Chest ACCP Career Connection
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gompertz, S.
Right arrow Articles by Stockley, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gompertz, S.
Right arrow Articles by Stockley, R. A.
(Chest. 2002;122:289-294.)
© 2002 American College of Chest Physicians

A Randomized, Placebo-Controlled Trial of a Leukotriene Synthesis Inhibitor in Patients With COPD*

Simon Gompertz, MD and Robert A. Stockley, DSc

* From the Department of Respiratory Medicine, Queen Elizabeth Hospital, Birmingham, UK.

Correspondence to: Simon Gompertz, MD, Lung Investigation Unit, First Floor, Nuffield House, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2 TH, UK; e-mail: sgomp{at}doctors.org.uk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objective: Patients with COPD classically have neutrophilic bronchial inflammation and raised airway concentrations of the neutrophil chemoattractant leukotriene B4 (LTB4). A small phase II trial was conducted to assess the effects of a leukotriene synthesis inhibitor on bronchial inflammation in patients with stable COPD.

Design: A randomized, double-blind, placebo-controlled, parallel-group study.

Setting: Respiratory medicine department of a university hospital.

Patients and intervention: Seventeen patients with chronic bronchitis and COPD (mean FEV1, 35.5% predicted; SD, 14.8% predicted) were randomized to receive 14 days of the oral leukotriene synthesis inhibitor BAYx1005 (500 mg bid) or placebo.

Measurements and results: Spontaneous sputum samples obtained at baseline and at the end of treatment were assayed for LTB4, myeloperoxidase (an indirect marker of neutrophil numbers and/or activation), and chemotactic activity (Boyden chamber). After 14 days, there were no significant differences (p > 0.05) in absolute LTB4 concentrations between the two treatment groups. However, BAYx1005 treatment produced a significantly greater median reduction in LTB4 of - 3.1 nM (interquartile range [IQR], - 9.6 to - 0.2 nM) vs 3.0 nM (IQR, - 0.3 to 8.5 nM) [p = 0.001], with concentrations decreasing from 8.0 nM (IQR, 4.3 to 24.4 nM) at baseline to 4.2 nM (IQR, 1.9 to 11.9 nM) at the end of treatment (p = 0.03). There were no changes in the placebo group and no differences in sputum myeloperoxidase concentration or chemotaxis between the two treatment arms (p > 0.05).

Conclusions: This small study suggests that a leukotriene synthesis inhibitor can produce modest reductions in some measures of neutrophilic bronchial inflammation in patients with COPD. This class of anti-inflammatory agent requires further study in larger numbers of patients to determine clinical benefit.

Key Words: bronchitis • COPD • inflammation • leukotriene B4 • neutrophils


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
COPD is classically associated with neutrophilic bronchial inflammation, although lymphocytes1 and possibly eosinophils2 may have a role. However the pathologic features are still considered to be mediated largely by the neutrophil,3 through the activity of proteolytic enzymes, such as neutrophil elastase. This protease damages bronchial epithelium, impairs ciliary beating,4 stimulates mucus secretion, and has the potential to disrupt endobronchial immunity.3 For these reasons, there has been increasing interest in the development of strategies to reduce neutrophilic inflammation in patients with COPD, with the aim of stabilizing the condition.

Leukotriene B4 (LTB4) is a proinflammatory derivative of arachidonic acid. It up-regulates the neutrophil adhesion molecule Mac-1,5 and is both a potent neutrophil chemoattractant6 and a neutrophil activator.7 LTB4 is synthesized by neutrophils6 and alveolar macrophages,8 where the conversion of arachidonic acid to the intermediate compound 5-hydroperoxyeicosatetraenoic acid requires both the enzyme 5-lipoxygenase (5-LO) and 5-lipoxygenase activating protein (FLAP). The formation of leukotriene A4 from 5-hydroperoxyeicosatetraenoic acid is also catalyzed by 5-LO, and LTB4 is finally produced by the activity of leukotriene A4 hydrolase.

