Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alveolar macrophages play a critical role in the pathophysiology of COPD and are a major target for future anti-inflammatory therapy. Macrophage numbers are markedly increased in the lung and alveolar space of patients with COPD and are localized to sites of alveolar destruction. The increased numbers of macrophages may result from increased recruitment of blood monocytes, prolonged survival in the lung and to a lesser extent to increased proliferation in the lung. Alveolar macrophages from COPD patients have an increased baseline and stimulated secretion of inflammatory proteins, including certain cytokines, chemokines, reactive oxygen species and elastolytic enzymes, which together could account for all of the pathophysiological features of COPD. Alveolar macrophages form COPD appear to be resistant to the anti-inflammatory effects of corticosteriods and this is linked to reduced activity and expression of histone deacetylase 2, a nuclear enzyme that switches off inflammatory genes activated through the transcription factor nuclear factor-KB. Alternative anti-inflammatory therapies that inhibit macrophages are therefore needed in the future to deal with the chronic inflammation of COPD. These drugs may include resveratrol, theophylline derivatives, MAP kinase inhibitors and phosphodiesterase-4 inhibitors.
COPD 2004 Apr
PMID:Alveolar macrophages as orchestrators of COPD. 1699 39

Phosphodiesterase-4 (PDE4) is an important cAMP-metabolising enzyme in immune and inflammatory cells, airway smooth muscle and pulmonary nerves. The phosphodiesterase 4 (PDE4) enzyme plays a significant role in modulating the activity of cAMP, an important second messenger that mediates the relaxation of airway smooth muscle and suppresses inflammatory cell function, thereby attenuating the inflammatory response. Selective inhibitors of this enzyme show a broad spectrum of activity in animal models of COPD and asthma. These drugs block the hydrolysis of cAMP via inhibition of PDE4 and are attractive candidates for novel anti-inflammatory drugs. At present, two second-generation PDE4 inhibitors for the treatment of COPD and asthma patients are being tested in clinical Phase III trials. The most advanced compound is the orally active, selective PDE4 inhibitor cilomilast (Ariflo, SB-207499, cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]-cyclohexanecarboxylic acid; GlaxoSmithKline). Cilomilast shows high selectivity for cAMP-specific PDE4, an isoenzyme that predominates in pro-inflammatory and immune cells and that is 10-fold more selective for PDE4D than for PDE4A, -B or -C. In vitro, cilomilast suppresses the activity of several pro-inflammatory and immune cells that have been implicated in the pathogenesis of asthma and COPD. Moreover, it is highly active in animal models of these diseases. Cilomilast has been shown to exert potent anti-inflammatory effects both in vitro and in vivo. It is orally active and may be effective in the treatment of asthma and COPD; however, complete assessment of the therapeutic value of this novel compound class must await the outcome of longer-term clinical trials. This review presents a summary of the preclinical and clinical profile of cilomilast in patients with COPD.
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PMID:Phosphodiesterase-4 inhibitors as a novel approach for the treatment of respiratory disease: cilomilast. 1715 57

COPD is one of the commonest causes of morbidity and mortality in the world and is increasing in prevalence. Current therapies are not very effective and no current treatment prevents the relentless progression of airflow limitation that characterizes this disease. Smoking cessation is the only strategy that reduces this decline in lung function and, although bupropion is the most effective aid to quitting, more effective treatments of nicotine addition are needed. The mainstay of treatment is bronchodilators for symptom relief and inhaled anticholinergics and beta2-agonists are useful by reducing hyperinflation of the lungs. A new once daily inhaled anticholinergic is the most effective bronchodilator, but long-acting inhaled beta2-agonsts are also useful. Theophylline is used as an additional bronchodilator in more severe patients and may have some anti-inflammatory action. By contrast, inhaled corticosteroids are poorly effective and do not reduce disease profession, although recent studies with combination inhalers (corticosteroid + long-acting beta2-agonist) have shown better effects. Long-term oxygen therapy is needed by patients with pulmonary hypertension and right heart failure. There is a pressing need to develop new classes of therapy, and several new drugs are currently in development, including inteleukin-8 antagonists, phosphodiesterase-4 inhibitors, protease inhibitors and antioxidants.
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PMID:Advances in chronic obstructive pulmonary disease. 1718 31

No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. However, several new treatments that target the inflammatory process are in clinical development. A group of specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include adhesion molecule and chemokine-directed therapy, as well as therapies to combat tumour necrosis factor-alpha and augment interleukin-10. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase, and leukotriene B4 receptor antagonists. Epidermal growth factor receptor kinase inhibitors and calcium-activated chloride channel inhibitors have potential to combat mucus overproduction. Therapy to inhibit fibrosis is being developed against transforming growth factor-beta1 and protease activated receptor-2. There is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that may even reverse this process. Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is the need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.
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PMID:Emerging targets for COPD therapy. 1730 23

