Aspirin-sensitive Asthmatic Patients Research Articles

Use of Nonsteroidal Anti-Inflammatory Drugs in Patients with Aspirin Hypersensitivity

This article provides information on the pathogenesis of aspirin hypersensitivity, cross-sensitivity, and cross-tolerance of different NSAIDs in patients with respiratory types of reactions. Hypersensitivity to aspirin may affect 5-20% of patients with chronic asthma and an unknown fraction of patients with chronic urticaria-angioedema. These patients develop cross-reactions to other, chemically non-related, NSAIDs with strong inhibitory activity towards cyclo-oxygenase (COX)-1 (e.g. indomethacin, naproxen, ketoprofen). Avoidance of aspirin and all cross-reacting NSAIDs as well as education of patients are crucial. As an alternative antipyretic or analgesic drug, aspirin-sensitive asthmatic patients may take acetaminophen (paracetamol) in low or moderate doses (<1000mg). Preferential COX-2 inhibitors (nimesulide, meloxicam) are tolerated by the majority but not all hypersensitive patients. Selective COX-2 inhibitors (celecoxib and rofecoxib [withdrawn from the market]) are well tolerated by almost all aspirin-sensitive asthmatic patients. In patients with coronary artery disease requiring treatment with aspirin, desensitization to aspirin may be an alternative approach. Thus, for the majority of patients with asthma and hypersensitivity to aspirin or other NSAIDs, an alternative anti-inflammatory drug can be found. However, in each individual case physicians must consider the choice of an alternative NSAID carefully.

Approach to "aspirin allergy" in cardiovascular patients.

Aspirin (ASA), by irreversibly inhibiting platelet cyclooxygenase-1 enzyme (COX-1), prevents platelet aggregation and is the mainstay of pharmacotherapy of patients with coronary artery disease (CAD). Long-term ASA therapy reduces mortality in CAD patients after an initial coronary event. Periprocedural ASA therapy significantly reduces major adverse cardiovascular events (MACE) after percutaneous coronary interventions.1,2 Despite a plethora of clinical data showing marked efficacy of ASA therapy in cardiovascular patients, ASA use continues to be less than optimal in real-world registries.3,4 A history of adverse reactions to ASA may prevent long-term use in a cardiovascular patient, thereby reducing optimal event protection. Most adverse reactions to ASA, such as gastrointestinal intolerance, are predictable and are dose and host related.5 However, ASA can also cause a hypersensitivity reaction, of which there are 3 types: respiratory sensitivity (asthma and/or rhinitis), cutaneous sensitivity (urticaria and/or angioedema), and systemic sensitivity (anaphylactoid reaction).6 Various terms have been used to describe the hypersensitivity reactions to ASA, including ASA intolerance, ASA idiosyncrasy, pseudoallergic reactions, and ASA sensitivity.7 The prevalence of ASA sensitivity in cardiovascular patients is not well known. Besides substitution with an alternative class of antiplatelet agents such as thienopyridines, ASA desensitization is an option for ASA-allergic patients who require long-term therapy for cardiovascular diseases.7 In this article, we review various hypersensitivity reactions to ASA and discuss desensitization protocols to allow ASA therapy in ASA-sensitive cardiovascular patients. ### ASA-Exacerbated Respiratory Disease ASA-exacerbated respiratory disease (AERD) is a triad of asthma, ASA sensitivity, and rhinitis/nasal polyps. Patients with AERD have aggressive mucosal inflammation and suffer from precipitation of asthma and rhinitis after ingestion of ASA and nonsteroidal antiinflammatory drugs (NSAIDs).8 AERD is also commonly referred to as ASA-sensitive, ASA-induced, or ASA-intolerant asthma. AERD is the cause of 10% to 15% of all cases of asthma,8 is usually …

Differential effects of aspirin and misoprostol on 15-hydroxyeicosatetraenoic acid generation by leukocytes from aspirin-sensitive asthmatic patients