In the healthy human, lung inhalation of aerosolized LTB4 leads to an influx of neutrophils into the airways.9 Furthermore, the concentration of LTB4 is raised in the bronchial secretions of patients with stable neutrophilic lung diseases such as COPD and bronchiectasis,10 and is increased further at the onset of purulent exacerbations of COPD,11 especially in subjects with {alpha}1-antitrypsin (A1AT) deficiency. Inhibition of the synthesis of leukotrienes, in particular LTB4, therefore provides an attractive therapeutic strategy for modulating the neutrophilic processes involved in the pathogenesis of COPD.

We have performed a preliminary double-blind, randomized, placebo-controlled trial to assess the effects of the FLAP antagonist, BAYx1005, on sputum LTB4 and myeloperoxidase (a marker of sputum neutrophil number and activation) concentrations, and on the chemotactic activity of the secretions in patients with COPD and chronic bronchitis. This article describes the experimental design of this small phase II study, and indicates the feasibility of "proof of principle" studies in these patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Variability Study
Six patients with COPD and chronic bronchitis12 but without A1AT deficiency each provided three spontaneous sputum samples over a 4-month period of clinical stability, in order to assess the normal variability in LTB4 and myeloperoxidase concentrations. The sputum samples were collected and assayed as described below.

FLAP Antagonist Study
Study Subjects: We studied 17 other patients with stable COPD (FEV1 < 65% of predicted for age and sex) and a history of chronic bronchitis,12 aged between 40 and 75 years, with a stable smoking history (no change in smoking status for 6 months). None had received inhaled or oral corticosteroids or any nonsteroidal inflammatory agents within the previous 4 weeks, and all other medication had remained unaltered. Patients were excluded if they had experienced a change in symptoms (shortness of breath, sputum characteristics, chest pain, or fever) suggestive of an acute exacerbation within the previous 4 weeks. In addition, those with a diagnosis or physiologic evidence of asthma (reversibility > 15% of predicted) or with a history of atopy were excluded. Individuals with a history or radiologic features (high-resolution CT scan) suggestive of bronchiectasis, clinically significant hepatic or renal disease, or significant hematologic or biochemical abnormalities including A1AT deficiency were also ineligible. Concomitant therapy with antihistamines, ß-blockers, calcium channel antagonists, warfarin, antiepileptics, or sulfonylureas was not permitted.

Study Design: The patients were randomized in a double-blind fashion to receive either active drug (BAYx1005, 500 mg bid) or matching placebo tablets for 14 days following a 1-week run-in period. Spontaneous sputum samples were collected (over the initial 4 h after waking) at the start of the run-in period (day - 7) and on the day of randomization (day 0) before the study drug was administered. Further sputum samples were collected on the last day of therapy (at the end of the 2-week treatment period).

FEV1 and vital capacity (VC) were measured on day - 7 according to standard criteria.13 Static lung volumes (total lung capacity [TLC], residual volume [RV]) and diffusion capacity of the lung for carbon monoxide corrected for alveolar volume (DLCO/VA) were also recorded. LTB4, myeloperoxidase, and sputum chemotactic activity were measured for all sputum samples. The results for the inflammatory parameters at the two baseline visits (day - 7 and day 0) were combined to produce a mean baseline value for each patient, in order to "smooth out" some of the effects of day-to-day variability inherent to any biological sampling. All patients gave written informed consent to participate in the study, which was approved by the South Birmingham Health Authority Ethics Committee.

Sputum Processing and Analysis
The sputum samples were ultracentrifuged at 50,000g (4°C) for 90 min, and the sol phase was harvested and stored at - 70°C until analyzed. Assays for LTB4 and for myeloperoxidase were all completed on the same day. Sputum chemotaxis assays were not all performed on the same day, but results were standardized as indicated below.

