Abstract
The aim of the study was to evaluate the protective effect of single-dose, combination treatment comprising montelukast (5 mg) and loratadine (10 mg), on exercise-induced bronchoconstriction in asthmatic children. The combination was compared to placebo, loratadine and montelukast alone.
Nineteen children were enrolled in a double-blind randomised, single-dose, crossover study. For each treatment patients undertook two treadmill exercise tests, 2 and 12 h respectively after single-dose administration.
No significant differences were seen in the maximum fall in forced expiratory volume in one second (FEV1) 2 h after treatment and placebo. Whereas significant differences in maximum fall in FEV1 were observed between treatment groups 12 h after administration. Loratadine alone did not show any significant protection or any additional effect in comparison with montelukast alone. Single doses of montelukast and montelukast plus loratadine were significantly more effective than loratadine at 12 h.
The present study, performed using single-dose treatments, demonstrated that maximal protective effect by montelukast was obtained 12 h after dosing and that montelukast plus loratadine did not result in significant additive bronchoprotective effects on exercise-induced bronchoconstriction.
The role of leukotrienes in asthma is demonstrated by several studies showing positive prechallenge effects by leukotriene-receptor antagonists (LTRAs) in exercise- 1, 2 and allergen-induced bronchoconstriction 3. The LTRAs, such as montelukast, provide protection against exercise-induced bronchoconstriction (EIB) attenuating the fall in pulmonary function following exercise with no induced tachiphylaxis. β2‐agonists are highly effective in reducing the symptoms. However, recent studies highlighted that the extent of protection diminishes with their exclusive regular use after 6–8 weeks both for short-acting and long-acting agonists (reviewed in 4). Histamine has been implicated in EIB but antihistamines have been shown to offer modest protection against EIB 5. However, there is some evidence that combined mediator blockade with both leukotriene and histamine-receptor antagonists results in greater symptom control than LTRAs alone in patients with persistent asthma 6. In fact, it has been demonstrated that cysteinyl-leukotrienes and histamine synergise in vitro as immunoglobulin (Ig) E‐dependent bronchoconstriction mediators 7. Furthermore, the combination of zafirlukast, a leukotriene antagonist, and loratadine was significantly more effective than either drug alone during allergen-induced early and late obstruction 3. The aim of this study was to investigate if single doses of the combination of a LTRA, montelukast, and a histamine-receptor antagonist, loratadine, may determine an addictive protective effect on EIB in children in comparison to either drug alone.
Methods
Patients
Allergic-asthmatic children (n=19) with a positive clinical history of EIB were evaluated whilst living at high altitude in the Italian Alps, in a house dust mite-free environment. The patient characteristics are summarised in table 1⇓. Because of the effects of prolonged stay at high altitude none of the patients were receiving inhaled or oral steroids, antihistamines or antileukotrienes. The patients had not presented with infectious diseases of the upper airways in the previous month. β2‐agonists were allowed for as-needed medication until at least 12 h before the challenges. On the day of admission to the study the subjects performed baseline exercise challenges at 10:00 and 20.00 h. A fall in the forced expiratory volume in one second (FEV1) after exercise of ≥15% of the pre-exercise value was considered diagnostic of EIB.
Patient characteristics
Study design
The study was performed during the winter in order to eliminate the influence of pollens. A double-blind randomised, single-dose, crossover design was used. For each patient four double-blind randomised single-dose treatments of placebo, loratadine, montelukast and the combination montelukast plus loratadine, were administered on four different days at 08:00 h. Each patient undertook two treadmill exercise tests following each drug administration 2 (10:00 h) and 12 h (20:00 h) after dosing. Each drug administration and the following exercise tests were performed 3–5 days apart.
Treadmill exercise tests
Children performed a baseline spirometry and then ran for 6 min on a treadmill, at speed, to obtain an increase of 80% in their maximum cardiac frequency in a specially designated room with constant temperature (21°C) and humidity (40–50%). Following the exercise challenge, FEV1 was obtained at 1, 5, 10, 15, 20 and 30 min. To assess bronchoconstriction after the exercise challenge, the maximal percentage fall in FEV1 (ΔFEV1) from the baseline value and the area under the curve (AUC0–30min) with percentage change in FEV1 data over time were considered. Percentage of protection was calculated as: 
where Ps is the percentage fall in FEV1 at the screening visit, and Pt is the fall after each treatment. Clinical protection was considered to be obtained if the percentage fall after receiving active drug was one-half or less of the percentage fall after receiving placebo.
Statistical analysis
The effects of treatment on the response to exercise challenge were compared using ΔFEV1 expressed as the percentage of the prechallenge baseline. An analysis of variance model for repeated measures (ANOVA) in a crossover design was used to compare treatment groups. The hospitals' ethical committee approved the study and the parents gave informed consent.
