Pulmonary Perspective
The Role of Leukotriene Modifiers in the Treatment
of Asthma
RANDY J. HORWITZ, KELLY A. MCGILL, and WILLIAM W. BUSSE
Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
Asthma is a complex syndrome characterized by variable ob-
struction to airflow, bronchial hyperresponsiveness, and in-
flammation. The initiation and propagation of airway inflam-
mation arises from many factors, including mediators generated
by resident airway cells and recruited leukocytes (1). Leuko-
trienes are biologically active fatty acids derived from the oxi-
dative metabolism of arachidonic acid, an integral component
of the cell membrane (2). A role for leukotrienes in the patho-
genesis of asthma has been suggested by their biologic activi-
ties, which produce effects that mimic those of clinical asthma,
and by the effects of either inhibition of leukotriene produc-
tion (5-lipoxygenase inhibitors) or antagonism of leukotriene
binding to cellular receptors (leukotriene D4-receptor antago-
nists). The recent U.S. Food and Drug Administration (FDA)
approval of a leukotriene-receptor antagonist, zafirlukast (Ac-
colate), and a leukotriene synthesis inhibitor, zileuton (Zyflo),
provides the first mediator-specific therapy for asthma. This
review will consider the biochemistry of the leukotrienes, their
biologic role in asthma, and the therapeutic potential of drugs
that alter the production or action of leukotrienes, as well as
provide guidelines for the use of leukotriene modifiers in pa-
tients with asthma.
LEUKOTRIENE SYNTHESIS AND METABOLISM
Leukotrienes are formed from arachidonic acid that is re-
leased from the cell-membrane phospholipid bilayer by phos-
pholipase A2 (PLA2) (Figures 1 and 2) (2). The liberated arachi-
donic acid may then be metabolized by one of several major
pathways: the cyclooxygenase pathway, to generate prosta-
glandins, thromboxanes, and prostacyclin; or the 5-lipoxygen-
ase pathway, to generate the cysteinyl leukotrienes C4, D4, and
E4 (2). In humans, 5-lipoxygenase is present only in myeloid
cells, i.e., monocytes, eosinophils, basophils, alveolar macro-
phages, and mast cells (3). The binding of arachidonic acid to
5-lipoxygenase appears to require the presence of an integral
nuclear membrane protein, 5-lipoxygenase-activating protein,
which serves as a cofactor to present arachidonate to the en-
zyme (3). Arachidonate is converted first to an unstable inter-
mediate, 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), and
then to the unstable epoxide leukotriene A4. Both of these reac-
tions are catalyzed by activated 5-lipoxygenase, which is trans-
located to the perinuclear membrane (3).
Leukotriene A4 is a pivotal intermediate in leukotriene
biosynthesis and is rapidly converted to either leukotriene B4
(Received in original form June 16, 1997 and in revised form November 12, 1997)
Correspondence and requests for reprints should be addressed to William W.
Busse, M.D., Professor, Department of Medicine, Head, Section of Allergy and
Clinical Immunology, University of Wisconsin Hospital and Clinics H6/360, 600
Highland Avenue, Madison, WI 53792.
Am J Respir Crit Care Med Vol 157. pp 13631371, 1998
(by the cytosolic enzyme leukotriene A4 hydrolase) or to leu-
kotriene C4 (through the action of leukotriene C4 synthase in
the nuclear membrane) (4). Once formed, leukotriene C4 is
actively transported extracellularly, where glutamic acid is re-
moved to form leukotriene D4 (by a-glutamyltranspeptidase),
followed by the removal of glycine (by dipeptidase) to form
leukotriene E4 (2). These compounds are degraded via an oxi-
dative mechanism, but some leukotriene E4 is excreted in the
urine (2).
LEUKOTRIENES AS MEDIATORS OF ASTHMA
Leukotrienes can impair mucociliary clearance, enhance mu-
cus secretion, chemotactically attract leukocytes to the air-
ways, and facilitate pulmonary vascular permeability to cause
edema (2, 3). Inhaled leukotrienes C4 and D4 are 1,000 times
more potent than histamine in causing airflow obstruction in
normal subjects, and have a longer duration of action (5). In
patients with asthma, the airways are 100 to 1,000 times more
sensitive to inhaled leukotrienes D4 and E4 than are the air-
ways of normal subjects (5). Inhaled leukotrienes C4 and D4
also increase bronchial hyperresponsiveness to pharmacologic
agents, such as methacholine or histamine (6). These re-
sponses to exogenous leukotrienes parallel clinical features of
airway obstruction in asthma and suggest a biologic role for
these compounds in this disease.
In addition, leukotrienes have been identified in plasma,
urine, nasal secretions, sputum, and bronchoalveolar lavage
fluid (BALF) from patients with spontaneous exacerbations
of asthma and after antigen challenge (7). Urinary leukotriene
E4 measurements can be used to monitor production of leu-
kotrienes in response to selected challenges; for example, basal
urinary leukotriene E4 excretion is elevated in aspirin-sensi-
tive asthmatic patients, and increases after aspirin challenge
(8). In addition, urinary leukotriene E4 excretion increases
during acute exacerbations of asthma (9). These findings, al-
though indirect and correlative, provide evidence that cys-
teinyl leukotrienes may cause a number of features of asthma.
Leukotriene B4 has been implicated in the airway inflam-
matory response as well (2, 3). As a potent proinflammatory
mediator, leukotriene B4 is an attractant for neutrophils,
which are associated with nocturnal asthma, and it induces
T-lymphocyte production of interleukin 5 (IL-5), which has
been correlated with eosinophilia in asthma (10). However, in
contrast to the cysteinyl leukotrienes, leukotriene B4 has not
been closely linked to asthma, and its specific role in this pro-
cess is not established.
MECHANISMS OF MODIFICATION OF
LEUKOTRIENE ACTION
Two approaches have been developed to decrease the action
of leukotrienes. One is to block leukotriene synthesis by en-
1364 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 157 1998

