Evaluation of PDE4 inhibition for COPD

Targeting type 4 phosphodiesterase (PDE4) for treatment of COPD has multilevel benefits to patients by reducing inflammation, relieving bronchoconstriction, and improving pulmonary circulation. The isoenzyme-specific narrow spectrum PDE4 inhibitors such as cilomilast and roflumilast may have limited clinical efficacy in managing severe and very severe COPD. Development of dual therapy by combining PDE4 inhibition with Ca²⁺ channel antagonism may introduce an effective novel armory for physicians to manage patients with severe COPD.     

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-μg 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.     

The novel phosphodiesterase 4 inhibitor, CI-1044, inhibits LPS-induced TNF-alpha production in whole blood from COPD patients

Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor alpha (TNF-alpha) plays a central role as a pro-inflammatory cytokine in COPD. TNF-alpha release is markedly inhibited by phosphodiesterase type 4 (PDE4) inhibitors that have proven efficacious in COPD clinical trials. The aim of this study was to compare the in vitro activities of the novel selective PDE4 inhibitors CI-1044 compared to well-known PDE4 inhibitors, rolipram and cilomilast, and to the glucocorticoid dexamethasone at reducing lipopolysaccharide (LPS)-induced TNF-alpha release in whole blood from COPD patients and healthy subjects. In the whole blood from COPD patients pre-incubation with PDE4 inhibitors or dexamethasone resulted in a dose-dependent inhibition of LPS-induced TNF-alpha release with IC(50) values of 1.3+/-0.7, 2.8+/-0.9 microM, higher to 10 microM and lesser than 0.03 microM for CI-1044, rolipram, cilomilast and dexamethasone, respectively. We observed a similar inhibition in the whole blood from healthy volunteers with, however, higher IC(50) values. These results indicate that CI-1044 inhibits in vitro LPS-induced TNF-alpha release in whole blood from COPD patients better than rolipram and cilomilast and suggested that it could be a useful anti-inflammatory therapy in COPD.     

Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors

Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity. We compared the anti-inflammatory effects of roflumilast with those of PDE4 inhibitors rolipram, piclamilast, and cilomilast in ovalbumin (OVA)-sensitized and challenged Brown-Norway rats. Animals were treated orally 1h before OVA challenge with roflumilast (0.3, 1.0, and 3.0mg/kg), rolipram (0.8, 2.8, and 8.3mg/kg), piclamilast (10.0, 20.0, and 30.0mg/kg), or cilomilast (10.3, 34.3, and 103.0mg/kg). Airway hyperresponsiveness (AHR) against adenosine was investigated by measuring airway resistance 200min after OVA challenge. Subsequently, neutrophil influx and tumor necrosis factor-alpha (TNF-alpha) release in the lungs were determined by bronchoalveolar lavage. Direct bronchodilation at the time point of AHR assessment by PDE4 inhibitors was examined in serotonin-challenged animals. Evaluation of neutropenic animals or treatment with anti-TNF-alpha antibody revealed that AHR was independent of neutrophil accumulation or TNF-alpha release. Roflumilast (50% inhibitory dose [ID(50)]=1.5mg/kg) inhibited AHR 3-, 16-, and 27-fold more potently than rolipram, piclamilast, and cilomilast, respectively. Likewise, roflumilast was a more potent inhibitor of neutrophil influx (ID(50)=0.9mg/kg) than rolipram (ID(50)=6.9mg/kg), piclamilast (ID(50)=28.1mg/kg), or cilomilast (ID(50)=37.7mg/kg). Roflumilast, rolipram, and piclamilast-but not cilomilast-suppressed OVA-induced TNF-alpha release in a dose-dependent manner. Roflumilast (ID(50)=0.9mg/kg) exhibited 9- and 23-fold more potent inhibition of TNF-alpha release than rolipram and piclamilast, respectively. Roflumilast did not inhibit serotonin-induced bronchoconstriction 4.5h after administration, suggesting that inhibition of AHR by roflumilast results from anti-inflammatory, not bronchodilatory, effects. This study suggests that roflumilast has anti-inflammatory action and provides rationale for the investigation of roflumilast in asthmatic patients.     

