 |
 |
|
|
|  PubMed
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 December 1993 | Volume 119 Issue 11 | Pages 1059-1066
Objective: To evaluate the effectiveness of inhibiting the formation of the 5-lipoxygenase products of arachidonic acid by the 5-lipoxygenase inhibitor zileuton in the treatment of mild-to-moderate asthma.
Design: Randomized, double-blind, placebo-controlled study.
Setting: University hospitals and private allergy and pulmonary practices.
Patients: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV1) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids.
Intervention: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks.
Measurements: Airway function, ß-agonist use, and symptoms; inhibition of 5-lipoxygenase assessed by measurement of urinary leukotriene E4 (LTE4).
Results: Zileuton produced a 0.35-L (95% CI, 0.25 to 0.45 L) increase in the FEV1 within 1 hour of administration (P < 0.001 compared with placebo), equivalent to a 14.6% increase from baseline. After 4 weeks of zileuton therapy, airway function and symptoms improved, with the greatest improvements occurring in the 2.4 g/d group: This group's FEV1 increased by 0.32 L (CI, 0.16 to 0.48 L), a 13.4% increase, compared with a 0.05-L (CI, –0.10 to 0.20 L) increase in patients taking placebo (P = 0.02). Symptoms and frequency of ß-agonist use also decreased with zileuton, 2.4 g/d. The mean urinary LTE4 level decreased by 39.2 pg/mg creatinine (CI, 18.1 to 60.4 pg/mg creatinine) and 26.5 pg/mg creatinine (CI, 6.6 to 46.5 pg/mg creatinine) in the 2.4 g/d and 1.6 g/d groups, respectively, compared with a slight increase in the placebo group (P = 0.007 and P = 0.05). No difference was noted in the number of adverse events among treatment groups.
Conclusions: Inhibition of 5-lipoxygenase can improve airway function and decrease symptoms and medication use in patients with asthma, suggesting that this inhibition can be useful therapy for asthma. Also, 5-lipoxygenase products may mediate part of the baseline airway obstruction in patients with mild-to-moderate asthma.
Recently, the salutary effects of specific leukotriene-receptor antagonists or synthesis inhibitors in persons with asthma have suggested that interventions in the 5-lipoxygenase pathway may be of therapeutic use in the treatment of asthma [12-20]. These observations are particularly interesting because of the increasing concerns about asthma therapies such as ß-agonists and theophylline [21-24] and the known toxicity of long-term steroid use [25, 26]. However, the conclusions about the efficacy of these new drugs in persons with asthma largely derive from studies in laboratory-induced, rather than spontaneously occurring, asthma.
Because cases of spontaneously occurring asthma may differ from those of laboratory-induced asthma, in mechanism or in response to therapy, we examined the effects of zileuton (N-1-[benzo(b)thien-2-ylethyl]-N-hydroxyurea), an investigational inhibitor of 5-lipoxygenase [27] currently in phase III trials of efficacy, in persons with asthma. In a double-blind, placebo-controlled trial in patients with mild-to-moderate airflow obstruction, we investigated the effects of inhibition of 5-lipoxygenase with zileuton (Leutrol; Abbott Laboratories, North Chicago, Illinois), during a 4-week period, on airway function, asthma symptoms, and the bronchodilator response to ß-agonists. We found that a dose of 600 mg four times per day (2.4 g/d), which produces more than 35% inhibition of leukotriene production as indicated by excretion of leukotriene E4 (LTE4) in the urine, had a salutary effect on airway function and asthma symptoms.
Patients with mild-to-moderate asthma were recruited at 14 centers, which included university hospitals and private allergy and pulmonary practices. Patients with symptoms that corresponded with the American Thoracic Society definition of asthma [28] were screened. All patients had to have a forced expiratory volume in 1 second (FEV1) of 40% to 75% of predicted value and a 15% or greater increase in FEV1 30 minutes after inhalation of two puffs of albuterol. Additionally, patients were required to be 18 to 65 years old; women of childbearing potential were excluded. Before enrollment in the study, none of the patients had used oral or inhaled steroids or cromolyn sodium for 4 weeks. Beta-blockers, calcium-channel blockers, and nonsteroidal anti-inflammatory drugs could not have been used for at least 1 week before entry into the study. All patients were required to be able to achieve adequate symptomatic asthma control without using theophylline, oral ß-agonists, or antihistamines; none of these medications was permitted throughout the entire study period.
Study Design and Intervention
A randomized parallel design was used in this double-blind, placebo-controlled study. Patients were chosen randomly to receive either 600 mg of zileuton (four times a day), 800 mg of zileuton (twice a day), or placebo. A 1-week, single-blind, placebo lead-in qualification period (dummy lead-in period) was followed by random allocation to one of the three treatment groups for a 4-week, double-blind phase.
During the single-blind, dummy lead-in and the double-blind study periods, all patients took capsules four times a day. Self-determined peak expiratory flow rates were recorded in the morning (before medication) and evening (2 hours after the third set of capsules) in a study diary. Albuterol inhaler use and asthma symptoms were recorded in the diary as well. Daytime asthma symptoms were self-rated on a scale of 1 to 5 (1 = no symptoms, 5 = severe symptoms; maximum weekly score of 35).