Results
Safety
No adverse effects on safety were observed during the study period.
Efficacy
There was no significant difference between patients' baseline FEV1 after each drug administration (table 2⇓). The ΔFEV1 during the screening test, expressed as mean±sem, were: −22.84±3.01 at 10:00 h and −21.31±2.60 at 20.00 h.
Baseline forced expiratory volume in one second (FEV1) with the different exercise-challenge tests
When the exercise test was performed 2 h after the drug administration the ΔFEV1 was −15.33±2.93 for placebo, −13.9±2.67 for loratadine, −13.33±2.03 for montelukast and −10.07±1.96 for the combination, with no significant differences. At 12 h the ΔFEV1 was −18.69±2.83 for placebo, −14.64±2.55 for loratadine, −9.78±1.85 for montelukast and −9.51±2.55 for montelukast plus loratadine. Significant differences were observed between placebo and montelukast (p<0.02), placebo and the combined treatment (p<0.02) and between respectively montelukast and the combination in comparison to loratadine (p<0.05). No significant difference was observed between placebo and loratadine.
At 2 h AUC0–30min, (% x min) expressed as mean±sem, was −34.32±11.5% for placebo, −50.66±20.46% for loratadine, −23.74±10.06% for montelukast and −18.87±7.14% for the combination, with no significant differences. When the challenges were performed 12 h after the drug administration, AUC0–30min was −43.60±9.34% after placebo, −39.6±10.89% after loratadine, −15.03±5.38% after montelukast and −7.76±6.14% after the combination, with significant differences between montelukast and montelukast plus loratadine in comparison to placebo (p<0.01) and to loratadine alone (=0.02).
Protection
At 2 h after dose administration, no significant difference in the percentage of protection was observed between placebo (33%), loratadine (43%), montelukast (47%) and montelukast plus loratadine (59%). At 12 h there was a significant difference in the percentage of protection between placebo (20%) and montelukast (63%) (p<0.01), and between placebo and the combination (59%) (p<0.01), but not between placebo (20%) and loratadine (45%). Montelukast provided clinical protection in three subjects (15%) at 2 h and in 12 subjects (63%) at 12 h. The combination of the two drugs gave a similar trend with clinical protection in six subjects (31%) at 2 h, and in 12 subjects (63%) at 12 h.
Discussion
The aim of the study was to verify if the association of a LTRA, montelukast, plus an antihistaminic drug, loratadine, may exert an additive effect in the prevention of EIB. It has been previously shown that LTRAs are able to protect against early and late allergen-induced responses, even without any changes in inflammatory indices such as sputum eosinophil percentage or activity 8. Furthermore, it has been demonstrated that the combination loratadine and zafirlukast, inhibited both early and late reactions following allergen challenge by ∼75% 3. As the efficacy has appeared to begin acutely, different anti-inflammatory mechanisms might be involved including effects on the vascular system, the airway oedema, mucous production and neurogenic inflammation 9. These events may also contribute to the development of the hypertonicity of airway lining fluid which seems to be the major determinant of EIB, determining mediator release by inflammatory cells. In the present study, the authors analysed drug efficacy at 2 and 12 h, and the effects of the combination at the beginning and the end of a once-daily single dosage were investigated. In several studies two or more doses of montelukast were used in order to achieve steady-state blood levels 1, 2. In the present study the use of a single administration of drugs was adopted in an attempt to clarify, as much as possible, the contribution of both antileukotriene and antihistaminic drugs in the protection from EIB. To the best of the authors' knowledge this is the first study examining the effect of a single dose of montelukast and loratadine alone and in combination. No statistically significant additive effect using the combination of the two drugs in comparison to montelukast alone was obtained. However, results showed that even after 2 h there was a trend towards protection when the children were treated with the combination. Mean values of the ΔFEV1 and the percentage of protection obtained after both drug administration (2 and 12 h respectively) did not change significantly, but at 2 h there was a strong placebo effect. This effect in EIB has been described previously in children, and it has been characterised by dose and duration time effect 10. At 12 h montelukast and the combination were significantly more effective than placebo and loratadine alone.
To conclude, the combination of montelukast and loratadine single-dose administration, demonstrated no additive effect in exercise-induced bronchoconstriction protection. However, since antileukotrienes in association with antihistamines have been demonstrated to provide a significant improvement in chronic asthma 6 and allergic rhinitis 11, 12 in adults, combined and prolonged oral therapy should also be evaluated in children. Further studies are necessary to evaluate long-term clinical effects of this and other therapeutic combinations on asthma and exercise-induced bronchoconstriction in childhood.
- Received April 17, 2001.
- Accepted March 1, 2002.
- © ERS Journals Ltd
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