Download Antihistamines in the treatment of asthma J . B

Eur Resplr J
1992, 5, 1137-1142
SHORT REVIEW
Antihistamines in the treatment of asthma
J . Bousquet, Ph. Godard, F.B. Michel
Antihistamines in the treatmelll of asthma. J. Bousquet, Ph. Godard, F.B. Michel.
ABSTRACT: Histamine Is an Im portant mediator of asthma. T he new antihistamines which block histamine at the Hlreceptor level also possess some antiallergic properties. At cut·rent dosages they appear to be safe. These drugs
are effective In the treatment of rhi nitis and conjunctivitis but their role in
asthma is still under Investigation. At a dose higher than usually recommended,
they were shown to block exercise-induced asthma and, inconstantly, the early
phase reaction after allergen challenge. T heir effect on the late phase allergic
reaction as well as their clinical efficacy during trials is, however, less consistent. The indication of H 1-blockers in the tr eatment of asthma is therefore limited, especially since doses higher than r ecommended may lead to adverse
reactions.
Eur Respir J., 1992, 5, 1137-1142.
Antihistamines, which block histamine at the H 1 receptor level, have been used for the treatment of
allergic and nonallergic rhinitis, conjunctivitis and skin
diseases, in which histamine has been shown to play
an important role.
In asthma, the use of antihistamines is still under
investigation. Not only do some investigators deny
that antihistamines are beneficial but ScHULLER [1] proposed that they might even be harmful. Based on a
very small number of asthmatic children, who apparently deteriorated during treatment with a drug
possessing both an H 1-blocking activity and anticholinergic properties, her report lead to the contraindication of these drugs in asthma in the US.
However, a Position Paper issued by the American
Academy of Allergy and Immunology [2] proposed
that the drugs are safe and may be used in the treatment of asthma. The efficacy of an tihistamines in
asthma needs to be reconsidered, as new drugs largely
devoid of side-effects have been available for the past
10 yrs [3-5].
Points in favour of a r ole of antihistamines in
asthm a
Histamine plays a role in the pathogenesis of asthma
Histamine plays a role in the mechanisms of asthma
[6). It is released during the early and late phase
allergic reactions following bronchial challenge with
allergen [7]; mast cells are present in lhe biopsies of
allergic and nonallergic asthmatics [8] and histamine
Clinique des Maladies Respiratoire,
Hapita l l'Aiguelo n gue, Centre
Hospitalier Universitaire, Montpellier,
France
Correspondence: J. Bousquet
Clinique des Maladies Respiratoires
H6pital l'Aiguelongue
Centre Hospitalier Universitaire
34059-Montpellier-Cedex, France
Keywords: Anti-histamines, asthma,
H 1-blockers, histamine
Received: May 12 1992
Accepted after revision June 16 1992
levels are increased in the bronchoalveolar lavage
(BAL) fluid of asthmatics [9]. Moreover, a significant correlation has been demonstrated between nonspecific bronchial hyperreactivity and histamine levels
in BAL fluid [9].
Histamine can induce the secretion of mucus by
bronchial glands, cause extravasation of plasma proteins leading to airways mucosal oedema, contract the
airway smooth muscle f6] and may play a role in the
immunomodulation of the immunoglobulin E (lgE)
immune response 10], as well as in the regulation of
the airway inflammation by the activation of epithelial cells and macrophages and possibly by inducing
smooth muscle hyperplasia.
The inhalation of histamine induces a bronchoconstrictive response in most subjects, but asthmatic
patients are hyperreactive to histamine [11 ].
r
Antihistamines possess some "anti-allergic" properties
Antihistamines block histamine at its H 1-receptor
level but many drugs possess other properties that may
be relevant for their efficacy [12]. Loratadine and
terfenadine reduce, in a dose-dependent manner, the
release of eicosanoids from human dispersed lung cells
and reduce the release of histamine and prostaglandin
D 2 (PGD 2) during nasal challenge with allergen.