After the 1-week dummy lead-in period, patients returned to their study center. Inhaled albuterol was withheld for at least 8 hours before the study visit. Spirometry was done on patients who had no clinically significant laboratory abnormalities, who had successfully completed their diary card, who had moderately symptomatic asthma (a total score of
During the 4-week double-blind period, patients returned to the study center at the same time of day on a weekly basis to have spirometry done and to review diary cards and medication use. During the second and third weeks of the double-blind randomization period, spirometry was also repeated 30 minutes after inhalation of two puffs of albuterol.
Urine Collection and Analysis
Urine was collected for 4 hours beginning at 8:00 a.m. before the dummy lead-in period and on day 28 of the study. Urinary LTE4 levels were determined by reverse-phase high-performance liquid chromatography and enzyme immunoassay using minor modifications of established procedures [29]. The recovery of the internal LTE4 standard was 74% ± 6%. The LTE4 content of the urine was expressed as picograms of immunoreactive LTE4 per milligram of creatinine.
Adverse Events
Routine complete blood counts, serum chemistries, urinalyses, and electrocardiograms were obtained throughout the study. Adverse symptoms were elicited daily through a diary question and were reviewed at the weekly visit to the study site.
Statistical Analysis
All values were expressed as means with associated 95% CIs; all outcome indicators were normally distributed. Paired t-tests were used to assess the statistical significance of any within-group changes from the baseline dummy lead-in phase. The statistical significance of differences among the placebo and active treatment groups during the 4 weeks of double-blind treatment was evaluated using a two-way analysis of variance model with effects for center, treatment, and center-treatment interaction. When statistical differences were noted among groups in the dummy lead-in, the groups were compared using an analysis of covariance adjusting for baseline differences. Available data were analyzed up to the point of withdrawal for patients who did not complete the study protocol. The Fisher test for the protected least significant difference was used to make pair-wise comparisons.
A total of 188 patients entered the single-blind dummy lead-in period; 143 fulfilled the enrollment criteria and were randomly assigned to receive study drug or placebo (46 patients received 2.4 g/d, 49 patients received 1.6 g/d, and 48 patients received placebo). Two patients withdrew during the first week of the double-blind study—1 for personal reasons and the other because of worsening asthma (both received 1.6 g/d of zileuton). Two patients were not included in the final analysis, because they were enrolled in a center that did not have representation in all three treatment groups (1 received 1.6 g/d of zileuton and 1 received placebo). The characteristics of the 139 evaluated patients are given in Table 1. Of the 139 patients who were still in the trial after 1 week, 12 evaluated patients left the study before completing the trial protocol (all their data were included up to the point of termination): 4 patients because of worsening asthma (1 received 2.4 g/d, 2 received 1.6 g/d, and 1 received placebo); 2 patients because of upper respiratory infections (1 received 2.4 g/d and 1 received placebo); 1 patient because of sinusitis (placebo); 1 patient because of urticaria (1.6 g/d); 3 patients because of personal reasons (1 in each group); and 1 patient because of headaches that had begun before randomization (2.4 g/d).
ARTICLE
The Effect of Inhibition of 5-Lipoxygenase by Zileuton in Mild-to-Moderate Asthma
Although intermittent episodic airway narrowing occurs in persons with asthma, the biochemical basis of this obstruction has not been elucidated. Nonetheless, inflammatory cells present in the airways of persons with asthma [1, 2] release various substances that narrow airways. Among these are cysteinyl leukotrienes, which are formed from arachidonic acid in part by the enzyme 5-lipoxygenase [3]. The evidence favoring a role for leukotrienes in asthma is that they are produced by various airway cells including eosinophils and mast cells [4, 5], they are potent bronchoconstrictor agonists [6-8], and they can be recovered from biological fluids during asthma attacks [9-11].
Methods
Top
Methods
Results
Discussion
Author & Article Info
References
Patient Selection
12 but 
28 in the previous 7 days), and who had used their albuterol inhaler at least 7 times during the dummy lead-in week. If the FEV1 was 40% to 75% of the predicted value, the patient was assigned randomly to a group according to a predetermined code. All patients took visually identical capsules four times per day that contained either 600 mg of zileuton four times daily, 800 mg of zileuton twice daily (active drug first and last dose daily), or placebo, which were supplied by Abbott Laboratories in a blind manner. The first dose of study medication was administered at the study center, and spirometry was done 30, 60, and 120 minutes later. In the 800-mg group, each day's drug card contained both placebo and active drug, and as a result, on the first day, an undetermined number of patients received placebo instead of 800 mg of zileuton as their first dose of drug. Therefore, the 800-mg group was not included in the analysis of the acute response to the first dose of drug.