LTB4: LTB4 was measured using a commercially available enzyme-linked immunosorbent assay kit (Amersham International; Buckinghamshire, UK). The characteristics and recovery of this assay have been described previously.14

Myeloperoxidase: Myeloperoxidase activity was measured by a chromogenic substrate assay relative to a standard preparation of lysed neutrophils as described previously,14 and used as a marker of sputum neutrophil content and activation. The results are expressed as arbitrary units per milliliter of sputum.

Sputum Chemotaxis: Sputum chemotactic activity was assessed using neutrophils isolated from the blood of healthy volunteers using the method of Jepsen and Skottun,15 as we have described previously.16 The assay was performed using the 48-well microchamber,17 18 with a 3-µm membrane pore size and sputum sol phase diluted 1:20 with RPMI 1640 medium containing 2 mg/mL of bovine serum albumin. Preliminary experiments (data not shown) indicated that this was the optimum dilution to assess migrational responses to changes in chemotactic signal. The number of neutrophils in each of five high-power fields was counted for each well and the average obtained. All assays were performed in triplicate, and the mean value of these was taken as the final result. Chemotactic activity was standardized by expressing the mean neutrophil count per high-power field as a percentage of the mean for the positive control (N-formyl-methionyl-leucyl-phenylalanine, 10-8 mol/L), which was also run in triplicate for each microchamber.

Statistical Analysis: Demographic data are expressed as mean (SD). Comparisons between the two treatment groups were made using nonpaired t tests for continuous variables, and the Fisher exact test for categorical data.

LTB4, myeloperoxidase, and sputum chemotactic activity were not normally distributed. The data are therefore expressed as median (interquartile range [IQR]), and comparisons with baseline values were made using the Wilcoxon sign rank test. The variability data were examined with the Friedman test and intraclass correlation coefficients.19 The differences between the two treatment groups at each time point and in the changes from baseline were compared using the Mann-Whitney U test. The level of statistical significance was taken as < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Variability Study
The six patients (four men; three current smokers and three ex-smokers; mean age ± SD, 68.8 ± 5.4 years) had moderate-to-severe airflow obstruction (FEV1 31.6 ± 22.2% of predicted; FEV1/VC, 29.5 ± 13.9%), significant gas trapping (RV/TLC, 148.6 ± 30.0% of predicted), and a reduced transfer coefficient (DLCO/VA, 60.7 ± 24.0% of predicted). The median (IQR) concentrations of LTB4 and myeloperoxidase for each of the three sets of sputum samples are indicated in Table 1 . There were no significant changes in the concentrations of either parameter compared to the first samples, and no significant differences between the three sets of results (Friedman test, p > 0.05). The intraclass correlation coefficient for LTB4 was 0.62, indicating good reproducibility of this parameter on repeated measurement, whereas the corresponding value for myeloperoxidase was only 0.29.


View this table:
[in this window]
[in a new window]

  		Table 1.. Variability Study*

 
FLAP Antagonist Study
Subjects: Eight patients were randomized to receive active drug, and nine patients were randomized to receive placebo. The characteristics of the study population are summarized in Table 2 . The patients in the two treatment groups were similar, and had evidence of moderate-to-severe airflow obstruction, significant gas trapping, and a reduced DLCO/VA, consistent with a degree of emphysema.


View this table:
[in this window]
[in a new window]

  		Table 2.. Patient Characteristics*

 
One of the 17 subjects was receiving no bronchodilator therapy, 13 patients were receiving a short-acting inhaled ß2-agonist, 10 patients were receiving inhaled anticholinergic agents, and 7 patients were receiving both classes of bronchodilator. Six patients had been prescribed a long-acting ß2-agonist, and two patients were receiving oral theophyllines. There were no significant differences in the proportion of patients receiving any class of agent between the two treatment groups (p > 0.05).

