Duration of the effect of astemizole on histamine-inhalation tests

Duration of the effect of astemizole histamine-inhalation tests

on

Jean-Luc Malo, MD, Christine LiYi Fu, MD, Jocelyne L’ArchevQque, RT, Heberto Ghezzo, PhD, and Andre Cartier, MD Montreal, Quebec, Canada The aim of the study was to investigate if astemizole, a new, long-acting antihistamine preparation, has an effect on histamine-inhalation tests and to assess the duration of action of this medication. The study included a group of 15 adult subjects with asthma in a clinically stable state. The subjects all demonstrated mild to severe bronchial hyperresponsiveness (geometric mean provocative concentration causing a 20% fall in FEV, (PC,,) histamine, 0.57; range, 0.20 to 4.7 mglml). The jirst part of the study was a double-blind, 7-day trial of astemizole (10 mglday) or placebo, assigned in random order for the first eight subjects. The seven subjects entering the trial subsequently were administered active medication only. PC?, histamine was assessed on the 3 consecutive days before starting the trial, on the last day of medication, 3 days later, and once a week thereafter until PC,, returned to baseline. PC,, methacholine was also assessed before the trial and regularly thereafter to ensure functional stability. No significant changes in PC, histamine were documented in the placebo-treated group, but the four subjects receiving active medication demonstrated marked changes in PC,, histamine (from a tenfold to a >I#-fold difference) (p = 0.001). There were no significant differences in changes in PC,, methacholine between the two treatment groups (p = 0.27). The duration of recovery of bronchial response to histamine in all 15 subjects ranged from 12 to 102 days (mean, 42 days) and was in some subjects, longer than the duration of the blocking effect of histamine reactivity found with skin testing. In conclusion, astemizole administered for only 1 week demonstrates a pronounced and prolonged blocking effect on bronchial responsiveness to histamine. (J ALLERGY CLIN IMMUNOL 1990;85:729-36.)

Bronchial hyperresponsivenessis the hallmark of asthma,although it is not exclusive to this condition. ’ Histamine- and methacholine-inhalation tests are frequently used in the laboratory to assessthe level of bronchial responsiveness.‘,3 Several drugs might affect the results as assessedby inhaling histamine or methacholine. Recommendationsfor timing the cessation of commonly used medication, such as bronchodilators, have been suggested.*When these proposals were developed, it was suggestedto stop the usual anti-HI-receptor histamine antagonists48 hours before histamine-inhalation tests. New antihistamine preparations have appearedsince that time. It is not known exactly when astemizole, a new antihistamine From the Departmentof Chest Medicine, Hopital du Sacre-Coeur, Montreal, Quebec, Canada. Supported in part by Foundation McAbbie, University of Montreal. Received for publication July 11, 1989. Revised Oct. 10, 1989. Accepted for publication Nov. 3, 1989. Reprint requests:Jean-LucMalo, MD, Department of Chest Medicine, Hopital du SackCoeur, 5400 W. Gouin Blvd., Montreal, Quebec, CanadaH4J lC5. l/1/18014

PCzO: Provocative concentration of histamine or

preparation, should be stopped. It has been demonstrated that astemizole blocks histamine-inhalation tests in humans4and in guinea pigs’ but does not appear to have any effect on methacholine-induced bronchoconstriction.5Astemizole is even more potent than standardantihistamines,6and there are good reasonsto believe that the duration of action on inhalation tests might be longer. Indeed, Davies et al.7 have demonstratedthat astemizole can block the reaction to histamine and allergen in skin tests for periods varying from 2 to 6 weeks. We believed that further information on the duration of action of astemizole would be relevant because subjects frequently come to the laboratory for histamine-inhalation tests. The use of astemizole is becoming more common, and recommendationsfor when to stop the medication before histamine testing should be establishedfor this recently introduced anti729

730 Mafo et al.

J. ALLERGY

TABLE I. Baseline anthropometric,

clinicsI,

and functional

PtNo.

sex

Age (yrl

Height (cm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Mean

F M F M M F M M F F

47 63 58 69 60 55 42 68 64 52 40

175 173 163 160 168 168 157 176 168 158 153

F

41

166

F M

55 20 52 52

158 161 163

13

7

M

F

SD

CLIN. IMMUNOL. APRIL 1990

results

Duration of asthma (yr)

