with chronic asthma treated with theophylline by the Pediatric Allergy and Pulmonary Clinic at the University of Iowa from 1990 to 1994 (n = 300) and at the Pediatric Pulmonary Clinic at the University of Florida from 1992 to 1995 (n = 93). We then compared these doses to previous dose requirements from 1978 to 1983 determined in the same manner. RESULTS: Despite similar mean peak serum concentrations during both time periods (14 micrograms/ml), mean theophylline dosage requirements during the period of this study were approximately 25% lower among all age groups than those previously observed (p < 0.001). There were no significant differences in mean dosage requirements between the Iowa and Florida patients in any age group examined. CONCLUSIONS: Theophylline dose requirements needed to attain serum concentrations of 10 to 20 micrograms/ml have decreased significantly from those on which current dosing recommendations are based. This suggests a decrease in mean clearance of the population.

Reliability of the Medtrac MDI Chronolog.

BACKGROUND: The Medtrac MDI Chronolog is an electronic device for monitoring adherence to metered-dose inhalers. It replaces previous models of the Nebulizer Chronolog and uses a different mechanism of recording actuations. OBJECTIVE: This study was carried out to determine whether the new model can accurately record and report the date, time, and number of metered-dose inhaler actuations. METHODS: Four canisters of beclomethasone (Beclovent) were discharged through four Chronologs with fresh batteries at a rate of 1, 2, 4, or 8 times twice daily for 7 days. Four additional canisters were used as controls and discharged simultaneously through the standard actuator. The weight of all canisters and Chronolog battery voltage were measured before and at the end of the 7-day experiment. The data retrieved from the Chronologs were compared with the information recorded manually during each discharge. RESULTS: The loss in canister weight was consistent for the number of puffs discharged from all four Chronolog units and controls. However, the accuracy of the Chronologs in recording the number of actuations varied between 50% and 100%. The largest amount of data loss occurred with the unit used to discharge 8 puffs and was associated with a dead battery at the end of the 7-day trial. For actuations that were retrievable, the Chronologs accurately recorded the date and time. CONCLUSIONS: Unexpected battery voltage drain and other mechanical problems that we encountered may cause data loss and the false appearance of missed doses. Thus the units that we tested were not sufficiently reliable to monitor patient adherence.