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Comparison of Formoterol and Salmeterol: Structures, Effects, and Mechanisms, Study Guides, Projects, Research of Acting

An abstract of a study comparing the long-acting beta-2-adrenoceptor agonists formoterol and salmeterol. The study discusses their chemical structures, bronchodilating effects, and potential mechanisms of action, including their interaction with exoreceptors and receptor affinity. The document also mentions their lipophilicity and effects on histamine release, leukotrienes, and airway microvascular leakage.

What you will learn

  • How do formoterol and salmeterol compare in terms of their bronchodilating effects and duration of action?
  • What are the chemical structures of salbutamol, formoterol, and salmeterol?

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Eur Aesplr J
1991' 4,
218-226
REVIEW
Long-acting
~
2
-adrenoceptor
agonists: a new perspective
in
the treatment of asthma
C.G.
L6fdahl,
K.
F.
Chung*
Long-acting
{3
2-adrenoceptor agonists: a new perspective
in
the treatment
of
asthma.
C.G.
Liifdahl, K.F. Chung.
Dept
of
Pulmonary
Medicine,
Gotbenburg
University,
Renstr!lmska
Hospital,
S-402
64
G!lteborg, Sweden.
ABSTRACT:
New
long-acting
~
1
-adrenoceptor
agonlsts, formoterol and
salmeterol, may soon appear
In
several European countries for treatment
of
asthma. This review examines currently available Information and
compares the basic pharmacology and describes the clinical effects of
these new drugs. The long duration of bronchodilatlon seen in clinical
studies seems to be similar, whereas
In
isolated tissues there might be a
difference
In
the binding characteristics to the
~
2
-adrenoceptor.
Long-
acting
~
2
-agonlsts
could have an inhibitory effect on Inflammatory events
related to asthma,
but
the clinical relevance of these effects
Is
not clear
at
present. Long-term studies up to one year with both new drugs have
not
shown
any
unexpected
side-effects,
and
no tachyphylaxis to
~-adrenoceptor
stimulation has been reported. Patients appear to strongly
prefer the new drugs compared to the short-acting
~
2
-agonists.
The
potential place for these drugs in the treatment of asthma
is
discussed
and
some pitfalls pointed out.
It
is
likely that the long-acting
~
-agonists
will be beneficial
to
many asthmatic patients. 2
Dept
of
Thoracic Medicine, National Heart and
Lung
Institute,
Royal
Brompton
Hospital,
Dovehouse Street, London, UK.
Correspondence: K.F. Chung, Dept
of
Thoracic
Medicine, National Heart and Lung Institute, Royal
Brompton Hospital, Dovehouse Street, London,
SW3
6LY
UK.
Keywords:
Asthma;
~
2
-adrenoceptor
agonist;
formoterol; salmeterol.
Received: August 1990; accepted September
8,
1990.
Supported by the Swedish Heart-Lung Foundation.
Eur Respir
J.,
1991,
4,
218-226.
~
2
-adrenoceptor
agonists used
as
bronchodilators have
played an important part in the treatment
of
asthma
during the last 20 yrs. These selective drugs have the
advantage over nonspecific
~-adrenoceptor
agonists such
as isoprenaline, being devoid particularly
of
cardiac side-
effects
[1
].
Selective
~
2
-agonists
such as salbutamol,
terbutaline and fenoterol are currently the most potent
and effective bronchodilators available for the treatment
of
asthma, particularly when administered by inhalation
[1]. They induce prompt symptomatic relief
of
wheezing
and breathlessness with a duration
of
action
of
3-5
h.
Repeated use
of
~
2
-adrenoceptor
agonists does not
appear
to
lead to tachyphylaxis on the bronchodilatory
effect in asthmatics [1].
~
2
-adrenoceptor
agonists are also potent in inhibiting
mast cell degranulation [2]. However, their effect on
various manifestations
of
the inflammatory events in
asthma has been controversial [3]. Studies
of
airway
microvascular leakage has provided conflicting results,
and there is evidence to suggest that
~
-agonists do not
inhibit activation
of
human eosinoph2
ils and alveolar
macrophages [
4,
5].
It
have also been difficult to show
any effect
of
the
~
2
-adrenoceptor
agonists on the late
phase reaction after allergen provocation [6]. Therefore,
currently available
~
2
-agonists
may not modify the
inflammatory
process
of
asthmatic
airways,
and
concomitant treatment with an inhaled glucocorticoid is
recommended, particularly
if
regular use
of
inhaled
~
-
adrenoceptor agonist is needed to control symptoms.
2
A new group
of
~
2
-adrenoceptor
agonists, formoterol
and salmeterol, characterized by their prolonged bron-
chodilator effect, has been under development during
the last few years. In clinical studies, formoterol was
found to have a long duration
of
bronchodilation when
given by inhalation but when given by oral route its
duration
of
action was similar to that
of
salbutamol [7].
Salmeterol
was
the
result
of
a
specific
research
programme to design long-acting bronchodilators by
molecular modification
of
the
~
2
-adrenoceptor
agonist
salbutamol [8-11]. Apart from their improved duration
of
action, these new drugs, salmeterol and formoterol,
may possess other properties
of
particular relevance to
asthma.
Salmeterol and formoterol may become available for
prescription in several European countries within the
next few years. In this article we will review the basic
and clinical pharmacological profiles
of
these new
~
-
agonists, and in the light
of
the information available s2
o
far we will speculate on how these drugs may be used
in the treatment
of
asthma and pinpoint some
of
the
possible problems that may arise with these drugs.
Basic pharmacology
The chemical structure
of
the two new compounds
are shown together with salbutamol, terbutaline and
fenoterol in figure 1 [11-13]. Both formoterol and
pf3
pf4
pf5
pf8
pf9

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Download Comparison of Formoterol and Salmeterol: Structures, Effects, and Mechanisms and more Study Guides, Projects, Research Acting in PDF only on Docsity!

Eur Aesplr J 1991' 4, 218-

REVIEW

Long-acting ~ 2 -adrenoceptor agonists: a new perspective

in the treatment of asthma

C.G. L6fdahl, K. F. Chung*

Long-acting {3 2 -adrenoceptor agonists: a new perspective in the treatment of asthma. C.G. Liifdahl, K.F. Chung.

Dept of Pulmonary Medicine, Gotbenburg University, Renstr!lmska Hospital, S-402 64 ABSTRACT: New long-acting ~ G!lteborg,^ Sweden. 1 -adrenoceptor^ agonlsts, formoterol and salmeterol, may soon appear In several European countries for treatment of asthma. This review examines currently available Information and compares the basic pharmacology and describes the clinical effects of these new drugs. The long duration of bronchodilatlon seen in clinical studies seems to be similar, whereas In isolated tissues there might be a difference In the binding characteristics to the ~ 2 -adrenoceptor. Long- acting ~ 2 -agonlsts could have an inhibitory effect on Inflammatory events related to asthma, but the clinical relevance of these effects Is not clear at present. Long-term studies up to one year with both new drugs have not shown any unexpected side-effects, and no tachyphylaxis to ~-adrenoceptor stimulation has been reported. Patients appear to strongly prefer the new drugs compared to the short-acting ~ 2 -agonists. The potential place for these drugs in the treatment of asthma is discussed and some pitfalls pointed out. It is likely that the long-acting ~ -agonists will be beneficial to many asthmatic patients.

2

  • Dept of Thoracic Medicine, National Heart and Lung Institute, Royal Brompton Hospital, Dovehouse Street, London, UK.

Correspondence: K.F. Chung, Dept of Thoracic Medicine, National Heart and Lung Institute, Royal Brompton Hospital, Dovehouse Street, London, SW 6LY UK.

Keywords: Asthma; ~ 2 -adrenoceptor agonist; formoterol; salmeterol.

Received: August 1990; accepted September 8, 1990.

Supported by the Swedish Heart-Lung Foundation.

Eur Respir J., 1991, 4, 218-226.

~ 2 -adrenoceptor agonists used as bronchodilators have

played an important part in the treatment of asthma during the last 20 yrs. These selective drugs have the advantage over nonspecific ~-adrenoceptor agonists such as isoprenaline, being devoid particularly of cardiac side-

effects [1 ]. Selective ~ 2 -agonists such as salbutamol,

terbutaline and fenoterol are currently the most potent and effective bronchodilators available for the treatment of asthma, particularly when administered by inhalation [1]. They induce prompt symptomatic relief of wheezing

and breathlessness with a duration of action of 3-5 h.
Repeated use of ~ 2 -adrenoceptor agonists does not

appear to lead to tachyphylaxis on the bronchodilatory effect in asthmatics [1].

~ 2 -adrenoceptor agonists are also potent in inhibiting

mast cell degranulation [2]. However, their effect on various manifestations of the inflammatory events in asthma has been controversial [3]. Studies of airway microvascular leakage has provided conflicting results, and there is evidence to suggest that ~ -agonists do not inhibit activation of human eosinoph

2 ils and alveolar macrophages [ 4, 5]. It have also been difficult to show

any effect of the ~ 2 -adrenoceptor agonists on the late

phase reaction after allergen provocation [6]. Therefore,

currently available ~ 2 -agonists may not modify the

inflammatory process of asthmatic airways, and concomitant treatment with an inhaled glucocorticoid is recommended, particularly if regular use of inhaled ~ - adrenoceptor agonist is needed to control symptoms.

2

A new group of ~ 2 -adrenoceptor agonists, formoterol

and salmeterol, characterized by their prolonged bron- chodilator effect, has been under development during the last few years. In clinical studies, formoterol was found to have a long duration of bronchodilation when given by inhalation but when given by oral route its duration of action was similar to that of salbutamol [7]. Salmeterol was the result of a specific research programme to design long-acting bronchodilators by

molecular modification of the ~ 2 -adrenoceptor agonist

salbutamol [8-11]. Apart from their improved duration of action, these new drugs, salmeterol and formoterol, may possess other properties of particular relevance to asthma. Salmeterol and formoterol may become available for prescription in several European countries within the next few years. In this article we will review the basic and clinical pharmacological profiles of these new ~ - agonists, and in the light of the information available s

2 o far we will speculate on how these drugs may be used in the treatment of asthma and pinpoint some of the possible problems that may arise with these drugs.

Basic pharmacology

The chemical structure of the two new compounds are shown together with salbutamol, terbutaline and fenoterol in figure 1 [11-13]. Both formoterol and

LONG·ACfiNG ~ 2 -AGONISTS 219

salmeterol possess a longer side-chain than salbutamol and terbutaline. The salmeterol side-chain is consider- ably longer th an that of formoterol , and it has been suggested that this long s id e-chain binds to an exo- receptor near the ~ -recep tor ; the exoreceptor may help to anchor th e t\ · agon ist to it s receptor and thi s may explain th e prolonged du ration of salmeterol [11- 14]. From a structural point of view it seems unlikely that the long action of formoterol is due to the same mechanism.

HO..CH2 OH

HO -o ~H·CH 2 ·NH·CH 2 ·CH 2 .CH 2 ·C~.CH 2 .CH 2 ·0.CH 2 ·CH 2 .CH 2 .CH 2 • -@

Salmeterol

Salbutamol 0 H~·NH OH CH

HO ::(g. ~H.c~·NH1H.CH2-o OCH

Formoterol Fig. 1. - Chemical structures for salbutamol, formoterol and sa!meterol.

Both co m po un ds are hig hl y sel ec ti ve f or ~ 2 -

adrenoceptors (9- 13]. Formoterbl is about 200 times more potent in in ducing re laxation of the precontracted gu inea-pig t ra cheal smooth mu scle than in incre as ing

the atrial ra te in isolated guinea-pig atria. By compa ri -

son salbutamol was 17 times more potent on the trachea than on the atria [13]. Formoterol and salmeterol are much more potent than salbutamol in the guinea-pig trachea, as seen both with extratracheal and intratracheal administration (table 1) [15]. The time of onset for the bronchodilator effect could be important when the drugs are used in the clinical situation. In vitro, salmeterol has a markedly increased time to half maximal relaxation, about 17 min in a carbachol-contracted guinea-pig trachea, whereas salbutamol and formoterol exerted half maximum relaxation within 2 min (15].

Table 1. - Potency (pD.2) for some j3 2 -adrenoceptor agonists, measured as Inhibition of the increase in intratracheal pressure induced by vagal nerve stimula- tion

Compound

Salbutamol Formoterol Salmeterol

Extratracheal admin pD

7.32±0. 13 9.23±0. 8.03±0.

Mean±SEM. Data from (15].

Intratracheal admin pD

5.75±0. 8.51±0. 7.97±0.

Salmeterol was shown to have a long duration of effect on isolated guinea-pig trachea and human bronchial tissue, and a sustained effect for many hours has been shown [9]. Also with formoterol a prolonged bron- chodilator effect has been demonstrated in vitro [15, 16]. In one study the remaining ~-stimulating effect on isolated guinea-pig trachea after wash-out and continu- ous flushing of the organ baths for 1 h was fo r salbutamol (0.1 ~-tM) only 9±4%, whereas for formotero l (10 nM) it was 78±7% and for salmeterol (50 nM) it was 93±7%. Thus, in vitro in the guinea-pig trachea the duration of the relaxation after continuous washing was longer for salmeterol than for formoterol [16]. In other in vitro models and with different doses the difference between salmeterol and formoterol has been more pronounced, with a longer remaining effect for salmeterol than for formoterol [15, 17, 18]. In a study of the effects of salmeterol, formoterol and salbutamol on the binding of C^25 I) iodopindolol ( 125 IPIN), a ~ 2 -antagonist, in rat lung membranes, both salmeterol and formoterol had similar affinities (53 and 76 nM, respectively), compared to 2. ~-tM for salbutamol. Preincubation of membranes with salmeterol prevented 12 ~IPIN binding, but both salbutamol and formoterol were rapidly displaced by (^125) IPIN [18]. Similar studies need to be performed on human lung membrane preparations. Lipophilicity may be related to the long duration of bronchorelaxation for these drugs. One study (15] showed that the octanol/water distribution coefficient, as a measurement of lipophilicity, was low for salbutamol, whereas formoterol was lipophilic, and

salmeterol was highly lipophilic. Other ~ 2 -adrenoceptor

agonists were also tested, and a relatively good corre- lation between the lipophilicity and the in vitro duration of action was seen. However, the lipophilicity may not

be the only explanation, as some ~ 2 -agonist drugs have

a high lipophilicity without having a prolonged duration of action. The prolonged duration of effect in vivo is unlikely to be due to effects on the airway epithelium, as there was no difference in duration of relaxant effect in guinea-pig tracheal rings with or without epithelium [16]. The effect of salmeterol can be blocked by sotalol, a

~ 2 -antagonist but reasserts itself after wash-out [11]. In

a recent comparison of salmeterol and formoterol in carbachol-contracted guinea-pig tracheal rings, treated with supramaximal salmeterol (1 ~-tM) and formoterol (50 nM) doses, sotalol (10 !J.M) rapidly reversed the relaxation in all rings. After wash-out procedures and 30 min continuous flushing of the muscle baths the effect of salmeterol and formoterol reasserted itself to a similar level as after the first treatment. In rings treated with supramaximal salbutamol doses there was no reassertion of the relaxation after sotalol treatment followed by wash out and flushing. After a second sotalol treatment the wash-out procedures and washing was repeated with a reassertion of the relaxant effect similar to that seen after the first washing period for formoterol and salmeterol, respectively [16]. These studies suggest that both compounds are bound in the smooth muscle mem- brane adjacent to the ~-receptor, and both compounds

LONG-ACTING {3 2 -AGONISTS 221

comparison we have chosen 100 1-1-g salbutamol, 250 1-1-g terbutaline and 100 1-1-g fenoterol as equipotent doses when given by the inhaled route (28-30]. The corre- sponding dose for formoterol is 6-12 j..tg and for salmeterol 25-50 1-1-g [7, 31-34].

Selectivity

Selectivity for the ~ 2 -adrenoceptor has in clinical

studies been shown to be similar for the new drugs and the old drugs. Formoterol was studied in cumula- tive dose-response experiments with both oral and inhaled administration. Similar increases in heart rate were observed for the same degree of bronchodilation when comparing salbutamol and formoterol [7]. For salmeterol no cumulative experi- ments have been performed, but single dose clinical studies have indicated that salmeterol has the same

~ 2 -selectivity as salbutamol (35].

Onset of action

The increase in specific airway conductance at one min after inhalation of formoterol (12, 24 and 48 j..tg) is more pronounced than after 0.2 mg salbutamol (36, 37]. Similar results were achieved in other comparisons with terbutaline and salbutamol [38, 39]. Thus, there is no evidence for a delayed onset of effect with formoterol. Studies with salmeterol have shown a tendency towards a slower onset of action (31 ], but evaluation of the effect during the first minutes after inhalation has not been performed. No direct comparison between sa lm eterol and formoterol has been performed on the question of onset of action.

