Terfenadine

Study objective: The duration of action of several new nonsedative antihistamine preparations as assessed by skin and bronchial reactivity to histamine has still not been well established. The aim of the study was to evaluate the duration of effect of loratadine (10 mg) and terfenadine (120 mg) administered once a day for one week on cutaneous and inhaled reactivity to histamine by comparison with a placebo.

Subjects: Twenty-four adult asthmatic subjects were included in a parallel group study that compared the duration of effect of two antihistamines and a placebo on cutaneous and inhaled reactivity to histamine.

Study design: Baseline cutaneous and inhaled reactivity (concentration causing a fall of 20 percent in [FEV.sub.1] [PC20]) to histamine was obtained on three consecutive days. Loratadine (10 mg), terfenadine (120 mg) and a placebo loratadine were administered daily for 1 week to 3 groups of subjects. The PC20 was measured at the end of the medication period, 3 days later, and weekly until PC20 returned to baseline value (upper limit of 2 SD from the mean baseline value).

Results: The mean blocking duration on cutaneous reactivity for loratadine was 6.9 days and for terfenadine, 7.2 days. The mean duration of the blocking effect on PC20 histamine was 8.5 days for loratadine and 7.2 days for terfenadine. These figures were significantly longer than for the placebo.

Conclusion: These data suggest that terfenadine and loratadine have a comparable blocking effect on reactivity to cutaneous and inhaled histamine. A daily dose taken for one week will result in a mean blocking effect of one week.

New antihistamine preparations, antagonists of the H1 receptors, have been developed in recent years. Several reports have documented that these agents are powerful in blocking skin reactivity to histamine as was reviewed by Simons and Simons[1] and Simons.[2] The effect of these preparations on bronchial responsiveness to histamine, and even more significant, the duration of the effect, have been less well documented. Astemizole blocks the effects of histamine inhalation tests in humans.[3] We recently showed that astemizole, a new antihistamine preparation, can have a prolonged effect on histamine-induced bronchial responsiveness, the mean duration being 42 days after a one-week course,[4] although the duration is only 24 to 48 h after a single dose.[5] Magnussen and coworkers[6] also showed that after a single dose of azelastine, another long-acting anti-H1 preparation, histamine provocation was blocked for more than 99 h in some subjects. Recommendations have been made for timing the cessation of usual medications before inhalation challenges with pharmacologic agents.[7] At the time (1975), it was suggested that anti-H1 receptor histamine antagonists be stopped 48 h before histamine inhalation tests. However, these recommendations did not apply for antihistamine preparations that were developed in recent years.

To the best of our knowledge, the duration of the effect of loratadine (Claritin, Schering Inc.) and terfenadine (Seldane, Merrell Dow) on histamine inhalation is unknown. We think that further information on the duration of action of loratadine would be relevant since histamine inhalation tests are frequently performed. The use of loratadine and terfenadine is becoming more common, and recommendations for when to stop the medication before histamine testing should be established for recently introduced antihistamine preparations.

We therefore assessed the effect and duration of action of loratadine and terfenadine on histamine-induced bronchoconstriction, as compared with skin reactivity, in asthmatic subjects.

MATERIALS AND METHODS

Subjects

Twenty-seven adult patients were included in this study. All met the criteria for the diagnosis of asthma set out by the American Thoracic Society.[8] Twenty-four of them remained in a clinically stable state throughout the study according to the following indicators: (1) no change in need for medication; (2) no exposure to relevant allergens (except house dust); (3) no respiratory tract infection; (4) no nocturnal awakenings due to asthma symptoms. Bronchodilators were stopped within the interval recommended by the American Academy of Allergy, 8 h before for inhaled [[beta].sub.2]-adrenergic agents and 48 h before for sustained-release theophylline derivatives.[7] Use of inhaled steroid preparations was kept constant. The study protocol was accepted by a local ethics committee, and a written consent form was obtained from each subject taking part in the study.

