Macrolides Exhibit Immunomodulatory Effects Valuable in the Treatment of Chronic Lung Diseases

Introduction

Macrolide antibiotics have been shown to have immunomodulatory effects that make them candidates for the therapy of chronic inflammatory airway diseases, reported Bruce K. Rubin, MD, speaking at a satellite symposium titled “Macrolide Effects: Beyond Bacterial” and sponsored by the American College of Chest Physicians at their annual meeting, Chest 2002, held November 2–7, 2002 in San Diego, California.

“First used for diffuse panbronchiolitis (DPB) in 1982 in Japan, the macrolide antibiotics have been established as the treatment of choice for this chronic airway disease,” stated Dr. Rubin, Professor and Vice-Chair for Research, Department of Pediatrics; Acting Section Chief, Pediatric Pulmonary Medicine; and Professor of Biomedical Engineering, Physiology, and Pharmacology, Wake Forest University School of Medicine. “Now, there is sustained interest in Europe and North America in using these macrolide antibiotics to treat a number of chronic inflammatory airway diseases.”

“In addition, Dr. Rubin continued, “data suggests that the macrolide antibiotics may not only have a steroid-sparing effect in patients with steroid-dependent asthma but also may have a synergistic anti-inflammatory or immunomodulatory effect. This would allow some steroid-dependent patients to discontinue oral systemic corticosteroids without an exacerbation of symptoms.”

Immunomodulatory Effects of Macrolides

Generally, there should be a balance between inflammation and immunomodulation. In many acute airway diseases, inflammation is good as it clears the airways. In the chronic forms of airway diseases, however, inflammation results in negative effects.

“In vitro,” macrolides have been shown to reduce neutrophil-denied airway inflammation decreasing neutrophil chemotaxis, the oxidative burst, and proinflammatory cytokine generation. These effects also have been demonstrated in animal models of lung disease and in bronchoalveolar lavage from patients with chronic lung disease. Macrolides also reduce mucus hypersecretion in patients with DPB, chronic bronchitis, and sinus disease. Evidence suggests that macrolides may protect the epithelium from attack by bioactive phospholipids generated as part of the inflammatory process. In addition, there is growing proof that many, if not all, of these properties are mediated by inhibition of transcription factors nuclear factor–kappa B (NF-kB) and activator protein–1 (AP-1).

Macrolides also have been shown to have a number of non-antibiotic properties, some of benefit and some leading to drug-related adverse effects. For example, early studies pointed out that steroid-dependent asthma patients treated with troleandromycin (Tao^®; Pfizer) showed a steroid-sparing effect, while the macrolides clarithromycin (Biaxin^®; Abbott Laboratories) or azithromycin (Zithromax^®; Pfizer) had positive immunomodulatory effects in patients with non-small-cell cancer. On the other side of the coin, macrolides stimulate motilin receptors leading to gastrointestinal (GI) kinesis, which can result in macrolide-associated side effects such as nausea and vomiting.

Macrolides and DPB

The chronic airway disease DPB is primarily seen in Japan and Korea. Macrolides were first used for the treatment of DPB in 1982 by Miyasawa, a general practitioner in Japan. In this initial study, after three months of continuous treatment with erythromycin, there was a clinical improvement rate of 60% in the DPB patients on erythromycin compared to 15% in the those not on erythromycin. Of particular interest, in 1984, the five-year survival rate for DPB was 26%. Since macrolide therapy was introduced, the ten-year survival rate has increased to 94%.

Now, it has been demonstrated that erythromycin, clarithromycin, and azithromycin all improve pulmonary function and decrease morbidity and mortality in patients with DPB. These macrolides decrease bronchoalveolar lavage, decrease mucus hypersecretion, protect the airway epithelium from damage and lower serum levels of proinflammatory cytokines such as tissue necrosis factor–a (TNF-a) and interleukin-8 (IL-8). In Japan, clarithromycin and erythromycin also are widely used for the treatment of chronic sinusitis, asthma, and COPD.

Macrolides and Other Chronic Lower Airway Diseases

Only in the last ten years have the immunomodulatory properties of the macrolides been investigated outside East Asia. In North America, macrolides like clarithromycin have been approved for the treatment of acute exacerbations of respiratory diseases such as chronic bronchitis, but have not yet been approved for long-term use as immunomodulatory agents. Now, however, clinical investigators in the United States are directing their interests toward the use of macrolides as adjunctive therapy for the treatment of asthma, COPD, chronic bronchitis, chronic sinusitis, and cystic fibrosis and clinical trials are underway.

Macrolides for Cystic Fibrosis Therapy

Although cystic fibrosis is uncommon in Japan, the first report of significant improvement in pulmonary function with erythromycin therapy was in a Japanese student with cystic fibrosis. Since that time, several multicenter studies from around the world have demonstrated impressive efficacy using macrolides for the treatment of cystic fibrosis lung disease, similar to that seen in the therapy of DPB. Gender, age, and the presence of Pseudomonas aeruginosa all appear to play a role. The effects appear to be more striking in older patients with an FEV₁ less than 80% predicted who expectorate sputum, who are not receiving dornase alfa (Pulmozyme^®; Genentech), and who are homozygous for the delta F508 CF gene defect.

Presently, the use of macrolides are being suggested in children with cystic fibrosis who are more than eight years with an FEV₁ less than 80% predicted. It is recommended that these youngsters undergo a six-month trial of either clarithromycin or azithromycin because 50% of these children will improve by more than 10%, particularly if they are homozygous for the delta F508 CF gene defect and are not taking dornase alfa. Both clarithromycin and azithromycin are well tolerated and are as effective as dornase alfa at a fraction of the cost.

This article was written by Larry M. Prescott, PhD, a frequent contributor to D&MD Newsletter.

©Drug and Market Development 2002

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