After allergen challenge, cetirizinc decreases the eosinophil influx into the skin but it is not yet clear if it
has the same effect on nasal and bronchial cells. Although the exact significance of these properties is still
not fully understood, they might be involved in
asthma.
1138
J. BOUSQUET, Ph. GODARD, F.B. MICHEL
Links between asthma and rhinitis
Many patients with allergic rhinitis present both
rhinitis and asthma. Many patients with allergic rhinitis alone have an increased nonspecific bronchial
hyperreactivity [13]. Finally, sinusitis is thought to be
a causative factor in asthma [14]. Although the exact
links between the nose and the lung are far from
understood, it has been proposed that the treatment of
the nasal symptoms may improve asthma.
specifically examining this bronchodilating effect are
lacking and long-term clinical studies of antihistamines
in asthma suggest that this activity disappears after one
or two weeks.
Thus, the bronchodilating activity of antihistamines
may be limited in intensity and duration and, with our
current knowledge, it does not support their use in
asthma.
Provocative challenges
Points against a role of antihistamines in asthma
Histamine is only one of the mediators of asthma and
does not explain chronic inflammation of the airways
Histamine is one of the mediators of "allergic" and/
or "asthmatic" inflammation. It is likely to play a role
in the spasmogenic phase of asthma but its importance
in chronic inflammation of the airways remains to be
determined. Moreover, mast cells and basophils are
not the only cell types involved in airways inflammation in asthma [15] and many other cells, mediators,
toxic metabolites, cytokines and growth factors appear
to be more important than histamine and/or metachromatic cells. Finally, asthma is not only an inflammatory disease but remodels the airways inducing
permanent abnormalities (16). Thus, it appears that
antihistamines may only be partly effective in the
treatment of chronic asthma and poorly effective in
either long-standing asthma or in the most severe
patients.
Anti-allergic drugs are usually poorly effective in the
treatment of severe asthma
Sodium cromoglycate appears to be more effective
in young asthmatics and in patients with mild asthma.
It is usually less effective in the treatment of severe
asthmatics (17]. The results obtained with ketotifen are
less consistent but similar conclusions may be drawn
[18) .
Clinical relevance of antihistamines in asthma
Bronchodilating activity of antihistamines
The bronchodilating activity of a single dose of antihistamine was reported in the early 1980s [19) and
confirmed in some but not all studies [20-26]. Many
studies found a significant difference between the
bronchodilating activity of the placebo and the active
drug, but they do not appear to be clinically relevant,
since differences are usually small. In studies showing a significant effect of antihistamines, there was
no dose-response effect [26]. Long-term studies
Exercise and cold air challenges. Several studies have
been performed to assess the protective effect of antihistamines in exercise-induced asthma and related challenges such as nebulized water, hypertonic saline or
cold air (table 1) [27-40]. Many of these studies
show that antihistamines result in significant protection, but in some studies the effect, although significant, is very small and does not appear to be clinically
relevant. Moreover, in such situations, calcium antagonists and a-blockers were found to be effective in the
laboratory but had little or no effect when they were
administered to patients in an attempt to improve
asthma.
Allergen challenge. Many studies have also been performed in allergic asthmatics in order to prove the
efficacy of antihistamines during the early and late
phase allergic reactions. However, there have been
discrepancies in the results published. Terfenadine (41,
42] and astemizole [43], but not loratadine [44] and
cetirizine [45), have been shown to reduce the early
phase reaction, but even with terfenadine the response
was usually small and varied considerably between
subjects.
Studies attempting to demonstrate an effect on the
late phase reaction have been carried out on a very
small number of patients and results are highly variable [46-48). At best, the effect is again small. It
is, therefore, impossible to ascribe any clinically relevant protective effect of antihistamines on the late
phase reaction.