Background Although the mechanisms of aspirin-induced rhinosinusitis-asthma appear to be related to arachidonic acid abnormalities, only recently has a specific aspirin-triggered enhancement of 15-hydroxyeicosatetraenoic acid (15-HETE) generation in nasal polyp epithelial cells from aspirin-sensitive patients been demonstrated. Objective The aim of this study was to assess generation of 15-HETE and other eicosanoids by peripheral blood leukocytes (PBLs) from aspirin-sensitive and aspirin-tolerant asthmatic patients and modulation of 15-HETE generation by a prostaglandin (PG) E 1 analogue (misoprostol). Methods Twenty-four aspirin-sensitive patients with asthma-rhinosinusitis and 18 aspirin-tolerant asthmatic patients were studied, and eicosanoids released from PBLs were assessed by means of enzyme immunoassays. Results Unstimulated PBLs from aspirin-sensitive and aspirin-tolerant patients generated similar amounts of PGE 2, leukotriene C 4, and 15-HETE, but lipoxin A 4 release was significantly less in aspirin-sensitive patients (300 ± 70 pg/mL) in comparison with that seen in aspirin-tolerant patients (690 ± 100 pg/mL, P < .05). Cell incubation with 2, 20, or 200 μmol/L aspirin resulted in a dose-dependent increase in 15-HETE generation (mean change of +85%, +189%, and +284% at each aspirin concentration, respectively) only in aspirin-sensitive asthmatic patients. Naproxen stimulated 15-HETE generation in aspirin-sensitive asthmatic patients, but indomethacin or specific COX-2 inhibitors (NS-398 and celecoxib) did not affect 15-HETE release. A synthetic PGE 1 analogue (misoprostol) inhibited aspirin-induced 15-HETE release but enhanced 15-HETE generation by aspirin in leukocytes from aspirin-tolerant patients. After preincubation with misoprostol, aspirin induced a dose-dependent production of lipoxin A 4 in both groups. Conclusion PBLs from patients with aspirin-sensitive rhinosinusitis-asthma might be specifically triggered by aspirin to generate 15-HETE. Metabolism of 15-HETE is differentially regulated by misoprostol in aspirin-tolerant and aspirin-sensitive asthmatic patients.

Differential Effects of Aspirin and Misoprostol on 15-Hydroxyeicosatetraenoic Acid Generation by Leukocytes from Aspirin-Sensitive Asthmatic Patients

BackgroundAlthough the mechanisms of aspirin-induced rhinosinusitis-asthma appear to be related to arachidonic acid abnormalities, only recently has a specific aspirin-triggered enhancement of 15-hydroxyeicosatetraenoic acid (15-HETE) generation in nasal polyp epithelial cells from aspirin-sensitive patients been demonstrated.ObjectiveThe aim of this study was to assess generation of 15-HETE and other eicosanoids by peripheral blood leukocytes (PBLs) from aspirin-sensitive and aspirin-tolerant asthmatic patients and modulation of 15-HETE generation by a prostaglandin (PG) E1 analogue (misoprostol).MethodsTwenty-four aspirin-sensitive patients with asthma-rhinosinusitis and 18 aspirin-tolerant asthmatic patients were studied, and eicosanoids released from PBLs were assessed by means of enzyme immunoassays.ResultsUnstimulated PBLs from aspirin-sensitive and aspirin-tolerant patients generated similar amounts of PGE2, leukotriene C4, and 15-HETE, but lipoxin A4 release was significantly less in aspirin-sensitive patients (300 ± 70 pg/mL) in comparison with that seen in aspirin-tolerant patients (690 ± 100 pg/mL, P < .05). Cell incubation with 2, 20, or 200 μmol/L aspirin resulted in a dose-dependent increase in 15-HETE generation (mean change of +85%, +189%, and +284% at each aspirin concentration, respectively) only in aspirin-sensitive asthmatic patients. Naproxen stimulated 15-HETE generation in aspirin-sensitive asthmatic patients, but indomethacin or specific COX-2 inhibitors (NS-398 and celecoxib) did not affect 15-HETE release. A synthetic PGE1 analogue (misoprostol) inhibited aspirin-induced 15-HETE release but enhanced 15-HETE generation by aspirin in leukocytes from aspirin-tolerant patients. After preincubation with misoprostol, aspirin induced a dose-dependent production of lipoxin A4 in both groups.ConclusionPBLs from patients with aspirin-sensitive rhinosinusitis-asthma might be specifically triggered by aspirin to generate 15-HETE. Metabolism of 15-HETE is differentially regulated by misoprostol in aspirin-tolerant and aspirin-sensitive asthmatic patients.

