Original Article
The Effects of a 5-Lipoxygenase Inhibitor on Asthma Induced by Cold, Dry Air
N Engl J Med 1990; 323:1740-1744December 20, 1990
- Abstract
- Abstract
Background.
The enzyme 5-lipoxygenase catalyzes the metabolism of arachidonic acid to form products that have been implicated in the airway obstruction of asthma. We hypothesized that if products of the 5-lipoxygenase pathway are important in mediating this obstruction, then prevention of their formation should decrease the severity of an induced asthmatic response.
Methods.
In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of A-64077, a 5-lipoxygenase inhibitor, on the bronchoconstriction induced by hyperventilation of cold, dry air in 13 patients with asthma. The completeness of 5-lipoxygenase inhibition was confirmed by examining the profile of eicosanoids produced in whole blood ex vivo after activation with the calcium ionophore A-23187.
Results.
A-64077 decreased the mean (±SEM) ionophore-induced synthesis of leukotriene B4, a 5-lipoxygenase product, by 74 percent (from 265.3±30.3 to 69.5±21.5 ng per milliliter, P<0.001), but it did not affect the ionophore-induced synthesis of thromboxane B2, a cyclooxygenase metabolite of arachidonic acid (80.0±17.1 ng per milliliter before A-64077 vs. 75.8±14.3 ng per milliliter after A-64077). In concert with the selective inhibition of 5-lipoxygenase by A-64077, the amount of cold, dry air (expressed as respiratory heat exchange) required to reduce the forced expiratory volume in one second by 10 percent was increased by 47 percent after A-64077 (3.0 kJ per minute for placebo vs. 4.4 kJ per minute for A-64077, P<0.002). Similar results were obtained when minute ventilation was used as an indicator of outcome (27.5 liters per minute for placebo vs. 39.8 liters per minute for A-64077, P<0.005).
Conclusions.
Selective inhibition of 5-lipoxygenase by A-64077 is associated with a significant amelioration of the asthmatic response to cold, dry air, suggesting that 5-lipoxygenase products are involved in this response. This approach may be useful in the treatment of asthma. (N Engl J Med 1990; 323:1740–4.)
Media in This Article
Figure 1
Mean (±SEM) Plasma Levels of Leukotriene B4 and Thromboxane B2 in Blood Activated with Ionophore before and after the Administration of A-64077 (Solid Bars) or Placebo (Open Bars).Figure 2
Airway Reactivity to Hyperventilation of Cold, Dry Air Three Hours after the Patients Received Placebo or A-64077.Article Activity
- Article
ASTHMA is a disease characterized by episodic bronchoconstriction, hypersecretion of mucus, and inflammation of the airways. Evidence suggests that substances derived from the action of the enzyme 5-lipoxygenase on arachidonic acid may have a role in mediating the physiologic events in asthma. The metabolites derived from the 5-lipoxygenase pathway include the sulfidopeptide leukotrienes, 5-hydroxyeicosatetraenoic acid (5-HETE), and leukotriene B4, which have been shown individually and collectively to be potent bronchoconstrictors,1 2 3 4 5 mucous secretagogues,6 , 7 and chemotactic agents.8 , 9 Products of the 5-lipoxygenase pathway have been detected in body fluids after experimentally induced bronchoconstriction and during spontaneous attacks of asthma.10 11 12 13 14 However, it remains to be shown that inhibition of the biosynthesis of these products is effective in preventing asthmatic responses.15 Indeed, previous work examining the efficacy of a number of 5-lipoxygenase inhibitors failed to demonstrate a positive effect on asthma.16 17 18 In those studies, however, adequate blockade of 5-lipoxygenase could not be demonstrated.
A-64077 (N-(1-(benzo[b]thien-2-yl)ethyl)-N-hydroxyurea; Abbott Laboratories, Abbott Park, Ill.) is a novel drug that has been shown to inhibit the activity of 5-lipoxygenase in lower animals.19 Because of the potential importance of 5-lipoxygenase products in asthma, we examined the ability of A-64077 to inhibit 5-lipoxygenase activity in patients with asthma and investigated its effectiveness in inhibiting the asthmatic response to the inhalation of cold, dry air.
