Astemizole

Chantale Benoit; Jean-Luc Malo, M.D.; Heberto Ghezzo, Ph.D.; and Andre Cartier, M.D.

Study Objective: Astemizole, administered for seven days to asthmatic subjects, had an effect of bronchoconstriction induced by inhaled histamine for a mean period of 42 days. This study evaluates whether a single dose of astemizole would have the same effect.

Subjects: Sixteen adult asthmatic subjects took part in the study.

Design: They first underwent three inhalation tests and skin prick tests with histamine on three different days. On the last day, a methacholine inhalation test was also performed. They subsequently received either a placebo or an active preparation of astemizole. The histamine inhalation test was repeated one day, two days, one week, and/or ten days after administering the drug.

Results: Overall, no significant change in mean PC20 or in the mean diameter of the skin reaction to histamine was observed. However, three out of the eight subjects (38 percent) receiving active and none receiving placebo medication showed significant increases in PC20 histamine (P=0.05). This effect lasted for one to two days.

Conclusions: We conclude that a single dose of 10 mg/ml of astemizole can have a significant effect on bronchial but not cutaneous reactivity to histamine. This effect is of short duration (one to two days).

Astemizole is a long-lasting, highly potent, anti-[H.sub.1] receptor that has no significant sedative or anticholinergic side effects.[1-3] Davies and coauthors[4] have shown that a daily dose of 10 mg of astemizole given for four weeks can block the cutaneous response to histamine for a period of two to six weeks. Tyolahti and Lahti[5] also found that a daily dose of 10 mg of astemizole administered for one week can block skin reactivity to histamine for four weeks. A 10-mg daily dose over ten days[6] or a 10 mg twice daily regimen for three days[7] also significantly blocks bronchial response to inhaled histamine.

We reported recently that astemizole, administered for one week at a daily dose of 10 mg, can block the response to inhaled histamine for a mean period of 42 days.[8] In the same study, we also showed that cutaneous reactivity to histamine was back to normal between 11 and 39 days after the drug was stopped, earlier than bronchial responsiveness to histamine.

To the best of our knowledge, no information is available on the magnitude and duration of the effect of a single dose of astemizole (10 mg) on both cutaneous reactivity and bronchial responsiveness to histamine. This point is relevant because subjects undergoing allergy skin testing or assessment of bronchial responsiveness to histamine may have taken astemizole as it is now commonly given in a single dose. This question was examined in a double-blind randomized trial involving 16 adult asthmatic subjects.

SUBJECTS AND METHODS

Subjects

Sixteen adult asthmatic subjects, 11 women and five men, took part in the study (Table 1). Half of them were atopic as defined by at least one immediate positive skin reaction to a battery of 15 common inhaled allergens. All of them were in a clinically steady state as determined by the following criteria: (1) no need for extrabronchodilator medication during the course of the study; (2) no exposure to a relevant allergen (to which they reacted by skin testing) excluding house dust; (3) no upper or lower respiratory tract infection; (4) no nocturnal awakening due to asthma symptoms; (5) a baseline [FEV.sub.1] within [+ or -]10 percent of the baseline [FEV.sub.1] value obtained on the first visit. The use of inhaled bronchodilator and sustained-release theophylline derivatives was stopped 8 h and 48 h, respectively, before the test. The dose of inhaled steroid was kept unchanged throughout the study period, but the tests were carried out at a constant interval in relation to the last dose inhaled. Each participant signed a consent form, and the protocol was accepted by the ethics committee of Hopital du Sacre-Coeur.

Spirometry and Assessment of Nonspecific Bronchial Responsiveness

After baseline spirometry was assessed, including [FEV.sub.1] and FVC according to the criteria of the American Thoracic Society,[9] each subject underwent the histamine inhalation test. PBS was nebulized, followed by doubling doses of histamine phosphate from 0.03 to a maximum of 32 mg/ml that were nebulized with the Wright's nebulizer (output = 0.14 ml/min) at tidal volume breathing for 2 min. The methacholine inhalation test was carried out in the same way using doubling concentrations from 0..3 to a maximum of 128 mg/ml.