Results
Top
Methods
Results
Discussion
Author & Article Info
References
Patients
|
A single 600-mg dose of zileuton produced rapid bronchodilation (Figure 1). Compared with the mean FEV1 measured just before study drug ingestion (0 minutes), the mean FEV1 improved 30 minutes after a single 600-mg dose of zileuton and remained increased for the entire 2-hour observation period (P < 0.005 for all observation points). The maximum increase (14.6%) in the mean FEV1 was 0.35 L (CI, 0.25 to 0.45 L) (P < 0.001), which occurred at 60 minutes. No improvement of the FEV1 occurred in the placebo group (0.09 L [CI, –0.01 to 0.19 L]; P = 0.075). The improvement in the mean FEV1 after zileuton was greater than that after placebo at 60 and 120 minutes (P < 0.001 and P = 0.01, respectively).
|
Effects of 4 Weeks of Zileuton Administration on Airway Obstruction
All three groups of patients had an initial improvement in mean FEV1 after enrollment (Figure 2). By the fourth week of the study, only the zileuton groups were still statistically improved compared with the dummy lead-in period. The 0.32-L (CI, 0.16 to 0.48 L) improvement in mean FEV1 at 4 weeks in the group receiving 2.4 g/d of zileuton was greater than that in the placebo group (P = 0.02). This represented a 13.4% improvement in FEV1 compared with the dummy lead-in period. The group receiving 1.6 g/d of zileuton had a mean 0.24-L (CI, 0.08 to 0.40 L) (10.9%) improvement (P = 0.09 compared with placebo). A similar pattern of improvement was seen in the forced vital capacity (FVC). At the end of 4 weeks, the FVC had increased by 0.35 L (CI, 0.17 to 0.53 L) (P < 0.001) and 0.23 L (CI, 0.07 to 0.39 L) (P = 0.006) compared with the dummy lead-in period in patients taking 2.4 g/d and 1.6 g/d of zileuton, respectively. No statistical improvement was noted in the FVC in the placebo group (0.07 L; CI, –0.09 to 0.23 L) (P > 0.2). At 28 days, improvement in FVC occurred with 2.4 g/d of zileuton compared with that in the placebo group (P = 0.02).
|
Figure 3 shows the weekly, average morning and evening peak expiratory flow rates throughout the study. Compared with placebo, 2.4 g/d of zileuton produced a statistical improvement in the weekly, mean morning peak expiratory flow starting with the second week of drug administration through the end of the study (Figure 3, left). The maximum weekly change in the mean, morning peak expiratory flow was 39.5 L/min (CI, 24.8 to 54.2 L/min) (P < 0.001 compared with the dummy lead-in period), which represented a 10% increase in peak expiratory flow. Although the evening peak expiratory flow using 2.4 g/d of zileuton (Figure 3, right) was statistically improved compared with the dummy lead-in period throughout the entire 4 weeks, the comparison with the placebo group was not different (P = 0.064 at 3 weeks). The maximum improvement in evening peak expiratory flow was 30.5 L/min (CI, 15.8 to 45.2 L/min) in the group receiving 2.4 g/d (P = 0.004 compared with the dummy lead-in value). During the last 2 weeks of the study, there was less difference between the evening and morning peak expiratory flow compared with placebo (P = 0.015) in the group taking 2.4 g/d of zileuton.
|
Baseline symptom scores ranged from 1.98 to 2.28 among treatment groups (see Table 1). After 4 weeks of treatment, the asthma symptoms reported by the patients decreased in all three treatment groups (P < 0.01), but the improvement was greater in the group receiving 2.4 g/d of zileuton (P = 0.02 compared with placebo). Overall symptom scores decreased by 37% (CI, 26.1% to 47.9%), 29% (CI, 20.3% to 37.7%), and 17% (CI, 5.7% to 28.3%) for the groups receiving zileuton, 2.4 g/d; zileuton, 1.6 g/d; and placebo, respectively.
ß-Agonist Use
The average daily frequency of ß-agonist use decreased only in the zileuton groups (Figure 4). During the last week of the trial, the frequency of ß-agonist use per day decreased compared with the dummy lead-in value by 0.76 (CI, 0.35 to 1.17) occasions in patients taking zileuton, 2.4 g/d (P < 0.001); 0.57 (CI, 0.19 to 0.95) occasions in patients taking zileuton, 1.6 g/d (P = 0.005); and 0.23 (CI, –0.15 to 0.61) occasions in patients taking placebo (P = 0.24). These represent a 24%, 17%, and 7% change in ß-agonist use, respectively (P = 0.03, 2.4 g/d of zileuton compared with placebo).
|
Bronchodilator Response
The improvement in the FEV1 after administration of the ß-agonist albuterol was assessed at the screening visit before the dummy lead-in period and after 2 and 3 weeks of therapy. Despite the fact that the pre-bronchodilator FEV1 had improved in the zileuton groups (see Figure 2), no reduction occurred in the acute bronchodilator response to albuterol in patients receiving zileuton compared with those given placebo. Before the dummy lead-in period, in response to inhaled albuterol, the FEV1 increased 0.76 L (CI, 0.64 to 0.88 L), 0.71 L (CI, 0.59 to 0.83 L), and 0.78 L (CI, 0.66 to 0.90 L) in patients receiving 2.4 g/d of zileuton, 1.6 g/d of zileuton, and placebo, respectively (P > 0.2 between groups). After 3 weeks of therapy, in response to albuterol, the FEV1 increased 0.62 L (CI, 0.50 to 0.74 L), 0.54 L (CI, 0.42 to 0.66 L), and 0.59 L (CI, 0.47 to 0.71 L) in the three groups, respectively (P > 0.2 between groups).