PDE4 inhibitors in COPD--a more selective approach to treatment

Chronic obstructive pulmonary disease (COPD) is a serious and mounting global public health problem. Although its pathogenesis is incompletely understood, chronic inflammation plays an important part and so new therapies with a novel anti-inflammatory mechanism of action may be of benefit in the treatment of COPD. Cilomilast and roflumilast are potent and selective phosphodiesterase (PDE)4 inhibitors, with an improved therapeutic index compared with the weak, non-selective PDE inhibitor, theophylline. Unlike theophylline, which is limited by poor efficacy and an unfavourable safety and tolerability profile, the selective PDE4 inhibitors are generally well tolerated, with demonstrated efficacy in improving lung function, decreasing the rate of exacerbations and improving quality of life, with proven anti-inflammatory effects in patients with COPD. Theophylline is a difficult drug to use clinically, requiring careful titration and routine plasma monitoring due to the risk of toxic side effects, such as cardiovascular and central nervous system adverse events, with dose adjustments required in many patients, including smokers, the elderly and some patients on concomitant medications. In contrast, the selective PDE4 inhibitors are convenient medications for both patient and physician alike. Hence these agents represent a therapeutic advance in the treatment of COPD, due to their novel mechanism of action and potent anti-inflammatory effects, coupled with a good safety and tolerability profile.     

磷酸二酯酶抑制剂与呼吸道疾病

磷酸二酯酶(PDE)存在于许多炎症细胞及结构细胞中,目前已发现11种.PDE抑制剂主要抑制体内环磷酸腺苷(cAMP)及环磷酸鸟苷(cGMP)水解,使细胞内cAMP及cGMP浓度增加,引起一系列生理功能,如平滑肌舒张、减轻细胞炎症及免疫反应等.PDE4特异性水解cAMP,选择性PDE4抑制剂具有广泛抗炎作用,如抑制细胞趋化,抑制中性粒细胞、嗜酸粒细胞、巨噬细胞及T细胞细胞因子及化学趋化物质释放.第二代PDE4抑制剂Cilomilast和Roflumilast已进入临床实验阶段,并已证实对支气管哮喘(简称哮喘)及慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)有效.由于胃肠道副作用,这类药物临床应用受到一定限制.PDE5可特异性水解cGMP,对缺氧性肺动脉高压和血管重塑有效.PDE3和PDE7特异性水解cAMP,PDE7参与T细胞激活.目前其他PDE抑制剂与PDE4抑制剂混合制剂正在研发中.PDE4-PDE7双重抑制剂可能对哮喘及COPD更有效.PDE3-PDE4双重抑制剂具有更强的支气管舒张作用及气道保护作用.     

The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro

Neutrophil-derived proteases such as neutrophil elastase (NE) and matrix metalloproteinase (MMP) are implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). In this study, the effects of selective phosphodiesterase (PDE) inhibition on NE and MMP-9 release, as well as Myeloperoxidase (MPO) activity and integrin-mediated neutrophil adhesion to human umbilical vein endothelial cells (HUVECs), were investigated. Human neutrophils were treated with PDE inhibitors (10(-11)-10(-4)M) in the absence and presence of TNF-alpha (tumour necrosis factor) (100 U ml(-1)) for 30 min, prior to fMLP activation. After 45 min, the cells were removed and NE, MPO and MMP-9 release assessed. In the adhesion studies, the neutrophils were radio-labelled with 51Cr, stimulated and immediately transferred to cultured HUVEC monolayers for 30 min, prior to assessment of adhesion. TNF-alpha (100 U ml(-1)) acted synergistically with fMLP in stimulating azurophil degranulation with respect to both MPO activity (P<0.01) and NE release (P<0.01). In contrast, an additive effect was observed with TNF-alpha and fMLP with regard to MMP-9 release and neutrophil adhesion to HUVECs. The PDE4 inhibitors, roflumilast, roflumilast N-oxide, cilomilast and rolipram significantly suppressed MPO, NE and MMP-9 release in both the presence and absence of TNF-alpha (P<0.05; n=6-10) and also reduced neutrophil adhesion to HUVECs. In contrast, milrinone, a PDE3 inhibitor and the non-selective PDE inhibitor, theophylline did not inhibit azurophil degranulation under any of the experimental conditions. These data provide further evidence that selective PDE4 isoenzyme inhibitors can inhibit neutrophil degranulation, effects not shared by PDE3 inhibitors or theophylline.     

Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is usually progressive. In addition, an abnormal inflammatory response of the lungs to noxious particles or gases can be seen throughout the airways, parenchyma, and pulmonary vasculature. So far, anti-inflammatory medications (eg, inhaled corticosteroids) have failed to show a major effect on the decline of lung function in COPD patients. Novel anti-inflammatory therapies such as selective phosphodiesterase 4 (PDE4) inhibitors are in clinical development. Their potential role in the management of COPD is described in this review. RECENT FINDINGS: Some of the selective PDE4 inhibitors have demonstrated in vitro and in vivo anti-inflammatory activity on cells commonly linked to airway inflammation in COPD, such as neutrophils. While these agents seem to offer only a modest improvement in lung function compared with other bronchodilators, their anti-inflammatory effects appear to provide some substantial benefits in reducing exacerbations and improving health-related quality of life. SUMMARY: Based on the available data, the second generation of selective PDE4 inhibitors will likely provide additional therapeutic options for the management of COPD. These agents may become an important tool in the treatment of this disease, since they target three important components of COPD: airway obstruction, inflammation, and structural changes.     

Additive anti-inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human peripheral blood mononuclear cells

The phosphodiesterase 4 inhibitor (PDE4i) roflumilast has been approved in the US and EU for treatment of GOLD stage 3 and 4 chronic obstructive pulmonary disease (COPD). Inhaled β2 adrenoceptor agonist bronchodilators and anti-inflammatory glucocorticosteroids are also used as standard of care in COPD. We investigated the anti-inflammatory interaction of roflumilast in combination with long-acting β2 agonists (LABA), salmeterol or formoterol, or a glucocorticosteroid, dexamethasone, on cytokine production from LPS-stimulated human primary peripheral blood mononuclear cells (PBMC). Salmeterol or formoterol caused a concentration-dependent inhibition of tumor necrosis factor-α (TNFα) secretion with an IC50 of 0.33 pM (C.I. 0.006-19) and 34 pM (C.I. 13-87), respectively. When roflumilast was evaluated, the addition of salmeterol (1 nM) to roflumilast caused the IC50 for roflumilast to shift from 1.8 nM (C.I. 0.8-4) to 4.1 pM (C.I.0.3-69) (p < 0.01), and maximal inhibition increased from 72.5 ± 3.2% to 90.9 ± 3.1%. Addition of formoterol to roflumilast also produced an increased TNFα inhibition more than either drug alone (p < 0.05). The inhibition of TNFα production with salmeterol was both β2 adrenoceptor- and protein kinase A-dependent. Addition of roflumilast (10 nM) in the presence of dexamethasone increased the inhibition of LPS-induced TNFα and CCL3. Roflumilast in combination with salmeterol, formoterol, or dexamethasone increased the inhibition of LPS-induced TNFα from human PBMC, in an additive manner. Addition of roflumilast to either a β2 adrenoceptor agonist or a glucocorticosteroid may provide superior anti-inflammatory activity and greater efficacy in COPD patients and be dose sparing.     

