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)

Theophylline has been in clinical use for the treatment of bronchial asthma and other respiratory diseases for well over 50 yrs. Over this time, a considerable body of evidence has accumulated to show that this drug has a wide range of pharmacological actions, in addition to the well-recognized action on airway smooth muscle function. Current evidence suggests that part of the therapeutic value of theophylline in the treatment of asthma is by virtue of an anti-inflammatory or immunomodulatory effect, although the actual mechanism of action remains unclear. It has been proposed that the observed anti-inflammatory effects of theophylline could be attributed to phosphodiesterase (PDE) inhibition, and recently the type III and IV isoenzymes have been characterized in a number of inflammatory cells. This article reviews the evidence that theophylline and the newer more selective type IV PDE isoenzyme inhibitors can inhibit the activation of inflammatory cell types, such as T-lymphocytes, eosinophils, mast cells and macrophages, in vitro. The evidence supporting the ability of theophylline and selective PDE IV isoenzyme inhibitors to modify allergic inflammation both in animal models and clinical asthma is also discussed. We conclude that theophylline possesses important anti-inflammatory and immunomodulatory activity and that, in light of this evidence, it is timely to reconsider the place of theophylline in the treatment of asthma.
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PMID:Theophylline and selective phosphodiesterase inhibitors as anti-inflammatory drugs in the treatment of bronchial asthma. 758 87

The link between increased usage of beta-adrenoceptor agonists and worsening of asthma symptoms has raised interest in the effects of agents such as salbutamol on airway wall remodelling, and particularly airway smooth muscle proliferation. In the present study we have investigated the role of increases in intracellular cAMP in the inhibitory effect of salbutamol on airway smooth muscle proliferation. The inhibitory effects of a combination of submaximally effective concentrations of salbutamol (10 nM) and the non-selective phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX, 100 microM) on thrombin (0.3 U/mL)-induced mitogenesis in human cultured airway smooth muscle cells was greater than that for either agent alone. In addition, agents known to increase cAMP-dependent protein kinase activity including forskolin (10 microM), 8-bromoadenosine-3',5'-cyclic monophosphate (100 microM), and prostaglandin E2 (1 microM) have an inhibitory effect on thrombin (0.3 U/mL)-induced induced proliferation. Furthermore, the cAMP antagonist, 8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (300 microM) significantly reduced the inhibitory effect of salbutamol (10 nM) on thrombin (0.3 U/mL)-induced DNA synthesis. In IBMX (100 microM)-pretreated cells, salbutamol (100 nM) increased intracellular cAMP levels via stimulation of a beta 2-adrenoceptor. Salbutamol (10 microM), at concentrations supramaximally effective for inhibition of mitogenesis, had no effect on thrombin (0.3 U/mL)-induced increases in intracellular calcium levels. Therefore, our results suggest that the previously reported inhibition of mitogen-induced proliferation in human cultured airway smooth muscle cells by the beta 2-adrenoceptor agonist, salbutamol (100 nM), is at least partly due to elevation of intracellular cAMP, while there is no effect of salbutamol on initial mitogen-induced increases in intracellular calcium.
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PMID:Salbutamol inhibits the proliferation of human airway smooth muscle cells grown in culture: relationship to elevated cAMP levels. 759 43

