Inflammation and Treatment in Asthma and COPD

By James F. Donohue, MD, FCCP; and Jill A. Ohar, MD, FCCP

Print This | TOC | Previous | Next

COPD

Therapy

Bronchodilators. The effect of therapy for COPD is difficult to assess because it is a progressive disorder with a long preclinical stage. Patients rarely present for medical therapy until their FEV₁ is < 50% predicted. COPD is characterized by irreversible destruction of the alveolar wall, loss of elasticity, and peribronchial fibrosis, leaving little reserve for clinical improvement. Therefore, much of the treatment for COPD is symptomatic in nature. Only two known interventions have been shown to change the natural history of COPD: smoking cessation and supplemental oxygen for hypoxemic patients. Smoking cessation is best achieved with a multimodal approach including bupropion, a nicotine replacement product such as the patch, and multidisciplinary behavior modification.

Bronchodilators are the mainstay of COPD management. These include long-and short-acting b-adrenergics and anticholinergics. Although available in Europe, long-acting anticholinergics are not yet on the market in the United States. The short-acting anticholinergic ipratropium has been shown to be superior to short-acting b-adrenergics such as albuterol; the efficacy of long-acting b-adrenergics such as salmeterol and formoterol appears equivalent to that of ipratropium, but they have a longer duration of action.¹³ Salmeterol has been shown to have several in vivo and in vitro nonbronchodilator anti-inflammatory effects. These include enhancement of mucociliary clearance, inhibition of allergen-induced airway edema, and bronchoprotection from the adherence and epithelial destruction of Haemophilus influenzae and Pseudomonas. The nonbronchodilator anti-inflammatory effects of salmeterol may be the mechanism involved in its ability to reduce the frequency of COPD exacerbations.

Tiotropium is a long-acting anticholinergic, with a duration of action of 24 h. In a recent head-to-head comparison with salmeterol, tiotropium produced superior bronchodilatation in COPD patients.^14,15 In a very preliminary report, tiotropium was shown to decrease the rate of FEV₁ decline in COPD patients from 58.8 mL/yr to 19.9 mL/yr.¹⁵ If replicated, tiotropium would be the only known bronchodilator that would affect the natural history of COPD. Combivent (Boehringer Ingelheim Corp; Ridgefield, CT) is a combination inhaler of albuterol and ipratropium that takes advantage of two concepts to provide enhanced efficacy. Both albuterol and ipratropium are marketed in submaximal strength; when combined, they have an additive effect on FEV₁. Furthermore, a greater percent of patients experience a bronchodilating response from the combination product than from either product alone.

Phosphodiesterase inhibitors. The methylxanthines (eg, theophylline) are bronchodilators thought to exert their effect by phosphodiesterase inhibition. Although a weak bronchodilator, theophylline has many salutary effects helpful to COPD patients. These include pulmonary arterial vasodilatation, enhancement of diaphragmatic contractility, and increased CNS respiratory drive. Theophylline is a cardiac ionotrope and chromotrope. It is a weak diuretic and increases mucociliary sweep. Theophylline is difficult to use because of its narrow therapeutic index and plethora of drug interactions. Theophylline has anti-inflammatory effects in COPD, reducing neutrophil counts, IL-8, and total inflammatory cells in the sputum.

New phosphodiesterase 4 (PDE4) inhibitors are in development. PDE4 inhibitors have been shown to increase intracellular cyclic adenosine monophosphate in neutrophils, leading to a decreased state of activation. They inhibit neutrophil chemotaxis, adhesion, degranulation, and release of proteases. PDE4 inhibitors decrease macrophage elaboration of LTB₄ and IL-8. They may also upregulate the anti-inflammatory cytokine IL-10 that increases secretion of tissue inhibitor of metalloproteases and inhibits macrophage secretion of IL-8, TNF-a, and MMPs.¹⁷ Cilomilast is a PDE4 inhibitor currently in clinical trials. In recent preliminary reports, use of cilomilast decreased hyperinflation, the frequency of COPD exacerbations, and the rate of FEV₁ decline.18,19 Roflumilast is another once-a-day oral PDE4 inhibitor being developed for both asthma and COPD.

Corticosteroids. The inflammation of COPD is not suppressed by corticosteroids.11 This is not totally unexpected because it is the neutrophil rather than the eosinophil that is prominent in the pathogenesis of COPD. Corticosteroids prolong neutrophil survival by suppressing apoptosis. Furthermore, they fail to inhibit the increased concentrations of neutrophil chemoattractants IL-8 and TNF-a seen in induced sputum from COPD patients. Despite this, two of five recent long-term clinical trials revealed that the use of ICSs was associated with a decrease in the frequency of COPD exacerbations but no change in the rate of FEV₁ decline.²⁰ Patients enrolled in these two trials tended to have a lower baseline FEV₁ than in the other three trials. A recent report shows that ICSs may also decrease mortality and repeat hospitalization after an exacerbation.²¹

Leukotriene modifiers. Inhibition of 5-lipoxygenase prevents LTB₄ synthesis. Zileuton is a 5-lipoxygenase inhibitor, and others are in development. No large-scale clinical trials have yet reported on the efficacy of 5-lipoxygenase inhibitors in COPD. LTB₄ antagonists are in also development.

Drugs in development. A plethora of drugs are in development that inhibit mediator and cytokine activity and/or synthesis. These include the following: (1) protease inhibitors such as inhibitors of neutrophil elastase, cathepsin G, proteinase 3, and the MMPs; (2) TNF-a inhibitors such as TNF-a-converting enzyme inhibitor, monoclonal antibodies to TNF-a, and TNF-a-soluble receptors; (3) IL-8 and CXCR1 and CXCR2 antagonists; and (4) antioxidants such as N-acetylcysteine, stable glutathione analogues, and nitrones. Drugs that are already available for other indications, such as tetracycline and marimastat, are nonselective MMP inhibitors. Macrolide antibiotics inhibit mucus secretion. Finally, retinoic acid has been shown in a rat model of elastase-induced emphysema to increase alveolar number by an apparent regrowth of new septae.

Print This | TOC | Previous | Next

3300 Dundee Road • Northbrook, Illinois 60062-2348 • (847) 498-1400 • (800) 343-2227
Copyright ©1999-2008 American College of Chest Physicians. All Rights Reserved.
ACCP Privacy Policy | ACCP Web Site Terms of Use