Study Design

The study was a single-blind seven-day trial of loratadine, terfenadine and a placebo, assigned in random order to a total of 24 subjects (8 receiving terfenadine, 9 receiving loratadine, 7 receiving a placebo). The study design is summarized in Figure 1. On the first three days (day 1, 2 and 3), subjects underwent a histamine inhalation test. On day 3, after obtaining a fall in [FEV.sub.1] followed by spontaneous functional recovery (approximately 30 min), a methacholine inhalation test was performed. We selected subjects within a wide range of bronchial hyperresponsiveness. On days 4 to 10, the medication (terfenadine [120 mg], loratadine [10 mg] or placebo) was administered in the morning: for the group receiving terfenadine, 120 mg was given; for the group receiving placebo, placebo loratadine was given; for the group receiving loratadine, 10 mg, was given. Subjects taking the medication were advised not to describe the shape or taste of the medication to the technician performing the test. All medications were in sealed envelopes. Subjects were not familiar with the medications. The histamine test was repeated on the last day of medication (day 10) and then weekly until the concentration causing a fall of 20 percent in [FEV.sub.1] (PC20) returned to the upper limit of 2 SD from the mean PC20 histamine results of the three baseline days. The methacholine inhalation test was also repeated on the last day of medication (day 10) and on the last visit to verify that it was reproducible, ie, within a 3.2-fold difference compared with the first test.[9] This guaranteed that the subjects were in a clinically steady state throughout the study, since loratadine and terfenadine have no effect on bronchial responsiveness to methacholine. The subjects were asked to keep a diary and record the peak expiratory flow rate (PEFR) every morning and evening throughout the study before taking bronchodilator medication to further verify that their condition was stable. Histamine and methacholine tests were performed at the same time of the day (morning or afternoon), and timing remained constant for each subject throughout the study.

Skin prick tests to histamine were performed before and after the active medication was administered on every visit. The test was performed in triplicate. Histamine phosphate (1 mg/ml) was used, and the mean of two perpendicular wheal diameters was recorded. The mean daily result of the three tests was kept for analysis.

Assessment of Spirometry and Bronchial Responsiveness

After assessment of baseline spirometry including [FEV.sub.1] and forced vital capacity according to the standards of the American Thoracic Society,[10] subjects underwent a histamine-methacholine inhalation test. The test was performed following the method of Cockcroft and coworkers as noted by Chai et al[7] with a Wright nebulizer (output = 0.14 ml/min) at tidal volume breathing for 2 min. The concentration of histamine and methacholine was progressively doubled from 0.03 to a maximum of 32 mg/ml.

Analysis of Results

Dose-response curves to histamine and methacholine were drawn on a noncumulative logarithmic scale and the PC20 was interpolated on the curve. Logarithmic transformation of PC20 was kept for statistical analysis. The mean result of the three skin tests to histamine phosphate was analyzed. Reference values for [FEV.sub.1] and the ratio of [FEV.sub.1] to forced vital capacity were taken from Knudson and coworkers.[11] The best of three reproducible PEFR values ([+ or -]20 L/min) was kept for analysis. Daily variations in PEFR ([maximum value -- minimum value/maximum value] x 100) were compared between subjects taking the placebo and the active medications.

The duration of the blocking effect on cutaneous and bronchial responsiveness to histamine was obtained by intrapolating the value to which values returned within 2 SD of the mean of the three daily baseline assessments on the individual curves relating time on the abscissa and the value on the ordinate. Statistical analysis was done using [[chi].sub.2], paired Student's [tau] test, linear regression, and a one-way analysis of variance, with contrasts whenever appropriate (Newman-Keuls). [TABULAR DATA OMITTED]

RESULTS

Baseline anthropometric, clinical, and functional results are shown in Table 1. Seventeen of 24 subjects (71 percent) were atopic (at least one immediate skin reaction to 15 common inhalants with skin prick testing) and 19 (79 percent) were taking inhaled steroid preparations. Baseline [FEV.sub.1] was less than 80 percent predicted and the ratio of [FEV.sub.1] to forced vital capacity was less than 85 percent predicted[11] in 11 of 24 subjects (46 percent). The PC20 for histamine and methacholine as assessed on the third day of the baseline period was reproducible within a 3.2-fold difference in 22 of 24 subjects (92 percent), the exceptions being subjects 13 and 15.