Urinary Leukotriene E4
Sulphidopeptide leukotriene production, as reflected by recovery of LTE4 in the urine, was decreased after 4 weeks of zileuton administration (Figure 5). Zileuton, 1.6 g/d, decreased the urinary LTE4 by 26.5 pg/mg creatinine (CI, 6.6 to 46.5 pg/mg creatinine) (P = 0.009), which was equivalent to a 26% decrease from the dummy lead-in value. Zileuton, 2.4 g/d, decreased urinary LTE4 recovery by 39.2 pg/mg creatinine (CI, 18.1 to 60.4 pg/mg creatinine) (P < 0.001), a 39% decrease. No change was noted in the urinary LTE4 level in the group receiving placebo (P > 0.2). The reduction in the groups using 1.6 g/d and 2.4 g/d of zileuton was significant compared with the placebo group (P = 0.049 and P = 0.007, respectively).
|
Adverse Events
No differences were noted in the occurrence of adverse events between the patients receiving zileuton and those given placebo. Adverse effects were reported by 39.7% of patients taking 2.4 g/d of zileuton, by 44.9% taking 1.6 g/d of zileuton, and by 44.9% taking placebo. The most common adverse event reported was headache (10% in patients receiving 2.4 g/d of zileuton, 16% in those receiving 1.6 g/d, and 14% in those receiving placebo [P > 0.2]). Three patients receiving 2.4 g/d of zileuton and three receiving 1.6 g/d reported dyspepsia, although no patients receiving placebo reported dyspepsia (P = 0.18 using a two-tailed Fisher exact test).
No clinically significant changes occurred in the hematology determinations, serum chemical analyses, electrocardiograms, or urinalysis test results. Hives and increased liver function test results occurred in one patient after 24 days of zileuton, 800 mg twice a day. Both the hives and the abnormal liver chemistry test results resolved after discontinuation of zileuton therapy.
Discussion
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
We observed acute bronchodilation after administration of the first dose of zileuton (see Figure 1). The maximum bronchodilator effect, a 14.6% increase in the FEV1, was observed within 1 hour of ingestion of the drug. Previous work has shown that zileuton has no significant effect on FEV1 in patients with minimal baseline airway obstruction [14, 17]. However, in patients with abnormal baseline function, antagonists active at the leukotriene receptor have been shown to produce bronchodilation [19, 31]. The bronchodilation that we observed after a single dose of a 5-lipoxygenase inhibitor suggests that ongoing synthesis of leukotrienes may be necessary to mediate part of the increased bronchomotor tone characteristic of asthma in patients with impaired baseline function.
Although zileuton appeared to have a substantial bronchodilator effect during 2 hours, the bronchodilation achieved was less than half that which could be achieved by the inhaled ß-agonist albuterol. There are two possible explanations for zileuton's failure to reverse airway obstruction as completely as inhalation of ß-adrenergic aerosols. First, the urinary leukotriene data show that zileuton does not completely inhibit 5-lipoxygenase. Because the inhibition of 5-lipoxygenase is not complete, part of the residual bronchoconstrictor effect observed may result from the action of 5-lipoxygenase products that are produced despite zileuton administration. Second, it is likely that a component of reversible airway obstruction exists in asthma that results from mechanisms other than the actions of 5-lipoxygenase products on contractile elements. However, it is important that the bronchodilation produced by 5-lipoxygenase blockade, approximately 40% of the bronchodilation observed after ß-agonists, compares favorably with the approximately 50% response seen with oral steroids or very-high-dose inhaled steroids [32].
In addition to the immediate bronchodilator action of zileuton, a progressive improvement was noted in airflow obstruction and asthma symptoms that occurred with continued administration during the 4 weeks of the study. For the FEV1, the importance of this effect became more apparent with resolution of the initial placebo effect frequently noted in studies of persons with asthma. That the observed change in FEV1 was due to zileuton's action on 5-lipoxygenase is further substantiated by the observation that greater and more consistent inhibition of 5-lipoxygenase, as measured by the decrease in urinary LTE4 to nearly normal levels [29] in patients using 2.4 g/d of zileuton, was also associated with a greater improvement in airway function. The progressive effects occurring during 4 weeks suggest that in addition to the acute effect on airway smooth muscle, inhibition of 5-lipoxygenase may affect a process other than smooth muscle constriction. For example, zileuton, by preventing the formation of the cysteinyl leukotrienes, could prevent microvascular leak and airway edema. It is also possible that preventing the formation of LTB4, another 5-lipoxygenase product with potent chemotactic properties, could partially prevent the cellular infiltration associated with asthma [33]. These processes may take days to weeks to reverse and could account for the additional actions of zileuton during the 4 weeks of the study beyond its acute effects. Our data do not allow us to distinguish among these potential mechanisms of the prolonged effects of zileuton. However, because the long-term improvement in airflow obstruction was not associated with any change in ß-agonist responsiveness compared with placebo, it appears that the long-term bronchodilation associated with 5-lipoxygenase inhibition occurs through a mechanism that differs from that of the ß-agonists.