164

14 16 16 6 10 6 24 7 10 3 8 8 2 7 2 9 6

Atopy’

+ + + + + + D +

+

Pf, Patient;pred, predicted; D, dermographism;PI. inhaled P,-adtenergicagent; Z’,sustained-releasetheophyllme preparation;Be, i&led beclomethasone;OS, oral steroids. *At least one positive skin reaction to 15 common inhalant allergens. ‘!‘PC, obtained on day 3; geometric meansand SD.

histamine preparation. We therefore designed this double-blind study to investigate the effect and the duration of action of astemizole on histamine-induced bronchoconstriction.

MATERIAL AND METHODS Subjects Fifteen adult patients were included in this study (Table I). All patients met the criteria for the diagnosis of asthma of the American Thoracic Society.’ All patients were in a clinically stable statethroughout the study, according to the following indicators: (1) no changein need for medication, (2) no exposure to relevant allergens (except house dust), (3) no respiratory tract infection, (4) no nocturnal awakenings becauseof asthmasymptoms, and (5) FEV, within 10% of baseline at each assessment.Bronchodilators were stoppedin the interval recommendedby the American Academy of Allergy, 8 hours for inhaled p,-adrenergic agents and48 hours for sustained-releasetheophylline derivatives.* Use of inhaled beclomethasonewas unchanged.The study protocol was acceptedby a local ethics committee, and a written consent form was requestedof each subject taking part in the study.

Assessment of spirometry bronchial responsiveness

and

After assessment of baseline spirometry, including FEV, and FVC, according to the standardsof the Ameri-

can Thoracic Society,s subjects underwent an histaminelmethacholine-inhalation test. The test was performed according to the method proposedby Cockcroft et al? with a Wright nebulizer (output, 0.14 ml/min) at tidal volume breathing for 2 minutes. The concentrationof histamine and methacholine was progressively doubled from 0.03 to a maximum of 32 mg/ml.

Study design The study was a double-blind, 7-day trial of astemizole (10 mg/day) and a placebo, assignedin random order to the first eight subjects(four receiving active drug and four patients receiving placebo medication). The study design is summarizedin Fig. 1. On the first 3 study days (days 1,2, and 3), subjects underwent an histamine-inhalation test. On day 3, after obtaining a fall in FEV, followed by spontaneousfunctional recovery (approximately 30 minutes), a methacholine-inhalation test was performed. We selected individuals within a wide range of PC, (Table I) and with a reproducibility of PC, (histamine and methacholine)corresponding to the reference values of our laboratory, that is, a 95% confidence interval based on a single determination of a <3.2-fold difference.“’ On days 4 to 10, the medication (active or placebo) was administered. As the blocking effect of astemizole was overwhelmingly demonstrated in the study of the first eight subjects, an open design was used for the remaining subjects to assessthe duration of the effect. The secondgroup of seven subjects (Nos. 9 to 15) were all treated with active medication

VOLUME NUMBER

Effect of astemizole

85 4

Treatment

L

% Pred

%

tests

% Pred

Histamine (mg/ml)

Methacholine (mglml)