LTB4: There was a significant reduction in sputum LTB4 (Fig 1 ) in the group treated with BAYx1005, from a median value of 8.0 nM (IQR, 4.3 to 24.4 nM) at baseline, to 4.2 nM (IQR, 1.9 to 11.9 nM) at the end of treatment (p = 0.03). There was no reduction in LTB4 in the placebo group, with a median value of 5.4 nM (IQR, 3.0 to 17.2 nM) at baseline and 8.3 nM (IQR, 2.3 to 39.1 nM) at the end of the treatment period.



View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1.. Individual values for sputum LTB4 concentrations are shown on a logarithmic scale for the patients treated with active drug (open circles) or placebo (closed circles). The narrow lines join the paired data for each patient. The horizontal bars represent the median values and the asterisk indicates a significant decrease compared to baseline values (p = 0.03). There were no significant differences between the two treatment arms at any point (p > 0.05).

 
There were no statistically significant differences between the treatment and placebo groups at baseline (p > 0.05) or at the end of treatment (p > 0.05); however, the median change in sputum LTB4 concentration was significantly different (active group, - 3.1 nM [IQR, - 9.6 to - 0.2 nM]; placebo group, 3.0 nM [- 0.3 to 8.5 nM]; p = 0.001).

Myeloperoxidase: There was a decrease in sputum myeloperoxidase concentration in the patients treated with BAYx1005, from a median value of 0.71 U/mL (IQR, 0.20 to 2.43 U/mL) at baseline, to 0.47 U/mL (IQR, 0.22 to 0.85 U/mL) at the end of treatment (Fig 2 ), although this failed to achieve statistical significance (p = 0.06). There were no changes in myeloperoxidase in the placebo group (p > 0.05); the median concentration at baseline was 0.35 U/mL (IQR, 0.21 to 0.98 U/mL) and 0.34 U/mL (IQR, 0.21 to 0.66 U/mL) at the end of the treatment period. Furthermore, there were no statistically significant differences between the active and placebo groups at either time point (p > 0.05) and no differences in the changes in myeloperoxidase compared to baseline between the two treatment arms (p > 0.05, data not shown).



View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2.. Individual values for sputum myeloperoxidase (MPO) concentrations are shown on a logarithmic scale for the patients treated with active drug (open circles) or placebo (closed circles). The narrow lines join the paired data for each patient. The horizontal bars represent the median values and the asterisk indicates the significance of the decrease compared to baseline values (p = 0.06). There were no significant differences between the two treatment arms at any point (p > 0.05).

 
Sputum Chemotactic Activity: There were no changes (p > 0.05) in total sputum chemotactic activity in the active treatment group. The median baseline value was 84.9% (IQR, 77.7 to 98.4%) of the positive control, compared with 85.4% (IQR, 75.8 to 118.4%) at the end of treatment (Fig 3 ). Similarly there were no changes (p > 0.05) in the placebo group: 87.9% (IQR, 72.6 to 123.5%) of the positive control at baseline and 82.1% (IQR, 70.4 to 96.5%) at the end of treatment. Furthermore, there were no differences in the absolute values of chemotaxis between the two treatment groups at any time point (p > 0.05), or in the changes from baseline (p > 0.05, data not shown).



View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3.. Individual values for sputum chemotactic activity are shown relative to the positive (N-formyl-methionyl-leucyl-phenylalanine [fMLP]) control for the patients treated with active drug (open circles) or placebo (closed circles). The narrow lines join the paired data for each patient. The horizontal bars represent the median values. There were no significant differences within or between the two treatment arms at any point (p > 0.05).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The results indicate that the FLAP antagonist, BAYx1005, produced a modest but significant reduction in sputum LTB4 concentrations in the patients studied in this trial. This agent has been shown to inhibit the formation of 5-LO products in vitro in a dose-related manner.20 Although the preclinical studies20 showed an almost complete inhibition of leukotriene synthesis, it is clear that the dose studied here was insufficient to completely suppress LTB4 production. However, the reductions in LTB4 concentration were comparable in magnitude to those seen during the resolution of purulent exacerbations of chronic bronchitis.11 Furthermore, in a similar but small group of untreated patients in stable clinical condition, sputum LTB4 concentrations showed little variability on repeated sampling. Clearly, the number of individuals was small and the analyses might be susceptible to type II errors. Overall, the results suggest that, although the changes were modest, the reductions may prove to be of a clinically important magnitude in the modulation of inflammation.