Nonspecific airway challenge. Nonspecific bronchial
hyperreactivity is a cardinal feature of asthma and
drugs such as inhaled corticosteroids and, to a lesser
extent, nedocromil sodium or sodium cromoglycate
have been found to reduce the magnitude of histamine
and/or methacholine inhalation challenge. Histamine
challenge has no value for testing the effect of antihistamines on nonspecific bronchial hyperreactivity
depending on the intrinsic activity of the drugs. Studies performed using methacholine challenge did not
show any difference before and after treatment
although it may be argued that the duration of the
studies was too short to observe any significant effect
[49-51]. Antihistamines can block challenge with
adenosine [52] or platelet-activating factor (PAF) [53]
but the clinical relevance of such challenges needs to
be characterized.
ANTIHISTAMINES IN ASTHMA TREATMENT
Table 1.
First
author
AzEVEDO
BACKER
BAD!ER
BARBERIO
BEWTRA
CLEE
FINNERTY
FJNNERTY
FlNNEY
GHOSH
GoNo
HOPP
O'HJCKEY
PATEL
-
1139
Effect of antihistamines in exercise challenge and related challenges
Ref.
Drug
(27]
(28]
[29]
(30]
(31]
[32]
(33]
(34]
[35]
(36]
[37]
(38]
(39]
[40]
Group of
patients
Dose
mg
Duration
n
T
A
T
180
30 o.d.
120 b.i.d.
1 dose
22 days
1 week
30
20
11
Children
Adult
T
T
A
T
T
T
Variable
240
10 o.d.
180
180
180
10 b.i.d.
5, 10, 20
240
120
180
1
1
1
1
1
1
1
1
1
2
1
14
12
9
10
9
12
12
16
12
10
10
Children
?
19-33 yrs
Adults
21-40 yrs
Adults
Adults
25-52 yrs
19-42 yrs
Adults
16-50 yrs
c
c
T
T
T
dose
dose
week
dose
dose
dose
week
dose
dose
doses
dose
Challenge
UNDW
Exercise
Hyperventilation
in cold air
Exercise
Cold air
Exercise
Exercise
Hypertonic saline
Nonisotonic aerosol
Exercise
Exercise + cold air
UNDW
Hypertonic saline
Exercise
p
Clinical
relevance
<0.001
NS
<0.001
Yes
Yes
Yes
NS
<0.05
<0.05
=0.03
<0.001
<0.02
NS
NS
<0.02
<0.02
<0.01
Yes
No
Yes
Abstract
Yes
Yes
Yes
Yes
NS results*
Minimal
Yes
UNDW: ultrasonized distilled water; T: terfenadine; A: astemizole; C: cetirizine; Ns: nonsignificant; •: when recalculated.
Clinical studies
Only studies performed during seasonal or perennial
asthma make it possible to assess the value of antihistamines in the treatment of asthma. Many inconclusive studies in both seasonal and perennial asthma
have been performed but never published and this represents a major gap in our knowledge of the efficacy
of antihistamines in asthma.
Seasonal asthma
Difficulties in designing the studies. There are
several drawbacks in the studies examining the effects
of antihistamines in the treatment of seasonal asthma.
Seasonal asthma is mainly caused by pollens and the
major symptoms of pollinosis are usually related to
rhinoconjunctivitis, with asthma occurring in the most
severe cases.
There have been a number of trials
performed in which no treatment for the nose or eyes
was administered and, as a result, most of the placebotreated patients dropped out of the study (54-55].
Nasal and ocular symptoms should be treated during
any asthma trial with drugs not affecting the interpretation of the study. There is no commonly accepted
treatment for nasal or ocular symptoms during asthma
trials and the choice depends on many parameters:
topical or oral drugs; all patients treated identically
(56] or only patients who require a treatment for
severe symptoms; treatment applied during the whole
trial or only during the peak of the season.