Methods
Patients
Thirteen men, who satisfied the American Thoracic Society criteria for asthma20 and were known to respond to isocapnic hyperventilation of cold, dry air with at least a 20 percent fall in the forced expiratory volume in the first second (FEV1), completed the study. In the six weeks before the study, none of the patients had used inhaled or oral steroids or had had symptoms of upper respiratory tract infection. Written informed consent for the protocol, which was reviewed and approved by the Beth Israel Hospital Committee on Clinical Investigations, was obtained from each patient.
Study Design
The patients received oral A-64077 or placebo in a double-blind, randomized manner before undergoing a challenge with cold, dry air. Ten to 18 days later they were crossed over to receive the alternative treatment and followed the identical procedure at the same time of day. The studies were performed after the patients had abstained from using an inhaled bronchodilator for 8 hours, drinking caffeinated beverages for 12 hours, and taking oral bronchodilators or cromolyn sodium for at least 48 hours. On each study day 30 minutes after the patients' arrival at the laboratory, spirometry was performed, blood was drawn for activation with the calcium ionophore, and drug was administered in a blinded fashion. Three hours later a second blood sample was drawn for activation with the calcium ionophore, and patients underwent inhalation challenge with cold, dry air. A-64077 (800 mg) and identical-appearing placebo capsules were supplied by Abbott Laboratories according to a blinded and randomized code.
The cold, dry air challenge, a modification of a technique described previously,21 consisted of successive three-minute periods during which patients breathed cold, dry, compressed air containing 5 percent carbon dioxide at increasing levels of ventilation until the FEV1 had decreased by 20 percent or until maximal voluntary ventilation had been reached. Inspired volumes were determined by integrating the flow signal from a pneumotachygraph placed before the cooling coils. An instantaneous graphical display of the inspiratory volume allowed the patients to match tidal volume and respiratory rate to preset targets. Inspiratory and expiratory air temperatures at the mouth were measured by rapidly responding thermocouples (Omega Engineering, Stamford, Conn.). The response to cold, dry air was measured as the percent change in the FEV1 at each level of ventilation as compared with the average of three FEV1 measurements made before the challenge.
Respiratory heat exchange was calculated according to the formula outlined by Deal et al.22 and was corrected for the conversion of kilocalories to kilojoules (1 kcal = 4.184 kJ). The responsiveness to cold, dry air was expressed as the interpolated respiratory heat exchange or minute ventilation required to produce a 10, 15, or 20 percent reduction in the FEV1 (PD10FEV1, PD15FEV1, and PD20FEV1, respectively) from the log10 dose–response curves obtained as already described. In one case, on the day placebo was administered, the patient's FEV1 fell more than 10 percent after the first level of ventilation, and the 10 percent decrease was conservatively calculated as the respiratory heat exchange or minute ventilation at that first level of ventilation.
Eicosanoid Production ex Vivo
To assess the effectiveness and specificity of 5-lipoxygenase inhibition by A-64077, we added the calcium ionophore A-23187 (Biomol, Plymouth Meeting, Pa.) to whole-blood samples obtained from our patients before and three hours after the administration of A-64077 or placebo. The activation of whole blood with A-23187 results in the release of arachidonic acid and the formation of leukotriene B4 and thromboxane B2, which are products of the 5-lipoxygenase and cyclooxygenase pathways, respectively. A-23187, dissolved in dimethylsulfoxide, was added to heparin-treated venous blood obtained from each patient to achieve a final concentration of 50 μmol per liter. Samples containing only dimethylsulfoxide were used as a control. The blood samples were incubated at 37°C for 30 minutes, and the reactions were stopped by placing the samples on ice. The samples were centrifuged at 1000×g at 4°C for 10 minutes, and the plasma was separated and stored under nitrogen gas at −70°C. At the time of assay, 0.5-ml aliquots of plasma were thawed, applied to prewetted C18 Sep-Pak cartridges (Waters, Milford, Mass.), and eluted sequentially with 5 ml of water, 5 ml of hexane, and 2 ml of methanol. The methanol fraction was evaporated to dryness under reduced pressure and temperature and resuspended in radioimmunoassay (RIA) buffer. The leukotriene B4 RIA (Amersham, Arlington Heights, Ill.) was performed in a blinded manner on these extracted samples. There was 0.4 percent cross-reactivity with 20-OH-leukotriene B4 and 6-trans-leukotriene B4 and less than 0.05 percent reactivity with leukotriene C4, leukotriene D4, 5-HETE, hydroxyheptadecatrienoic acid, thromboxane B2, prostaglandin F2α, 6-keto-prostaglandin F1α, and arachidonic acid.