The magnitude of improvement in airway function after 4 weeks of administration of 2.4 g/d of zileuton (that is, a 13.4% increase in the FEV1 and an approximately 40-L/min increase in morning peak expiratory flow) is similar to the effects of many of the therapeutic agents used in asthma treatment, such as theophylline [34] or inhaled steroids [35-37]. Of particular importance is the magnitude of the effect of 5-lipoxygenase inhibition compared with the effects of long-term administration of moderately high doses of inhaled steroids in persons with mild-to-moderate asthma. For example, Dutoit and colleagues [35] noted a 12% improvement in the FEV1 after treatment with the equivalent of 19 puffs per day of inhaled beclomethasone dipropionate for 4 weeks, and Haahtela and colleagues [36] and Vathenen and colleagues [37] noted an improvement in the morning peak flow rate of approximately 30 to 35 L/min after 4 weeks of treatment with 1200 and 1600 µg/d of inhaled budesonide, respectively. Because the doses of inhaled steroids used in these studies may result in some degree of adrenal suppression [38] and possibly increased bone turnover [39, 40], the magnitude of the effect of 5-lipoxygenase inhibition is likely to be clinically important.
The effects of zileuton compared with ß-agonists are also of interest in view of recent data that have questioned increased [22] or regular use [21, 24] of ß-agonists for the treatment of asthma and their effects on asthma symptoms and airway reactivity. At the completion of 4 weeks of treatment, there was a statistically significant 24% decrease in ß-agonist use and a 37% decrease in asthma symptoms. The magnitude of the decrease in ß-agonist use (0.76 occasions/d) compares favorably with that seen with high-dose inhaled steroids [36]. At the same time that ß-agonist use decreased, an improvement occurred in baseline airway function without a change in the acute bronchodilator response to ß-agonists compared with placebo, thus suggesting that inhibition of 5-lipoxygenase can preserve the acute response to ß-agonists while decreasing the need for their regular use. Additionally, high-dose zileuton narrowed the difference between morning and evening peak expiratory flow. Because the magnitude of the variation between morning and evening peak expiratory flow has been associated with the degree of airway responsiveness in asthma [41, 42], this outcome suggests the possibility that the decrease in ß-agonist use may be because of, or associated with, a decrease in airway responsiveness.
Zileuton has not been associated with substantial toxicity. More than 1700 people have received the drug, and adverse events have been generally mild and self-limited, with an incidence that has not been different from that in the placebo group. Isolated cases of increased serum transaminase levels have occurred, with a rapid return to normal levels without therapy.
In conclusion, this double-blind, placebo-controlled trial shows that treatment of mild-to-moderate chronic asthma with an inhibitor of 5-lipoxygenase is associated with improved airway function and decreased symptoms and a need for less bronchodilator therapy. The degree of improvement compares favorably with that achieved by clinically useful drugs such as theophylline and inhaled steroids. In addition to an acute bronchodilator effect, progressive improvement in airway function was observed during 4 weeks of treatment by a mechanism that appears to be separate from that of ß-agonist-induced relaxation of bronchial smooth muscle. Dosing regimens associated with greater inhibition of leukotriene production were also associated with greater clinical and physiologic improvement. These findings provide important evidence for the role of the 5-lipoxygenase products of arachidonic acid in the pathogenesis of spontaneously occurring asthma and indicate that agents that can prevent the formation of these products are of therapeutic value in asthma. It is possible that even greater improvement may be seen with more prolonged therapy or more complete enzyme inhibition.
Author and Article Information
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
References
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
1. Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis. 1989; 140:1745-53.
2. Bousquet J, Chanez P, Lacoste JY, Barneon G, Ghavanian N, Enander I, et al. Eosinophilic inflammation in asthma. N Engl J Med. 1990; 323:1033-9.
3. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987; 237:1171-6.
4. Owen WF Jr, Soberman RJ, Yoshimoto T, Sheffer AL, Lewis RA, Austen KF. Synthesis and release of leukotriene C4 by human eosinophils. J Immunol. 1987; 138:532-8.[Abstract]
5. Lewis RA, Austen KF, Drazen JM, Clark DA, Marfat A, Corey EJ. Slow reacting substances of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources. Proc Natl Acad Sci U S A. 1980; 77:3710-4.
6. Drazen JM. Inhalation challenge with sulfidopeptide leukotrienes in human subjects. Chest. 1986; 89:414-9.
7. Smith LJ, Greenberger PA, Patterson R, Krell RD, Bernstein PR. The effect of inhaled leukotriene D4 in humans. Am Rev Respir Dis. 1985; 131:368-72.
8. Adelroth E, Morris MM, Hargreave FE, O'Byrne PM. Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls. N Engl J Med. 1986; 315: 480-4.
9. Taylor GW, Taylor I, Black P, Maltby NH, Turner N, Fuller RW, et al. Urinary leukotriene E4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet. 1989; 1:584-8.
10. Westcott JY, Smith HR, Wenzel SE, Larsen GL, Thomas RB, Felsien D, et al. Urinary leukotriene E4 in patients with asthma. Effect of airways reactivity and sodium cromoglycate. Am Rev Respir Dis. 1991; 143:1322-8.
