Archivos para 11 junio 2008












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Pretreatment with Albuterol versus Montelukast for Exercise-Induced Bronchospasm in Children

Hengameh H. Raissy, PharmD; Michelle Harkins, MD; Franceska Kelly, BS; H. William Kelly, PharmD
Author Information


Study Objectives: To compare pretreatment with albuterol versus montelukast added to the current asthma regimen for protection against exercise-induced bronchospasm in children with mild-to-moderate asthma, and to determine whether cysteinyl leukotriene (Cys-LT) concentrations measured in the exhaled breath condensate correlated with response to montelukast.
Design: Prospective, randomized, double-blind, double-dummy, crossover study.
Setting: Asthma clinic at a university-affiliated medical center.
Patients: Eleven children aged 7–17 years with physician-diagnosed mild-to-moderate asthma for at least 6 months and with self-reported exercise-induced bronchospasm (defined as ≥ 15% decrease in forced expiratory volume in 1 sec [FEV1] at screening and baseline visit).
Intervention: Patients were randomly assigned to receive 3–7 days of oral montelukast 5–10 mg/day or 2 puffs of an albuterol metered-dose inhaler just before an exercise challenge and then were crossed over to the alternate therapy for the last visit.
Measurements and Main Results: Serial spirometry was performed before and at 0, 5, 10, 15, 30, 45, and 60 minutes after the exercise challenge at each visit. Measurement of exhaled breath condensate was performed at the screening visit and study visits 1 and 2. The primary outcome was the maximum change in FEV1 after exercise. Secondary outcomes were the area under the curve for FEV1 (expressed as percentage decrease from baseline) during the first 60 minutes (AUC0–60) after exercise and the proportion of patients in whom exercise-induced bronchospasm was prevented (defined as < 15% decrease in FEV1 after exercise challenge). The mean ± SD maximum decrease in FEV1 was 27.5 ± 7.9% at baseline. Patients receiving montelukast had an 18.3 ± 13.7% decrease in FEV1 compared with 0.7 ± 1.6% in patients receiving albuterol (p=0.002, paired t test). Exercise-induced bronchospasm was prevented in 100% of the patients receiving albuterol compared with 55% receiving montelukast (p<0.05, McNemar’s test). The AUC0–60 was significantly smaller with albuterol compared with montelukast (p<0.001, Wilcoxon signed rank test). No correlations were found between Cys-LT concentration and the severity of exercise-induced bronchospasm or the response to montelukast.
Conclusion: Pretreatment with albuterol is more effective than montelukast for prevention of exercise-induced bronchospasm in children with asthma.


Exercise-induced bronchospasm is common in children with asthma,[1,2] and exercise limitation is a primary complaint in children with mild-tomoderate asthma. Although exercise-induced bronchospasm may be the only asthma symptom or some patients, it may result from an overall lack of asthma control.

Exercise-induced bronchospasm has a discrete pathophysiology that remains poorly understood. The cysteinyl leukotrienes (Cys-LTs) LTC4, LTD4, and LTE4 have been detected in exhaled breath condensate in children with asthma[3-5]and have been reported to be higher in those with exercise-induced bronchospasm.[6]

Long-term controller drugs may have a role in the management of exercise-induced bronchospasm. Inhalation of corticosteroids has been shown to attenuate the exercise-induced bronchospasm response, although not completely abate it.[7,8] The long-acting β2-agonist salmeterol inhibits exercise-induced bronchospasm for 12 hours after a single dose; however, after long-term monotherapy the duration of protection is only about 4 hours.[9,10] Results of comparative studies of long-term montelukast and salmeterol monotherapy for exercise-induced bronchospasm, where the exercise-induced bronchospasm challenge is performed 12 hours after the last dose of montelukast or salmeterol, show that montelukast provides superior attenuation of the bronchospasm.[11] Long-term treatment with montelukast reduces exercise-induced bronchospasm by 20-50%[11-13] but does not appear to prevent the bronchospasm to the same extent as pretreatment with an inhaled short-acting β2-agonist administered just before exercise, although no direct comparisons have been performed. In addition, up to 50% of patients may not respond to montelukast.[14] Recently, it has been suggested that a reduction in the Cys-LTs correlates with initial Cys-LT concentrations before treatment with montelukast.[15,16]