I% T; Be (3,$e

2.6 1.3 1.7

84 57 55

66 54 61

82 67 76

0.21 0.41 0.49

0.14 0.20 0.52

IS; T P2;T; Be IS; T; Be p2; T; Be; OS Pz

2.7 1.6 2.7 1.6 1.9

127 56 90 65 58

77 57 71 58 64

98 71 87 68 80

3.1 0.33 0.34 0.20 0.42

4.8 0.55 0.55 0.11 1.0

Fr fi,; Be P:!;Be I%; T; Be

2.6 2.7 3.1 2.3 1.5 3.5 1.6 2.2 0.7

110 94 125 78 63 111 62 82 26

78 73 88 86 69 85 59 70 11

97 88 102 103 84 97 72 85 12

4.7 1.9 2.5 0.29 0.37 0.21 0.34 0.57 2.9

10.5 2.4 3.3 0.69 0.20 0.23 0.14 0.62 4.1

(10 mg/day) for 7 days. The histamine test was repeated on the last day of medication (day 10) as well as on days 14, 21, 28, and then weekly until PC, had returned to approximatlzly a 3.2-fold difference from the mean of the three baseline PC,, histamine results. The methacholineinhalation test was also repeatedon the last day of medication (day 10) and on the last visit to verify that it was reproducible, that is, within a 3.2-fold difference as compared with the first test.‘” This guaranteedthat the subject had been in a clinically steady state throughout the study since astemizole has no effect on bronchial responsiveness to methacholine. The subjects were also asked to keep a diary and to record their PEFR every morning and evening throughout the study beforetaking their bronchodilator medication, further verifying that their condition was stable. Histamine and methacholine tests were performed at the sametime of the day (morning or afternoon) and remained constant for each subject throughout the study. Skin prick tests to histamine were performedbefore and after the active medication was administeredon every visit for the last seven subjects. The test was performed in triplicate. Histamine phosphate(1 mg/ml) was used, and the mean of two perpendicular wheal diameters was kept for analysis. Analysis

of results

Dose-responsecurves to histamine and methacholine were drawn on a noncumulative logarithmic scale, and the PC, histamine/methacholine was interpolatedon the curve. Logarithmic transformation of PC, was kept for statistical analysis. The mean result of three skin tests to histamine phosphate was analyzed. Reference values for FEV, and

731

P&t

FEVJFVC

FEV,

on histamine

FEV,/FVC were taken from Knudsonet al.” The best of three reproducible PEFR values (~20 L/min) was kept for analysis. Daily variations in PEFR ([maximum value - minimum value/maximum value] X 100) were comparedfor the subjectsreceiving the placebo and active drug treatmentswho were included in the first part of the study. Statistical analysis was done with a two-way analysis of variancecomparingmeanPC, histamineor the initial PC, methacholineresults with the correspondingresults on days 10, 14, and 21 for the first eight subjects(the double-blind section of the study). The differences between PC, histamine and methacholinewere also comparedfor the 11 subjects receiving active medication on the third day preceding administration of the drug (day 3), after 1 week of treatment (day lo), and at the end of the study. This was done with a Student’s paired t test. Student’s unpaired t test was used to comparethe duration of the blocking effect in atopic and nonatopic subjectsand the variation in a PEFR. A p value CO.05 was consideredto be statistically significant. RESULTS

Individual and mean baseline FEV,, FEV, /FVC, andPC, valuesarepresentedin TableI. Eight subjects had a significantly reduced” FEV, or FEV, / FVC . The PC, histamine and methacholine results for each of the 15 subjects are illustrated in Figs. 2 and 3. Treatment with astemizole resulted in a marked reduction in histamine-induced bronchial responsivenessin all 11 subjects. For the eight subjects included in the double-blind part of the study, changes in PC,, his-

732 Malo et al.

J. ALLERGY

TABLE II. Results of skin testing (mean wheal diameter)

with histamine

phosphate

Days* Subject No.

9

1,2,3

10

5.3

0

14

CLIN. IMMUNOL. APRIL 1990

(1 mg/ml) Duration of the blocking effect on histamine responsiveness (days)

21

28

35

42

49

56

63

0

0

0

0

0

4.3

4

-

54

0

2

1

2

-

3.7

4.3

4

-

61

0

0

0

-

3.7

4.3

4

-

-

61

0

0

2

3.7

4.3

4

4

4

-

36

0

-

0

2

3.7

5

5

5

-

53

0

1.7

4

4.3

-

-

-

-

-

22

0

1.7

3.7

3.7

4

-

4.3

4.3

4

48

(0.6) 10 11 12 13 14 15

4.6 (0.7) 4.4 (0.7) 4.7 (0.7) 4.6 (0.7) 3.7 (0.7) (E)

The mean and SD (in parentheses) wheal diameter of days 1, 2, and 3 are presented; the estimated time for return of the wheal diameter to baseline (days 1, 2, and 3) is presented in bold character. *See Fig. 1 for sequence of days in the treatment period.

