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Biomedical subjects

L Hendeles

Publications and source records attributed to L Hendeles.

At least 19 recordsLinked to original sources

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.

Administration, Inhalation

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.

Administration, Inhalation

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.

Acetates

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.

Adolescent

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.

Bronchial Provocation Tests

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.

Adult

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.

Acetates

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.

Adolescent

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.

Anti-Asthmatic Agents

Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist.

BACKGROUND: A study was undertaken to determine whether montelukast, a new potent cysteinyl leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction. The relationship between the urinary excretion of LTE4 and exercise-induced bronchoconstriction was also investigated. METHODS: Nineteen non-smoking asthmatic patients with a forced expiratory volume in one second (FEV1) of > or = 65% of the predicted value and a reproducible fall in FEV1 after exercise of at least 20% were enrolled. Subjects received placebo and montelukast 100 mg once daily in the evening or 50 mg twice daily, each for two days, in a three-period, randomised, double blind, crossover design. In the evening, approximately 20-24 hours after the once daily dose or 12 hours after the twice daily dose, a standardised exercise challenge was performed. Data from 14 patients were available for complete analysis. RESULTS: The mean (SD) maximal percentage decrease in FEV1 after exercise was 29.6 (16.0), 17.1 (8.2), and 14.0 (9.4) for placebo, once daily, and twice daily regimens, respectively. The mean (95% CI) percentage protection was 37 (15 to 59) for the group who received 50 mg twice daily and 50 (31 to 69) for those who received 100 mg once daily. Active treatments were not different from each other. The mean (SD) plasma concentrations of montelukast were higher after the twice daily regimen (1.27 (0.81) microgram/ml) than after the once daily regimen (0.12 (0.09) microgram/ml); there was no correlation between the percentage protection against exercise-induced bronchoconstriction and plasma concentrations. After exercise urinary excretion of LTE4 increased significantly during placebo treatment (from 34.3 to 73.7 pg/mg creatinine; p < 0.05) but did not correlate with the extent of exercise-induced bronchoconstriction. CONCLUSIONS: Montelukast protects similarly against exercise-induced bronchoconstriction between plasma concentrations of 0.12 and 1.27 micrograms/ml. The increase in the urinary excretion of LTE4 after exercise and the protection from exercise-induced bronchoconstriction with a cysteinyl leukotriene receptor antagonist provide further evidence of the role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.

Acetates

Theophylline attenuation of airway responses to allergen: comparison with cromolyn metered-dose inhaler.

BACKGROUND: The purpose of this study was to compare the protection afforded by individualized doses of theophylline and a cromolyn metered-dose inhaler (MDI) during allergen challenge. METHODS: The study design was randomized, double-blind, and crossover. Responses to inhaled allergen were measured in 16 subjects with allergic asthma (age range, 18 to 35 years) after 7 days of treatment with either placebo, once daily slow-release theophylline producing a mean +/- SD serum concentration of 16 +/- 5 micrograms/ml during the late phase, or 2 mg of cromolyn administered by MDI four times daily. Forced expiratory volume in 1 second was measured at frequent intervals, and airway responsiveness to histamine was measured before and 3 hours after allergen challenge. RESULTS: The mean +/- SD maximum decrease in forced expiratory volume in 1 second during the late phase was 30% +/- 14% during placebo treatment, 16% +/- 13% during theophylline treatment, and 13% +/- 14% during cromolyn treatment (placebo vs theophylline and cromolyn, p = 0.0001; theophylline vs cromolyn, p = 0.1). The geometric mean fold increase in airway responsiveness was 3.0 +/- 1.7 during placebo treatment, 1.7 +/- 1.7 during theophylline treatment, and 1.5 +/- 1.6 during cromolyn treatment (placebo vs theophylline and cromolyn, p = 0.0001; theophylline vs cromolyn, p = 0.1). CONCLUSIONS: Theophylline, when administered once daily as a slow-release formulation, was as effective as cromolyn, administered four times daily through an MDI, in attenuating airway responses to inhaled allergen. The protection afforded by both treatments, however, was modest when compared with the results of similar studies with inhaled corticosteroids or other cromolyn formulations that deliver more drug to the lungs than the MDI available in the United States.

Adolescent

Clinical pharmacology of pancreatic enzymes in patients with cystic fibrosis and in vitro performance of microencapsulated formulations.

Improving protein and fat absorption in patients with cystic fibrosis relates to the amount of biologically active enzyme reaching the duodenum. Microencapsulated formulations are more effective than conventional products but differ in content, ability to retard acid inactivation and the pH at which they release enzymes. Contaminants in these products contribute to hyperuricosuria.

Adolescent