Study Design

The study was double-blind and randomized (randomized numbers from 1 to 16, balanced for 16 subjects, eight receiving active and eight receiving placebo preparations, by groups of eight subjects), using either a placebo or an active astemizole (10 mg/ml) preparation. The study design in illustrated in Figure 1. Histamine inhalation and skin tests were performed on the three initial study days. On day 3, after spontaneous recovery of [FEV.sub.1] to [+ or -]5 percent baseline after administering the last dose of histamine, the methacholine test was carried out. The subject then took active or placebo medication, under supervision to make sure it had been ingested. The next day (day 4), the histamine and methacholine inhalation tests and the histamine skin tests were repeated in the same way as on day 3. The histamine inhalation and skin tests were repeated on day 5 (13 instances) and/or day 7 (ten instances) and/or day 10 (six instances), until PC20 histamine was no longer different (ie, <3.2-fold difference as compared with the geometric mean of the three baseline values of PC20 obtained on days 1, 2, and 3) and was within 2 SD of this mean during two consecutive visits. At the last visit, after functional recovery from the histamine test, a methacholine inhalation test was performed to confirm functional stability throughout the study. Bronchial responsiveness to methacholine is not influenced by astemizole as shown in a previous study.[8] Subjects were also asked to record their PEFR values the morning and evening before taking their bronchodilator medication throughout the study interval. This was to ensure that subjects stayed in a reasonably stable state during the course of the study and to see whether the active medication could alter daily changes in PEFR. Three maneuvers were requested, and the best of two reproducible values ([+ or -]20 L/min) was kept for analysis. Subjects visited the hospital for the histamine and methacholine tests at the same time of the day, either in the morning or the afternoon. [TABULAR DATA OMITTED]

Skin Tests

Skin testing by the prick method was performed in triplicate using histamine phosphate (1 mg/ml) and physiologic saline solution. The mean of the two perpendicular diameters of the wheal was assessed 10 min after introducing the agent. The mean wheal size (Table 2) of the triplicate assessment was kept for analysis in the absence of reaction to physiologic saline solution.

Analysis of Results

Dose-response curves to histamine and methacholine were drawn on a semilogarithmic noncumulative scale. The PC20 was interpolated on the individual curves. Logarithmic transformation of PC20 was used for the statistical analysis of results. Predicted values for [FEV.sub.1] and [FEV.sub.1]/FVC were obtained from Knudson and co-workers.[10] Daily variations in PEFR (maximum value -- minimum value/maximum value x 100) were compared between subjects taking a placebo and subjects taking an active medication.

An analysis of variance (ANOVA) for repeated measures partitioning the interaction with orthogonal polynomials was used to compare the following: (1) PC20 histamine and methacholine; (2) daily variation in PEFR; (3) diameter of skin reactions to histamine. These tests were performed using 4.0 statistical software (SYSTAT). For 16 subjects, the power to detect changes in PC20 of a [is greater than or equal to] 3.2-fold difference is 96 percent. Such changes in PC20 histamine or methacholine are physiologically significant as they correspond to the upper limit of the 95 percent confidence interval of the within-subject between-days variability of PC20 as assessed in our department using histamine[11] or as assessed by others using methacholine.[12] The Fisher exact probability test was used to compare the proportion of subjects in each treatment group who significantly changed their PC20 or cutaneous reactivity. [TABULAR DATA OMITTED]

RESULTS

As shown in Table 1, six subjects (2, 4, 5, 7, 15, and 16) had significant baseline bronchial obstruction as defined both by a [FEV.sub.1] <80 percent predicted and by a [FEV.sub.1]/FVC ratio <85 percent predicted.[10] Three subjects (1, 8, and 12) met either one or the other of these criteria. Individual baseline PC20 histamine values varied from 0.29 to 2.9 mg/ml, corresponding to mild to moderate bronchial hyperresponsiveness.[13] The PC20 histamine on day 1 and the PC20 methacholine value on day 3 were generally reproducible to a [+ or -]1.6-fold difference[11] except in subjects 3, 7, 9, and 10.