Administration of the antihistamine may start before
the season in a prophylactic treatment or very soon
after the patients develop asthma. It is critical that
long-standing asthmatics should be excluded from such
studies since antihistamines are likely to have maximal effect on patients who have a low degree of bronchial inflammation.
Inclusion criteria are not standardized but it is
commonly accepted that patients should present a
reversibility of the airway obstruction after the inhalation of ~ 2 -agonists. However, in grass pollen
asthma, few patients have a reversible airways obstruction of > 15% of forced expiratory volume in one
second (FEV1).
The grass pollen season lasts 6-8 weeks in most
countries but it is highly heterogeneous, pollen counts
varying daily and from year to year. The tree pollen
season (birch primarily) is shorter, usually intense in
terms of pollen counts and symptoms, but highly variable from year to year. The ragweed pollen season
is the most constant in terms of onset, peak and
duration but it lasts only 4--6 weeks. It is, therefore,
difficult to propose crossover trials with washout
periods between treatments.
The analysis of the data is not easy. All trials
examine symptom and medication scores, some evaluate the evolution of the pulmonary function tests or
peak flow rates. However, in grass pollen asthma
mean peak flow rates usually show little decrease of
this interesting parameter. Ther~ is no study of nonspecific bronchial hyperreactivity available.
Results of double-blind studies with control or placebo
groups. Table 2 summarizes the results of the controlled studies performed with cetirizine and
terfenadine in seasonal asthma [54- 62). It must be
pointed out that the doses of antihistamines were
always greater than those administered for rhinoconjunctivitis and, in the study of RAFFERTY et al. [60)
the dose was 4.5 fold greater than recommended. If
this increased dose is to become the recommended
dose for asthma, the short- and long-term safety of the
drug should be monitored in specific studies.
In two studies, the patients received no treatment for
rhinitis and most of those under placebo dropped out
from the study. These studies cannot be analysed further since it is unclear whether the patients dropped
out because of nasal or bronchial symptoms [55, 59).
J. BOUSQUET, Ph. GODARD, F.B. MICHEL
1140
Table 2.
First
author
-
Controlled studies examining the efficacy of oral antihistamines In the treatment of asthma
Ref.
Duration
n
Age
yrs
Study
design
Asthma
20 o.d.
10, 15 b.i.d.
15 o.d.
22 days
14 days
14 days
20
80
57
fr15
18-73
19-40
DB-PC-CO
DP-PG*
DB-PC-PG
Chronic
Pollen
Pollen
b.i.d.
o.d.
b.i.d.
b.i.d.
6 weeks
8 weeks
?
28 days
43
17
20
60
12-74
25-63
?
?
DB-PG•
DB-PC-CO
DB-PG•
DB-PC-PG
Pollen
Chronic
Birch pollen
Pollen
s
c
c
10
10
10
10
Drug
Dose
mg
Stat.
sign.
Clinical
relevance
NS
Yes
Minimal
Too many
dropouts
Yes
Yes
BACKER
BousQUET
BRUTMAN
[28]
[54]
[55]
DIRKMAN
DIIKSEN
KuRZEJA
PEDRALI
[56}
[57]
[58]
(59)
RAFFERTY
[60]
T
180 t.i.d.
4 weeks
18
34.7:t5.6
DB-PC-CO
Pollen
s
TAYTARD
TEALE
[61]
[62]
T
T
120 b.i.d.
120
2 weeks
1 dose
46
8
12-53
29-72
DB-PC-CO
DB-PC
Mite
Nocturnal
s
s
A
c
c
c
L
s
s
NS
s
?
s
Too many
dropouts
Very high
dose
Yes
Minimal
A: astemizole; C: cetirizine; L: Joratadine; T: terfenadine; DB: double-blind; PC: placebo-controlled; CO: cross-over; PG:
parallel group; Stat. sign.: statistical significance; Ns: nonsignificant; s: significant. *: the control group received T 60 mg
b.i.d. to control nasal and ocular symptoms.