In April 2007, montelukast gained United States Food and Drug Administration (FDA)-approved labeling as a single dose for prevention of exercise-induced bronchospasm in patients aged 15 years or older. Currently, to our knowledge, no data exist that compare standard of care (i.e., pretreatment with albuterol) with montelukast for prevention of exercise-induced bronchospasm in children. Therefore, our primary hypothesis in this study was that pretreatment with albuterol would provide superior protection against exercise-induced bronchospasm compared with montelukast in children with asthma. A secondary objective was to determine whether Cys-LT concentrations measured in the exhaled breath condensate correlated with response to montelukast.


This prospective, randomized, double-blind, double-dummy, crossover clinical trial was conducted from November 1, 2005-April 30, 2007. Patients aged 7-17 years with physiciandiagnosed asthma for at least 6 months in addition to self-reported exercise-induced bronchospasm were screened. Long-term controller drugs were allowed if patients were receiving a stable dosage for at least 4 weeks. Patients were excluded if they had a history of cardiac dysfunction, were unable to perform exercise challenge or spirometry, used montelukast for asthma management, had upper respiratory infection in the previous 4 weeks, or used oral corticosteroids in the previous 3 months. Informed consent and authorization for the use and disclosure of Protected Health Information were obtained according to institutional review board-approved processes of the University of New Mexico.

The study consisted of four visits: screening visit, baseline visit, study visit 1, and study visit 2 (Figure 1). Exercise-induced bronchospasm was assessed at the screening visit followed by a baseline visit in 1-14 days, when a second exercise challenge was performed. Patients were required to have a positive exercise challenge, defined as a 15% or greater decrease in forced expiratory volume in 1 second (FEV1), at both the screening and baseline visits to qualify. At the end of the baseline visit, eligible patients were randomly assigned to receive either montelukast capsules 5-10 mg (depending on age) or matching placebo capsules to be taken every night. Study visit 1 was scheduled 3-7 days later (Figure 1). At this visit, exhaled breath condensate was measured, and baseline spirometry was performed. Patients who had received montelukast were then instructed to use 2 puffs of a placebo metered-dose inhaler (MDI) without a spacer 15 minutes before the exercise challenge; patients who had received placebo used 2 puffs (90 µg/puff) of an albuterol MDI 15 minutes before the exercise challenge. At the end of study visit 1, patients were crossed over to the alternative therapy and scheduled for study visit 2.


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Figure 1.  (click image to zoom)Schematic of the study procedures.



To allow double blinding of the study drug, placebo and montelukast capsules were prepared from chewable tablets by the investigational pharmacist, based on experience from another study.[17] The study drugs were dispensed for each subject according to a random code. Patients were instructed to take placebo or montelukast capsules at 9:00 P.M. every night and to bring all their unused study drugs to the clinic at study visits 1 and 2 in order to monitor adherence. All visits were scheduled for 7:30 A.M. (± 30 min), so the exercise challenge could be performed approximately 12 hours (± 30 min) after the last dose of montelukast.

Exercise Challenge

Preexercise spirometry was performed 5 minutes before the challenge. The preexercise FEV1 was required to be at least 70% of the predicted value and within 20% of the baseline visit value at study visits 1 and 2. A standardized exercise challenge was performed on a treadmill. Workload was increased until 80-90% of the maximum heart rate (220 minus age) was achieved in the first 2 minutes, and exercise was sustained for 6 minutes. The individual workload established at enrollment for each patient was used as a starting point at each visit and was adjusted as needed to achieve 80-90% of the maximum heart rate.