Misoprostol therapeutics revisited.

Misoprostol, a prostaglandin E1 analog, is a racemate of four stereoisomers. On administration it rapidly de-esterifies to its active form, misoprostolic acid. Misoprostolic acid is 85% albumin bound and has a half-life of approximately 30 minutes. It is excreted in urine as inactive metabolites. No significant drug interactions have been reported. Besides its gastrointestinal protective and uterotonic activities, misoprostol regulates various immunologic cascades. It inhibits platelet-activating factor and leukocyte adherence, and modulates adhesion molecule expression. It protects against gut irradiation injury, experimental gastric cancer, enteropathy, and constipation. It improves nutrient absorption in cystic fibrosis. Misoprostol has utility in acetaminophen and ethanol hepatotoxicity, hepatitis, and fibrosis. It is effective in asthmatics and aspirin-sensitive asthmatic and allergic patients. It lowers cholesterol and severity of peripheral vascular diseases, prolongs survival of cardiac and kidney transplantation, synergizes cyclosporine, and protects against cyclosporine-induced renal damage. It works against drug-induced renal damage, interstitial cystitis, lupus nephritis, and hepatorenal syndrome. It is useful in periodontal disease and dental repair. Misoprostol enhances glycosoaminoglycan synthesis in cartilage after injury. It prevents ultraviolet-induced cataracts and reduces intraocular pressure in glaucoma and ocular hypertension. It synergizes antiinflammatory and analgesic effects of diclofenac or colchicine and has been administered to treat trigeminal neuralgic pain. It reduces chemotherapy-induced hair loss and recovery time from burn injury, and is effective in treating sepsis, multiple sclerosis, and pancreatitis.

Rhinosinusitis and nasal polyposis in aspirin sensitive and aspirin tolerant patients: are they different?

Hypersensitivity to aspirin (acetylsalicylic acid; ASA) is present in 5–10% of asthmatic patients and is associated with chronic rhinosinusitis and nasal polyposis, a syndrome referred to as the aspirin triad.1...

The protective effects of leukotriene modifiers in aspirin-induced asthma.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase activity and, in aspirinintolerant patients, can precipitate life-threatening asthma attacks. In aspirin-sensitive asthmatic patients, exposure to aspirin results in a dramatic increase in cysteinyl leukotriene production, the precise mechanism of which remains unclear. However, clinical studies of the 2 types of leukotriene modifiers--the leukotriene synthesis inhibitors and the leukotriene receptor antagonists (LTRAs)--have established the critical pathogenic role played by leukotrienes in aspirin-induced asthma (AIA). Zileuton, the only leukotriene synthesis inhibitor now available, increased pulmonary function and alleviated the cardinal signs of AIA. Montelukast, a potent LTRA, blocked the airway obstruction induced by lysine-aspirin inhalation in aspirin-sensitive asthmatic patients. Pulmonary function improved significantly, and both ss-agonist use and frequency of nocturnal awakening decreased. Pranlukast, a LTRA available only in Japan, produced results similar to those reported for montelukast. Despite these agents' protective effects, aspirin-sensitive asthmatic patients should be cautioned to avoid the use of any drug that inhibits cyclooxygenase activity.

Montelukast: data from clinical trials in the management of asthma.

To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of montelukast, a leukotriene receptor antagonist used to treat asthma, and to discuss the therapeutic role of montelukast as long-term medication and difficulties associated with the management of asthma. A MEDLINE search (up to May 1999) was conducted to identify relevant English-language publications, including preclinical studies, clinical trials, and recent reviews. All available published reports of controlled, clinical trials of montelukast in adults and children with asthma were summarized, including pharmacokinetic and pharmacologic effects of montelukast. Information on the safety and efficacy of montelukast was evaluated on the basis of patient selection, study design, methodology, and statistical significance as compared with placebo or inhaled corticosteroid treatment. Montelukast is approved for the prophylaxis and chronic treatment of asthma at a dose of 10 mg once daily for adolescents (> or =15 y) and adults and 5 mg once daily for children (6-14 y). In placebo-controlled clinical trials, montelukast significantly improved pulmonary lung function (as measured by forced expiratory volume in 1 sec), significantly reduced beta2-agonist use, and significantly improved patient-reported end points in adults and children (> or =6 y) with chronic asthma. In adults, a similar magnitude of improvement in lung function is seen with or without inhaled corticosteroid use; the effects of montelukast may be additive to those of inhaled corticosteroids and permit the reduction of the required dose of inhaled corticosteroids. In cases of exercise-induced asthma (adults and children), montelukast treatment attenuates the fall in pulmonary function following exercise. It attenuates both the early- and late-phase responses of asthma after allergen inhalation. Improvements in asthma control are similar in asthmatic patients who are aspirin-sensitive or not aspirin-sensitive and can be seen within one day of treatment. Tolerance does not develop, and the adverse events do not differ from those of placebo. Montelukast is indicated for the prophylaxis of chronic asthma in adults and children (> or =6 y). It may be considered for use as first-line therapy in patients with mild persistent asthma or for additional control in patients who are still symptomatic while receiving treatment with inhaled corticosteroids. It may also be used for additional control in aspirin-sensitive asthmatic patients. Consideration may be given for using montelukast to allow tapering of the dose of inhaled corticosteroids while maintaining clinical stability. Chronic treatment with montelukast can provide additional control of symptoms during exercise, but inhaled beta2-agonists remain first-line therapy for prophylaxis and treatment.

Immunohistochemical Characterization of Cellular Infiltrate in Nasal Polyp from Aspirin-Sensitive Asthmatic Patients

The immunopathologic mechanism of nasal polyp in aspirin-sensitive asthma remains to be further defined. To characterize the features of the inflammatory cellular infiltrate in the nasal polyp tissue from aspirin-sensitive asthmatic patients. We have taken nasal polyp tissue during nasal polyp resection from 13 aspirin-sensitive asthma, 6 allergic, and 12 non-allergic subjects. Immunohistochemistry was employed to stain and enumerate the individual inflammatory cell types using monoclonal antibodies against tryptase (AA1) to identify mast cells, against secreted forms of eosinophil cationic protein (EG2), to identify activated eosinophils, against neutrophil elastase (NE) for neutrophils and against T cell surface markers (CD3) to identify total T cells. There were no significant differences in AA1 + cells among three groups (P>.05). EG2 + cells tended to be higher in ASA-sensitive asthmatic patients than in allergic and non-allergic subjects, but no statistical significance was observed. NE+ cells were found in most subjects of the three groups and their numbers were significantly higher in allergic subjects than in aspirin-sensitive asthma (P<.05). Some patients had CD3+ cells with no statistical significance among the three groups. Significant correlation was found in numbers between NE+ cell and AA1+ cell (r=.44, P=.01), and between NE+ cell and EG2+ cell (r=.40, P=.02). These findings suggested that major effector cells such as mast cells and eosinophils might be placed in the center of the inflammatory response of nasal polyps, regardless of their association with aspirin sensitivity.

Zafirlukast (Accolate).