TABLE 1
REPRESENTATIVE LEUKOTRIENE ANTAGONISTS AND INHIBITORS

Leukotriene D4 Receptor Antagonists 5-Lipoxygenase Activating-Protein Antagonists 5-Lipoxygenase Inhibitors

Tomelukast (LY 171,883) MK-886 Zileuton (A 64077)*

MK-571 MK-0591 ZD 2138
Verlukast (MK-0679) BAY X1005 A-79175
Montelukast (MK-0476)
Zafirlukast (ICI 204,219)*
Pobilukast (SKF 104,353)
Pranlukast (ONO 1078)

* FDA-approved.

Under investigation and development.

zyme inhibition, and the other is to interfere with the binding
of a leukotriene to its receptor (Figure 2).
Inhibitors of leukotriene synthesis block the formation of
both the cysteinyl leukotrienes and leukotriene B4. These in-
hibitors can be grouped into two types of compounds based on
their site of action. Inhibitors of 5-lipoxygenase bind at or near
the active site of this enzyme, and prevent the formation of
leukotriene A4; zileuton is a representative 5-lipoxygenase in-
hibitor (3). Alternatively, leukotriene synthesis can be inhib-
ited by blocking the action of the 5-lipoxygenase-activating
protein (11). Inhibition of the action of this activating protein
prevents the translocation of 5-lipoxygenase and subsequent
synthesis of leukotriene A4 (11). Specific inhibitors of the
5-lipoxygenase-activating protein with clinical efficacy in
asthma are still being investigated, as are competitive antago-
nists of the leukotriene B4 receptor (11, 12). Development of
the leukotriene B4-receptor antagonists will facilitate the reso-
lution of the involvement of leukotriene B4 in asthma.
Work on competitive antagonists of the actions of cysteinyl
leukotrienes has focused largely on the leukotriene D4 recep-
tor Cys-LT1, one of two leukotriene receptors identified in hu-
mans (13). This receptor probably mediates bronchial smooth-
muscle contraction, as opposed to Cys-LT2, which plays a role
in pulmonary-vein contraction (14). Leukotrienes C4 and E4
also bind to the Cys-LT1 receptor, but the potency of leuko-
triene E4 is diminished by a factor of 10 to 100 (13). Although
early studies of antagonists of these receptors in the treatment
of asthma were disappointing, probably because of their lack
of specificity and potency, newer receptor antagonists shift the
leukotriene D4 doseresponse curve to the right by as much as
100-fold (13). Antagonists of the leukotriene D4 receptor also
block the effects of leukotrienes C4 and E4. Representative
cysteinyl leukotriene-receptor antagonists, either available
now or under investigation, include zafirlukast, pranlukast,
and montelukast.
A list of drugs that inhibit leukotriene synthesis and action
is shown in Table 1.
EFFICACY OF LEUKOTRIENE MODIFIERS ON
AIRFLOW OBSTRUCTION
Asthma is unique among chronic inflammatory conditions of
the airways in that diverse factors provoke a reaction with
similar symptoms and similar pathologic and physiologic
changes. As a consequence, experimental models have been
developed to study the pathophysiology of asthma in humans,
and have proven useful to assess the efficacy of drugs that re-
duce leukotriene action in asthma. A representative sample of
clinical studies with these agents is summarized in Table 2.
Antigen-induced Asthma
Antigen inhalation in sensitive patients elicits immediate
bronchoconstriction secondary to the release of mast-cell me-
diators, including leukotrienes (15). Airflow obstruction can
also occur 6 to 8 h after antigen challenge; this late-phase reac-
tion is thought to represent an acute inflammatory response,
and provides a model for the inflammatory component of
asthma (15). Leukotriene receptor antagonists and inhibitors
of 5-lipoxygenase-activating protein reduce both early- and
late-phase reactions to inhaled antigen. 5-lipoxygeanse inhibi-
tors have not improved airflow in such studies, but have atten-