11. Drazen JM, O'Brien JB, Sparrow D, Weiss ST, Martins MA, Israel E, et al. Recovery of leukotriene E4 from the urine of patients with airway obstruction. Am Rev Respir Dis. 1992; 146:104-8.
12. Taylor IK, O'Shaughnessy KM, Fuller RW, Dollery CT. Effect of cysteinyl-leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet. 1991; 337:690-4.
13. Israel E, Juniper EF, Callaghan JT, Mathur PN, Morris MM, Dowell AR, et al. Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics. Am Rev Respir Dis. 1989; 140:1348-53.
14. Israel E, Dermarkarian R, Rosenberg M, Sperling R, Taylor G, Rubin P, et al. The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med. 1990; 323:1740-4.
15. Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O'Byrne PM. Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med. 1990; 323:1736-9.
16. Cloud ML, Enas GC, Kemp J, Platts-Mills T, Altman LC, Townley R, et al. A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma. Am Rev Respir Dis. 1989; 140:1336-9.
17. Hui KP, Taylor IK, Taylor GW, Rubin P, Kesterson J, Barnes NC, et al. Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax. 1991; 46:184-9.
18. Finnerty JP, Wood-Baker R, Thomson H, Holgate ST. Role of leukotrienes in exercise-induced asthma. Inhibitory effect of ICI 204219, a potent leukotriene D4 receptor antagonist. Am Rev Respir Dis. 1992; 145:746-9.
19. Hui KP, Barnes NC. Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist. Lancet. 1991; 337:1062-3.
20. Findlay SR, Barden JM, Easley CB, Glass M. Effect of the oral leukotriene antagonist, ICI 204,219, on antigen-induced bronchoconstriction in subjects with asthma. J Allergy Clin Immunol. 1992; 89:1040-5.
21. Sears MR, Taylor DR, Print CG, Lake DC, Li QQ, Flannery EM, et al. Regular inhaled ß-agonist treatment in bronchial asthma. Lancet. 1990; 336:1391-6.
22. Spitzer WO, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockcroft D, et al. The use of ß-agonists and the risk of death and near death from asthma. N Engl J Med. 1992; 326:501-6.
23. Lam A, Newhouse MT. Management of asthma and chronic airflow limitation. Are methylxanthines obsolete? Chest. 1990; 98:44-52.
24. van Schayck CP, Dompeling E, van Herwaarden CL, Folgering H, Verbeek AL, van der Hoogen HJ, et al. Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomized controlled study. BMJ. 1991; 303:1426-31.
25. Axelrod L. Glucocorticoid therapy. Medicine (Baltimore). 1976; 55: 39-65.
26. Adinoff AD, Hollister JR. Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med. 1983; 309:265-8.
27. Carter GW, Young PR, Albert DH, Bouska J, Dyer R, Bell RL, et al 5-lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther. 1991; 256:929-37.
28. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis. 1987; 136:225-44.
29. Westcott JY, Johnston K, Batt RA, Wenzel SE, Voelkel NF. Measurement of peptidoleukotrienes in biological fluids. J Appl Physiol. 1990; 68:2640-8.
30. Rubin P, Dube L, Braeckman R, Swanson L, Hansen R, Albert D, et al. Pharmacokinetics, safety, and ability to diminish leukotriene synthesis by zileuton, an inhibitor of 5-lipoxygenase. Agents Actions Suppl. 1991; 35:103-16.
31. Kips JC, Joos GF, Pauwels RA. Bronchodilatory action of cysteinyl-leukotriene receptors (Letter). Lancet. 1991; 337:1618.
32. Wempe JB, Postma DS, Breederveld N, Alting-Hebing D, van der Mark TW, Koeter GH. Separate and combined effects of corticosteroids and bronchodilators on airflow obstruction and airway hyperresponsiveness in asthma. J Allergy Clin Immunol. 1992; 89:679-87.
33. Drazen JM, Austen KF. Leukotrienes and airway responses. Am Rev Respir Dis. 1987; 136:985-98.
34. Pierson WE, LaForce CF, Bell TD, MacCosbe PE, Sykes RS, Tinkelman D. Long-term, double-blind comparison of controlled-release albuterol versus sustained-release theophylline in adolescents and adults with asthma. J Allergy Clin Immunol. 1990; 85:618-26.
35. Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in asthma but oral theophylline does not. Am Rev Respir Dis. 1987; 136:1174-8.
36. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, et al. Comparison of a ß 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med. 1991; 325:388-92.
37. Vathenen AS, Knox AJ, Wisniewski A, Tattersfield AE. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. Am Rev Respir Dis. 1991; 143:1317-21.
38. Toogood JH. Complications of topical steroid therapy for asthma. Am Rev Respir Dis. 1990; 141:S89-96.
39. Toogood JH, Jennings B, Hodsman AB, Baskerville J, Fraher LJ. Effects of dose and dosing schedule of inhaled budesonide on bone turnover. J Allergy Clin Immunol. 1991; 88:572-80.
40. Hodsman AB, Toogood JH, Jennings B, Fraher LJ, Baskerville JC. Differential effects of inhaled budesonide and oral prednisolone on serum osteocalcin. J Clin Endocrinol Metab. 1991; 72:530-40.