The individual results for PC20 histamine and methacholine are illustrated in Figures 2 and 3. The analysis of variance for repeated measures partitioning the interaction with orthogonal polynomials did not show any significant linear effect of the active as compared to the placebo medication on PC20 histamine (F=1.97, p=0.18). However, on day 4 or 5, six of 16 subjects (3, 6, 9, 14, 15, and 16), of whom five were receiving active medication, had PC20 histamine results >2 SD from the mean PC20 baseline results (p=0.04). Three of them (3, 9, and 15) and no subject receiving placebo medication had changes beyond 3.2-fold of the mean baseline results (p=0.05). In these three subjects, all of them receiving active medication, the significant blocking effect was transient and lasted for only one to two days. The PC20 histamine went from a mean of 1.58 to 5.82 mg/ml in subject 3, from 2.03 to 17.2 mg/ml in subject 9, and from 0.51 to 2.8 mg/ml in subject 15 on day 4 or 5 (Figs 1 and 2). Three other subjects (one receiving placebo mediation [No. 11] and two receiving active medication [Nos. 12 and 14]) changed their PC20 values by a 2- to 3.2-fold difference on day 4 or 5 by comparison with baseline results. There were no significant changes in PC20 methacholine (analysis of variance for repeated measures partitioning the interaction with orthogonal polynomials, F=0.19, p=0.67) and no instance of an increase in PC20 methacholine beyond the 3.2-fold difference compared with the value obtained on day 3.

The individual results for skin reactivity to histamine are shown in Figures 4 and 5. None of the subjects, including those who showed a significant increase in PC20 histamine, had a significant (beyond 1 SD from the mean of the three results obtained on the three baseline days) decrease in the size of the skin reaction on day 4 or 5 (NS). Overall, there were no significant changes in cutaneous reactivity to histamine (F=3.04, p=0.10 for the linear component of the orthogonal polynomial partitioning of the ANOVA).

There were no differences in the daily variations in peak expiratory flow rates between the active and placebo groups (F=0.08, p=0.78) (variations were 8.5 [+ or -] 6.8 percent and 7.9 [+ or -] 7.8 percent for the placebo and active groups, respectively).

DISCUSSION

This study shows that a single dose of 10 mg of astemizole can inhibit bronchial responsiveness to inhaled histamine in asthmatic subjects in a physiologically significant manner. Such a blocking effect was found in three subjects receiving active medication (38 percent), but this effect was transient (lasting one to two days). Several studies have documented the significant blocking effect of astemizole on skin[4,5] and bronchial[6,7] reactivity, but the research involved administering astemizole for several days without assessing the duration of the effect, or administering more than the usual daily dose of 10 mg.[3] In a preclinical and unpublished report, Van Neuten demonstrated a blocking effect on the bronchoconstriction induced in guinea pigs with inhaled histamine evaluated 24 h after administering a single dose of astemizole (0.63 mg/kg). Recently, Simons and co-workers[14] studied the time course of the blocking effect of several antihistamine preparations on the wheal and flare reaction induced by histamine phosphate administered by the epicutaneous test in normal subjects. Although some blocking effect of astemizole administered at a single dose of 10 mg/ml was shown between 6 and 12 h after giving the medication, the blocking effect had disappeared by 24 h.

The explanation for the presence of a significant blocking effect in three subjects, given its absence in the five other subjects receiving active medication, remains hypothetical. The blocking effect was clearly present, physiologically significant, and not attributable to chance because it appeared in no subjects receiving placebo medication. It is also interesting to note that the bronchial blocking effect was not paralleled by a similar effect on skin reactivity to histamine. None of the subjects receiving active medication demonstrated a significant blocking effect on skin reactivity to histamine. Bronchial histamine receptors may be proportionally more sensitive to histamine than skin receptors. In a previous study,[8] we found that the effect of astemizole was more prolonged on bronchial responsiveness than on skin reactivity to histamine. As was found by Laduron and co-workers,[15] astemizole occupies [H.sub.1] receptors in the lungs at very low doses without binding to acetylcholine muscarinic receptors. It is therefore possible that the response of the target organ might be variable in terms of intensity and duration. The absence of cutaneous reactivity to histamine after administering a single dose of 10 mg of astemizole as assessed by the wheal diameter, agrees with the results of Vanden Bussche and colleagues (Janssen Research, internal report) in four subjects.

However, they found an inhibition of the erythematous diameter, the blocking effect being proportional to the dose administered. We did not examine the erythematous diameter in this study. When a single but larger dose (30 mg or 40 mg) of astemizole was administered, a significant effect on the wheal reaction was seen with a maximum blocking effect documented two days after the drug had been given (Vanden Bussche and colleagues, Janssen Research, internal report; 3).