Myeloperoxidase is a biochemical marker of neutrophil numbers and activation. Since LTB4 can induce both migration of neutrophils into the lungs and their activation, it is of interest that myeloperoxidase also fell on treatment. However, the reproducibility of repeated measurements of myeloperoxidase was less satisfactory, and it is possible that the changes demonstrated may be related simply to the variability of this parameter.

In order to investigate these changes further, we assessed the chemotactic activity of the secretions using a 48-well microchemotaxis chamber. In this study, we were unable to demonstrate any change in total chemotactic activity when patients were receiving therapy. However, only approximately 27% of the total chemotactic activity of such samples can be attributed to LTB4.21 Thus, the modest changes in LTB4 may have been overwhelmed by the continued influence of the many other neutrophil chemoattractants found in the airways of patients with COPD (including interleukin-8, tumor necrosis factor-{alpha}, plasmin-activated complement 5, modified A1AT, elastase-A1AT complexes, peptide fragments of matrix proteins, and bacterial products22 ), resulting in no overall change in chemotactic signal. However, in previous studies21 23 we have found that this experimental model is able to detect small changes in chemotactic molecules, as have other authors.17

As far as we are aware, there have been no clinical trials of leukotriene inhibitors in patients with COPD; however, there has been much interest in the role of leukotrienes in the pathology of asthma. The cysteinyl leukotrienes leukotriene C4, leukotriene D4 (LTD4), and leukotriene E4 all bind to the LTD4 cysteinyl leukotriene receptor, causing smooth-muscle contraction, mucus secretion, and eosinophil migration and are thought to be important in the inflammatory processes underlying the asthmatic response.24 A variety of studies reviewed by Busse et al24 have shown beneficial effects of leukotriene blockade at the LTD4 receptor, and of direct inhibition of 5-LO or of FLAP, including studies of BAYx1005.25 26 27 BAYx1005 reduces bronchial responses to allergen challenge,25 27 attenuates the bronchial response to cold dry air challenge,26 and reduces urinary leukotriene E4 excretion.25 Furthermore Fischer et al26 demonstrated that a single dose of BAYx1005 reduced the ex vivo release of LTB4 from aliquots of whole blood stimulated with the calcium ionophore A23187. Although an LTB4 receptor antagonist had no effect on asthmatic airway responses, it did reduce both the number and proportion of neutrophils in BAL fluid 24 h after allergen challenge.28

In the present study, BAYx1005 reduced LTB4 levels and may have had some effect on sputum neutrophil content and/or activation (as assessed indirectly by sputum myeloperoxidase) in patients with stable COPD; however, it has yet to be determined whether this approach will lead to clinical benefits. The study of more effective inhibitors of LTB4 for longer periods, in larger numbers of patients, is needed to clarify this possibility, together with a direct assessment of sputum neutrophil numbers. LTB4 contributes to the recruitment of inflammatory cells into the airway both in the stable state,10 21 and during acute exacerbations.11 Reductions in this process may therefore protect the airways from neutrophil-mediated damage and from the effects of an acute exacerbation.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
The results from this small, preliminary study have established that a leukotriene synthesis inhibitor may affect neutrophilic bronchial inflammation in patients with stable COPD and chronic bronchitis, and that this class of drug merits further studies in a larger number of patients.


   Footnotes
 
Abbreviations: A1AT = {alpha}1-antitrypsin; DLCO/VA = diffusion capacity of the lung for carbon monoxide corrected for alveolar volume; FLAP = 5-lipoxygenase activating protein; IQR = interquartile range; 5-LO = 5-lipoxygenase; LTB4 = leukotriene B4; LTD4 = leukotriene D4; RV = residual volume; TLC = total lung capacity; VC = vital capacity

Financial support was provided by a noncommercial scientific grant from Bayer.