Cysteinyl-leukotrienes are important mediators in the pathogenesis of asthma. Zafirlukast is a selective and competitive leukotriene receptor antagonist that has been developed for the treatment of asthma. It inhibits exercise-induced asthma, both the early- and late-phase response after allergen challenge in asthmatic subjects, and aspirin-induced asthma in aspirin-sensitive asthmatic patients. Published data indicate that zafirlukast 20 mg twice daily causes an improvement in lung function (FEV(1) and peak expiratory flow measurements) and symptom control, together with a reduction in the use of short-acting beta-agonist inhaled therapy in patients with mild to moderate asthma. Studies presented in abstract form have shown that zafirlukast 20 mg twice daily had similar efficacy as sodium cromoglycate aerosol or dry powder inhalation; in one of the studies, no advantage of the active drugs was reported over placebo. Compared to inhaled beclomethasone dipropionate therapy (200-250 microg b.i.d.), improvements in morning peak flow, FEV(1) and daytime symptom score were significantly less with zafirlukast 20 mg twice daily than with inhaled steroids. A steroid-sparing effect of zafirlukast (20 mg b.i.d.) was not observed in studies of 12-20 weeks duration in patients on inhaled steroid therapy. A significant improvement in lung function and symptom control was observed on addition of zafirlukast 80 mg twice daily in symptomatic patients maintained on high-dose inhaled steroid therapy. Meta-analysis of 5 large studies indicate that there is a significant reduction in the number of asthma exacerbations compared to placebo. Zafirlukast at 20 mg twice daily dosage appears to be well-tolerated comparable to placebo. High doses of 80 mg twice daily have been associated with reports of elevated liver enzymes. Zafirlukast is a useful addition to existing antiasthma therapies. It may be used in combination with inhaled or oral corticosteroid therapy. Further investigation of its efficacy and antiinflammatory effects will clarify its use as a first-line antiinflammatory agent in mild asthma. Zafirlukast is administered orally and may therefore be useful in patients poorly compliant with inhaled steroid therapy and with a poor inhaler technique.

Complete resolution of airway hyperresponsiveness in aspirin-sensitive asthmatic patients.

Appreciable numbers of aspirin-sensitive asthmatic patients have chronic steroid-dependent severe asthmatic symptoms. We report four cases of aspirin-sensitive asthmatics who had mild to severe asthmatic symptoms, whose methacholine PC20 level ranged from 0.6 to 22 mg/ml at the first visit. The aspirin sensitivity was confirmed by lysine-aspirin bronchoprovocation. After anti-asthmatic medications and avoidance of salicylate-containing agents, airway hyperresponsiveness and respiratory symptoms disappeared for two to 30 months. These results suggest that early detection and careful avoidance of salicylate-containing agents may have a beneficial effect resulting in the resolution of airway hyperresponsiveness in aspirin-sensitive asthmatic patients.

Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects

Objective: Cross-sensitivity between aspirin and acetaminophen in aspirin-sensitive asthmatic patients has been reported with frequencies ranging from 0% to 29%. The relationship is dose-dependent for acetaminophen challenges, ranging between 300 and 1000 mg. Methods: To determine the prevalence of cross-sensitivity to high-dose acetaminophen, we performed single-blind acetaminophen oral challenges with 1000 mg and 1500 mg in 50 aspirin-sensitive asthmatic patients and in 20 non-aspirin-sensitive asthmatic control subjects. Results: Overall, 17 of 50 (34%) of aspirin-sensitive asthmatic patients reacted to acetaminophen in doses of 1000 to 1500 mg (95% confidence interval: 20% to 49%). By contrast, none of the 20 non-aspirin-sensitive asthmatic patients reacted to acetaminophen (95% confidence interval: 0% to 14%). This difference was highly significant ( p = 0.0013), supporting the hypothesis that cross-sensitivity between aspirin and acetaminophen is unique in aspirin-sensitive asthmatic patients. Conclusion: Although high-dose (>1000 mg) acetaminophen cross-reactions with aspirin were significant with respect to frequency (34%), such reactions included easily reversed bronchospasm in only 22%, and were generally mild. We recommend that high doses of acetaminophen (1000 mg or greater) should be avoided in aspirin-sensitive asthmatic patients. ( J Allergy Clin Immunol 1995;96:480-5.)

Mediator assays in aspirin-induced asthma.