In other studies, patients received either cetirizine (20
or 30 mg daily) or a rescue medication given to all
patients in the control group, terfenadine, at a dose
that was suggested to be ineffective in asthma (60 mg
b.i.d.). The results of the study of BousauET et al.
[54] are not very convincing, possibly because the
control group was under terfenadine. Finally, there are
only two studies published in detail showing some
efficacy of antihistamines in asthma [56, 60]. However, not all parameters were improved and the pulmonary function, peak flow rates or ~ 2 -agonist rescue
medication were similar in the treated and placebo
groups.
These studies show a moderate effect of antihistamines in the treatment of seasonal asthma but, since
many inconclusive studies have not been published,
more data are needed before a firm conclusion can be
reached.
Perennial asthma
Difficulties in designing the studies.
There are also
several drawbacks in the studies examining the effects
of antihistamines in the treatment of perennial asthma
Results of double-blind studies with control group.
The study of TAYTARD et al. [61] is the only published
study showing a favourable effect of antihistamines in
chronic symptoms of perennial asthma. Using
terfenadine at a dose of 120 mg b.i.d. in a cross-over
study carried out in mild asthmatics, they observed that
when patients were treated with the antihistamine they
presented significantly less symptoms, needed significantly less ~ 2 -agonists and presented an improvement
in pulmonary function as assessed by FEV1 and peak
flow rates. However, the improvement in pulmonary
function was small and may have little clinical relevance. Many other inconclusive studies have been
performed but never published.
Indications for antihistamines in asthma
The indications for antihistamines in the treatment
of asthma are still vague and more data are needed
before a firm conclusion can be drawn. New studies
are needed to compare the efficacy of antihistamines
with accepted anti-asthma treatment.
[28, 57, 60-62].
The design of the trial is critical. Asthma is a
chronic inflammatory disease leading to a remodelling
of the airways. It is, therefore, suggested that antihistamines will be more effective in patients with mild
asthma and in the younger asthmatics. In perennial
asthma, rhinitis and conjunctivitis are not always severe and nasal or ocular treatments are not required
by most patients. Anti-inflammatory drugs should be
carefully avoided for a long period of time, since it
is unlikely that antihistamines will add significant benefit to inhaled corticosteroids. The duration of the
run-in period is critical, since asthma is highly variable. The study may be performed in parallel groups
or in a cross-over manner but in the latter case the
washout period is critical.
References
1. Schuller DE. - The spectrum of antihistamines adversely affecting pulmonary function in asthmatic children.
J Allergy Clin lmmunol, 1983; 71: 147-150.
2. Sly RM, Kemp JP, Anderson JA et al. - The use of
antihistamines in patients with asthma. Position statement
of the Committee on Drugs of the American Academy of
Allergy and Immunology. J Allergy C/in lmmunol, 1988;
83: 481-482.
3. Rafferty P. - Antihistamines in the treatment of clinical asthma. J Allergy Clin lmmunol, 1990; 88: 647-650.
4. Pierson WE, Virant FS. - Antihistamines in asthma.
Ann Allergy, 1989; 63: 601-608.
5. Holgate ST, Finnerty JP. - Antihistamines in asthma.
J Allergy C/in lmmunol, 1989; 83 (2: Pt 2): 537- 547.
ANTIHISTAMINES IN ASTHMA TREATMENT
6. White MV, Slater JE, Kaliner MA. - Histamine and
asthma. Am Rev Respir Dis, 1987; 135: 1165-1176.
Immu7. Durham SR, Lee TH, Cromwell 0 et al. nologic studies in allergen-induced latephase asthmatic
reactions. J Allergy Clin lmmunol, 1984; 74: 49-59.
8. Laitinen LA, Heino M, Laitinen A, Kava T, Haathela
T. - Damage of the air;vay epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis, 1985;
131: 599-606.
