TOKYO AND YOKOHAMA, JAPAN--Although corticosteroids are the mainstays of asthma therapy, patients with asthma may benefit from two other drugs that few physicians currently view as potential treatments: the macrolide antibiotic clarithromycin and the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. Two recent Japanese studies suggest that both may have important antiasthma properties.

In the first study, clarithromycin reduced asthma symptoms, airway responsiveness, blood and sputum eosinophil counts, and sputum eosinophilic cationic protein (ECP) levels in adults with mild or moderate bronchial asthma.[1] In the second study, inhaled indomethacin was found to have a steroid-sparing effect in patients with moderate or severe steroid-dependent asthma.[2]

AN ANTI-INFLAMMATORY EFFECT?

In the clarithromycin study, researchers led by Hideaki Amayasu, MD, of the Yokohama Rosai Hospital in Japan, randomized 17 subjects in double-blind fashion to 200 mg of clarithromycin or placebo twice daily for eight weeks. After a washout period of at least four weeks, the two groups of patients were then given the alternative treatment for eight weeks.

Before the study began, all patients had stable asthma, and all had been free from symptoms of respiratory infection for at least six weeks. None were smokers. Patients were permitted to use an inhaled ß-agonist for symptom control. However, those who used theophylline, antileukotriene agents, clarithromycin, or an anti-inflammatory agent (including oral or inhaled corticosteroids) were excluded from the study.

During the study, the patients recorded their symptom severity once a week, using a 0 to 3 scale (0 indicated that a patient was asymptomatic on at least four days that week, and 3 indicated that a patient had had severe asthma attacks on more than four days and/or nocturnal asthma symptoms almost daily; 1 and 2 indicated intermediate levels of disease severity). In addition, they underwent laboratory testing as well as a methacholine challenge for evaluation of bronchial responsiveness.

Neither forced expiratory volume in one second (FEV1) nor forced vital capacity were affected by clarithromycin use. Thus, say the authors, it is unlikely that clarithromycin has a bronchodilating effect. However, symptoms (ie, nocturnal cough, wheezing, and severity and frequency of asthma attacks) improved in 15 patients following clarithromycin use. "Overall, the symptom score decreased significantly after treatment with clarithromycin," the authors added. Blood and serum eosinophil counts and ECP levels also decreased; however, blood and sputum neutrophil levels remained unchanged.

Methacholine challenge caused airway obstruction in all patients at baseline and during the study. The amount of methacholine required to cause obstruction (PC20) was significantly greater when the patients received clarithromycin, however, suggesting lower airway hyperresponsiveness in this group. Yet no statistical association emerged between the increase in PC20 and the decrease in ECP levels during clarithromycin administration.

"Although [the researchers] did not find a direct relationship between the changes in ECP concentrations and the changes in airway hyperresponsiveness, their study suggests that prolonged treatment with a macrolide may reduce the symptoms and bronchial hyperresponsiveness of asthma through an anti-inflammatory action," wrote Pedro C. Avila, MD, and Homer A. Boushey, MD, in an accompanying editorial.[3]

Clarithromycin may also improve asthma symptoms by treating airway infection. Indeed, some studies of asthma patients have found evidence of chronic Chlamydia or Mycoplasma airway infection, which may exacerbate or perhaps even cause asthma, pointed out Dr. Avila in an interview with RESPIRATORY REVIEWS. "There is a lot of evidence suggesting macrolides can be helpful in asthma," said Dr. Avila, an Assistant Clinical Professor of Medicine and Pediatrics at the University of California in San Francisco. "At this point, however, we just don't know exactly who will respond to them."

CYCLOOXYGENASE INHIBITION

Because it is a cyclooxygenase inhibitor, indomethacin may improve asthma by preventing the formation of thromboxane A2, prostaglandin D2, and other metabolites of arachidonic acid. These metabolites have been implicated in the asthmatic inflammatory cascade because they produce bronchoconstriction, airway microvascular leakage, and bronchial hyperreactivity.[4]

To assess inhaled indomethacin's effect on asthma control during a reduction in inhaled corticosteroid use, a second Japanese team, led by Jun Tamaoki, MD, of the Tokyo Women's Medical University, performed a randomized, double-blind, parallel-group study of 38 steroid-dependent asthma patients. All patients had been using high dosage (1,500 µg/d or more) of inhaled beclomethasone for at least six weeks before the study began, and all had their asthma symptoms under good control. None had been given NSAIDs or oral corticosteroids during the previous eight weeks.

The patients continued to use the same inhaled beclomethasone dosages during a two-week run-in period. During the next six weeks, half the patients were given an inhaled aerosol preparation, each puff containing 6.25 mg/mL of indomethacin; the rest received an inhaled placebo. Both indomethacin and placebo were taken twice daily. During this time, each patient's daily beclomethasone dosage was reduced to half at week 2 and to one third at week 4. All patients were permitted to take an inhaled ß 2-agonist as needed for symptom relief.

Sixteen patients in the indomethacin group and 18 in the placebo group completed treatment. During treatment, FEV1, peak expiratory flow (PEF), and asthma symptoms worsened in both groups, but the extent of the decline was markedly less in the indomethacin group. The mean concentration of exhaled nitric oxide, a marker of the severity of airway inflammation, rose only in the placebo group. ß 2-agonist use was the same in both groups. The study also found that asthma relapse occurred in 89% of the placebo group versus only 38% of the indomethacin group. A greater than 15% decline in morning PEF was the most common sign of a relapse. Side effects were minimal with indomethacin administration; only three recipients complained of transient pharyngeal irritation and dry mouth.

"The authors basically achieved their goal of reducing the steroid dose while using indomethacin to control asthma symptoms," Arthur N. Freed, PhD, told RESPIRATORY REVIEWS. "However, there was still a drop in lung function over time with this therapy." Thus, the safety of indomethacin use in this setting is still not clear.

Nevertheless, the investigation was well-performed, said Dr. Freed, an Associate Professor of Environmental Health Sciences at the Johns Hopkins Medical Institutions in Baltimore. He suggested repeating this study with a larger number of patients and restricting the decrease in the inhaled steroid dose to one half, rather than two thirds. "This may still be a significant reduction from the clinician's standpoint," he noted.

--Timothy Begany

References
1. Amayasu H, Yoshida S, Ebana S, et al. Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma. Ann Allergy Asthma Immunol. 2000; 84:594-598.
2. Tamaoki J, Nakata J, Nishimura K, et al. Effect of inhaled indomethacin in asthmatic patients taking high doses of inhaled corticosteroids. J Allergy Clin Immunol. 2000;105:1134-1139.
3. Avila PC, Boushey HA. Macrolides, asthma, inflammation, and infection [editorial]. Ann Allergy Asthma Immunol. 2000;84:565-568.
4. Wenzel SE. Arachidonic acid metabolites: mediators of inflammation in asthma [review]. Pharmacotherapy. 1997;17:3S-12S.