tamine from the three baselinevalues (days 1, 2, and 3) to results obtained on days 10, 14, and 21 were significantly different between the group receiving active medication and the group taking the placebo (p = 0.001 for the drug effect and p = 0.006 for the time effect), whereas there were no significant differences in the changesin PC,, methacholine from baseline to the result obtained on day 10 (p = 0.27 for the drug effect andp = 0.08 for the time effect). Moreover, although the difference between PC,, histamine and methacholine was not significant on day 3 (t = 1.71; p = 0.12), this was highly significant on day 10 (t = 12.1; p = 0.0001) for all 11 subjects receiving active medication. At the end of the study period, the difference between PC, histamine and methacholine was still significant (Student’s unpaired f test, 6.2; p = 0.0001). Although sevenof the 11 subjectsreceiving active medication had returned to baseline PC, histamine ( + 3.2-fold difference over the mean value), the duration of effect had to be extrapolatedfor the remaining subjects(Nos. 7, 10, 12, and 13). The final results were, however, close to the selected threshold of a ?3.2-fold difference. The duration of action of astemizole on histamine-inhalation test ranged from a minimum of 12 days (No. 14) to a maximum of 102 days (No. 2) (mean, 42 days). Durations of the blocking effect were not significantly different (Student’s unpaired t test, 0.7; p > 0.05) in the five atopic subjects (Nos. 2, 3, 7, 10, and 14) (58 ? 37 days) as

compared with the five nonatopic individuals (Nos. 8, 11, 12, 13, and 15) (45 ? 14 days) receiving the active medication. Mean daily variations in PEPR were 7.0 + 5.7% and 7.9 -t 7.2% in the placebo-treatedand activetreated groups included in the first part of the study throughout the study period (Student’s t test, 0.85; p > 0.05). Baseline skin test wheal diameters with histamine ranged from 3.7 to 5.3 mm among the last sevensubjectsto enter the trial (Table II). Significant suppressionof histamine reactivity on skin tests was documentedin all sevensubjectsafter 1 weekof active treatment. Skin test reactivity with histamine gradually returned to baseline levels (defined as at least 2 SD of the mean baseline values) between 21 days to 49 days later (Table II). In five subjects(Nos. 10, 11, 12, 13, and 15), the duration of the blocking effect was shorter by at least 1 week for skin tests than for inhalation tests; in the remaining two subjects,it was within 1 week. DISCUSSION Antihistamines provide effective therapy for many allergic and nonallergic conditions. Astemizole is a new long-lasting HI-histamine antagonistwith greatly increased potency and no significant sedative and anticholinergic side effects.4,‘* It is devoid of Badrenergic activity.” In recent years, the use of this medication has become widespread in clinical practice. Some studies have demonstratedthat the medication is eliminated quite slowly, with an estimated

VOLUME NUMBER

Effect of astemizole

85 4

on histamine

tests

733

day 2 histamine PC20

placebo

or active

medication

FIG. 1. Study design. Placebo or active medication first eight subjects. The remaining seven subjects

half-life of 104 hours.13Holgate et a1.6suggesta prolonged H, blockade that extends from 15 to 30 days after the end of therapy. The results of this study demonstratedthat astemizole has a significant blocking effect on histamineinduced bronchoconstriction. Four subjects even reacheda PC, histamine that is consideredto be normal (>32 mg/ml) after administration of this antihistamine preparation. Holgate et aL6 documenteda geometric mean dose ratio of 17.4 against the bronchoconstrictor effect of histamine after administering the drug for 14 days to seven subjects with asthma. This finding corresponds to the magnitude of the blocking effect documentedin our study, which varied from a tenfold to > lOO-fold difference. However, the duration o-Fthis effect had not previously beenstudied, to the best of our knowledge. In our subjects, the blocking effect was longer than 1% weeks from the end of the: course of medication in all subjects who were administered the active medication. One subject’s (No. 2) duration of recovery was 14 weeks. Antihistamine preparations differ greatly in their suppressionof skin reactivity to histamine.14Astemizole is more potent and hasa longer duration of action on skin test results than standardantihistamine preparations. Our data demonstratethat skin reactivity to histamine returned to baseline levels between 11 and 39 days later. These findings agree with the data of Davies et al. ,7 who demonstratedthat astemizolecan block the reaction to histamine and allergen in the skin testsfor periods between2 and 6 weeks. Bantz et a1.15 have demonstratedthat terfenadine, another recently introduced antihistamine preparation, has a more potent blocking effect on histamine reactivity than a standarda.ntihistamine.The duration of effect on histamine skin testing appearsto be shorterthan the effect