9. Jarjour NN, Calhoun WJ, Schwanz LB, Busse WW. Elevated bronchoalveolar lavage fluid histamine levels in
allergic ast hmatics are associated with increased airway
obstruction. Am Rev Respir Dis, 1991; 144: 83-87
10. Falus A, Meretky K. - Histamine: an early messenger in inflammatory and immune reactions. lmm unol
Today, 1992; 13: 154-156.
lL Eiser NM, Kerrebijn KF, Quanjer PR. - Guidelines
for standardisation of bronchial challenges with nonspecific
bronchoconstricting agents. Bull Eur Physiopathol Respir,
1983; 19: 495-514.
12. Bousquet J, Campbell AM, Michel FB. - Antiallergic properties of H1-blockers. In : Church M.K. Rihoux
J.P. eds. Therapeutic index of an tihistamines. Toronto,
Hogrefe & Hu ber Publishers, 1992: pp 57-95.
13. Townley RO, Ryo UY, Kolotin BM, Kang B.
Bronchial sensitivity to methacholine in current and fom1er
asthmatic and allergic rhinitis patients and control subjects.
J Allergy Clin lmmunol, 1975; 56: 429-437.
14. Druce HM, Slavin RG. - Sinusitis: a critical need
for further study. J Allergy Clin lmmunol, 1991; 88: 675677.
15. Djuranovic R, Roche WR, Wilson JH et al. - Mucosal inflammation in asthma. Am Rev Respir Dis, 1990;
142: 434-457.
16. Bousquet J, Chanez P, Lacoste JY et al. - Asthma;
a disease remodeling the airways. Allergy, 1992; 47: 311.
17. Cockroft DW. - Therapy for airway inflammation in
asthma. 1 Allergy Clin lmmunol, 1991; 87: 914-919.
18. Finke lman DG, Moss BA, Bukantz SC et a/: A
multicenter triaJ of the prophylactic effect of ketotifen,
theophylline and placebo in atopic asthma. J Allergy Clin
lmmuno/, 1985; 76: 487-497.
Effec t of an H 1-blocker, chlor19. Popa VT.
pheniramine, on inhalation tests with histamine and allergen in allergic ast hma. Chest, 1980; 78: 442-451.
20. Nogrady SO, Hartley JPR, Handslip PDJ, Hurst NP. Bronchod ilatation after inhalation of the antihistam ine
clemastine. Thorax, 1978; 33: 479-482.
21. Eiser NM, Mills J, Snashall PD, Ouz A. - The role
of histamine receptors in asthma.. C/in Sci, 1981; 60: 363370.
22. Cookson WOCM. - Bronchodilator action of the
antihistamine, terfenadine. Br J Clin Pharmacol, 1987; 24:
120-121.
23. Pate! KR, Gosh SK. - Bronchodilator activity of H1receptor antagonists. In: Pischler W.J. et al. eds. Progress
i n Allergy and Clinical Immunology. Toronto, Hogrefe &
Ruber Publishers, 1989: pp. 222-226.
24. Rafferty P, Holgate ST. - Terfenadine is a potent and
selective H1-receptor antagonist in asthmatic airways. Am
Rev Respir Dis, 1987; 135: 181-184.
25. MacFarlane PI, Heaf DP. - Selective histamine blockade in childhood asthma; the effect of terfenadine on resting bronchial tone and exercise-induced bronchoconstriction.
Respir Med, 1989; 83: 19-24.
26. Pate ! KR, Gosh SK, Matcham J.
Lack of
1141
dose-response effect of terfenadine on resting bronchomotor
tone in patients with asthma. Clin Exp Allergy, 1991; 21:
363-366.
27. Azevedo M, da Costa JT, Pontes P, da Silva JP, Araujo
0 . - Effect of terfenadine and ipratropium bromide on
ultrasonically nebulized distilled water-induced asthma. J
lnt Med Res, 1990; 18: 37-49.