Received for publication August 6, 2001. Accepted for publication February 6, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Saetta, M, Di Stefano, A, Maestrelli, P, et al (1993) Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am Rev Respir Dis 147,301-306[ISI][Medline]
  2. Lacoste, J-Y, Bousquet, J, Chanez, P, et al (1993) Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis and chronic obstructive pulmonary disease. J Allergy Clin Immunol 92,537-548[CrossRef][ISI][Medline]
  3. Gompertz, S, Stockley, RA (2000) Inflammation: role of the neutrophil and the eosinophil. Semin Respir Infect 15,14-23[Medline]
  4. Smallman, LA, Hill, SL, Stockley, RA (1984) Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect. Thorax 39,663-667[Abstract]
  5. Sengelov, H, Kjeldsen, L, Diamond, MS, et al (1993) Subcellular localization and dynamics of Mac-1 ({alpha}mßm) in human neutrophils. J Clin Invest 92,1467-1476[ISI][Medline]
  6. Ford-Hutchinson, AW, Bray, MA, Doig, MV, et al (1980) Leukotriene B, a potent chemotactic and aggregating substance released from polymorphonuclear leukocytes. Nature 286,264-265[CrossRef][Medline]
  7. Feinmark, SJ, Lindgren, JA, Claesson, H-E, et al (1981) Stimulation of human leukocyte degranulation by leukotriene B4 and its {omega}-oxidised metabolites. FEBS Lett 136,141-144[CrossRef][ISI][Medline]
  8. Martin, TR, Altman, LC, Albert, RK, et al (1984) Leukotriene B4 production by the human alveolar macrophage: a potential mechanism for amplifying inflammation in the lung. Am Rev Respir Dis 129,106-111[ISI][Medline]
  9. Martin, TR, Pistorese, BP, Chi, EY, et al (1989) Effects of leukotriene B4 in the human lung: recruitment of neutrophils into the alveolar space without a change in protein permeability. J Clin Invest 84,1609-1619[ISI][Medline]
  10. Crooks, SW, Stockley, RA (1998) Molecules in focus: leukotriene B4. Int J Biochem Cell Biol 30,173-178[CrossRef][ISI][Medline]
  11. Gompertz, S, O’Brien, C, Bayley, DL, et al (2001) Changes in bronchial inflammation during acute exacerbations of chronic bronchitis. Eur Respir J 17,1112-1119[Abstract/Free Full Text]
  12. . Medical Research Council. (1965) Definition and classification of chronic bronchitis for clinical and epidemiological purposes. Lancet i,775-779
  13. BTS/ARTP guidelines. Guidelines for the measurement of respiratory function. Respir Med 1994;88,165-194[ISI][Medline]
  14. Stockley, RA, Bayley, D (2000) Validation of assays for inflammatory markers in sputum. Eur Respir J 15,778-781[Abstract]
  15. Jepsen, LV, Skottun, T (1982) A rapid one-step method for the isolation of human granulocytes from whole blood. Scand J Clin Lab Invest 42,235-238[ISI][Medline]
  16. Stockley, RA, Shaw, J, Afford, SC, et al (1990) Effect of {alpha}-1-proteinase inhibitor on neutrophil chemotaxis. Am J Respir Cell Mol Biol 2,163-170
  17. Falk, W, Goodwin, RH, Leonard, EJ (1980) A 48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J Immunol Methods 33,239-247[CrossRef][ISI][Medline]
  18. Llewellyn-Jones, CG, Hill, SL, Stockley, RA (1994) Effect of fluticasone propionate on neutrophil chemotaxis, superoxide generation, and extracellular proteolytic activity in vitro. Thorax 49,207-212[Abstract]
  19. Bland, M (2000) An introduction to medical statistics 3rd ed. Oxford Medical Publications Oxford, UK.
  20. Hatzelmann, A, Fruchtmann, R, Mohrs, KH, et al (1993) Mode of action of the new selective leukotriene synthesis inhibitor BAYx1005 {(R)-2-[4-(quinolin-2-YL-methoxy)phenyl]-2-cyclopentyl acetic acid} and structurally related compounds. Biochem Pharmacol 45,101-111[CrossRef][ISI][Medline]
  21. Mikami, M, Llewellyn-Jones, CG, Bayley, D, et al (1998) The chemotactic activity of sputum from patients with bronchiectasis. Am J Respir Crit Care Med 157,723-728[Abstract/Free Full Text]
  22. Hill, A, Gompertz, S, Stockley, R (2000) Factors influencing airway inflammation in chronic obstructive pulmonary disease. Thorax 55,970-977[Free Full Text]
  23. Ip, M, Lomas, DA, Shaw, J, et al (1990) Effect of non-steroidal anti-inflammatory drugs on neutrophil chemotaxis: an in vitro and in vivo study. Br J Rheumatol 29,363-367[Abstract/Free Full Text]
  24. Busse, WW, McGill, KA, Horwitz, RJ (1999) Leukotriene pathway inhibitors in asthma and chronic obstructive pulmonary disease. Clin Exp Allergy 29,110-115
  25. Dahlen, B, Kumlin, M, Ihre, E, et al (1997) Inhibition of allergen-induced airway obstruction and leukotriene generation in atopic asthmatic subjects by the leukotriene biosynthesis inhibitor BAYx1005. Thorax 52,342-347[Abstract]
  26. Fischer, AR, Rosenberg, MA, Roth, M, et al (1997) Effect of a novel 5-lipoxygenase activating protein inhibitor, BAYx1005, on asthma induced by cold dry air. Thorax 52,1074-1077[Abstract]
  27. Hamilton, AL, Watson, RM, Wyile, G, et al (1997) Attenuation of early and late phase allergen-induced bronchoconstriction in asthmatic subjects by a 5-lipoxygenase activating protein antagonist, BAYx1005. Thorax 52,348-354[Abstract]
  28. Evans, DJ, Barnes, PJ, Spaethe, SM, et al (1996) Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma. Thorax 51,1178-1184[Abstract]