The pharmacological profile of a novel cyclic nucleotide phosphodiesterase (PDE) inhibitor, Org 20241, has been characterized. The compound selectively inhibits PDE IV (pIC50, 5.2-6.1) and PDE III (pIC50, 4.4-4.6) from animal and human tissues. Org 20241 relaxed preparations of bovine trachea (pD2, 5.9 and 5.4), guinea pig trachea (pD2, 6.2 and 4.9) and human bronchi (pD2, 5.3 and 4.7) for histamine and methacholine-induced contractions, respectively. Rolipram and Org 20241 inhibited leukotriene B4-induced thromboxaneB2 (IC50, 0.3 and 1.4 microM, respectively) and H2O2 (IC50, 2.1 and 0.4 microM, respectively) production in guinea pig eosinophils. In phenylephrine (0.3 microM) precontracted rabbit aorta preparations, the PDE III inhibitor Org 9935 (pD2, 6.3 and 6.1 in the presence and absence of endothelium, respectively) was the most effective relaxant, whereas Org 20241 (pD2, 5.3 and 5.4 in the presence and absence of endothelium, respectively) was more effective than rolipram (pD2, 4.6 and 4.1 in the presence and absence of endothelium, respectively). Org 20241 relaxed rabbit aorta preparations and airway preparations at similar concentrations. In electrically stimulated rabbit cardiac papillary muscles, Org 20241 had little effect on contractility at concentrations up to 30 microM. Lower concentrations (10 microM) potentiated the inotropic effect of Org 9935. Whereas the PDE III inhibitor milrinone (1-100 microM) enhanced the rate of repolarization of guinea pig papillary muscles and shortened the effective refractory period, Org 20241 and rolipram (1-100 microM) did not reduce the action potential duration. In the presence of Org 20241 or rolipram, isoproterenol did not produce a greater increase in the rate of repolarization or reduction in the effective refractory period than in the absence of these PDE inhibitors. Org 20241 is a dual PDE IV/III inhibitor with some PDE IV selectively. This compound relaxes airways smooth muscle and inhibits eosinophil activation. The data indicate that such PDE IV/III inhibitors may be effective for the long-term therapy of asthma.
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PMID:Characterization of ORG 20241, a combined phosphodiesterase IV/III cyclic nucleotide phosphodiesterase inhibitor for asthma. 763 28

1. We have investigated the inhibitory potency of RP 73401, a novel, highly selective and potent inhibitor of cyclic AMP-specific phosphodiesterase (PDE IV), against partially-purified PDE isoenzymes from smooth muscle and the particulate PDE IV from guinea-pig eosinophils. The inhibitory effects of RP 73401 on the generation of superoxide (.O2-), major basic protein (MBP) and eosinophil cationic protein (ECP) from guinea-pig eosinophils have also been studied. 2. RP 73401 potently inhibited partially-purified cyclic AMP-specific phosphodiesterase (PDE IV) from pig aortic smooth muscle (IC50 = 1.2 nM); it was similarly potent against the particulate PDE IV from guinea-pig peritoneal eosinophils (IC50 = 0.7 nM). It displayed at least a 19000 fold selectivity for PDE IV compared to its potencies against other PDE isoenzymes. Rolipram was approximately 2600 fold less potent than RP 73401 against pig aortic smooth muscle PDE IV (IC50 = 3162 nM) and about 250 times less potent against eosinophil PDE IV (IC50 = 186 nM). 3. Solubilization of the eosinophil particulate PDE IV increased the potency of rolipram 10 fold but did not markedly affect the potency of RP 73401. A similar (10 fold) increase in the PDE IV inhibitory potency of rolipram, but not RP 73401, was observed when eosinophil membranes were exposed to vanadate/glutathione complex (V/GSH). 4. Reverse transcription polymerase chain reaction (RT-PCR), using primer pairs designed against specific sequences in four distinct rat PDE IV subtype cDNA clones (PDE IVA-D), showed only mRNA for PDE IVD in guinea-pig eosinophils. PDE IVD was also the predominant subtype expressed in pig aortic smooth muscle cells. 5. RP 73401 (Kiapp = 0.4 nM) was 4 fold more potent than (+/-)-rolipram (Kiapp = 1.7 nM) in displacing[3H]-(+/-)-rolipram from guinea-pig brain membranes.6. In intact eosinophils, RP 73401 potentiated isoprenaline-induced cyclic AMP accumulation(EC50 = 79 nM). RP 73401 also inhibited leukotriene B4-induced generation of *02- (IC50 = 25 nM), and the release of major basic protein (ICo = 115 nM) and eosinophil cationic protein (IC50 = 7 nM). Rolipram was 3-14 times less potent than RP 73401.7. Thus RP 73401 is a very potent and selective PDE IV inhibitor which suppresses eosinophil function suggesting that it may be a useful agent for the treatment of inflammatory diseases such as asthma. The greatly different inhibitory potencies of rolipram against PDE IV from smooth muscle and eosinophils(in contrast to the invariable effects of RP 73401) are unlikely to be attributable to diverse PDE IV subtypes but suggest distinct interactions of the two inhibitors with the enzyme.
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PMID:Suppression of eosinophil function by RP 73401, a potent and selective inhibitor of cyclic AMP-specific phosphodiesterase: comparison with rolipram. 764 82