TABLE 2
OVERVIEW OF REPRESENTATIVE STUDIES WITH LEUKOTRIENE ANTAGONISTS AND 5-LIPOXYGENASE INHIBITORS

Asthma Model Drug Daily Dosage Study Duration No. of Patients Outcome Reference

Exercise-induced asthma Zafirlukast 20 mg Single dose 8 Attenuation of mean FEV1* decrease of 22% Finnerty, et al. (18)
Zileuton 2.4 g 2d 24 Bronchospasm inhibited 41% versus placebo Meltzer, et al. (20)
Aspirin-induced asthma Pobilukast 893 mg inhaled Single dose 6 FEV1* drop attenuated 47% Christie, et al. (22)
Verlukast 750 mg Single dose 8 4.4-fold right shift of doseresponse curve in Dahln, et al. (23)
all patients
Zileuton 2.4 g 1 wk 8 FEV1* unchanged after challenge/nasal, Israel, et al. (8)
gastrointestinal, dermal symptoms blocked
Chronic asthma Zafirlukast 10 mg, 20 mg, 40 mg 6 wk 276 FEV1*/ symptoms, b-agonist use; Spector, et al. (24)
Dose dependent improvement noted
Zileuton 2.4 g, 1.6 g, 4 wk 139 FEV1*, PEFR/ symptoms, Israel, et al. (29)
or placebo b-agonist use
Zileuton 2.4 g, 1.6 g, 13 wk 401 FEV1*, quality of life/ asthma Israel, et al. (30)
or placebo exacerbations requiring oral corticosteroids

* FEV1 denotes the forced expiratory volume in 1 s.

PEFR denotes the peak expiratory flow rate.
Pulmonary Perspective 1365

uated the influx of eosinophils into the airwaya hallmark of function in these subjects, but inhibited exercise-induced
allergic inflammation in asthma. bronchospasm by an average of 41% as compared with pla-
Zafirlukast inhibits the action of inhaled leukotriene D4 in cebo. Furthermore, 5 min after exercise, the zileuton-treated
both asthmatic patients and normal subjects. In double-blind, group had a mean FEV1 value that was 86% of their baseline
placebo-controlled trials, zafirlukast significantly attenuated value, as compared with a 74% value in the placebo group
both the early and the late responses to inhaled antigen, and (p , 0.01). On the basis of these studies, 5-lipoxygenase inhib-
reduced the bronchial hyperresponsiveness to histamine that itors and leukotriene D4 antagonists appear equally effective
normally accompanies antigen inhalation (16). In eight atopic in the treatment of patients with exercise-induced broncho-
asthma patients given a single 40-mg oral dose of zafirlukast, spasm.
the FEV1 decreased in response to antigen (grass pollen or
dust mite) by only 6%, as compared with a 32% decrease in
patients given placebo. The late-phase response to antigen
was also significantly weaker in patients treated with zafirlukast
(13% decrease in FEV1 versus a 28% decrease in subjects given
placebo) (16).
Zileuton has also been evaluated for its effects on antigen-
induced allergic airway responses, with varied results. When
given in a single 800-mg dose 3 h before an inhaled antigen
challenge, zileuton did not significantly diminish either early
or late airflow obstruction (9). However, urinary leukotriene
E4 excretion, a marker of leukotriene production, was reduced
by 50%. In another study, BALF obtained 24 h after bronchial
challenge with ragweed antigen contained less leukotriene
and fewer eosinophils in subjects pretreated with zileuton (2.4
g/d for 8 d) than in those given placebo (17). Overall, eosino-
phil migration into the airway was inhibited by more than
80% after administration of zileuton. The effect of zileuton on
eosinophil recruitment to the lung suggests an ability to alter
this component of the inflammatory response to antigen.
With antigen challenge taken as a model for a compo-
nent of clinical asthma, leukotriene-receptor antagonists and
5-lipoxygenase-activating-protein inhibitors afford significant
protection from bronchoconstriction when given before anti-
gen exposure. Although zileuton does not appreciably alter
airway obstruction caused by inhaled antigen, it does inhibit
inflammatory-cell egress into the airway. These studies suggest
that leukotriene modifiers have antiinflammatory activity.

Exercise-induced Bronchospasm
Several leukotriene antagonists have been tested in subjects
with exercise-induced bronchospasm (18, 19). In eight asthma
patients with documented exercise-induced bronchospasm
(defined as at least a 25% decrease in FEV1 from baseline af-
ter exercise), pretreatment with a single 20-mg dose of zafirlukast
2 h before exercise reduced the mean maximum decrease in
FEV1 after exercise to 22%, as compared with a 36% decrease
after placebo (18). In several subjects, zafirlukast completely
inhibited exercise-induced bronchospasm. Similar protective
effects were found with an inhaled formulation of zafirlukast.
In a double-blind, placebo-controlled crossover study, ad-
ministration of the leukotriene D4 antagonist MK-571 20 min
before an exercise challenge significantly reduced broncho-
constriction; the mean maximal decrease in FEV1 was 9%, as
compared with a 25% decrease after placebo (19). Further-
more, the mean time to recovery of baseline FEV1 after exer-
cise was shortened to 8 min after MK-571 administration, as
compared with 33 min after placebo administration. These Figure 1. Structure of leukotrienes relevant to asthma. Cysteinyl
studies suggest a role for leukotriene D4 in exercise-induced leukotrienes C4, D4, and E 4 are potent mediators that induce
bronchospasm, as well as revealing the effectiveness of leuko- smooth-muscle contraction, vascular leakage (or airway edema),
triene antagonists in this condition. mucus secretion, and eosinophil recruitment into the airway. Leu-
Zileuton has also been evaluated in patients with exercise- kotriene C4 is formed when the tripeptide glutathione is adducted
induced bronchospasm. Twenty-four asthma patients who had onto leukotriene A 4. Sequential reactions remove amino acids,
at least a 20% decrease in FEV1 following an exercise chal- yielding leukotrienes D4 and E4. Leukotriene B4 does not have a
lenge received either zileuton (2.4 g/d) or placebo for 2 d prior cysteine residue but is a potent chemotactic factor for neutrophils
to exercise (20). Zileuton did not alter baseline pulmonary and eosinophils.
1366 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 157 1998

Figure 2. Biosynthesis of the leukotrienes. Arachidonic acid is produced by the action of phospholipase A2
on the nuclear membrane. Further metabolism is effected by the action of 5-lipoxygenase (5-LO) and its
cofactor, 5-lipoxygenase activating protein (FLAP), and yields the epoxide leukotriene A4. This leukotriene
is rapidly converted to either leukotriene B4 or C4. Leukotriene C4 is transported from the cell, where pepti-
dases sequentially remove amino acids from the compound to yield leukotrienes D4 and E4. Sites of pharma-
cologic inhibition are shown in boldface (black arrows); representative compounds from each class are listed
(in box). Further details of pathway are in the text.

Aspirin-induced Asthma
Approximately 10% of adult patients with asthma have aspi-
rin-induced asthma, and severe, life-threatening asthma can
follow ingestion of aspirin or other nonsteroidal antiinflam-
matory drugs (NSAIDs) (21). Although the pathophysiology
of this condition is unclear, aspirin inhibits the cyclooxygenase
pathway and shunts arachidonic acid through the 5-lipoxygen-
ase pathway to produce more leukotriene B4, C4, D4, and E4
(21). Selective bronchial hyperresponsiveness to leukotriene
E4 may contribute to the pathophysiology of aspirin-induced
asthma (21).
At present, the most effective treatment for aspirin-
induced asthma is avoidance of aspirin and NSAIDs. Aspirin
desensitization has been successful in some patients, but is not
without risk. Two leukotriene D4-receptor antagonists have
shown efficacy in patients with aspirin-induced asthma. The
inhaled leukotriene D4 antagonist pobilukast partly protected
five of six sensitive patients after oral aspirin challenge; the
decline in FEV1 was reduced by an average of 47% (22). An-
other leukotriene D4 antagonist, verlukast, reduced the sensi-
tivity to inhaled lysine-aspirin in sensitive patients by a factor
of four, affording some protection from acute bronchospasm;
several patients had complete protection from usually provoc-
ative doses of aspirin (23).
In a study of eight patients with aspirin-induced asthma
treated with zileuton (2.4 g/d for 7 d) or placebo, and given in-
creasing doses of aspirin every 2 h (8), the FEV1 fell by 19%
after placebo, whereas zileuton prevented this fall in FEV1.
Zileuton also prevented nasal, gastrointestinal, and dermal
symptoms, and inhibited aspirin-induced angioedema in three
patients.
Together, these results indicate that leukotriene-induced
bronchoconstriction is one component of the pathophysiology
of aspirin- or analgesic-induced asthma, and that this response
can be effectively attenuated by leukotriene modifiers. More-
over, leukotriene modifiers are currently the only medical
therapy effective in attenuating aspirin-induced asthma.
Efficacy of Modifiers of Leukotriene Action in
Chronic Asthma
Perhaps the most important and clinically relevant studies of
the efficacy of the leukotriene modifiers are those involving
patients with chronic asthma. Interpretation of these studies is
often difficult, owing to restricted patient populations (pa-
tients with mild to moderate asthma), the relatively short du-
ration of the trials, and most importantly, the question of the
clinical relevance of modest, albeit statistically significant, im-
provements in airflow. Despite these drawbacks, measure-
ments of clinical importance, such as the patients daily re-
quirement for b-adrenergic-agonist drug therapy, nocturnal
Pulmonary Perspective
asthma symptoms, or the number of exacerbations of asthma
requiring systemic corticosteroid treatment can be assessed
and compared.
To evaluate the long-term efficacy of zafirlukast, patients
with moderate asthma, treated with either a b2-adrenergic ag-
onist drug or theophylline, were randomly assigned to treat-
ment with either one of three daily dosages of zafirlukast (10,
20, or 40 mg in divided doses) or to placebo for 6 wk (24).
The zafirlukast-treated patients improved both subjectively
(asthma symptom score) and objectively (FEV1, number of
nocturnal awakenings, and use of b-adrenergic agonist drugs
for rescue), and the degree of improvement showed some de-
gree of a dose-dependent response. The 10-, 20-, and 40-mg
doses of zafirlukast were associated with 7%, 6%, and 11% in-
creases in FEV1 values, respectively.
In an examination of the effect of leukotriene modifiers on
asthma exacerbations, an important marker of clinical stabil-
ity, pranlukast was utilized in 79 asthma patients requiring
high-dose inhaled beclomethasone (1,500 mg or more) (25).
After a 2-wk run-in period, the dose of beclomethasone was
halved and patients were randomly assigned to receive pran-
lukast 450 mg twice daily or placebo for 6 wk. Pulmonary
function measures remained unchanged after 6 wk in the
pranlukast-treatment group, whereas the FEV1 decreased by
10.2% from baseline in the placebo group. Daytime asthma
symptoms increased 3-fold in the placebo group, as did the use
of relief b2-adrenergic agonists. Asthma symptoms remained
unchanged in the pranlukast group, and mean morning and
evening peak-flow measurements remained at or above base-
line during treatment. Two patients in the placebo group were
withdrawn because of asthma exacerbations. Deterioration of
asthma control resulting from reductions in high-dose inhaled
beclomethasone was curtailed by pranlukast; thus, pranlukast
may provide steroid-sparing effects in patients who require
high-dose inhaled corticosteroids to control their asthma (25).
In a 3-mo double-blind, placebo trial involving 681 pa-
tients, another leukotriene-receptor antagonist, montelukast,
administered in a dose of 10 mg daily, produced significant im-
provements in pulmonary function endpoints as well as a 31%
decrease in asthma exacerbation days, and a 37% increase in
asthma-free days (26). In patients requiring inhaled cortico-
steroids (300 to 3,000 mg/d), montelukast at 10 mg daily al-
lowed 40% of montelukast-treated patients to eliminate in-
haled steroid use, versus 29% in the placebo group (27). In
another study, aspirin-intolerant patients using inhaled and/or
oral corticosteroids received 10 mg of montelukast or placebo
in a double-blind, parallel-group, 4-wk trial. Those in the mon-
telukast-treatment group had significantly improved peak ex-
piratory flow rates, diminished nocturnal symptoms, and a de-
crease in b2-adrenergic agonist use; fewer days with asthma
exacerbations were also reported by the montelukast-treated
group (28).
The efficacy of zileuton in patients with chronic asthma has
been assessed in several large, multicenter trials. In one study,
139 patients with mild to moderate asthma were treated for
4 wk with placebo or zileuton at 1.6 g/d or 2.4 g/d (29). The pa-
tients treated with 1.6 g/d had a 10.9% increase and those
treated with 2.4 g/d had a 13.4% increase in FEV1 (Figure 3).
Symptom scores and peak expiratory flow measurements also
improved in the treatment groups.
In the largest trial of zileuton, 401 patients with mild to
moderate asthma were treated for 13 wk (30). The zileuton-
treated patients had an increase of 13.4% in FEV1 at 3 h after
the first dose; after 13 wk of treatment, patients treated with
2.4 g/d of zileuton had a mean 15.7% increase in FEV1 as com-
pared with a 7.7% increase in the placebo group (p 5 0.006).
1367
Figure 3. Change in FEV1 after 4 wk of treatment with zileuton
(2.4 g/d or 1.6 g/d) or placebo in patients with chronic asthma.
One hundred thirty-nine patients with mild to moderate asthma
were treated with one of two doses of zileuton (2.4 g/d [46 pa-
tients] or 1.6 g/d [46 patients]), or were given placebo (47 pa-
tients), and their pulmonary function was monitored. The mean
change (6 SE) in weekly FEV1 at 4 wk is compared with values at
the end of the lead-in period (Week 1). The zileuton-treated pa-
tients (2.4 g/d) were significantly improved as compared with the
placebo group at 4 wk (*p 5 0.02). A doseresponse effect was
seen with zileuton, as evidenced by the intermediate improvement
in FEV1 in patients treated with the lower dose of zileuton. (From
Israel and colleagues [29], with permission.)
The gradual improvement in FEV1 suggests that zileuton may
influence underlying inflammatory processes in patients with
chronic asthma. Six percent of the patients in the zileuton-
treatment group required oral corticosteroid treatment for ex-
acerbations of asthma during the study, as compared with
15.6% of the patients receiving placebo (p 5 0.02). This ste-
roid-sparing effect of zileuton was most evident in patients
with a baseline FEV1 of less than 50% predicted. These results
suggest that zileuton may stabilize asthma and prevent exacer-
bations, a therapeutic action often associated with antiinflam-
matory activity.
In the longest study of zileuton, 373 patients with mild to
moderate asthma were given zileuton at 2.4 g/d or 1.6 g/d or
placebo over a 6-mo period (31). Improvements in FEV1 were
demonstrated by Day 8, and patients in the 2.4 g/d group con-
tinued to have a significant improvement in FEV1 measures of
up to 19% after 120 d. Daytime and nocturnal symptoms de-
creased in the zileuton-treatment groups, but were significant
only in the 2.4 g/d group. Supplemental systemic corticoster-
oid use for treatment of asthma exacerbations decreased in
both zileuton-treatment groups, with the greatest decrease oc-
curring in the 2.4 g/d group. Zileuton at 2.4 g/d was more ef-
fective than at 1.6 g/d in alleviating symptoms and asthma ex-
acerbations and improving pulmonary function measures (31).
In another study of the role of leukotrienes in airway in-
flammation, zileuton was evaluated in patients with nocturnal
asthma. In this trial, 12 patients with nocturnal asthma and six
normal subjects were randomly assigned within each group to
receive zileuton at 2.4 g/d or placebo for 7 d, at which time
they underwent bronchoscopy and lavage both at 4:00 P.M. and
4:00 A.M. (7). Following a 1-wk washout period, the protocol
1368 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
was repeated in a crossover design, with the placebo-treated
patients now receiving zileuton and vice-versa. BALF ob-
tained at 4:00 A.M. from patients with nocturnal asthma had in-
creased leukotriene B4 and cysteinyl leukotriene concentrations,
and high eosinophil counts. Treatment with zileuton decreased