This article has been cited by other articles:


Home page
 ChestHome page
K.-L. Huang, C.-W. Chen, S.-J. Chu, W.-C. Perng, and C.-P. Wu
Systemic Inflammation Caused by White Smoke Inhalation in a Combat Exercise
Chest, March 1, 2008; 133(3): 722 - 728.
[Abstract] [Full Text] [PDF]

Home page
 ERRHome page
P. J. Barnes
New approaches to COPD
Eur. Respir. Rev., September 1, 2005; 14(94): 2 - 11.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
P. J. Barnes and R. A. Stockley
COPD: current therapeutic interventions and future approaches
Eur. Respir. J., June 1, 2005; 25(6): 1084 - 1106.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
R. Buhl and S. G. Farmer
Future Directions in the Pharmacologic Therapy of Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, April 1, 2005; 2(1): 83 - 93.
[Abstract] [Full Text] [PDF]

Home page
 Annals of Clinical & Laboratory ScienceHome page
G. Riccioni, C. Di Ilio, P. Conti, T. C. Theoharides, and N. D'Orazio
Advances in Therapy with Antileukotriene Drugs
Ann. Clin. Lab. Sci., October 1, 2004; 34(4): 379 - 387.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
P Montuschi, S A Kharitonov, G Ciabattoni, and P J Barnes
Exhaled leukotrienes and prostaglandins in COPD
Thorax, July 1, 2003; 58(7): 585 - 588.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
B. Balbi
COPD: Is Chemotaxis the Key?
Chest, April 1, 2003; 123(4): 983 - 986.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gompertz, S.
Right arrow Articles by Stockley, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gompertz, S.
Right arrow Articles by Stockley, R. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS