The discovery of roflumilast for the treatment of chronic obstructive pulmonary disease.

Cazzola M ，Calzetta L ，Rogliani P ，Matera MG ... -  《-》

Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease.

Phosphodiesterase 4 (PDE4) is a member of the PDE enzyme superfamily that inactivates cyclic adenosine monophosphate and cyclic guanosine monophosphate, and is the main PDE isoenzyme occurring in cells involved in inflammatory airway disease such as chronic obstructive pulmonary disease (COPD). COPD is a preventable and treatable disease and is characterized by airflow obstruction that is not fully reversible. Chronic progressive symptoms, particularly dyspnoea, chronic bronchitis and impaired overall health are worse in those who have frequent, acute episodes of symptom exacerbation. Although several experimental PDE4 inhibitors are in clinical development, roflumilast, a highly selective PDE4 inhibitor, is the first in its class to be licensed, and has recently been approved in several countries for oral, once-daily treatment of severe COPD. Clinical trials have demonstrated that roflumilast improves lung function and reduces exacerbation frequency in COPD. Furthermore, its unique mode of action may offer the potential to target the inflammatory processes underlying COPD. Roflumilast is effective when used concomitantly with all forms of bronchodilator and even in patients treated with inhaled corticosteroids. Roflumilast thus represents an important addition to current therapeutic options for COPD patients with chronic bronchitis, including those who remain symptomatic despite treatment. This article reviews the current status of PDE4 inhibitors, focusing on the pharmacokinetics, efficacy and safety of roflumilast. In particular, it provides an overview of the effects of roflumilast on lung function and exacerbations, glucose homoeostasis and weight loss, and the concomitant use of long-acting beta(2)-adrenergic receptor agonists and short-acting muscarinic receptor antagonists.

Rabe KF 《-》

Roflumilast : the new orally active, selective phophodiesterase-4 inhibitor, for the treatment of COPD.

Tashkin DP 《-》

The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease.

After more than two decades of research into phosphodiesterase 4 (PDE4) inhibitors, roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) may become the first agent in this class to be approved for patient treatment worldwide. Within the PDE family of 11 known isoenzymes, roflumilast is selective for PDE4, showing balanced selectivity for subtypes A-D, and is of high subnanomolar potency. The active principle of roflumilast in man is its dichloropyridyl N-oxide metabolite, which has similar potency as a PDE4 inhibitor as the parent compound. The long half-life and high potency of this metabolite allows for once-daily, oral administration of a single, 500-microg tablet of roflumilast. The molecular mode of action of roflumilast--PDE4 inhibition and subsequent enhancement of cAMP levels--is well established. To further understand its functional mode of action in chronic obstructive pulmonary disease (COPD), for which roflumilast is being developed, a series of in vitro and in vivo preclinical studies has been performed. COPD is a progressive, devastating condition of the lung associated with an abnormal inflammatory response to noxious particles and gases, particularly tobacco smoke. In addition, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), significant extrapulmonary effects, including comorbidities, may add to the severity of the disease in individual patients, and which may be addressed preferentially by orally administered remedies. COPD shows an increasing prevalence and mortality, and its treatment remains a high, unmet medical need. In vivo, roflumilast mitigates key COPD-related disease mechanisms such as tobacco smoke-induced lung inflammation, mucociliary malfunction, lung fibrotic and emphysematous remodelling, oxidative stress, pulmonary vascular remodelling and pulmonary hypertension. In vitro, roflumilast N-oxide has been demonstrated to affect the functions of many cell types, including neutrophils, monocytes/macrophages, CD4+ and CD8+ T-cells, endothelial cells, epithelial cells, smooth muscle cells and fibroblasts. These cellular effects are thought to be responsible for the beneficial effects of roflumilast on the disease mechanisms of COPD, which translate into reduced exacerbations and improved lung function. As a multicomponent disease, COPD requires a broad therapeutic approach that might be achieved by PDE4 inhibition. However, as a PDE4 inhibitor, roflumilast is not a direct bronchodilator. In summary, roflumilast may be the first-in-class PDE4 inhibitor for COPD therapy. In addition to being a non-steroid, anti-inflammatory drug designed to target pulmonary inflammation, the preclinical pharmacology described in this review points to a broad functional mode of action of roflumilast that putatively addresses additional COPD mechanisms. This enables roflumilast to offer effective, oral maintenance treatment for COPD, with an acceptable tolerability profile and the potential to favourably affect the extrapulmonary effects of the disease.

Hatzelmann A ，Morcillo EJ ，Lungarella G ，Adnot S ，Sanjar S ，Beume R ，Schudt C ，Tenor H ... -  《-》

Roflumilast for COPD.

Patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis have a reduction in lung function and a higher risk of suffering exacerbations, which result in a deterioration in their quality of life, an accelerated progression of the disease and a greater mortality. COPD is currently considered an inflammatory disease involving airways and lung parenchyma. The symptoms that are typical of chronic bronchitis (chronic cough and sputum production) are markers of underlying inflammation, characteristic of COPD. Roflumilast, an antiinflammatory drug that belongs to the new therapeutic class of phosphodiesterase PDE4 inhibitors, is the first drug developed for the treatment of a specific phenotype of COPD (COPD associated with chronic bronchitis). The results of clinical trials indicated that in patients with COPD associated with chronic bronchitis and a history of exacerbations, roflumilast improves lung function and reduces the frequency of exacerbations that require medical interventions. This effect remained when it was added to a regular treatment with long-acting bronchodilators such as tiotropium or long-acting β₂-adrenoceptor agonists (LABAs) such as salmeterol. Roflumilast has been shown to be generally well tolerated. Side effects were typically mild to moderate and included diarrhea, nausea, weight decrease and headache. Gastrointestinal side effects mainly occurred within the first weeks of therapy and mostly resolved on continued treatment.

Izquierdo JL ，Aparicio J 《-》