leukotriene concentrations and the nocturnal influx of eosino-
phils, a marker of airway inflammation. In addition, urinary
leukotriene E4 excretion decreased by 75% after zileuton
treatment. Zileuton had no statistically significant effect on
pulmonary function, a finding probably due to sample size.
Nonetheless, these results suggest that leukotrienes may be
involved in the pathobiology of nocturnal asthma, and that
5-lipoxygenase inhibitors can inhibit eosinophil recruitment to
the airways in patients with nocturnal asthma.
Currently, there is insufficient information to determine
whether inhibitors of 5-lipoxygenase-activating protein are ef-
fective in patients with chronic asthma. A recently developed
5-lipoxygenase-activating protein antagonist, MK-0591, has
been tested in a placebo-controlled trial in 109 patients taking
inhaled corticosteroids (beclomethasone or budesonide at an
average dose of 800 mg/d) (32). The addition of MK-0591 im-
proved the mean FEV1 by 7%, with parallel improvements in
peak-flow readings and significant reductions in bronchodila-
tor usage.
THERAPEUTIC ROLE OF THE LEUKOTRIENE
MODIFIERS IN ASTHMA
Several questions need to be considered when evaluating the
clinical effectiveness of the new drugs that reduce leukotriene
action in asthma. First, do the drugs alter the underlying dis-
ease process? Second, are these new drugs primarily bron-
chodilators, antiinflammatory drugs, or both? Lastly, how do
these drugs compare with existing asthma medications?
At present, it is difficult to translate the improvement in
symptoms, the objective changes in airflow (such as in peak
expiratory flow rate or FEV1), and the alterations in ingress of
inflammatory cells into airways that have been noted in clini-
cal trials into specific recommendations for clinical practice. A
clinically relevant measure of long-term control of asthma is
the number of exacerbations that require systemic corticoster-
oid therapy. Using this criterion as one marker of effectiveness,
zileuton decreased exacerbations of asthma by nearly 50% dur-
ing 13 wk of therapy when compared with use of a placebo
(30). Moreover, both zafirlukast and zileuton decrease noctur-
nal awakenings, b-adrenergic-agonist drug use, and symptoms
of asthma. These results suggest that leukotrienes may modify
the severity of asthma and possibly those factors that lead to
symptoms.
The classification of leukotriene modifiers as either bron-
chodilators or antiinflammatory drugs is difficult, and it is
more correct to classify them for precisely what they do: mod-
ify leukotriene activity. This activity may include effects on
airway tone and inflammation. For example, leukotriene mod-
ifiers have modest bronchodilator activity; although no leu-
kotriene modifier has actions that match the rapid onset and
overall potency of b-adrenergic agonists, the latter may have
additive bronchodilator effects when used in combination
with leukotriene modifiers (33). Consequently, leukotriene
modifiers affect components of airflow obstruction that are
distinct from those affected by b-adrenergic agonists, making
them useful adjunctive therapy. It is also conceivable that leu-
kotriene modifiers may have a role in the treatment of acute
bronchospasm that is refractory to b-adrenergic-agonist ther-
apy. Clinically, a difference between blocking the end-organ
response with leukotriene modifiers, such as zafirlukast and
VOL 157 1998
pranlukast, and blocking the synthesis of leukotrienes with
5-lipoxygenase inhibitors, such as zileuton, has not been
shown. 5-Lipoxygenase is a ubiquitous enzyme, and blocking
the biosynthesis of both the cysteinyl leukotrienes and leuko-
triene B4 may confer additional benefits; at present, however,
those benefits are not established.
One indication of antiinflammatory activity is a gradual in-
crease in FEV1 values during treatment. Inhaled corticoster-
oids have such an action. For example, in patients with newly
diagnosed mild chronic asthma treated with inhaled bude-
sonide (600 mg twice daily) for 2 yr, the mean FEV1 value in-
creased by 0.13 L (4%), and morning peak expiratory flow
rates increased by 32.8 L/min (7.5%) (34). Inhaled corticoster-
oids and leukotriene modifiers have been compared in several
trials, and early data suggest that the addition of a leukotriene
modifier, such as zileuton, may be as effective for asthma con-
trol as higher doses of inhaled corticosteroids alone, and that
the addition of these compounds may be an alternative to
higher doses of inhaled corticosteroids (35). Pranlukast at 300
mg twice daily and 450 mg twice daily has been shown to be
comparable to beclomethasone 84 mg four times daily in con-
trolling asthma symptoms, and pranlukast-treated patients
have maintained a stable FEV1 and peak expiratory flow over
a 12-wk period (36). A consistent finding in long-term treat-
ment with leukotriene modifiers is a gradual increase in FEV1.
Zileuton, administered over a 13-wk study, increased FEV1
values to nearly 16% over baseline (30). Moreover, both zileu-
ton and budesonide demonstrate systemic steroid-sparing ef-
fects (as evidenced by a marked decrease in oral corticoster-