Thromboxane B2 was first extracted from plasma with Sep-Pak cartridges that had been rinsed with ethanol and water and then eluted sequentially with 20 ml of water, 20 ml of ethanol and water (15:85), 20 ml of petroleum ether, and 10 ml of methyl formate. The thromboxane B2 present in the methyl formate fraction was determined by RIA (Amersham). There was 1.2 percent cross-reactivity with prostaglandin D2, 0.15 percent with prostaglandin F2α, 0.13 percent with 13,14-dihydro-15-keto-thromboxane B2, and 0.10 percent with 6β-prostaglandin I1. The mean fractional recoveries (±SD) of leukotriene B4 and thromboxane B2, determined in a separate set of samples, were 43.3±1.8 percent and 51.5±3.4 percent, respectively; the values reported are corrected for these recoveries.
We further quantitated the products of the 5-lipoxygenase pathway synthesized by activated whole blood after treatment with A-64077 by determining the integrated optical density after resolution on reverse-phase high-performance liquid chromatography. The dried and redissolved eluate of C18 Sep-Pak cartridges23 was applied to a 5-μm octadecylsilane column prewashed with a buffer of 0.1 percent (vol/vol) glacial acetic acid—ammonium acetate (pH 5.6):methanol:acetonitrile (70:15:15 vol/vol/vol), and eluted with 4-minute, 20-minute, and 41-minute linear gradients to 20, 52.5, and 68.5 percent methanol, respectively. Retention times in this system were based on the elution of synthetic standards. The mean (±SD) recoveries of [3H]leukotriene B4 and [3H]5-HETE were 65.4±4.6 percent and 46.0±1.8 percent, respectively; the values reported are corrected for these recoveries.
Statistical Analysis
A two-tailed Student's t-test for paired data was used to compare the effects of A-64077 with placebo directly. Values are expressed as means ±SEM or, in the case of geometric means, as the means divided or multiplied by the geometric SEM.
Results
Thirteen nonsmoking men with atopy who were 19 to 43 years of age (mean, 25±2) completed the study. The mean FEV1 before randomization was 3.63±0.13 liters, which was 81±3 percent of the predicted value (range, 65 to 100 percent). All patients used inhaled beta-sympathomimetics, and one also used an oral preparation; five regularly used methylxanthine preparations, and one used cromolyn sodium.
Ex Vivo Verification of Specific 5-Lipoxygenase Blockade
The ionophore-induced production of leukotriene B4, a 5-lipoxygenase-pathway product of arachidonic acid,24 was used as a marker of the activity of 5-lipoxygenase. RIA of plasma samples from blood activated with ionophore showed that three hours after the administration of A-64077, just before the challenge with cold, dry air, there was a 74 percent decrease in the amount of leukotriene B4 produced (265.3±30.3 ng per milliliter before A-64077 and 69.5±21.5 ng per milliliter after A-64077, P<0.001) (Fig. 1Figure 1
Mean (±SEM) Plasma Levels of Leukotriene B4 and Thromboxane B2 in Blood Activated with Ionophore before and after the Administration of A-64077 (Solid Bars) or Placebo (Open Bars).). The administration of placebo had no effect on ionophore-induced production of leukotriene B4 (237.4±29.4 ng per milliliter before placebo and 235.5±24.8 ng per milliliter three hours after placebo, P>0.5). The capacity of patients to produce leukotrienes was similar on different days, in that there was no difference in ionophore-induced leukotriene B4 levels at base line, before the administration of either placebo or A-64077 (P>0.5) (Fig. 1). In contrast to the inhibition of the A-23187—induced production of leukotriene B4, the representative product of the 5-lipoxygenase pathway, thromboxane B2 production by the cyclooxygenase pathway was not affected by treatment with A-64077 (80.0±17.1 ng per milliliter before A-64077 and 75.8± 14.3 ng per milliliter after A-64077) (Fig. 1).To confirm the radioimmunoassay findings, 5-lipoxygenase products in the plasma samples from blood activated with calcium ionophore were resolved by reverse-phase high-performance liquid chromatography and quantitated by measuring the integrated optical density. The results confirmed the RIA findings. A-64077 decreased the generation of leukotriene B4 by 81 percent (from 273±20 to 53±16 ng per milliliter of plasma, P<0.001). Concomitantly, the production of 5-HETE, another 5-lipoxygenase product, was reduced by 91 percent (from 487±104 to 44±14 ng per milliliter of plasma, P = 0.001). A 61 percent decrease in the production of 6-trans-leukotriene B4, a 5-lipoxygenase metabolite of leukotriene B4, was observed after the administration of A-64077 (from 151±15 to 59±16 ng per milliliter of plasma, P<0.001). Although precise quantitation of 20-COOH leukotriene B4, another metabolite of leukotriene B4, was not possible because of some overlap with A-64077 metabolites in its Chromatographic elution profile, there was not an identifiable 20-COOH leukotriene B4 peak after the administration of A-64077, suggesting that the amount produced was significantly decreased.
Physiologic Results
There was no significant difference in the patients' mean FEV1 immediately before the administration of placebo or A-64077 (3.49±0.13 vs. 3.41±0.14 liters). Similarly, there was no significant difference between the mean FEV1 three hours after placebo and that three hours after A-64077 (3.39±0.17 vs. 3.53±0.12 liters).
The PD10FEV1 (calculated as a function of respiratory heat exchange) of the 13 patients after the administration of A-64077 or placebo is shown in Figure 2Figure 2
Airway Reactivity to Hyperventilation of Cold, Dry Air Three Hours after the Patients Received Placebo or A-64077.. A-64077 produced a 47 percent increase in the amount of respiratory heat exchange needed to induce a 10 percent drop in the FEV1 The geometric mean PD10FEV1 increased from 3.0×÷1.15 kJ per minute after placebo to 4.4×÷1.10 kJ per minute after A-64077 (P<0.002). A-64077 increased the PD15FEV1 by 38 percent (from 3.7 to 5.1 kJ per minute, P<0.005) and the PD20FEV1 by 26 percent (from 4.7 to 5.9 kJ per minute, P<0.02). A-64077 produced differences of similar magnitude and significance when reactivity to cold, dry air was expressed as a function of minute ventilation. These effects are shown in Figure 3Figure 3
Composite Dose–Response Curves Illustrating the Decrease in FEV1 in Relation to Minute Ventilation after Subjects Received Placebo (O) or A-64077 (●).. The PD10FEV1 increased by 45 percent (from 27.5 to 39.8 liters per minute, P<0.005), the PD15FEV1 increased by 38 percent (from 34.7 to 47.9 liters per minute, P<0.005), and the PD20FEV1, increased by 28 percent (from 43.7 to 56.2 liters per minute, P<0.02).Discussion
The 5-lipoxygenase metabolites of arachidonic acid can be produced by cells implicated in the asthmatic response, these agents can be recovered from body fluids during asthma attacks, and they are potent bronchoconstrictors.1 2 3 4 5 , 10 11 12 13 14 In the present study we demonstrated that a single oral dose of A-64077 inhibited ex vivo formation of 5-lipoxygenase products in blood from patients with asthma and that this inhibition was accompanied by a significant blunting of the asthmatic obstruction induced by the inhalation of cold, dry air.
