ReviewNew treatments for chronic obstructive pulmonary disease
Introduction
Chronic obstructive pulmonary disease (COPD) is one of the commonest diseases in the world and its incidence is increasing, particularly in developing countries. It is characterised by slow, progressive development of airflow limitation that is not fully reversible [1•]. COPD is an umbrella term and encompasses chronic obstructive bronchiolitis (characterised by mucus obstruction of small airways) and emphysema (characterised by enlargement of airspaces and destruction of lung parenchyma, loss of lung elasticity and closure of small airways. Most patients with COPD have all three pathological mechanisms—chronic obstructive bronchiolitis, emphysema and mucus plugging—but the relative contribution from emphysema and obstructive bronchiolitis may differ.
No currently available drug is known to reduce the relentless progression of COPD and there is a pressing need to develop new drugs to control the inflammatory and destructive processes that underlie the disease. The few therapeutic advances in the drug therapy of COPD are in stark contrast to the enormous advances made in asthma management. There are several possible reasons for the difficulty in drug development for COPD: patients with COPD have been treated with anti-asthma therapies, but these drugs may be inappropriate in a disease with a different pathophysiology; until recently, there has been little research interest in the molecular biology and cell biology of COPD to identify new therapeutic targets; there are no satisfactory animal models for early drug testing; and there are uncertainties about how to test drugs for COPD in humans—long-term studies in large numbers of patients will be required and there is a lack of surrogate markers to monitor the short-term efficacy of new treatments.
Section snippets
Smoking cessation
Before pharmacological therapy for COPD is discussed, the cause of the disease must be recognised. Cigarette smoking is the major cause of COPD and smoking cessation is the only therapeutic intervention so far shown to prevent disease progression. However, achieving cessation is not easy, nicotine addiction is the major problem. An important advance has been the discovery that the antidepressant bupropion given as a short course (for between six and nine weeks) is the most effective treatment
Long-acting β2-adrenoceptor agonists
An important advance in the management of COPD is the recognition that long-acting inhaled β2-adrenoceptor agonists (e.g. salmeterol and formoterol) provide some useful clinical benefit in COPD [6•]. Long-acting inhaled β2-adrenoceptor agonists may also decrease adhesion of bacteria to epithelial cells in the airway and thus of bacteria to epithelial cells in the airway and thus reduce the risk of infective exacerbations.
Tiotropium bromide
Tiotropium bromide is a new long-acting anticholinergic drug that has a
Inflammatory-mediator antagonists
Several inflammatory mediators are likely to be involved in COPD as many inflammatory cells and structural cells are activated in the disease, and there is an ongoing inflammatory process even in patients who have given up smoking. The profile of inflammatory mediators implicated in COPD differs from that in asthma, so that different drugs are likely to be effective. As COPD is characterised by a neutrophilic inflammation, attention has largely focused on mediators involved in recruitment and
New anti-inflammatory treatments
COPD is characterized by chronic inflammation of the respiratory tract; the inflammation persists even in ex-smokers. There is evidence for recruitment and activation of macrophages, neutrophils and cytotoxic (CD8?) T lymphocytes in airways and lung parenchyma, and activation of epithelial cells in COPD patients [1•]. This suggests that anti-inflammatory treatments may be of value in COPD; several possible approaches to control the inflammation are shown in Table 2 and Fig. 1.
PI3-kinase inhibitors
Phosphoinositide-3-kinases (PI3Ks) are a family of enzymes that lead to the generation of lipid second messengers that regulate a number of cellular events. The PI3Kγ isoform is involved in neutrophil recruitment and activation; knockout of the PI3Kγ gene results in inhibition of neutrophil migration and activation, as well as impaired T lymphocyte and macrophage function [45]. This suggests that selective PI3Kγ inhibitors may have relevant anti-inflammatory activity in COPD and such drugs are
Protease inhibitors
There is compelling evidence for an imbalance between proteases that digest elastin (and other structural proteins) and antiproteases that protect against this in COPD. This suggests that either inhibiting these proteolytic enzymes or increasing the activity of antiproteases may be beneficial, and theoretically should prevent the progression of airflow obstruction in COPD. Considerable progress has been made in identifying the enzymes involved in elastolytic activity in emphysema and in
Routes of drug delivery
Bronchodilators are currently administered using inhalers — metered dose inhalers or dry powder inhalers—that have been optimised to deliver drugs to the respiratory tract in asthma. In emphysema the inflammatory and destructive processes take place further down the respiratory tract in the lung parenchyma. This implies that if a drug is to be delivered by inhalation, it should have a smaller particle size, so that there is preferential deposition in the lung periphery. It may be more
Conclusions and future directions
New drugs for the treatment of COPD are needed. Although preventing the patient from smoking is the obvious preferred approach, persuading patients to quit proves to be very difficult in the majority of cases. Even with bupropion only ∼30% of patients are sustained quitters [2•]. In addition, it is likely that the inflammatory processes initiated by cigarette smoking may continue even when smoking has ceased [49]. Furthermore, COPD may be caused by environmental factors (cooking fumes,
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
•of special interest
••of outstanding interest
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