Roflumilast (daliresp): a novel phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease.

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by a gradual and progressive loss of lung function. The consensus guidelines adopted by the American Thoracic Society and the European Respiratory Society define COPD as a “preventable and treatable disease state characterized by airflow limitation that is not fully reversible.”1 COPD is caused by an abnormal inflammatory response of the lungs to the inhalation of noxious gases or suspended particles in the air. Cigarette smoke is the most common source of exposure. Extended exposure to these irritants may lead to emphysema or obstructive bronchitis, the two hallmark conditions associated with COPD. The pathophysiology of COPD involves a complex series of chronic inflammatory processes that progressively destroy the pulmonary vasculature and lung parenchyma. Two main pathophysiological processes occur in COPD: inflammation and unopposed oxidation. The inflammatory process is believed to be mediated by chemical factors, such as tumor necrosis factor–alpha (TNF-α), interleukin-8 (IL-8), and leukotriene B4.2,3 When noxious gases or particles have been introduced into the lungs and irritation has occurred, the chemical “messengers” propagate the inflammatory process and recruit neutrophils, macrophages, and lymphocytes to the site of injury. The second pathophysiological process involves a shift in the balance of normal defense mechanisms, resulting in unopposed oxidation. Guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) identify disruption of the oxidant/antioxidant or trypsin/antitrypsin balance as a major determinant of damage to the lung parenchyma.4 Tobacco has been implicated in the disruption of both processes by (1) increasing oxidation, thereby overwhelming antioxidant protective factors, and (2) inducing proteases from macrophages and neutrophils. Tobacco smoke has thus been identified as the single greatest risk factor for COPD because of the processes of cellular damage and because of the high incidence of tobacco use worldwide. The socioeconomic impact of COPD is substantial. Quality of life, morbidity, and mortality are all negatively affected by the disease. In the National Health and Nutrition Examination Sur vey (NHANES), conducted from 1988 to 1994, the estimated prevalence of mild COPD in Americans 25 to 75 years of age was 6.9% and the prevalence of moderate COPD was 6.6%.5 This was equivalent to approximately 35 million individuals living with COPD in the U.S. Moreover, morbidity data suggest that emergency department visits and hospitalization are significantly more common in persons with COPD than in the general population; this trend is expected to increase as the population ages.6,7 COPD is currently the fourth major cause of death in the U.S. and is expected to become the third major cause of death by 2020.8 With these high morbidity and mortality rates, the economic burden of the disease is significant. Sullivan et al. estimated that the combined direct and indirect cost of COPD in 1993 was $23.9 billion.9 Because COPD is a heterogeneous disease state with increasing degrees of severity, pharmacotherapy is multimodal. According to the GOLD guidelines,4 COPD is stratified by severity based on two spirometry parameters: forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). A summary of the COPD types and their basic treatment is shown in Table 1 (see page 150).4 Table 1 GOLD Guideline Criteria and Recommended Drug Therapy Options The GOLD guidelines focus primarily on two classes of pharmacotherapeutic agents for COPD: bronchodilators and inhaled corticosteroids. Other drugs are generally used as adjunctive or second-line agents. One adjunctive agent, roflumilast (Daliresp, Forest), is the first new therapy for COPD in nearly 20 years. Early clinical trials sought to obtain indications for roflumilast in asthma and allergic rhinitis because of its anti-inflammatory properties. However, in March 2011, the FDA approved roflumilast only for patients with COPD.10