X 7 days

was assigned in double-blind fashion received only the active preparation.

to the

for inhalation testing. Five of our sevensubjectswho underwent both skin and inhalation testing with histamine demonstrateda moreprolongedblocking effect to the inhalation tests. Although no explanation for this phenomenoncould be proposed, a direct implication of the different blocking times is that the return of skin responsivenessto baseline cannot be used as being the indication of any further antihistamineeffect in the lung. Our results therefore suggest that the recommended interval for stopping astemizolebeforehistaminechallenges should be different than the interval for the other anti-H, preparations. Standard antihistamines are usually stopped 48 hours before a test.* Results of our study indicate that astemizoleshould be stopped at least 6 weeks before histamine-inhalation testing. This recommendationmight well apply to anothernew antihistamine preparation, azelastine. Indeed, Magnusen et al.16have recently demonstratedthat after a single doseof this medication, histamine provocation was blocked for more than 99 hours in somesubjects. Becauseazelastineand astemizolehave a similar time course of action,‘” it can be expectedthat both medications will block histamine-induced bronchoconstriction for similar periods of time. The role of antihistamine preparation in the treatment of asthmais still controversial, as reviewed recently. ” Clemastine, an antihistamine, hasbeendemonstrated to have an acute bronchodilatator effect’* but did not demonstrateany benefit for the long-term treatmentof asthma.I9Azelastine, anotherlong-acting antihistamine, can block the immediate asthmaticresponseto allergen-provocationtesting.*’ Although the aim of this study was not examining the efficacy of astemizolein the treatmentof asthma,clinical symptoms, fluctuations in PEFRs, and methacholinebron-

734 Malo et al.

J. ALLERGY

No. 1

No.

(PLACEBO)

CLIN. IMMUNOL. APRIL 1990

2

(ACTIVE) -

HISTAMINE

-

METHACHOLINE

No. 6 (PLACEBO)

No.

7

(ACTIVE)

DAYS FIG. 2. Individual results for PCzOhistamine and methacholine for subjects (Nos. 1 to 8) in the double-blind section of the study. Active or placebo medication was administered between days 3 and 10. The mean and a2 SD of the three baseline P&, histamine results are illustrated. The horizontal dotted line represents the upper limit of the 95% confidence interval. Duration of effect was obtained by interpolation of the dotted line on the line joining PCx histamine results. This point was extrapolated for subject No. 7 for whom PC,, histamine nearly returned to baseline values.

chial responsiveness remain stable and not significantly different in the placebo-treated and activetreated groups. Therefore, it appears that astemizole would not be a useful adjunct treatment for asthma. Methacholine might be preferable to histamine in the routine assessment of bronchial responsiveness. It is known that methacholine elicits reproducible results as compared to histamine on a milligram per milliliter basis and results in fewer side effects.” Results of

this study also demonstrate that responsiveness to methacholine is not affected by the use of the new antihistamine preparations that are becoming widely used. We thank Jocelyne Normandin for her secretarial assistance, JanssenPhannaceutica Canada, Inc. for supplying the active and placebo medications, Katherine Tallman for reviewing the manuscript, and the subjectsfor participating in the study.

VOLUME NUMBER

85 4

Effect of astemizole

2.0

on histamine

No. 9

No. 10

(ACTIVE)

(ACTIVE)

1.0 0.50 0.25 _

-

js.0

-

No.11

No.12

(ACTIVE)

(ACTIVE)

1

8.0 4.0 . 3

2.0-I

E

1.0-

5

0.50 -

g

0.25 E

0.125 -

mn”.,

1

4.0

I

.

I

.

I

.