28. Backer V, Bach-Mortensen N, Becker U et al. The
effect of astemizoJe on bronchial hyperresponsiveness and
exercise-induced asthma in children. Allergy, 1989; 44:
209-213.
29. Badier M, Beaumont D, Orehek J. - Attenuation of
hyperventiJation-induced bronchospasm by terfenadine: a
new antihistamine. J Allergy Clin Immunol, 1988; 81: 437440.
30. Barberio G, Ruggeri C, Pajno GB et al. - Terfenadine and prevention of exercise-induced asthma. Rev Fr
Allergol, 1990; 30: 17-19.
31. Bewtra AK, Hopp RJ, Nair NM, Townley RG. - Effect of terfenadine on cold air-induced bronchospasm. Ann
Allergy, 1989; 62: 299s.
32. Clee MD, Ingram CG, Reid PC, Robertson AS. - The
effect of astemizole on exercise-induced asthma. Br J Dis
Chest, 1984; 78: 180-183.
33. Finnerty JP, Holgate ST. - Effects of terfenadinc and
ipratropium alone and in combination on exercise-induced
asthma. Thorax, 1989; 44: 851P.
34. Finnerty JP, Wilmot C. Holgate ST. - Tnhibiti.on of
hypertonic saline-induced bronchoconstriction by terfenadine
and flurbiprofen. Evidence for the predominant role of histamine. Am Rev Respir Dis, 1989; 140: 593-597.
35. Finney MJB, Anderson SD, Black JL. - Terfenadine
modifies airway narrowing induced by the inhala tion of
nonisotonic aerosols in subjects with asthma. Am Rev
Respir Dis, 1990; 141: 1151-1157.
36. Ohosh SK, De Vos C, Mcllroy I, Patel KR. - Effect
of cetirizine on exercise-induced asthma. Thorax, 1991; 46:
242-244.
37. Gong H, Tashkin DP, Dauphinee B, Djahed B, Wu TZ. Effect of oral cetirizine, a selective H1 antagonist,
on allergen- and exercise-induced bronchoconstriction in
subjects with asthma. J Allergy Clin Immunol, 1990; 85:
632-641.
38. Hopp RJ, Bewtra AK, Nair NM, Townley RG. - Effect of terfenadine on the bronchoconstriction induced by
ultrasonic nebulized water. Ann Allergy, 1988; 61: 13-16.
39. O'Hickey SP, Belcher NO, Rees PJ, Lee TH. - Role
of histamine release in hypertonic saline induced bronchoconstriction. Thorax, 1989; 44: 650-653.
40. Pate! KR. - Terfenadine in exercise-induced asthma.
Br Med J, 1984; 288: 1496-1497.
41. Rafferty P, Beasley R, Holgate ST. - The contribution of histamine to immediate bronchoconstriction provoked
by inhaled allergen and adenosine 5'monophosphate
in atopic asthma . Am Rev Respir Dis, 1987; 136:
369-373.
42. Curzen N, Rafferty P, Holgate ST. - Effects of a
cyclo-oxygenase inhibitor, flurbiprofen and an H1-histamine
receptor antagonist, terfenadine, alone and in combination
on allergen-induced immediate bronchoconstriction in man.
Thorax, 1987; 42: 946-952.
43. Vanderschueren R, Van Nierop R, Vanden Bussche G.
- Astemizole in asthmatic patients. Effect on histamine
and allergen challenge. Journal for Drug Therapy and
Research, 1986; 11: 432-435.
44. Town GI, Holgate ST. - Comparison of the effect
of loratadine on the airway and skin responses to histamine,
1142
J. BOUSQUET, Ph. GODARD, F.B. MICHEL
methacholine and allergen in subjects with asthma.
J Allergy Clin lmmunol, 1990; 86: 886-893.
