Food and Drug Reactions and Anaphylaxis
Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclooxygenase 2-selective analgetic drug celecoxib,☆☆,

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Abstract

Background: Subjects with aspirin-intolerant asthma (AIA) respond with bronchoconstriction and extrapulmonary adverse reactions to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit the cyclooxygenase (COX) step in the biosynthesis of prostaglandins. Recently, 2 isotypes of COX have been identified, and COX-2-selective NSAIDs have been developed for treatment of inflammatory disorders. Objective: We investigated whether 33 subjects with a typical history of AIA tolerated the new COX-2-selective NSAID celecoxib. Methods: All subjects displayed current aspirin sensitivity in oral or inhalation challenge tests. The subjects first underwent a double-blind, randomized, cross-over, increasing-dose challenge with placebo or celecoxib (10, 30, or 100 mg in suspension) on 2 occasions 7 days apart. Thereafter, all subjects were exposed to 400 mg of celecoxib administered during an open challenge session as two 200-mg doses 2 hours apart. Lung function, clinical symptoms, and urinary excretion of leukotriene E4 (LTE4) were monitored, with the latter being a sensitive biochemical marker of aspirin intolerance. Results: There were no changes in lung function or extrapulmonary symptoms during the double-blind sessions or in urinary excretion of LTE4. Also, the highest recommended daily dose of celecoxib was well tolerated, with no symptoms, lung function changes, or alterations in urinary LTE4 levels. Conclusions: A group of subjects with clinically well-documented AIA tolerated acute challenge with the selective COX-2 inhibitor celecoxib. The findings indicate that the intolerance reaction in AIA is due to inhibition of COX-1. Large long-term studies of COX-2 inhibitors in AIA should be undertaken. (J Allergy Clin Immunol 2003;111:1116-21.)

Section snippets

Subjects

Thirty-three subjects (Table I) with asthma and aspirin intolerance were recruited from the University Hospitals in Stockholm (n = 12), Krakow (n = 11), and Nashville (n = 10).

. Subject characteristics

Subject no.Age (y)SexFEV1 (L)FEV1 (% predicted)Regular drug treatment (explanations below)
153F2.1684.7ICS, LAB, LTRA, SAB
230M3.9997.8SAB
369F1.5385.0ICS, LAB, SAB
429F3.01100.3ICS, NCS, LAB, LTRA, SAB
536F2.4689.8SAB
647F2.1882.0ICS, NCS, LAB, LTRA, SAB
756F2.1588.1ICS, SAB
846F2.0375.5ICS, LAB, LTRA, SAB

Airway responses

There were no significant bronchoconstrictor responses after placebo or active drug administration during the double-blind phase (Fig 2, A ).

. A, Pulmonary function measured as FEV1 in liters (n = 33, mean ± SD) during the cross-over, double-blind, increasing-dose challenge with celecoxib and placebo. Four subjects who were sensitive to very low doses of aspirin entered this protocol after having been subjected to placebo and 5 mg of celecoxib at -2 hours without any reactions. B, Pulmonary

Discussion

In this study of 33 patients with asthma and documented aspirin intolerance, all subjects tolerated the selective COX-2 inhibitor celecoxib. Although celecoxib was administered in increasing doses up to twice the normal clinical dose, there were no untoward reactions observed from the lower or upper airways, the eyes, the skin, the gastrointestinal system, or any other organ system. Neither was there a change in urinary LTE4 after the exposure to celecoxib. Thus clinical symptoms, pulmonary

Acknowledgements

We thank Margareta Andersson, Heléne Blomqvist, Margitha Dahl, Ingrid Delin, Gunnel DeForest, Christina Larsson, Brendie Keane, and Lee Morgan for expert technical assistance.

References (28)

  • A Szczeklik et al.

    Aspirin-induced asthma: advances in pathogenesis and management

    J Allergy Clin Immunol

    (1999)
  • S Yoshida et al.

    Selective cyclo-oxygenase 2 inhibitor in patients with aspirin-induced asthma

    J Allergy Clin Immunol

    (2000)
  • DD Stevenson et al.

    Lack of cross-reactivity between rofecoxib and aspirin in aspirin-sensitive patients with asthma

    J Allergy Clin Immunol

    (2001)
  • A Szczeklik et al.

    Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients

    BMJ

    (1975)
  • J Raud et al.

    Enhancement of acute allergic inflammation by indomethacin is reversed by prostaglandin E2: apparent correlation with in vivo modulation of mediator release

    Proc Natl Acad Sci U S A

    (1988)
  • TV Hartert et al.

    Prostaglandin E2 decreases allergen-stimulated release of prostaglandin D2 in airways of subjects with asthma

    Am J Respir Crit Care Med

    (2000)
  • WL Smith et al.

    Why there are two cyclooxygenase isozymes

    J Clin Invest

    (2001)
  • LJ Scott et al.

    Rofecoxib

    Drugs

    (1999)
  • D Clemett et al.

    Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain

    Drugs

    (2000)
  • FE Silverstein et al.

    Gastrointestinal toxicity with celecoxib vs non-steroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study, a randomized controlled trial

    JAMA

    (2000)
  • I Bjarnason et al.

    COX-2 inhibitors and the gastrointestinal tract [letter]

    Gut

    (2001)
  • JF Fries

    Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs

    N Engl J Med

    (1999)
  • JR Vane et al.

    Cyclooxygenases 1 and 2

    Annu Rev Pharmacol Toxicol

    (1998)
  • B Dahlén et al.

    Plasma acetylsalicylic acid and salicylic acid levels during aspirin provocations in aspirin-sensitive subjects

    Allergy

    (1994)
  • Cited by (0)

    Drs Gyllfors and Bochenek contributed equally.

    ☆☆

    Supported by an operating grant from Pharmacia Corp and infrastructure research support from The Swedish Heart Lung Foundation, The Swedish Medical Research Council (project 71X-9071), the Foundation for Health Care Sciences and Allergy Research, and National Institutes of Health grant GM15431.

    Reprint requests: Sven-Erik Dahlén, MD, PhD, Experimental Asthma and Allergy Research, The National Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden.

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