4

No.13

8.0

8.0

735

-__----__ I‘ :b

J

>32.0

tests

1

No.14

1

(ACTIVE)

(ACTIVE)

No.15 (ACTIVE) -

HISTAMINE METHACHOLINE

DAYS FIG. 3. Same legend as for Fig. 2; the remaining seven subjects were administered active medicatiop b&wean days 3 and 10. The mean and 22 SO of the three baseline PC, histamine results are,iflustrated. The horizontal dotted line represents the upper limit of tha 95% confidence interval. Duration of effect was obtained by interpolation of the dotted lirie on the line joining PC, histarpine results. This point was extrapolated for subjects Nos. 10,12, and 13 for whom PC, histamine nearly returned to baseline values.

736 Malo et al. REFERENCES 1. ATS Statement. Chronic bronchitis, asthma, and pulmonary emphysema.Am Rev Respir Dis 1982;85:762-8. 2. Chai H, Farr RS, Froehlich LA, et al. Standardizationof bronchial inhalation challenge procedures. J ALLERGY CLIN IMMUNOL 1975;56:323-7. 3. Hargreave FE, Ryan G, Thomson NC, et al. Bronchial responsivenessto histamine or methacholine in asthma: measurementand clinical significance. J ALLERGY CLIN IMMUNOL 1981;68:347-55.

4. VanderschuetenR, Van Nierop R, VandenBusscheG. Astemizole in asthmatic patients. JDR J Drug Therapy Res 1986; 11:432-5. 5. Van Nueten JM, SchuurkesJAJ. Antagonism of histamineinduced bronchoconstriction by astemizole: preclinical researchreport. Researchproducts information N27498. Piscataway, N.J.: JanssenPharmaceutics,1980. 6. Holgate ST, EmanuelMB, Howarth PH. Astemizole and other H,-antihistaminic drug treatment of asthma. J ALLERGY CLIN IMMLINOL 1985;76:375-80.

7. Davies R, Brooke M, Griffiths J. Skin test recovery after astemizole therapy [Abstract]. Rev Esp Alergol Immunol Clin 1987;2:79. 8. ATS Statement. Standardization of spirometry-1987 update. Am Rev Respir Dis 1987;136:1285-98. 9. Cockcroft DW, Killian DN, Mellon JJA, HargreaveFE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977;7:235-43. 10. Dehaut P, Rachiele A, Martin RR, Malo JL. Histamine doseresponsecurves in asthma: reproducibility and sensitivity of different indices to assessreponse. Thorax 1983;38:516-22. 11. KnudsonRD, Lebowitz MD, Holberg CJ, Burrows B. Changes

J. ALLERGY

CLIN. IMMUNOL. APRIL 1990

in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983;127:725-34. 12. Norman PS. Newer antihistaminic agents. J ALLERGY CLIN IMMUNOL 1985;76:366-8.

13. ChapmanPH. A randomized single-blind study of astemizole and chlorpheniramine in normal volunteers. Br J Clin Pharmacol 1983;13:593. 14. Long WF, Taylor RJ,WagnerCJ, LeavengoodDC, Nelson HS. Skin test suppressionby antihistaminesand the development of subsensitivity. J ALLERGY CLIN IMMUNOL 1985;76: 113-7. 15. Bantz EW, Dolen WK, Nelson HS. A double-blind evaluation of skin test suppressionproducedby two dosesof terfenadine. J ALLERGYCLIN IMMUNOL 1987;80:99-103. 16. MagnussenH, ReussG, Jijrres R, Aurich R. Duration of the effect of a single doseof azelastineon histamine-inducedbronchoconstriction. J ALLERGY CLIN IMMUNOL 1989;83:467-71. 17. Eiser N. H, 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. Bronchodilatation after inhalation of the antihistamine clemastine. Thorax 1978;33:479-82. 19. PartridgeMR, SaundersKB. Effect of an inhaled antihistamine (clemastine)asa bronchodilatorandasa maintenancetreatment in asthma. Thorax 1979;34:771-6. 20. Oilier S, Gould CAL, Davies RJ. The effect of single and multiple dose therapy with azelastine on the immediate asthmatic responseto allergen provocation testing. J ALLERGYCLIN IMMIJh’OL 1986;78:358-64.

21. Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargmave FE. Reproducibility and comparison of responsesto inhaled histamine and methacholine. Thorax 1978;33:705-10.