45. Kopferschmidt-Kubler MC, Couchot A, Pauli G. Evaluation of the effect of oral cetirizine on antigen-induced
immediate asthmatic response. Ann Allergy, 1990; 65: 501503.
46. Eiser N. - The effect of a ~ 2 -adrenergic agonist and
a histamine H 1-receptor antagonist on the late asthmatic
response to inhaled allergen. Respir Med, 1991; 85: 393399.
47. Lai CKW, Beasley R, Holgate ST. - The effect of
an increase in inhaled allergen dose after terfenadine on the
occurrence and magnitude of the last asthmatic response.
Clin Exp Allergy, 1989; 19: 209-16.
48. Hamid M, Rafferty P, Holgate ST. - The inhibitory
effect of terfenadine and flurbiprofen on early- and latephase bronchoconstriction following allergen challenge in
atopic asthma. Clin Exp Allergy, 1990; 20: 261-267.
49. Pate! KR. - Effect of terfenadine on methacholineinduced bronchoconstriction in asthma. J Allergy Clin
lmmunol, 1987; 79: 355-358.
SO. Finnerty JP, Holgate ST, Rihoux JP. - The effect of
2 week treatment with cetirizine on bronchial reactivity to
methacholine in asthma. Br J C/in Pharmacal, 1990; 29:
79-84.
51. Ruffin RE, Latimer KM. - Lack of effect of 4 weeks
of oral H 1 antagonist on bronchial responsiveness. Eur
Respir J, 1991; 4: 575-579.
52. Pbillips G, Rafferty P, Beasley R, Holgate ST. Effect of oral terfenadine on the bronchoconstrictor response
to inhaled histamine and adenosine 5'-monophosphate in
non-atopic asthma. Thorax, 1987; 42: 939-945.
53. Hopp RJ, Townley RO, Agrawal DK, Bewtra A. Terfenadine effect on the bronchoconstriction, dermal
response and leukopenia-induced by platelet-activating
factor. Chest, 1991; 100: 994-998.
54. Bousquet J, Emonot A, Germouty J et al. - Doubleblind multicenter study of cetirizine in grass pollen-induced
asthma. Ann Allergy, 1990; 65: 504-508.
55. Bruttmann G, Pedrali P, Arendt C, Rihoux JP. - Protective effect of cetirizine in patients suffering from pollen
asthma. Ann Allergy, 1990; 64: 224-228.
56. Dijkman JH, Hekking PRM, Molkenboer JF et al. Prophylactic treatment of grass pollen-induced asthma with
cetirizine. C/in Exp Allergy, 1990; 20: 483-490.
57. Dirksen A, Engel T, Frolund L, Heinig JH, Svendsen
UO, Weeke B. - Effect of a non-sedative antihistaminic
(loratadine) in moderate asthma. A double-blind,
controlled, clinical cross-over trial. Allergy, 1989; 44: 566571.
58. Kurzeja A, Riedelsheimer B, Hulhoven R, Bernheim J.
- Cetirizine in pollen-associated asthma. Lancet, (letter),
1989; i: 556.
59. Pedrali P, Arendt C. - The preventive effect of
cetrizine 10 mg b.i.d. in the treatment of seasonal allergic
asthma: a double-blind, placebo-controlled study. Health
Sci Rev, 1989; 3: 31-32.
60. Rafferty P, Jackson L, Smith R, Holgate ST.
Terfenadine, a potent histamine H1-receptor antagonist in the
treatment of pollen sensitive asthma. Br J Clin Pharmacal,
1990; 30: 229-235.
61. Taytard A, Beaumont D, Pujet JC, Sapene M, Lewis
PJ. - Treatment of bronchial asthma with terfenadine: a
randomized controlled trial. Br J Clin Pharmacal, 1987;
24: 743-746.
62. Teale C, Morrison JFJ, Pearson SB. - Effects of H1receptor blockade with terfenadine in nocturnal asthma. Br
J Clin Pharmacal, 1991; 32: 371-373.