PDE4 inhibitors as potential therapeutic agents in the treatment of COPD-focus on roflumilast

Chronic obstructive pulmonary disease is characterized by a rapid decline in lung function due to small airway fibrosis, mucus hypersecretion and emphysema. The major causative factor for COPD is cigarette smoking that drives an inflammatory process that gives rise to leukocyte recruitment, imbalance in protease levels and consequently matrix remodeling resulting in small airway fibrosis and loss of alveolar tissue. Current drug treatment improves symptoms but do not alter the underlying progression of this disease. The failure of anti-inflammatory drugs like glucocorticosteroids to have a major impact in this disease has hastened the need to develop novel therapeutic strategies. Phosphodiesterase (PDE)4 inhibitors are novel anti-inflammatory drugs that have recently been show to document clinical efficacy in this disease, although their utility is hampered by class related side-effects of nausea, emesis and diarrhea. Whilst it is not yet clear whether such drugs will prevent emphysema, this is a distinct possibility provided experimental observations from preclinical studies translate to man. This review will discuss the current standing of PDE4 inhibitors like roflumilast as novel treatments for COPD and the potential for developing nonemetic anti-inflammatory drugs.     

Phosphodiesterase-4: selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease

Phosphodiesterase-4 isoenzymes have absolute specificity for cyclic adenosine-3',5'-monophosphate and are considered potential therapeutic targets for the treatment of chronic inflammatory disorders, such as chronic obstructive pulmonary disease, with small-molecule inhibitors. Several selective phosphodiesterase-4 inhibitors are in clinical trials of chronic obstructive pulmonary disease, including cilomilast and roflumilast. Despite some encouraging data from phase III clinical trials, the current generation of phosphodiesterase-4 inhibitors is hampered by a low therapeutic ratio. Indeed, a major obstacle is their propensity to evoke non-steroid-like side effects, of which nausea, diarrhea, abdominal pain, vomiting, and dyspepsia are the most common. In addition, a particularly worrying potential toxicity of phosphodiesterase-4 inhibitors, also shared by phosphodiesterase-3 inhibitors and other vasodilators, is arteritis/periarteritis. One potential means of improving the therapeutic ratio and safety of phosphodiesterase-4 inhibitors may lie in the development of compounds that have broader phosphodiesterase specificity. Of the 11 phosphodiesterase families that have been unequivocally identified, dual-specificity compounds that inhibit phosphodiesterase-4 and phosphodiesterase-1, phosphodiesterase-3, or phosphodiesterase-7 may offer the best opportunities to enhance clinical efficacy.     

The Potential Role of Phosphodiesterase Inhibitors in the Management of Asthma

Asthma is a chronic inflammatory condition characterised by reversible airflow obstruction and airway hyperreactivity. The course of the illness may be punctuated by exacerbations resulting in deterioration in quality of life and, in some cases, days lost from school or work. That asthma is common and increasingly prevalent magnifies the importance of any potential economic costs, and promoting asthma control represents an important public health agenda. While lifestyle changes represent a valuable contribution in some patients, the majority of asthmatic patients require therapeutic intervention. The recognition of the role of inflammation in the pathogenesis of asthma has led to an emphasis on regular anti-inflammatory therapy, of which inhaled corticosteroid treatment remains the most superior. In selected patients, further improvements in asthma control may be gained by the addition of regular inhaled long-acting beta(2)-adrenoceptor agonists or oral leukotriene receptor antagonists to inhaled corticosteroid therapy. However, a significant minority of patients with asthma remain poorly controlled despite appropriate treatment, suggesting that additional corticosteroid nonresponsive inflammatory pathways may be operative. Furthermore, some patients with asthma display an accelerated decline in lung function, suggesting that active airway re-modeling is occurring. Such observations have focused attention on the potential to develop new therapies which complement existing treatments by targeting additional inflammatory pathways. The central role of phosphodiesterase (PDE), and in particular the PDE4 enzyme, in the regulation of key inflammatory cells believed to be important in asthma - including eosinophils, lymphocytes, neutrophils and airway smooth muscle - suggests that drugs designed to target this enzyme will have the potential to deliver both bronchodilation and modulate the asthmatic inflammatory response. In vivo studies on individual inflammatory cells suggest that the effects are likely to be favorable in asthma, and animal study models have provided proof of concept; however, first-generation PDE inhibitors have been poorly tolerated due to adverse effects. The development of second-generation agents such as cilomilast and roflumilast heralds a further opportunity to test the potential of these agents, although to date only a limited amount of data from human studies has been published, making it difficult to draw firm conclusions.     