41. Neukirch F, Liard R, Segala C, Korobaeff M, Henry C, Cooreman J. Peak expiratory flow variability and bronchial responsiveness to methacholine. An epidemiologic study in 117 workers. Am Rev Respir Dis. 1992; 146:71-5.
42. Brand PL, Postma DS, Kerstjens HA, Koeter GH. Relationship of airway hyperresponsiveness to respiratory symptoms and diurnal peak flow variation in patients with obstructive lung disease. The Dutch CNSLD Study Group. Am Rev Respir Dis. 1992; 143:916-21.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  C. H. Fanta Asthma N. Engl. J. Med., March 5, 2009; 360(10): 1002 - 1014. [Full Text] [PDF]
|
|
|
|
|
|
M. Peters-Golden and W. R. Henderson Jr. Leukotrienes N. Engl. J. Med., November 1, 2007; 357(18): 1841 - 1854. [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. O'Byrne How much is too much? The treatment of mild asthma Eur. Respir. J., September 1, 2007; 30(3): 403 - 406. [Full Text] [PDF]
|
|
|
|
 |
|
 C. K. Grissom, L. D. Richer, and M. R. Elstad The Effects of a 5-Lipoxygenase Inhibitor on Acute Mountain Sickness and Urinary Leukotriene E4 After Ascent to High Altitude Chest, February 1, 2005; 127(2): 565 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Wetter, Z. Xiang, D. A. Sonetti, H. C. Haverkamp, A. J. Rice, A. A. Abbasi, K. C. Meyer, and J. A. Dempsey Role of lung inflammatory mediators as a cause of exercise-induced arterial hypoxemia in young athletes J Appl Physiol, July 1, 2002; 93(1): 116 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. O. Meltzer, R. F. Lockey, B. F. Friedman, C. Kalberg, S. Goode-Sellers, S. Srebro, L. Edwards, K. Rickard, and Fluticasone Propionate Clinical Research Study Gro Efficacy and Safety of Low-Dose Fluticasone Propionate Compared With Montelukast for Maintenance Treatment of Persistent Asthma Mayo Clin. Proc., May 1, 2002; 77(5): 437 - 445. [Abstract] [PDF]
|
|
|
|
|
|
J. E. Fish, E. Israel, J. J. Murray, A. Emmett, R. Boone, S. W. Yancey, and K. A. Rickard Salmeterol Powder Provides Significantly Better Benefit Than Montelukast in Asthmatic Patients Receiving Concomitant Inhaled Corticosteroid Therapy Chest, August 1, 2001; 120(2): 423 - 430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Salvi, M. T. Krishna, A. P. Sampson, and S. T. Holgate The Anti-inflammatory Effects of Leukotriene-Modifying Drugs and Their Use in Asthma Chest, May 1, 2001; 119(5): 1533 - 1546. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Eccles, N. Rousseau, B. Higgins, and L. Thomas Evidence-based guideline on the primary care management of asthma Fam. Pract., April 1, 2001; 18(2): 223 - 229. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Bisgaard Leukotriene Modifiers in Pediatric Asthma Management Pediatrics, February 1, 2001; 107(2): 381 - 390. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. D. HASDAY, S. S. MELTZER, W. C. MOORE, P. WISNIEWSKI, J. RICHARD HEBEL, C. LANNI, L. M. DUBÉ, and E. R. BLEECKER Anti-inflammatory Effects of Zileuton in a Subpopulation of Allergic Asthmatics Am. J. Respir. Crit. Care Med., April 1, 2000; 161(4): 1229 - 1236. [Abstract] [Full Text]
|
|
|
|
|
|
P. M. O'BYRNE Why Does Airway Inflammation Persist? Is It Leukotrienes? Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S186 - 187. [Full Text] [PDF]
|
|
|
|
|
|
I. W. RODGER From Bench to Bedside . The Hurdles of Discovering a New Leukotriene Receptor Antagonist Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): S7 - 10. [Full Text] [PDF]
|
|
|
|
|
|
B. K. LAM and K. FRANK AUSTEN Leukotriene C4 Synthase . A Pivotal Enzyme in the Biosynthesis of the Cysteinyl Leukotrienes Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): S16 - 19. [Full Text] [PDF]
|
|
|
|
|
|
N. C. BARNES Effects of Antileukotrienes in the Treatment of Asthma Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): S73 - 76. [Full Text] [PDF]
|
|
|
|
|
|
E. S. SILVERMAN and J. M. DRAZEN Genetic Variations in the 5-Lipoxygenase Core Promoter . Description and Functional Implications Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): S77 - 80. [Full Text] [PDF]
|
|
|
|
|
|
B. DAHLEN Treatment of Aspirin-intolerant Asthma with Antileukotrienes Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): S137 - 141. [Full Text] [PDF]
|
|
|
|
 |
|
 Leukotriene-receptor antagonists and related compounds Can. Med. Assoc. J., November 1, 1999; 161(90111): s31 - 34. [Full Text]
|
|
|
|
|
|