It had been postulated from earlier studies that platelets of aspirin-sensitive asthmatics reacted to aspirin and other cyclo-oxygenase inhibitors. Similarly, a generalized abnormality had been suggested in the regulation of arachidonic acid oxidative pathways in blood leukocytes of patients with aspirin-induced asthma. Studies of activation in vitro as well as in vivo assessment of polymorphonuclear leukocytes have not been conclusive of metabolic pathways inducing bronchospasm in aspirin-sensitive asthmatic patients. Serum levels of tryptase, a specific marker of mast cell activation, appear to increase during bronchoconstriction following ingestion of oral aspirin. Eosinophil cationic protein (ECP) levels in serum are concomitantly elevated. Leukotriene antagonists may partially protect individuals with allergen-provoked or aspirin-provoked bronchoconstriction.

Agonist‐induced lipoxin A4 generation: Detection by a novel lipoxin A4‐ELISA

Lipoxin A4 (LXA4) possesses potent bioactions. To facilitate its detection, an enzyme-linked immunosorbent assay (ELISA) was developed that proved sensitive and selective. Quantitation by ELISA of LXA4 generated from cellular sources strongly correlated (r = 0.99) with values obtained by high-pressure liquid chromatography (HPLC). We used this LXA4-ELISA to examine parameters influencing LXA4 generation from endogenous substrates during human platelet-neutrophil (PLT-PMN) interactions in vitro. Agonist-induced LXA4 production was clearly evident at a PLT-PMN ratio of 10:1, and recombinant human granulocyte/monocyte colony stimulating factor-priming of PMN augmented LXA4 generation 5-6 fold. The chemotactic peptide formylmethionyl-leucyl-phenylalanine, platelet-derived growth factor and arachidonic acid (20:4n-6) each stimulated formation of immunoreactive LXA4 (iLXA4) in these co-incubations. The presence of iLXA4 was also evaluated in vivo in aspirin-sensitive asthmatic patients who, in a randomized, double-blind crossover design, underwent nasal lavage after they each ingested a predetermined threshold dose of aspirin or placebo. Aspirin challenge provoked statistically significant increases in iLXA4 in each patient (P < 0.005). These results validate the use of a solid-phase ELISA for detection of LXA4. Furthermore, the use of this ELISA has allowed the first documentation of iLXA4 formation in human subjects with aspirin-sensitive asthma following specific antigenic challenge.

Acetyl-CoA:lyso-Platelet-Activating Factor Acetyltransferase Activity in Neutrophils from Asthmatic Patients and Normal Subjects

1. Platelet-activating factor is a putative mediator of inflammation in asthma and the enzyme acetyl-CoA:lyso-platelet-activating factor acetyltransferase appears to be important in regulating platelet-activating factor production by leucocytes. To determine whether there are differences in acetyltransferase activity between asthmatic patients and normal subjects, enzyme activity was assayed in neutrophil lysates from atopic asthmatic patients (n = 20), aspirin-sensitive asthmatic patients (n = 12) and healthy, non-atopic, non-asthmatic control subjects (n = 20), both basally and after stimulation with the calcium ionophore A23187. 2. For a range of acetyl-CoA concentrations, acetyltransferase activity (nmol of [acetyl-3H]PAF min-1 mg-1 of protein) in unstimulated neutrophils from atopic asthmatic patients was significantly higher than that for normal subjects (P = 0.038) and the mean Vmax. for atopic asthmatic patients [18.4 (SD 6.9) nmol min-1 mg-1 of protein] was significantly greater than that for the control subjects [14.9 (SD 4.6) nmol min-1 mg-1 of protein P < 0.05]. The mean Vmax. for aspirin-sensitive asthmatic patients [15.9 (SD 6.9) nmol min-1 mg-1 of protein] was not significantly different from that for the normal subjects. 3. The mean ratio Vmax. stimulated/Vmax. unstimulated for acetyltransferase from atopic asthmatic patients (1.71, SD 0.45) was significantly less than that for the normal subjects (2.13, SD 0.63, P < 0.05), suggesting that acetyltransferase from atopic asthmatic patients was less sensitive to stimulation with A23187 in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and tolerability of nimesulide in asthmatic patients intolerant to aspirin.