Pulmonary fibroblast to myofibroblast conversion is a pathophysiological feature of idiopathic pulmonary fibrosis and COPD. This conversion is induced by transforming growth factor (TGF)-beta derived from epithelial cells as well as activated macrophages that have infiltrated the lung. Preventing this conversion might be a favourable therapeutic approach. Within this study we examined the activity of different members of the phosphodiesterase (PDE) family in primary human lung fibroblasts and various lung fibroblast cell lines both before and after TGF-beta induced differentiation to myofibroblasts as reflected by the expression of alpha-smooth muscle actin. We showed that the predominant PDE activities in lung fibroblasts are attributed to PDE5, PDE1 and to a smaller extent to PDE4. cyclic GMP (cGMP)-hydrolyzing activity declines by about half after differentiation to myofibroblasts in all pulmonary fibroblasts investigated, which is accompanied by a down-regulation of PDE5 protein. Lung fibroblast to myofibroblast differentiation is blocked by treatment with the PDE4 inhibitor piclamilast alone, depending on the TGF-beta concentration applied, and in combination with prostaglandin E(2) (PGE(2)) in a synergistic manner. Despite the high PDE5 activity the PDE5 inhibitor sildenafil by itself as well as in combination with brain natriuretic peptide or the nitric oxide-donor DETA-NONOate shows no inhibiting effects. However, combining sildenafil with the guanylyl cyclase (GC) activator BAY58-2667 and ODQ (which sensitizes GC for activation by BAY58-2667) suppressed TGF-beta induced differentiation. In summary, our data indicate that drugs interfering with the cyclic AMP (cAMP)-as well as with the NO-cGMP-pathway offer the therapeutic opportunity to prevent the differentiation of pulmonary fibroblasts to myofibroblasts in lung fibrosis.
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PMID:Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase. 1765 76

Pulmonary artery hypertension secondary to chronic lung diseases is a clinical entity with no specific symptoms that can develop as a result of parenchymal lung disorders (COPD-emphysema, sleep apnea syndrome, diffuse parenchymal lung diseases, etc.) and pulmonary vascular disorders (vasculitis, sarcoidosis, etc.). In the clinical history of these chronic and invalidating diseases, pulmonary vasculature goes through various degenerative and/or proliferative changes, responsible of the pulmonary arterial hypertension appearance. The rise in pulmonary artery pressure can be subtle and the progression from an asymptomatic disease to a more severe syndrome is often common in all forms of secondary pulmonary arterial hypertension. Etiopathology of pulmonary artery hypertension secondary to chronic lung diseases is based on one or more of the following mechanisms: hypoxic vasoconstriction, decreased area of pulmonary vascular bed, volume/pressure overload. In these forms, the above three mechanisms show common mediators, all responsible of disease progression but singularly potential reversible. Therapies for secondary pulmonary artery hypertension consist primarily on the treatment of the underlying disease. Therapy is most effective when initiated prior to the onset of irreversible pulmonary vascular damage. In the last two decades, new medical treatments (prostacyclins, endothelin receptor antagonists, phosphodiesterase inhibitors) for pulmonary arterial hypertension have been available for the sporadic and the secondary to systemic sclerosis forms. The role of these drugs in the other forms of pulmonary arterial hypertension has not been well studied yet. This review will go through the pathogenesis and the several therapeutic approaches for pulmonary artery hypertension secondary to chronic pulmonary diseases or pulmonary vasculature disorders.
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PMID:Pulmonary arterial hypertension secondary to chronic lung diseases: pathogenesis and medical treatment. 1803 16

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.
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PMID:Evaluation of PDE4 inhibition for COPD. 1804 94

The mainstay of current drug therapy is long-acting bronchodilators; several longer acting inhaled beta(2)-agonists and muscarinic antagonists (and combinations) are now in development. No treatments have so far been shown to reduce the progression or suppress the inflammation of COPD. With better understanding of the inflammatory and destructive processes in the pathophysiology of COPD, several new targets have been identified. Several mediator antagonists tested in COPD patients have so far been disappointing, but CXC receptor 2 antagonists that block pulmonary neutrophil and monocyte recruitment may be more promising. Broad-spectrum antiinflammatory drugs, including inhibitors of the enzymes phosphodiesterase 4, p38 mitogen-activated protein kinase, nuclear factor-kappaB, and phosphoinositide-3-kinase-gamma, may be more effective, but the side effects will be a major limitation so that inhaled delivery may be necessary. Perhaps the most promising approach is the reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by theophylline-like drugs, more effective antioxidants, and nonantibiotic macrolide agents.
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PMID:Emerging pharmacotherapies for COPD. 1905 58

Described herein is design, synthesis, and biological evaluation of novel series of 2-aryl-7-(3',4'-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidines acting as inhibitors of type 4 phosphodiesterase (PDE4) which is known as a good target for the treatment of asthma and COPD. For this purpose, structure optimization was conducted with the aid of structure-based drug design using the known X-ray crystallography. Also, biological effects of these compounds on the target enzyme were evaluated by using in vitro assays, leading to the potent and selective PDE-4 inhibitor (IC(50)<10nM).
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PMID:Design, synthesis, and evaluation of 2-aryl-7-(3',4'-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidines as novel PDE-4 inhibitors. 2005 59

In April 2010, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of roflumilast, a selective phosphodiesterase 4 inhibitor, for the "maintenance treatment of severe chronic obstructive pulmonary disease (COPD, FEV(1) postbronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add-on to bronchodilator treatment". This decision was based, in part, on the results of several large, international, multicenter, randomized, placebo-controlled trials of either six or 12 months' duration that had been undertaken in COPD patients. Roflumilast 500 mug daily improved lung function and reduced exacerbations in patients with more severe COPD, especially those with chronic bronchitis, frequent exacerbations, or who required frequent rescue inhaler therapy in the placebo-controlled trials. It also improved lung function and reduced exacerbations in patients with moderately severe COPD treated with salmeterol or tiotropium. Advantages of roflumilast over inhaler therapy are that it is an oral tablet and only needs to be taken once daily. While taking roflumilast, the most common adverse effects patients experienced were gastrointestinal upset and headache. Weight loss, averaging 2.2 kg, occurred in patients treated with roflumilast. Patients taking roflumilast were more likely to drop out of the trials than patients in the control groups. Patients who discontinued therapy usually did so during the first few weeks and were more likely to have experienced gastrointestinal side effects. Roflumilast is the first selective phosphodiesterase 4 inhibitor and will offer physicians another treatment option for patients with more severe COPD.
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PMID:Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. 2068 41


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