J. M. Drazen, E. Israel, and P. M. O'Byrne Treatment of Asthma with Drugs Modifying the Leukotriene Pathway N. Engl. J. Med., January 21, 1999; 340(3): 197 - 206. [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Barnes, K. F. Chung, and C. P. Page Inflammatory Mediators of Asthma: An Update Pharmacol. Rev., December 1, 1998; 50(4): 515 - 596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. DRAZEN Leukotrienes as Mediators of Airway Obstruction Am. J. Respir. Crit. Care Med., November 1, 1998; 158(2007): S193 - S200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nakamura, M. Hoshino, J. J. Sim, K. Ishii, K. Hosaka, and T. Sakamoto Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma Thorax, October 1, 1998; 53(10): 835 - 841. [Abstract] [Full Text]
|
|
|
|
 |
|
 W.-W. Huang, E. A. Garcia-Zepeda, A. Sauty, H. C. Oettgen, M. E. Rothenberg, and A. D. Luster Molecular and Biological Characterization of the Murine Leukotriene B4 Receptor Expressed on Eosinophils J. Exp. Med., September 21, 1998; 188(6): 1063 - 1074. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. F. Reiss, P. Chervinsky, R. J. Dockhorn, S. Shingo, B. Seidenberg, T. B. Edwards, and for the Montelukast Clinical Research Study Group Montelukast, a Once-Daily Leukotriene Receptor Antagonist, in the Treatment of Chronic Asthma: A Multicenter, Randomized, Double-blind Trial Arch Intern Med, June 8, 1998; 158(11): 1213 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. DAHLEN, E. NIZANKOWSKA, A. SZCZEKLIK, O. ZETTERSTROM, G. BOCHENEK, M. KUMLIN, L. MASTALERZ, G. PINIS, L. J. SWANSON, T. I. BOODHOO, et al. Benefits from Adding the 5-Lipoxygenase Inhibitor Zileuton to Conventional Therapy in Aspirin-intolerant Asthmatics Am. J. Respir. Crit. Care Med., April 1, 1998; 157(4): 1187 - 1194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G Ayres, J. F Miles, and P. J Barnes Brittle asthma Thorax, April 1, 1998; 53(4): 315 - 321. [Full Text]
|
|
|
|
|
|
H. J. Schwartz, T. Petty, L. M. Dube, L. J. Swanson, J. F. Lancaster, and for the Zileuton Study Group A Randomized Controlled Trial Comparing Zileuton With Theophylline in Moderate Asthma Arch Intern Med, January 26, 1998; 158(2): 141 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. DRAZEN Clinical Pharmacology of Leukotriene Receptor Antagonists and 5-Lipoxygenase Inhibitors Am. J. Respir. Crit. Care Med., June 1, 1997; 157(6): 233S - 237. [Abstract] [Full Text]
|
|
|
|
|
|
R. J. HORWITZ, K. A. MCGILL, and W. W. BUSSE The Role of Leukotriene Modifiers in the Treatment of Asthma Am. J. Respir. Crit. Care Med., May 1, 1997; 157(5): 1363 - 1371. [Full Text]
|
|
|
|
|
|
F. P. GÓMEZ, R. IGLESIA, J. ROCA, J. A. BARBERÁ, K. FAN CHUNG, and R. RODRIGUEZ-ROISIN The Effects of 5-Lipoxygenase Inhibition by Zileuton on Platelet-activating-factor-induced Pulmonary Abnormalities in Mild Asthma Am. J. Respir. Crit. Care Med., May 1, 1997; 157(5): 1559 - 1564. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. L. Bell, R. R. Harris, P. E. Malo, J. B. Bouska, T. K. Shaughnessy, K. I. Hulkower, C. D. W. Brooks, and G. W. Carter ABT-761 Attenuates Bronchoconstriction and Pulmonary Inflammation in Rodents J. Pharmacol. Exp. Ther., March 1, 1997; 280(3): 1366 - 1373. [Abstract] [Full Text]
|
|
|
|
|
|
L. J. Smith Leukotrienes in Asthma: The Potential Therapeutic Role of Antileukotriene Agents Arch Intern Med, October 28, 1996; 156(19): 2181 - 2189. [Abstract] [PDF]
|
|
|
|
|
|
M. Weinberger and L. Hendeles Theophylline in Asthma N. Engl. J. Med., May 23, 1996; 334(21): 1380 - 1388. [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Penrose, J. Spector, M. Baldasaro, K. Xu, J. Boyce, J. P. Arm, K. F. Austen, and B. K. Lam Molecular Cloning of the Gene for Human Leukotriene C(4) Synthase J. Biol. Chem., May 10, 1996; 271(19): 11356 - 11361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Israel, J. Cohn, L. Dube, J. M. Drazen, Zileuton Clinical Trial Group, P. Ratner, W. Pleskow, A. DeGraff Jr, P. Chervinsky, S. Wasserman, et al. Effect of Treatment With Zileuton, a 5-Lipoxygenase Inhibitor, in Patients With Asthma: A Randomized Controlled Trial JAMA, March 27, 1996; 275(12): 931 - 936. [Abstract] [PDF]
|
|
= dummy lead-in urinary leukotriene E4 (LTE4); \#9632; = urinary LTE4 after 4 weeks of treatment. Patients receiving zileuton at 1.6 g/d and 2.4 g/d had decreased urinary LTE4 levels of 26% and 39%, respectively, compared with dummy lead-in (* P < 0.05; ** P = 0.007).