Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: A 6-month randomized multicenter trial

Liu, Mark C.; Dubé, Louise M.; Lancaster, John F.

doi:10.1016/s0091-6749(96)80002-9

Cited by 227 publications

(114 citation statements)

References 31 publications

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“…The findings suggest that ongoing leukotriene formation in inflamed airways is a prerequisite for a bronchodilator response to antileukotrienes. The finding that the 5-lipoxygenase inhibitor zileuton also causes a prompt bronchodilator response in asthmatics with decreased baseline pulmonary function [222,225] is consistent with this view and illustrates the rapid turnover of leukotrienes in the airways.…”

Section: Acute Bronchodilationsupporting

confidence: 68%

“…Although some antileukotriene drugs have been registered for treatment of asthma (Table 1), relatively few studies have yet appeared as full papers in the scientific literature [221][222][223][224][225][226][227][228][229][230][231][232]. Nevertheless, there is a pattern of effects which consistently have been observed in treatment trials using different antileukotrienes (Table 2).…”

Section: Effects Of Antileukotrienes In the Treatment Of Asthmamentioning

confidence: 99%

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Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

Claesson¹,

1999

Journal of Internal Medicine

101

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Section: Acute Bronchodilationsupporting

confidence: 68%

Section: Effects Of Antileukotrienes In the Treatment Of Asthmamentioning

confidence: 99%

Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

Claesson¹,

1999

Journal of Internal Medicine

101

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“…However, there was a significant difference observed in the frequency of the ALOX5-ht1 [G-C-G-A] haplotype between the AIA group and the ATA group and the normal controls, suggesting a possible involvement of this ALOX5 haplotype in the development of AIA. ALOX5 is the first committed enzyme in the biosynthetic pathway leading to the production of the LTs (Foegh et al 1998), and clinical studies in patients with asthma have shown a therapeutic benefit with ALOX5 inhibitors (Liu et al 1996). Recently, analysis of the promoter region of the ALOX5 gene has revealed VNTRs of the Sp1-binding motif, which have potential influence on the transcription rate of the gene and drug response to ALOX5 inhibitors (Drazen et al 1999a(Drazen et al , 1999bIn et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase

et al. 2004

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A recent study has demonstrated the possible involvement of a leukotriene C4 synthase (LTC4S) gene polymorphism in ASA-intolerant asthma (AIA) in a Polish population, whereas no significant association was noted in other populations. To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) of the key enzymes involved in arachidonate metabolism, and the cysteinyl leukotriene receptor 1 (CYSLTR1) in a large Korean population with AIA: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls. The single-base extension method was used to genotype SNPs in 5-lipoxygenase (ALOX5, -1708G→A, 21C→T, 270G→A, 1728G→A), ALOX5-activating protein (ALOX5AP, 218A→G), prostaglandin-endoperoxide synthase 2 (PTGS2, COX2, -162C→G, 10T→G, R228H, V511A), LTC4S (-444A→C), and CYSLTR1 (927T→C). Haplotype analyses were undertaken for the SNPs in ALOX5. No significant differences in allele and genotype frequencies of single SNPs were observed between the patient groups (P>0.05). However, the frequency of the ALOX5-ht1 [G-C-G-A] haplotype in the AIA group was significantly higher than its frequency in the ATA group with a probability (P) of 0.01, odds ratio (OR) of 5.0, and 95% confidence interval (95%CI) of 1.54-17.9, and in the normal controls (P=0.03, OR=4.5, 95%CI=1.1-18.4), by using a dominant model. These results suggest a lack of association between the ALOX5AP, PTGS2, LTC4S, and CYSLTR1 gene polymorphisms and the AIA phenotype in the Korean population. However, the possible involvement of ALOX5-ht1 [G-C-G-A] in AIA development is suggested.

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“…Results from other studies suggest that the effect on airway tone depends on the degree of pre-existing bronchoconstriction. LIU et al [20] reported in their results from a 6 month trial with zileuton a mean increase in FEV1, of 38% in the patients with FEV1 <50% pred compared to 15% for the whole group. As the asthmatics from the current study had a mean FEV1, of 92% pred a marked bronchodilator effect was not likely to occur.…”

Section: Discussionmentioning

confidence: 97%

Efficacy and duration of action of the antileukotriene zafirlukast on cold air-induced bronchoconstriction

2000

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Efficacy and duration of action of the antileukotriene zafirlukast on cold air-induced bronchoconstriction. K. Richter, R.A. Jo Èrres, H. Magnussen. #ERS Journals Ltd 2000. ABSTRACT: The objectives of the study were to assess the magnitude of the effect of the leukotriene receptor antagonist, zafirlukast, against cold air-induced bronchoconstriction following the first dose and to assess magnitude and duration after 5 days of dosing.Nineteen patients with asthma were included. In a randomized cross-over design, either zafirlukast 20 mg or 80 mg b.d. or placebo were given over 5 days. Challenges were performed 3 h post first dose and 3, 8, 12 and 24 h post last dose. The authors assessed the provocative ventilation rate necessary to achieve a 10% (PV10) and 20% (PV20) fall in forced expiratory volume in one second.The median PV20 3 h post first dose was 69.1 L . min -1 for zafirlukast 80 mg compared to 40 L . min -1 for placebo (p=0.004). The corresponding median value for zafirlukast 20 mg was 59.9 L . min -1 (p=0.06). At steady state the differences in PV20, between zafirlukast 80 mg and placebo were significant at 8 h and 12 h post last dose. The corresponding difference for zafirlukast 20 mg was statistically significant at 8 h post last dose. The analysis of PV10 yielded compatible results. There was no significant protection 24 h after last dose.This study has demonstrated that zafirlukast offers significant protection against cold air-induced bronchoconstriction in asthma. The degree and duration of protection were dose-dependent. However, there was a large interindividual variability for the protective effect of this leukotriene receptor antagonist. Exercise and isocapnic hyperventilation of cold, dry air are similar stimuli causing airway narrowing in asthmatic subjects. Even though there is still an ongoing discussion about the exact mechanism by which exercise or cold air induces asthmatic responses there is substantial evidence that bronchoactive mediators like histamine, prostaglandins and leukotrienes play an important role [1±3]. Antileukotrienes have repeatedly been shown to be effective in attenuating bronchoconstriction induced by exercise [4±8] or hyperventilation of cold air [9,10]. As exercise is a naturally occurring stimulus which is of clinical relevance the authors have studied the onset and the duration of the inhibitory effect of antileukotrienes. Recently preliminary reports have shown inconsistent results for the protective effect on cold air induced bronchoconstriction after a single dose of the leukotriene receptor antagonist zafirlukast [11,12].The authors studied the effect of zafirlukast on airway obstruction induced by hyperventilation of cold air in 19 stable asthmatics. The objectives of the present study were to assess the magnitude of the effect of zafirlukast against cold air-induced bronchoconstriction (20 mg b.d. and 80 mg b.d.) compared with placebo 3 h following the first dose and to assess magnitude and duration of the effect of zafirlukast at steady state conditions a...

show abstract

Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: A 6-month randomized multicenter trial

Cited by 227 publications

References 31 publications

Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase

Efficacy and duration of action of the antileukotriene zafirlukast on cold air-induced bronchoconstriction

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