Baseline [FEV.sub.1] remained constant throughout the study period (p>0.05), with only five subjects showing changes between 10 and 20 percent comparing the lowest with the highest [FEV.sub.1] value before the histamine test on any of the study days. The PC20 methacholine results also remained unchanged throughout the study period (p>0.05), with only two subjects (No. 12 and 20, Table 1) showing changes greater than a 3.2-fold difference comparing PC20 results on the third and final study days. Mean maximum variability in PEFR ([highest value any time -- lowest value any time/highest value any time] x 100) was 27 ([+ or -] 13) percent for placebo, 25 ([+ or -] 13) percent for loratadine, and 24 ([+ or -] 16) percent for terfenadine (p>0.05).

Individual results for the duration of the effect on cutaneous and bronchial responsiveness to histamine for each medication are listed in Table 2. The mean duration of the blocking effect on cutaneous reactivity to histamine was equivalent for loratadine and terfenadine (close to seven days) (F = 2.7, 0.05 <p<0.1). The between-subject variability was significant. Two of seven subjects taking the placebo showed a significant blocking effect as compared with five of nine subjects receiving loratadine and seven of eight subjects taking terfenadine ([[chi].sup.2] = 5.4; degrees of freedom = 2; p = 0.07).

The mean duration of the blocking effect on bronchial responsiveness to histamine was 9 days for loratadine and 7 days for terfenadine, compared with no significant blocking effect for the placebo (F = 9.2, p<0.001), the contrasts (Newman-Keuls, p<0.05) being significant between the placebo and loratadine, the placebo and terfenadine but not between loratadine and terfenadine. All subjects receiving loratadine and terfenadine showed some blocking effect ranging from 3 to 20 days. For the 17 subjects taking active medication, there was no significant difference in the duration of the blocking effect on cutaneous reactivity and bronchial responsiveness (paired Student's [tau] test, t = 0.6, p>0.05) and these two parameters were not significantly related (r = 0.15, p>0.05). The PC20 methacholine was not significantly affected comparing baseline values with those obtained at the end of each of the treatment periods (p>0.05).

[TABULAR DATA OMITTED]

DISCUSSION

Antihistamines provide effective therapy for many allergic and nonallergic conditions. The new sustained-release anti-H1 antihistamines are now widely used, the most relevant advantages over short-acting standard antihistamines being their efficacy, longer duration of action and minimal side effects, especially on the central nervous system.

Very few studies have examined the duration of the effect of the new antihistamine preparations on bronchial responsiveness to a commonly used agonist bronchoconstrictor agent, histamine. Results of these studies also can be difficult to interpret, since the duration of treatment with antihistamines varies from one study to the next. The results of a previous study[4] showed that astemizole administered for 1 week has a significant blocking effect on histamine-induced bronchoconstriction that can last for a mean of 42 days. The magnitude of this effect (changes in PC20 varying from a tenfold to greater than 100-fold difference) was comparable to what was found by Holgate and coworkers.[12] In a recent study,[5] we investigated the duration of the blocking effect of a single 10-mg dose of astemizole. We found that there was a blocking effect on bronchial responsiveness to histamine in a significant proportion of subjects. However, this blocking effect was short-lived, lasting for only 1 to 2 days, and it was not accompanied by a corresponding effect on cutaneous reactivity to histamine. In this study, using a similar design as for the previous study on astemizole,[4] we found that the duration of the blocking effect of loratadine and terfenadine administered for 1 week was shorter, since the mean duration was 7 to 8 days with a maximum of 20 days.

The design of the study was single-blinded because we did not have placebo preparations of terfenadine. However, we tried to circumvent the potential pitfalls of this design by selecting subjects who had not taken loratadine or terfenadine preparations before the study. Moreover, the technician performing the nonspecific challenge was not informed about the shape or taste of the preparation by the subject who underwent the test.

Nineteen of the 24 subjects included in the study (79 percent) were taking inhaled steroid preparations. The dose of inhaled steroids was kept constant throughout the study. It is unknown whether routine use of inhaled steroids could modify the duration of effect or oral antihistamine preparations. Although this seems unlikely, a similar study performed on asthmatic subjects not taking inhaled antiinflammatory preparations would answer this question.