Spirometry was performed immediately after exercise (time 0) and at 5, 10, 15, 20, 30, and 60 minutes. Patients performed two or three maneuvers at each testing time. A positive exercise challenge was defined as a decrease in FEV1 from the preexercise value by at least 15%. A standard spirometer (Sensormedics, Yorba Linda, CA) was used to perform spirometric maneuvers that achieved American Thoracic Society acceptability and reproducibility criteria,[18] and the best FEV1 from each set of measurements was used for the analysis. Patients were discharged from the clinic when their FEV1 was at least within 5% of their baseline. After 60 minutes of exercise, if patients were still symptomatic or their FEV1 was not within 5% of baseline, 2-4 puffs of albuterol MDI were administered, and their FEV1 was measured in 15 minutes. Patients were instructed to withhold their short-acting β2-agonist and cromolyn for 6 hours and long-acting β2-agonist for 12 hours before the exercise challenge.

At the investigators’ discretion, the challenge could be stopped and albuterol could be administered. Patients were discontinued from the study if they were not compliant with their drug therapies, had an upper respiratory infection with worsening of asthma symptoms, required treatment with oral corticosteroids, or had a change in regular asthma drug therapy.

Collection of Exhaled Breath Condensate

Samples of exhaled breath condensate were collected at the beginning of study visits 1 and 2 with use of a disposable collection kit (RTube; Respiratory Research, Inc., Charlottesville, VA). Patients were asked to breathe tidally for 10 minutes with no nose clip. The samples were stored at -70°C until analyzed at the end of the study.

The Cys-LT concentrations were measured by Cayman Chemical (Ann Arbor, MI) using a specific enzyme immunoassay with a lower limit of detection of 7 pg/ml. Samples below the lower limit of detection were concentrated by a factor of 3-4 to determine their concentration. The exhaled breath condensate was collected and analyzed in all of the qualified patients and the last 11 patients with a negative exercise challenge.

End Points

The primary outcome was the maximum change in FEV1 after exercise. Secondary outcomes were the area under the curve for FEV1 (expressed as percentage decrease from baseline FEV1 before challenge on each day) in the first 60 minutes (AUC0-60) after exercise and the proportion of patients in whom exercise-induced bronchospasm was prevented. Only the area below the preexercise baseline FEV1 was used in calculating the AUC.

Statistical Analysis

This study was designed to have a 90% power to detect at least 13.7% difference in the mean change for the maximum percentage decrease in FEV1 between albuterol and montelukast based on an estimated standard deviation of 25.0 and with a significance level (α) of 0.05 by using a two-sided one-sample t test and a correlation of 0.25.[13]

Data are presented as mean ± SD. The clinical outcomes and Cys-LT levels were compared by using the paired t test and Wilcoxon signed rank test as appropriate. Correlations were evaluated by Spearman rank test between Cys-LT levels and severity of exercise-induced bronchospasm or the response to montelukast compared with baseline visit.

McNemar’s test was used to compare the percentage of patients in whom exercise-induced bronchospasm was prevented (defined as < 15% decrease in FEV1 after exercise) in each treatment group. Leer el resto de esta entrada »

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Antiflea Pet Shampoos with Pyrethrin May Play a Role in Autism


May 20, 2008 (London, United Kingdom) — Compared with mothers of typically developing children, mothers of children with autism spectrum disorders were twice as likely to report that they had shampooed their pets with pyrethrin-containing antiflea/antitick shampoos around the time of their pregnancy, in a Californian case-control study that looked at household pesticide use.


The findings were presented by lead study author Irva Hertz-Picciotto, PhD, from the University of California, Davis, at the 7th Annual International Meeting for Autism Research.

When participants in the study, the Childhood Autism Risks and the Environment (CHARGE) trial, were questioned about their prenatal, gestational, and postnatal use of pesticides, the researchers found that products containing pyrethrin — pet shampoos and certain sprays for controlling flies, ants, and cockroaches — were associated with an increased risk for autism spectrum disorders.