oids needed during active medication). Subjects and observation
periods in the two studies described here were obviously dif-
ferent, necessitating future comparisons to validate the posi-
tioning of the leukotriene inhibitors.
SAFETY OF THE LEUKOTRIENE MODIFIERS
Safety issues with the use of leukotriene modifiers remain to
be fully addressed. Long-term safety and efficacy trials are
necessary and are ongoing. Most adverse events with these
medications have been mild, with headache, dyspepsia, pharyn-
gitis (zafirlukast), macular rash (MK-0591), and reversible ele-
vations in liver transaminase enzyme activities (zileuton) most
frequent. Tachyphylaxis has not been reported with the leu-
kotriene modifiers pranlukast and montelukast in exercise
studies or long-term chronic asthma studies lasting more than
1 yr (37, 38).
During a 4-wk trial of zileuton, one patient (of 92 treated)
had hives and increased serum aminotransferase concentra-
tions after 24 d of treatment with the drug (1.6 g/d) (29). In the
13-wk trial of zileuton (30), five patients of 132 (4%) receiving
2.4 g/d, and three patients of 134 (2%) who were receiving 1.6
g/d, had increases in serum aminotransferase values of at least
three times the upper limit of normal. These increases were
noted an average of 60 d into treatment, and improved after
discontinuation of the drug. None of the 135 patients who re-
ceived placebo had increased liver enzymes in the study (30).
A 6-mo study evaluating zileuton therapy in patients with mild
to moderate asthma found that 4% and 5% of those receiving
1.6 g/d or 2.4 g/d, respectively, had liver enzyme elevations in
the moderate (3-fold above normal) and severe (more than
8-fold above normal) categories (31). The risk of liver toxicity
with zileuton is not fully established, and it is recommended
that patients have their liver enzyme activities monitored dur-
ing therapy. The greatest risk of enzyme elevation appears to
occur within the first 3 mo of zileuton treatment. Liver en-
zymes should be evaluated at the initiation of zileuton therapy
Pulmonary Perspective
and monthly thereafter for the first 3 mo, followed by tests ev-
ery 2 to 3 mo for the remainder of the first year of treatment.
Patients should be instructed to report symptoms of liver dys-
function, such as lethargy, nausea, jaundice, right-upper-quad-
rant pain, or pruritus.
Trials with zafirlukast have revealed that the drug is gener-
ally well tolerated. In a 6-wk trial, 206 asthma patients were
divided equally into three groups, and received 10, 20, or 40
mg of zafirlukast twice daily (24). The majority of reported
adverse events were mild or transient and included headache,
nausea, and diarrhea. There were no significant differences
in liver enzymes between treatment groups. Four percent of
patients treated with 40 mg of zafirlukast twice daily, and 4%
of those receiving placebo, experienced slight increases in
hepatic aminotransferase levels (specifically gamma-glutamyl
transferase). However, one case of symptomatic hepatitis and
hyperbilirubinemia was reported in a patient receiving zafirlukast
40 mg daily for 3 months; the patients liver enzymes returned
to normal within 3 mo of zafirlukast discontinuation. Although
detailed recommendations for liver function tests with zafirlukast
therapy have not been described, laboratory studies may be
conducted at the initiation of zafirlukast therapy as a baseline,
and repeated at appropriate intervals thereafter.
A possible association between zafirlukast and Churg
Strauss syndrome, a rare multisystem allergic granulomatous
vasculitis, was proposed after six patients developed this dis-
ease while receiving zafirlukast at a time when concomitant
doses of oral corticosteroids were being tapered. A causal rela-
tionship has not been established between zafirlukast and
ChurgStrauss syndrome; however, patients who are decreas-
ing their oral corticosteroid dose while taking zafirlukast
should be closely monitored for presenting flulike symptoms
such as fevers, myalgia, headaches, and weight loss, since
these symptoms may reflect development of the Churg
Strauss syndrome.
INDICATIONS FOR LEUKOTRIENE MODIFIERS
Zileuton and zafirlukast, two oral leukotriene modifiers, have
been approved for prophylaxis and chronic treatment of
asthma in adults and children 12 yr of age and older. Current
experience with zileuton and zafirlukast suggests that these
drugs may be first-line therapy in the following patients with
persistent asthma. (1) Patients with mild to moderate disease
who fail to respond adequately to inhaled corticosteroid ther-
apy. (2) Patients with moderate to severe asthma who have
systemic side-effects from high doses of inhaled corticoster-
oids or who are at risk for these adverse effects. These patients
should be considered for a trial of leukotriene modifiers to de-
termine whether these agents will allow a reduction in the cor-
ticosteroid dose. (3) Patients with poor adherence to a regi-
men of inhaled corticosteroids because of improper technique
or physical limitations. (4) Patients receiving inhaled cortico-
steroids who are still poorly controlled and who cannot toler-