Antihistamine preparations differ greatly in their suppression of skin reactivity to histamine.[13,14] The mean duration of the effect of loratadine was found to vary from 4 to 7 days as compared with from 17 to 28 days for astemizole.[14] The magnitude of the blocking effect of the various new antihistamines (astemizole, loratadine, terfenadine, cetirizine) administered in a single dose also is highly variable as was shown by Simons and coworkers recently.[15] In this study, we also found great variability in the blocking effect of loratadine and terfenadine on skin reactivity to histamine. This large between-subject variability may explain why the differences in the blocking effect compared with the placebo were only borderline from the statistical point of view. We also found that the duration of the blocking effect on bronchial responsiveness to histamine was not related to the duration of the blocking effect on skin reactivity. Similar discrepancies also were found in previous studies in which astemizole was tested.[4,5]

The results of this study have relevant clinical implications. Standard antihistamines usually are stopped 48 h before a histamine inhalation test.[7] Our results indicate that loratadine and terfenadine perhaps should be stopped for a much longer interval before histamine inhalation testing, at least when they are used on a daily basis for 1 week. No changes in PC20 methacholine could be observed. This might favor the use of methacholine over histamine for routine assessment of bronchial responsiveness since long-acting antihistamines are widely used and may interfere with the results of histamine inhalation tests for longer intervals. Furthermore, methacholine inhalation induces less severe side effects than histamine.[16]

The role of antihistamine preparations in the treatment of asthma is still controversial as was reviewed recently.[17] Clemastine, another antihistamine, has been shown to have an acute bronchodilator effect[18] but no benefit in long-term treatment of asthma could be found.[19] Azelastine, another long-acting antihistamine, can block the immediate asthmatic response to allergen provocation testing.[20] Although this study was not aimed at examining the efficacy of loratadine and terfenadine in the treatment of asthma, PEFR and methacholine bronchial responsiveness were monitored and did not show any significant differences within the three groups of subjects. It is to be noted that the majority of our subjects (19 of 24, [79 percent]) were already taking inhaled steroids, which may have masked any potential effect of the active medications. A proper prospective study examining this point is required.

REFERENCES

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[2] Simons FER. H1-receptor antagonist: clinical pharmacology and therapeutics. J Allergy Clin Immunol 1989; 84:845-61

[3] Vanderschueren R, Van Nierop R, Vanden Bussche G. Astemizole in asthmatic patients. J Drug Therapy Res 1986; 11:4332-35

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[5] Benoit C, Malo JL, Ghezzo H, Cartier A. Single dose effect of astemizole on bronchoconstriction induced by histamine in asthmatic subjects. Chest 1992; 101:1318-25

[6] Magnussen H, Reuss G, Jorres R, Aurich R. Duration of the effect of a single dose of azelastine on histamine-induced bronchoconstriction. J Allergy Clin Immunol 1989; 83:467-71

[7] Chai H, Farr RS, Froehlich LA, Mathison DA, McLean JA, Rosenthal RR, et al. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975; 56:323-27

[8] American Thoracic Society. Chronic bronchitis, asthma, and pulmonary emphysema: statement by the committee on diagnostic standards for nontuberculous respiratory diseases. Am Rev Respir Dis 1962; 85:762-68

[9] Dehaut P, Rachiele A, Martin RR, Malo JL. Histamine dose-response curves in asthma: reproducibility and sensitivity of different indices to assess response. Thorax 1983; 38:516-22

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[11] Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983; 127:725-34

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[13] Long WF, Taylor RJ, Wagner CJ, Leavengood DC, Nelson HS. Skin test suppression by antihistamines and the development of subsensitivity. J Allergy Clin Immunol 1985; 76:113-17

[14] Aimind M, Dirsksen A, Nielsen NH, Svendsen UG. Duration of the inhibitory activity on histamine-induced skin weals of sedative and non-sedative antihistamines. Allergy 1988; 43:593-96

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[16] Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave FE. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 1978; 33:705-10

[17] Eiser N. H1 antihistamines. In: Buckle DR, Smith H, eds. Development of anti-asthma drugs. London: Butterworths, 1984; 121-31

[18] Nogrady SG, Hartley JPR, Handslip PDJ, Hurst NP. Bronchodilation after inhalation of the antihistamine clemastine. Thorax 1978; 33:479-82

[19] Partridge MR, Saunders KB. Effect of an inhaled antihistamine (clemastine) as a bronchodilator and as a maintenance treatment in asthma. Thorax 1979; 34:771-76

[20] Ollier S, Gould CAL, Davies RJ. The effect of single and multiple dose therapy with azelastine on the immediate asthmatic response to allergen provocation testing. J Allergy Clin Immunol 1986; 78:358-64

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