These are initial findings and need to be confirmed in other population studies, Dr. Hertz-Picciotto told Medscape Psychiatry, adding: “The bottom line here is [that pyrethrin] is something that really deserves further study.”

It is important to remember that autism is multifactorial, she stressed, explaining that “generally speaking, probably most cases of autism arise from multiple genetic as well as multiple environmental factors.”

Outdoors, pyrethrin has a very short half-life, but indoors it lingers for a long time — for example, in pet hairs — so that people continue to be exposed, she noted. Concerned consumers can seek out more natural, nontoxic alternatives (such as boric acid for cockroaches).

Potent Chemicals

Pesticides are designed to attack the central nervous system of lower species such as insects and rodents, Dr. Hertz-Picciotto explained.

A recent study suggests that there is a link between maternal exposure to commercially applied organochlorine pesticides and subsequent risk of autism in the child, she said. Eric M. Roberts, MD, from the California Department of Public Health, in Richmond, and colleagues reported that pregnant mothers who lived in the California Central Valley close to fields where organochlorine pesticides were being applied had an increased risk of giving birth to a child with autistic spectrum disorder (Roberts EM et al. Environ Health Perspect. 2007;115:1482-1489).

The current study aimed to examine the relationship between use of household pesticides during pregnancy and subsequent autism in the child.

The researchers looked at data from the CHARGE study of 2- to 5-year-olds living in California — 333 children with autism spectrum disorder and 198 typically developing children. The children’s diagnosis of autism was confirmed using the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview (ADI).


In a 90- to 100-minute telephone interview, the children’s mothers were asked about their use of household pest-control products (such as insecticide sprays, ant poisons, pet shampoos, and weed-control products) during the exposure period (which was defined as 3 months prior to conception until the child was 1 year old).

After adjustment for socioeconomic variables, compared with mothers of typically developing children, mothers of children with autistic spectrum disorders were twice as likely to report having shampooed their pets with antiflea/antitick shampoos during the exposure period (odds ratio [OR], 2.0; 95% CI, 1.2 – 3.6). The adjusted odds ratio for this association was strongest for the second trimester (OR, 2.6; 95% CI, 1.3 – 6.0).

The researchers determined that the active ingredient in these pet shampoos was pyrethrin, which came into use about 20 years ago to replace organophosphates, said Dr. Hertz-Picciotto.

When the researchers went back and analyzed the data according to products containing pyrethrin (which included some sprays for controlling flies, ants, and cockroaches, as well as pet shampoos) instead of by product type, the association between pyrethrin and autism spectrum disorder remained.

Was Recall Bias a Factor?

Because these data were collected retrospectively, it is possible that the mothers of typically developing children tended to forget about their use of pesticides around the house, unlike the mothers of the children with autistic spectrum disorders, who may have been more attuned to thinking about this. However, since the researchers did not find an association between autism and products not containing pyrethrin, recall bias was not likely to be a strong factor.

What Does This Mean?

Pyrethrins have largely replaced organophosphates for flea control, the group writes. In insects, pyrethrins affect the nervous system and sodium channels, which results in repeated firing of neurons and death. In rodent studies, pyrethrin exposure when the fetal brain is developing was found to compromise the blood-brain barrier.

Although pyrethrin-containing pesticides have been tested for safety, animal findings and the current study findings raise concerns about the long-term neurodevelopmental effects from prenatal, gestational, and early postnatal exposure to pyrethrin-based products.

The group is planning to submit this work for publication in the near future.

Toxic Organophosphates

In another presentation at the meeting, Brenda Eskenazi, PhD, from the University of California, Berkeley, reported that in a study of low-income Mexican farmworker families in California, organophosphates were associated with pervasive developmental disorder (or autism spectrum disorder) in children.

The study participants, from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort study, included over 400 children as well as their mothers. Urine samples from pregnant mothers and from their offspring were analyzed to detect organophosphate metabolites. The presence of these agents was linked with increased odds of the mothers reporting that their children had pervasive developmental disorder at age 2 years.

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