New phosphodiesterase inhibitors as therapeutics for the treatment of chronic lung disease

Phosphodiesterase 4 (PDE4) is a member of the growing family cyclic AMP and cyclic GMP. Earliest described inhibitors of PDE4, such as rolipram, demonstrate marked anti-inflammatory and bronchodilatory effects in vitro and in vivo. The clinical utility of these earlier compounds was limited by their propensity to elicit gastrointestinal side effects. This has led to an extensive effort to identify novel PDE4 inhibitors that maintain the anti-inflammatory activity and bronchodilatory activity of rolipram but with a reduced potential to produce side effects. This article summarizes the evidence supporting the utility of selective PDE4 inhibitors in the treatment of asthma and chronic obstructive pulmonary disease, discusses the recent results obtained in clinical trials with second-generation inhibitors, and presents two approaches designed to identify additional novel selective PDE4 inhibitors.     

Phosphodiesterase 4-selective inhibition: novel therapy for the inflammation of COPD

Chronic obstructive pulmonary disease (COPD), which is increasing in prevalence and a leading cause of death worldwide, is characterised by an 'abnormal' inflammatory response. There is a predominance of CD8(+) T cells, CD68(+) macrophages and, in exacerbations-neutrophils, in both conducting airways and lung parenchyma. Smoking is the most common etiological factor leading to COPD and smoking cessation is the most effective approach to the management of COPD, but it does not resolve the underlying inflammation of COPD, which persists, even in ex-smokers. The presence of mucosal inflammation serves as the rationale for anti-inflammatory therapy. However, while there are reductions in the numbers of mast cells following treatment with inhaled steroids, CD8(+), CD68(+) cells and neutrophils are refractory to such treatment, highlighting a need for additional, more targeted interventions. Phosphodiesterase 4 (PDE4) inhibitors are a promising and novel drug class that have potent activity against several key components of the inflammatory process in COPD. A recently published study has shown that the selective PDE4 inhibitor, cilomilast, reduces the numbers of bronchial mucosal CD8(+) and CD68(+) cells and neutrophils. This review focuses on the nature of the inflammation in COPD and considers how selective PDE4 inhibitors may optimize and advance our treatment of this chronic condition.     

Roflumilast: clinical benefit in patients suffering from COPD

Background and aims: Chronic obstructive pulmonary disease (COPD) is associated with substantial morbidity and mortality and is characterised by persistent airway inflammation, which leads to impaired airway function, quality of life and intermittent exacerbations. In spite of recent advances in the treatment of COPD, new treatment options for COPD are clearly necessary. The oral phosphodiesterase‐4 (PDE4) inhibitor roflumilast represents a new class of drugs that has shown efficacy and acceptable tolerability in preclinical and short‐term clinical studies in patients with COPD. Methods and results: The available long‐term clinical studies reviewed here suggest that the clinical efficacy of roflumilast is likely because of the suppression of airway inflammation and not through bronchodilation. Furthermore, the clinical studies have shown a modest improvement in airway function, including FEV₁, and a reduction in frequency and severity of COPD exacerbations, as well as a positive effect on several patient‐reported outcomes. The clinical benefit of roflumilast appears to be greatest in patients with more symptomatic and severe disease who experience exacerbations. The most common adverse effects are gastrointestinal events, primarily diarrhoea, nauseas and weight loss. Conclusion: Roflumilast is beneficial for maintenance treatment of patients with severe and symptomatic COPD and with a history of frequent acute exacerbations as an add‐on to treatment with long‐acting bronchodilators. It may have a role as an alternative to inhaled corticosteroids in more symptomatic COPD patients with frequent exacerbations, although direct comparisons are currently lacking. Please cite this paper as: Ulrik CS and Calverley PMA. Roflumilast: clinical benefit in patients suffering from COPD. Clin Respir J 2010; 4: 197–201.     