Inflammation of the airways accompanied by eosinophil infiltration appears to play a fundamental role in the pathogenesis of bronchial asthma. Therefore, anti-inflammatory agents (at present corticosteroids, cromoglycate and nedocromil) are the first-line treatment for this condition. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin (acetylsalicylic acid) and indomethacin, however, have never been used in this setting, mainly for fear of adverse effects (e.g. severe obstructive reactions); these can occur, in a consistent number of patients as a consequence (according to the most widely accepted theory) of inhibition of prostaglandin synthesis. In a double-blind crossover placebo-controlled study involving 20 aspirin-sensitive patients with asthma, we found that oral nimesulide 100mg was well tolerated both clinically and functionally (no significant changes in forced expiratory volume in 1 second and specific airway resistance after drug intake). In a more recent study, we observed a mild obstructive reaction (easily controlled with inhaled bronchodilators) after oral administration of nimesulide 400mg to 3 patients who had previously tolerated a 100mg dose. On the basis of clinical experience, nimesulide (unlike most other NSAIDs) in the recommended doses appears to be well tolerated in aspirin-sensitive asthmatic patients. Furthermore, this distinctive anti-inflammatory agent might provide a novel approach to the treatment of bronchial asthma.

Arachidonic acid metabolism in monocytes of aspirin-sensitive asthmatic patients before and after oral aspirin challenge

Aspirin and nonsteroidal antiinflammatory drugs induce bronchospastic reactions in patients with aspirin-sensitive respiratory disease. Although the mechanism of this reaction is unknown, all drugs that induce the respiratory reaction also Inhibit the cyclooxygenase enzyme. The ensuing changes in arachidonate metabolism are presumed to play a role in the pathogenesis of the reaction. We measured generation of leukotrienes and thromboxane by calcium ionophore stimulated blood monocytes. Before aspirin challenge, monocytes released significantly more thromboxane B 2 in patients with aspirin sensitivity than in patients without aspirin sensitivity or in healthy control subjects ( p < 0.02). During aspirin-induced bronchospasm, release of leukotriene B 4 increased significantly (45.5%, p = 0.018), whereas release of thromboxane B 2 decreased (−46.9%, p = 0.028). Two hours after ingestion of 60 mg aspirin, normal monocyte release of thromboxane B 2 did not drop, whereas leukotriene B 4 release increased. Monocytes formed only minimal amounts of leukotriene C 4. We conclude that the profile of released eicosanoids from aspirin-sensitive monocytes is distinct from non-aspirin-sensitive subjects, and that these differences could contribute to the development of bronchospasm after aspirin ingestion.

326 Elevated thromboxane B2 (TXB2) and leukotriene B4 (LTB4) secretion from monocytes of aspirin (ASA) sensitive asthmatic patients

326 Elevated thromboxane B2 (TXB2) and leukotriene B4 (LTB4) secretion from monocytes of aspirin (ASA) sensitive asthmatic patients

96 Plasma high molecular weight kininogen (HMWK) is cleaved in aspirin (ASA) sensitive asthmatic patients during aspirin challenge

96 Plasma high molecular weight kininogen (HMWK) is cleaved in aspirin (ASA) sensitive asthmatic patients during aspirin challenge

Bronchial hyperreactivity to histamine in aspirin sensitive asthmatics: relationship to aspirin threshold and effect of aspirin desensitisation.

Twenty seven aspirin sensitive asthmatic patients were studied to determine the relationship between non-specific bronchial responsiveness to inhaled histamine and the degree of sensitivity to aspirin (aspirin threshold dose). No correlation was found between provocative concentration of histamine (PC20H) and aspirin threshold dose. In 11 patients the influence of aspirin desensitisation on bronchial reactivity to inhaled histamine was examined. Mean PC20H measured the day after the patients were desensitised to 600 mg of aspirin did not change significantly from the values before desensitisation. These observations suggest that sensitivity to aspirin and non-specific bronchial hyperreactivity in asthmatic patients are independent phenomena.