One may question the relatively high threshold (a 3.2-fold difference) which we selected for defining a significant change from the three baseline PC20 values. A value of 3.2-fold different was kept instead of twofold which is the within-subject variability of PC20 found by others.[16] A mean twofold change meant that some values could have changed by fourfold while a zero change would have been present in others. It is interesting to note that whereas two subjects receiving active medication changed their PC20 result by a 2-to 3.2-fold difference, one receiving placebo medication had similar changes. The difference in proportion of subjects who changed their PC20 by a [is greater than or equal to]2-fold difference in the two treatment groups remains significant (p=0.04). With a cut point value of 3.2-fold, we calculated that the approximate minimum observed value would have been of the order of one of more log doses for the mean to be above 3.2-fold. Using our criteria, this model protected us from concluding that there was a significant response when some subjects presented a negative or zero change. The high level of the cut point together with a ceiling in the possible observed changed resulted in forcing a minimum change for the average change to be able to reach the significance level. In a similar way, considering significant changes in cases where PC20 changed by 2 SD or more from the three baseline values meant that six subjects would have experienced a blocking effect. However, one of these six subjects was receiving the placebo medication. Consequently, using lower thresholds (2 SD and twofold change differences from the mean) would have resulted in one false-positive response in each instance.

The parallel group design which we selected is less powerful than a crossover design. However, we felt that we had to use such a design because, in a previous study,[8] we determined that astemizole was still active after a mean interval of 42 days (range: 12 to 102 days) after a treatment administered for seven days. The duration of the blocking effect could hardly be extrapolated a priori to predict a washout period. This study called for only one day of treatment but the duration of the effect could have possibly been longer than 30 days. This means one month to ensure a complete washout. This implies a study duration of two and half months for each subject. Under these circumstances, the stability of asthma can be jeopardized. Even if long-term stability of bronchial responsiveness has been shown in asthmatic subjects by some,[17] others have demonstrated that the stability of PC20 varied greatly between individual patients and could not be explained on the basis of the variability of asthma or of therapy during the study period.[18]

It is unlikely that by assessing skin and bronchial reactions one, two, four, and/or seven days after administering the drug, we would have missed the reaction. Although maximum plasma concentrations of astemizole and metabolites occurred 1 to 4 h after single oral doses (10 to 40 mg) and generally varied with dose,[2] the time taken before peak effect on skin reactivity (78 and 108 h) and 50 percent of peak effect (16 and 17h) was well within the interval during which we should have documented a significant blocking effect in our assessment of skin and bronchial responses.

A secondary aim of this study which was not explored would have been to see whether such factors as age, atopy, and duration of asthma are determinants of the blocking effect. The effect of commonly used antihistamines is not influenced by these factors. Although there is no reason to suspect that these variables could be influenced by the new anti-[H.sub.1] receptor antagonists, this point could be further examined in a larger group of subjects.

Our findings have practical implications. Astemizole is now a widely used antihistamine, and subjects might well forget to report having taken it before being seen. Also, a significant proportion of subjects may take this preparation on an as-needed basis, that is, for example, if they have morning symptoms. The results of this study, in which a single daily dose of 10 mg was administered, show that it blocks bronchial responsiveness to histamine for one to two days in a significant, although not a major, proportion of subjects (38 percent). However, it does not cause any blocking effect on skin reactivity to histamine. The magnitude of the effect resulted in bringing PC20 histamine within the normal range[13] in one subject (No. 9). These effects are much smaller than what was found after administering the drug for one week.[8] It would obviously be interesting to assess the duration of the effect for an intermediate interval of three to four days. However, according to the results of this study, recommendations for stopping astemizole for one and preferably two days after a single administration would seem reasonable. Very little is indeed known about the effect of anti-[H.sub.1] receptor antihistamine preparations on cutaneous and, more important, bronchial responsiveness. These preparations are now much more commonly used than standard antihistamines. We therefore feel that considering the frequency of use of skin testing and assessment of bronchial responsiveness in asthmatic subjects, it is important to examine this question for each of the new antihistamine preparations before interpreting the result of a test.

ACKNOWLEDGEMENTS: We would like to thank Janssen Pharmaceutica Canada, Inc., for supplying the active and placebo medications; Katherine Tallman for reviewing the manuscript; and the subjects for participating in the study. Chantale Benoit was a summer research student from the Universite de Montreal School of Medicine, and the recipient of grants from the Association of Drug Industries of Canada and the Medical Research Council of Canada.

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