Cilomilast for COPD: results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4

BACKGROUND: COPD is a relentless, progressive disease. This study evaluated the efficacy of cilomilast, a selective phosphodiesterase (PDE) 4 inhibitor, in the treatment of COPD. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study in subjects with COPD. After a 4-week, single-blind, placebo run-in period, eligible subjects were randomized in a 2:1 ratio to receive oral cilomilast, 15 mg bid, or placebo for 24 weeks. Subjects between 40 and 80 years of age who had received a diagnosis of COPD were eligible for the study. The primary efficacy variables were changes from baseline in trough (ie, predose) FEV1 and in total score of the St. George's Respiratory Questionnaire (SGRQ). A key secondary end point was the incidence rate of COPD exacerbations. RESULTS: The average change from baseline in FEV1 over 24 weeks in the cilomilast group was an increase of 10 mL compared with a decrease of 30 mL in the placebo group (difference, 40 mL; p = 0.002). When averaged over 24 weeks, there was a clinically significant reduction in the mean total SGRQ score in subjects receiving cilomilast therapy, with a difference of 4.1 U compared with subjects who received placebo (p = 0.001). A greater percentage of subjects in the cilomilast group were exacerbation-free at 24 weeks (74%; p = 0.008) compared with placebo (62%). Adverse events were generally mild or moderate and were not unexpected for this class of medications. GI adverse events that interfered with daily activities (cilomilast, 17%; placebo, 8%) predominantly occurred within the first 3 weeks of initiating cilomilast therapy. CONCLUSION: Cilomilast is an orally active, potent, and selective inhibitor of PDE-4. Cilomilast maintained pulmonary function and improved health status, and reduced the rate of COPD exacerbations during 24 weeks of treatment. This study supports the use of cilomilast, a novel, selective PDE-4 inhibitor, in subjects with COPD.     

Treating COPD with PDE 4 inhibitors

While the pathogenesis of chronic obstructive pulmonary disease (COPD) is incompletely understood, chronic inflammation is a major factor. In fact, the inflammatory response is abnormal, with CD8⁺ T-cells, CD68⁺ macrophages, and neutrophils predominating in the conducting airways, lung parenchyma, and pulmonary vasculature. Elevated levels of the second messenger cAMP can inhibit some inflammatory processes. Theophylline has long been used in treating asthma; it causes bronchodilation by inhibiting cyclic nucleotide phosphodiesterase (PDE), which inactivates cAMP. By inhibiting PDE, theophylline increases cAMP, inhibiting inflammation and relaxing airway smooth muscle. Rather than one PDE, there are now known to be more than 50, with differing activities, substrate preferences, and tissue distributions. Thus, the possibility exists of selectively inhibiting only the enzyme(s) in the tissue(s) of interest. PDE 4 is the primary cAMP-hydrolyzing enzyme in inflammatory and immune cells (macrophages, eosinophils, neutrophils). Inhibiting PDE 4 in these cells leads to increased cAMP levels, down-regulating the inflammatory response. Because PDE 4 is also expressed in airway smooth muscle and, in vitro, PDE 4 inhibitors relax lung smooth muscle, selective PDE 4 inhibitors are being developed for treating COPD. Clinical studies have been conducted with PDE 4 inhibitors; this review concerns those reported to date.     

PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease

Roflumilast is a selective once daily, oral phosphodiesterase-4 inhibitor that has recently been registered in all European Union countries as novel targeted therapy for COPD, while FDA approval for the USA market is expected in 2011. In several phase III trials in patients with moderate to (very) severe COPD and in patients with symptoms of chronic bronchitis and recurrent exacerbations, roflumilast showed sustained clinical efficacy by improving lung function and by reducing exacerbation rates. These beneficial effects have also been demonstrated when added to long-acting bronchodilators (both LABA and LAMA), underscoring the anti-inflammatory activity of roflumilast in COPD. Pooled data analysis showed overall mild to moderate, mostly self-limiting adverse events, mainly consisting of nausea, diarrhea and weight loss. In this review we discuss the results of the 4 registration studies showing promising effects of roflumilast in COPD and provide an overview of the topics that still need to be addressed.     

Roflumilast in Asian patients with COPD: A randomized placebo-controlled trial

Background and objective: Roflumilast, an oral, selective phosphodiesterase 4 inhibitor, has been shown to reduce exacerbations and improve pulmonary function in patients with COPD. This study examined the efficacy, safety and tolerability of roflumilast in Asian patients with COPD. Methods: Patients with COPD were randomized 1:1 to enter a 12‐week treatment period and receive either oral roflumilast, 500 µg once daily, or placebo, following a single‐blind, 4‐week baseline period in which all patients received placebo. The primary end point was mean change in FEV₁ from baseline to each postrandomization visit during the treatment period. Other spirometric lung function measurements were evaluated as secondary end points. COPD exacerbations were monitored. Safety was assessed from clinical laboratory tests, vital signs, physical examination (including electrocardiogram) and monitoring of adverse events (AEs). Results: Of 551 patients recruited, 410 were randomized and received at least one dose of study medication (roflumilast, n = 203; placebo, n = 207). Superiority of roflumilast over placebo was demonstrated by a statistically significant difference in postbronchodilator FEV₁ (79 mL, P < 0.0001). Other spirometry end points, including prebronchodilator FEV₁, pre‐and postbronchodilator FEV₆, forced vital capacity and peak expiratory flow significantly favoured roflumilast over placebo. AEs were more common with roflumilast than with placebo, but were comparable with those reported in previous studies. Conclusions: Roflumilast, 500 µg once daily, improves pulmonary function in Asian patients with COPD. The safety and tolerability of roflumilast in this population was similar to that in a Caucasian population.     

The airway pathophysiology of COPD: implications for treatment

The pathophysiology of chronic obstructive pulmonary disease (COPD) is complex and can be attributed to multiple components: mucociliary dysfunction, airway inflammation and structural changes, all contributing to the development of airflow limitation, as well as an important systemic component. Current pharmacotherapies vary in their ability to address the underlying multi-component nature of COPD. Long-acting anticholinergics and long-acting beta2-agonists (LABAs) can both provide effective and convenient bronchodilation in moderate COPD (Stage II-GOLD) and are recommended as regular therapy in global treatment guidelines. However, there is evidence to suggest that LABAs can mediate additional benefits independent of their bronchodilatory effects and may help address the multi-component nature of COPD. Effects on mucociliary dysfunction and reduced bacterial-induced damage have been experimentally proven with LABAs, and anti-inflammatory activity and structural effects have also been suggested. The use of inhaled corticosteroids (ICSs) is now recommended for the treatment of COPD patients with frequent exacerbations. In addition, ICSs provide a range of anti-inflammatory effects in COPD and thus have effects that are complementary to those of LABAs. Recent data indicate that LABA/ICS combinations produce wide-ranging clinical benefits that are greater than with either agent alone. Other new strategies include selective phosphodiesterase 4 (PDE4) inhibitors, which in addition to anti-inflammatory activity, have been shown to provide bronchodilation in COPD. In summary, the potential to address the multicomponent nature of COPD with strategies such as LABA/ICS combination therapy, and the development of new treatments directed at novel targets means that the future for sufferers of COPD can be more optimistic.