We used the production of leukotriene B4 in ionophore-stimulated blood as a marker for the activity of 5-lipoxygenase. RIA, with confirmation of the results by reverse-phase high-performance liquid chromatography, showed that the ingestion of A-64077 significantly reduced the amount of leukotriene B4 recovered from ionophore-activated blood, by 74 to 81 percent (Fig. 1). The production of thromboxane B2, a cyclooxygenase product of arachidonic acid, was unchanged, indicating that A-64077 is specific for 5-lipoxygenase and that the inhibition of 5-lipoxygenase does not result in substantial shunting of arachidonic acid to the cyclooxygenase pathway.
Hyperventilation of cold, dry air is a naturally occurring stimulus that is known to induce bronchoconstriction in the majority of patients with asthma.25 Concomitantly with the partial biochemical blockade of 5-lipoxygenase, A-64077 increased asthmatic tolerance to the hyperventilation of cold, dry air by 47 percent. It is not known whether more complete lipoxygenase inhibition would be accompanied by greater physiologic inhibition; however, the 47 percent increase in the PD10FEV1 is substantial when compared with the effects of other agents used in the treatment of asthma or allergic diseases. Cromolyn sodium, inhaled terbutaline,26 and high-dose inhaled atropine27 produce 33, 43, and 32 percent increases in the PD10FEV1, respectively. Theophylline results in a 20 percent increase in the PD20FEV1,28 measured as a function of minute ventilation, as compared with the 28 percent increase that we noted with A-64077.
A-64077 does not antagonize the contractile activity of other potential bronchoconstrictors,29 making it unlikely that receptor blockade by A-64077 accounts for its effect on the airway narrowing induced by cold air. It therefore seems likely that the salutary effects of A-64077 result from the inhibition of the formation of bioactive mediators that are 5-lipoxygenase derivatives of arachidonic acid. Since A-64077 was significantly more effective in inhibiting airway narrowing due to cold, dry air than a relatively weak leukotriene D4 antagonist,21 it is possible that other 5-lipoxygenase products, such as 5-HETE, leukotriene B4, or alternate sulfidopeptide leukotrienes (e.g., leukotriene C4 or E4)30 may play a part in this response. Potential cellular sources of these 5-lipoxygenase products include cells of myeloid lineage, such as polymorphonuclear leukocytes (basophilic, eosinophilic, and neutrophilic), monocyte/macrophages, and mast cells, which possess substantial amounts of 5-lipoxygenase. Some of these specific cells may be activated to release 5-lipoxygenase products during an asthmatic reaction induced by cold, dry air.
Our study suggests that 5-lipoxygenase derivatives of arachidonic acid play a part in the airway narrowing caused by a common stimulus of asthmatic bronchoconstriction — hyperventilation of cold, dry air. The data establish the importance of a 5-lipoxygenase product in mediating or modulating the observed airway obstruction, but they cannot distinguish among possible mechanisms thought to link the stimulus of cold, dry air and the response of airway obstruction.31 32 33 In this model of asthmatic obstruction the magnitude of effect achieved with A-64077 compares favorably with that of the effect of other drugs currently used in the treatment of many forms of asthma. This suggests that blockade of 5-lipoxygenase may be of potential therapeutic use in spontaneous asthma.
Supported in part by a grant from Abbott Laboratories, a grant (HL07633–05) from the National Institutes of Health, and the Daniel Coven Pulmonary Endowment Fund.
In accordance with Journal policy, the authors have stated that Dr. Rubin is an employee of Abbott Laboratories and holds stock in the company.
We are indebted to Mr. Anthony Benincaso for his technical assistance with the chromatography and to Ms. Vivian Simonelli for her assistance with the preparation of the manuscript.
Source Information
From the Departments of Medicine, Beth Israel Hospital (E.I., R.D., M.R., J.M.D.), Brigham and Women's Hospital (E.I.,R.D.,R.S.,J.M.D.), Children's Hospital (J.M.D.), and Harvard Medical School, all in Boston; the Department of Immunology and Rheumatology, Brigham and Women's Hospital, Boston (R.S.); Abbott Laboratories, Abbott Park, Ill. (P.R.); and the Department of Clinical Pharmacology, Hammersmith Hospital, London (G.T.). Address reprint requests to Dr. Israel at the Pulmonary Division, Beth Israel Hospital, 330 Brook-line Ave., Boston, MA 02215.
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