ate theophylline or long-acting bronchodilators. There does
appear to be a group of patients who respond early (within
2 wk of the beginning of treatment) to leukotriene modifiers
with improved peak expiratory flow rates and FEV1 values
(36). When these agents are recommended, patients who fit
into one of the foregoing categories may benefit from a trial
period of zileuton or zafirlukast administration. If the drug ap-
pears beneficial after 6 to 8 wk of therapy, a longer treatment
period may be indicated, especially for patients receiving oral
corticosteroids or high doses of inhaled corticosteroids. Peak
expiratory flows monitored at home, along with symptom dia-
ries, are helpful in documenting the efficacy of these agents
1369
and indicating the patients who would most benefit from leu-
kotriene modifier therapy.
The updated National Heart, Lung and Blood Institute Ex-
pert Panel on Asthma classifies persistent or chronic asthma
into four categories, ranging from intermittent (step 1) to se-
verepersistent (step 4), based on such factors as pulmonary
function, symptom frequency, and use of bronchodilators (39).
A stepped-care algorithm is provided for the treatment of
patients in each category, with each step building upon the
drugs used in the previous step. Antiinflammatory therapy is
introduced at step 2 for patients with persistent asthma requir-
ing b-agonist drugs more than three times per week. The Ex-
pert Panel classifies the leukotriene inhibitors as alterna-
tives to inhaled corticosteroids for the treatment of patients
with mild, persistent asthma (step 2) or worse. Inhaled corti-
costeroids are still regarded as preferred antiinflammatory
agents in this protocol, and it is unlikely that leukotriene mod-
ifiers would replace corticosteroid therapy entirely in any pa-
tient group.
Therapeutic choices in asthma must be based on the overall
disease pattern, rather than simply on baseline airway obstruc-
tion. Patients with clinically indistinguishable forms of asthma
are likely to have biochemically heterogeneous diseases in
which different mediators are important pathophysiologically.
Further studies of the pathophysiology of asthma (i.e., specific
gene activation, cytokine profile, or mediator predominance)
may identify subgroups of patients who may derive the great-
est benefit from the leukotriene modifiers. Patients with aspi-
rin-sensitive asthma, for example, are ideal candidates for leu-
kotriene-modifier therapy, because no other treatment regimen
provides satisfactory results with such a high margin of safety.
Although the exact percentages of patients are unknown, a
significant number of aspirin-intolerant patients may be able
to utilize full-dose aspirin and NSAID therapy for concomi-
tant diseases, such as arthritis, while utilizing leukotriene
modifiers for their protective effects on lung function and in-
hibition of nasal, gastrointestinal, and dermal responses. Simi-
larly, subjects who have exercise-induced bronchospasm that
is unresponsive to b-adrenergic-agonist drugs and cromolyn de-
rivatives now have an alternative therapy.
SUMMARY
Substantial evidence exists for involvement of the cysteinyl
leukotrienes in the pathophysiology of asthma. Once synthe-
sized, leukotrienes exert a number of important pharmaco-
logic actions that contribute to airflow obstruction in asthma:
airway smooth-muscle contraction, edema formation, and mu-
cus secretion (2, 3). Not only are exogenously administered
leukotrienes capable of reproducing many features of asthma,
but there are abundant data demonstrating their in vivo re-
lease in episodes of airflow obstruction following laboratory-
induced bronchoconstrictor challenges, and supporting a con-
tributory role of leukotrienes in the resting bronchomotor
tone of airway smooth muscle (3, 7, 13).
Numerous studies have shown that leukotriene modifiers
have protective effects against bronchoprovocative challenges
and ease bronchial obstruction in asthma patients (9, 20, 29).
Moreover, the beneficial impact of these drugs on asthma may
be cumulative, include antiinflammatory effects, and have
long-term benefit. The available evidence suggests that block-
ing leukotriene synthesis or effects on specific receptors will
be an effective strategy in asthma treatment. Furthermore, it
is possible that combination therapy, using drugs with differ-
ent sites of action in the leukotriene pathway, might provide
additional efficacy, since it is unlikely that either the 5-lipoxy-
1370 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
genase pathway or the leukotriene D4 receptor is completely
blocked by the currently available respective antagonists. De-
spite the current information from clinical trials, specific rec-
ommendations about the exact role of these compounds in
asthma cannot yet be made. Nonetheless, leukotriene modifi-
ers are the first new class of antiasthma drugs to become avail-
able in the past 25 yr, and further clinical trials and clinical ex-
perience should eventually provide the information needed to
determine their role in the treatment of patients with asthma.
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