Duration of bronchodilation

Formoterol and salmeterol have a bronchodilating effect lasting up to 12 h, as has been shown in several studies. Formoterol was studied in an 8 h study, in 8 asthmatic patients, and inhaled formoterol (6 ~-tg) and inhaled salbutamol (0.1 mg) induced a rapid bronchodilation, up to about 80% of maximum achiev- able response. With salbutamol the bronchodilator effect had disappeared after 4-5 h, whereas 8 h after forrnoterol about 75% of the initial response remained [7, 40]. In several other later studies on formoterol a 12 h duration of effect has been shown both in adults [34, 36, 41, 42] and in children [32, 33, 43]. A prolonged bronchodilator effect has also been shown in healthy smokers and nonsmokers [44]. It should be noted that the duration of effect may va ry from individual to indivi du al, an d some asthma patients seem to lose th e effect after 9- 10 h [41, 45]. However, in one study the me di an duration tb return to baseline forced ex piratory vo lu me in one second (FEV 1 ) was greater than 12 h for 12 and 24 llg forrnoterol [41].

Salmeterol was studied in a similar study in 8 asth- matic patients, and a good sustained bronchodilation was achieved for more than 12 h [31, 35]. Other studies have confirmed the 12 h duration for salmeterol [ 46-49]. An individual variation of duration of bronchodilation has not been commented upon in these presentations. There are no direct comparative studies between formoterol and salmeterol concerning clinical bronchodilating effect.

Duration of protective effect against bronchoconstrictor challenges

Acute studies of the protective effect on provoked bronchoconstriction in asthma patients or in normal in- dividuals have been performed for both drugs. A pro- longed duration of the protective effect up to 12 h against methacholine in asthmatic patients has been demonstrated [50, 51]; one study showed protection lasting for at least 5 h [52]. In children the provocative methacholine dose remained elevated for more than 12 h after formoterol treatment [53, 54]. Protection against histamine in chil- dren showed similar duration after formoterol treatment [54]. For salmeterol the protection against histamine- induced bronchoconstriction in healthy subjects had a duration up to 12 h, whereas salbutamol on ly showed a protective effect after 1 h but not after 4 h [55]. In asthmatics salmeterol also had a protective effect up to 12 h for methacholine-induced bronchoconstriction [56]. Exercise-induced bronchoconstriction has been evaluated in some studies with formoterol. Both in adults and in children it had a protective effect which lasted for at least 8 h [54, 57-59]. One study with forrnoterol (20 ~-tg) showed a protection against the late-phase allergic reaction, an effect more pronounced than the protection achieved by salbutamol (500 ~-tg) [26]. Both drugs had an effect on the early allergic response.

Long-term effect in asthma

Forrnoterol treatment for up to two weeks was studied in a cross-over study in 20 asthmatic patients [60]. Peak expiratory flow values, maximum as well as minimum values, during the days were significantly better during the formoterol treatment (12 llg b.i.d., and extra doses as and when needed) compared to salbutamol (0.2 mg b.i.d. plus extra doses). The need for additional doses of bronchodilator decreased significantly. Subjective evaluation of symptoms was better both during day and night du ri ng formo terol treatmen t compared to the values dur in g sa lb utamo l t reatment. T he eva l uation of tachyphylaxis to, ~-stim ul a ti o n was performed with dose- response cu rv es for increasing doses of sa lbutamol up to 1.3 m g. Before and af ter 2 wks of salbutamo l treat- ment the dose-response curves were almost ide nt ical, similar to the pre-formoterol curve. After the formoterol

222 C.G. L6FDAHL, K.F. CHUNG

treatment period, mean basal FEV 1 level was higher and FEV 1 increased further after the highest dose of salbutamol. Thus, there was no evidence of tachyphy- laxis during this two week treatment period [60]. There was a marked preference for formoterol; 15 preferred the formoterol period, two preferred the salbutamol period and three could not make a choice [60]. Another one month study with formoterol and salbutamol has recently been published with very similar results [61]. In a 3 month study of 301 patients in parallel groups comparing 12 !!g formoterol b.i.d. to salbutamol 200 !!g q.i.d., formoterol treatment gave higher morning peak flow values, fewer acute asthma attacks, with less rescue medication [62]. In a smaller parallel group study (66 patients) no difference was shown for formoterol compared to terbutaline, but there was a trend for decreased use of rescue medication in the formoterol-treated group [63]. A two week cross-over study has been performed with salmeterol (50 !!g b.i.d.) compared to salbutamol ( !!g q.i.d.) in 12 patients [64]. Ten patients preferred salmeterol and two could not make a choice. Peak flow measurements improved and the use of rescue medica- tion decreased during the salmeterol treatment. In addition, there was no evidence of tachyphylaxis. Subjective evaluation of sleep quality and breathless- ness was better after salmeterol treatment. In a multicentre study, 692 patients were randomized to 3 different dose levels of salmeterol. It showed that there was a dose-dependent improvement of peak flow, fewer episodes of nocturnal wakenings, a lower requirement of additional bronchodilator usage and no evidence of tachyphylaxis [65].

Other studies have evaluated the effect of the new ~ 2 -

agonists on nocturnal asthma. Both formoterol and salmeterol had a protective effect on nocturnal wheeze [66-69], and this effect was maintained for 1 yr in one study with formoterol [67]. One study could not show any difference between formoterol and salbutamol concerning nocturnal symptoms [70]. Several studies with formoterol have followed patients for up to 1 yr. Eighteen patients participated in a comparison of salbutamol 0.2 mg twice daily with formoterol 12 !!g twice daily [71]. Extra doses were allowed. Ten patients were randomly allocated to treatment with formoterol and 8 with salbutamol. After 1, 2 and 3 months the patients were allowed to shift over to the other treatment if they were not satisfied with their asthma control. Two patients did not complete the study. After one year 13 of 16 patients were on formoterol showing a significant long-lasting preference for this drug. Dose-response curves for inhaled salbutamol were recorded repeatedly during the study. No evidence of development of tachyphylaxis was found. Peak flow values were maintained at a high level, similar to the level these patients reached during the initial formoterol treatment. Other studies have also found a sustained good effect of formoterol up to 1 yr without any sign of tachyphylaxis to the ~-stimulating effect [67, 72, 73].

To date only two studies in children have evaluated bronchial hyperresponsiveness during prolonged treat- ment with formoterol [53, 54]. These studies have not shown any enhanced responsiveness after treatment for 3 [54] or 12 months [53]. It has been argued that short-

acting ~ 2 -agonists such as terbutaline transiently increase

bronchial hyperreactivity on discontinuing treatment [74], but this has not been demonstrated with formoterol in the two studies in children [53, 54]. More long-term studies of these new ~fagonists on bronchial hyperresponsiveness and evaluatiOn of effects after discontinuing treatment are warranted. Studies to examine directly inflammatory indices of the asthmatic airway such as bronchial biopsies and bronchoalveolar lavage are also needed.

Place of long-acting ~ 2 -agonists in the

treatment of asthma

Several issues need to be sorted out before the exact

place of the long-acting ~ 2 -agonists in the treatment of

asthma can be determined. Although there does not seem to be any evidence for development of tachyphylaxis to

the bronchodilating effect of long-acting ~ 2 -agonists, as

compared to the short-acting drugs [60, 61, 64] it is not known whether this can occur in the face of worsening or more severe asthma.

Should long-acting {3 2 -agonists replace short-acting {3 2 - agonists?

The most obvious place for the new ~ 2 -adrenoceptor

agonists may be to replace currently available short-

acting ~ 2 -agonists. Several clinical cross-over studies in

stable asthmatic patients with regular use of short-

acting ~ 2 -agonists have shown a very strong preference

for the new long-acting drugs compared to salbutamol [60, 61, 64]. Patients with nocturnal asthma have also shown preference for the long-acting drugs [66-69]. Thus, it seems clear that patients needing regular daily

intake of short-acting ~ 2 -agonists with or without noc-

turnal symptoms should be treated with the new long- acting drugs. The duration of action may vary from patient to patient. Patients with more severe asthma have not been studied and could possibly show shorter duration of

effect. Furthermore, long-acting ~ 2 -agonists will be

prescribed on a twice daily schedule and therefore the question of symptomatic relief for breakthrough symptoms is important. At the present stage it is rec- ommended to educate the patient to seek medical help when this happens, in order to obtain specific anti- inflammatory therapy with corticosteroids. It is not clear

how frequently long-acting ~ 2 -agonists can be safely used

in the face of worsening asthma. Whether a conventional

~ 2 -agonist for rescue medication would be more

appropriate is not known although, with such an approach patients need to be taught to use both short-

and long-acting ~ 2 -agonists.

224 C.G.^ L6FDAHL,^ K.F.^ CHUNG

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  6. Liifdahl CG, Svedmyr N. - Formoterol fumarate, a new ~ 2 -adrenoceptor agonist. Acute studies of selectivity and duration of effect after inhaled and oral administration. Allergy, 1989, 44, 264-271.
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