Theophylline, a nonspecific phosphodiesterase inhibitor, has only recently been reconsidered as a potential anti-inflammatory drug. Its ability to inhibit late asthmatic responses has pointed to possible inhibition of mechanisms regulating the influx and activity of inflammatory cells into the airways. Increasing evidence points to an anti-inflammatory action of theophylline at doses lower than those necessary for a bronchodilator effect. Withdrawal of theophylline from regular treatment results in an increase both in CD4+ and CD8+ T-cells in the bronchial mucosa and a concomitant decrease in the blood, suggesting that theophylline prevents T-cell trafficking from blood into the airways. Furthermore, pretreatment with theophylline significantly attenuates the influx of eosinophils into the airways associated with an allergen-induced late asthmatic response. In keeping with these observations, in a double-blind, placebo-controlled trial involving mild to moderately severe atopic asthmatics, treatment with theophylline resulted in a significant reduction in the numbers of epithelial CD8+ T-cells. In addition, the numbers of cells containing cytokines, interleukin 4 and 5 (IL-4 and IL-5), decreased in the theophylline-treated group and increased in the placebo-treated group, with the difference between the changes being significant. It would, therefore, appear that theophylline may contribute to asthma control due to its ability to reduce the suppressor/cytotoxic T-cells and cytokines which are relevant to allergic mucosal responses.
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PMID:The effects of theophylline on mucosal inflammation in asthmatic airways: biopsy results. 765 58

In addition to its emerging immunodulatory properties, theophylline is a bronchodilator and also decreases mean pulmonary arterial pressure in vivo. The mechanism of action of this drug remains controversial; adenosine antagonism, phosphodiesterase (PDE) inhibition and other actions have been advanced to explain its effectiveness in asthma. Cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) are involved in the regulation of smooth muscle tone, and the breakdown of these nucleotides is catalysed by multiple PDE isoenzymes. The PDE isoenzymes present in human bronchus and pulmonary artery have been identified, and the pharmacological actions of inhibitors of these enzymes have been investigated. Human bronchus and pulmonary arteries are relaxed by theophylline and by selective inhibitors of PDE III, while PDE IV inhibitors also relax precontracted bronchus and PDE V/I inhibitors relax pulmonary artery. There appears to be some synergy between inhibitors of PDE III and PDE IV in relaxing bronchus, and a pronounced synergy between PDE III and PDE V inhibitors in relaxing pulmonary artery. In neither tissue does 8-phenyltheophylline, a xanthine exhibiting adenosine antagonism but not PDE inhibition, cause any significant relaxation, implying that theophylline does not exert its actions through adenosine antagonism. The close correspondence of theophylline concentrations inhibiting bronchus or pulmonary artery PDE and those causing relaxation points towards PDE inhibition as the major mechanism of action of theophylline in smooth muscle relaxation.
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PMID:Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. 766 66

Asthma is a complex, multifactorial disease that is underpinned by airway inflammation. A variety of cytotoxic substances are released into the airway from infiltrating inflammatory cells, especially the eosinophil. These cytotoxic substances, including reactive oxygen metabolites, produce damage to the airway epithelium, a histologic feature of chronic asthma. Damage to the airway epithelium, in turn, is thought to be a major factor responsible for the development of airway hyperreactivity, a hallmark of asthma. One notable molecular target for novel antiasthmatic drugs is the cyclic AMP-specific phosphodiesterase (PDE) or PDE IV. This isozyme is the predominant form of cyclic nucleotide PDE activity in inflammatory cells. Thus, in view of the putative role of cyclic AMP as an inhibitory second messenger in these cells, PDE IV inhibitors have been shown to suppress inflammatory cell activity. The purpose of the present experiments was to examine the effect of the PDE IV inhibitor, R-rolipram, on three key functions of the guinea pig eosinophil: a) superoxide anion (O2-) production, b) adhesion to human umbilical vein endothelial cells (HUVECs), and c) infiltration into the airway. R-rolipram-elevated eosinophil cyclic AMP content (EC50 = 1.7 microM) and inhibited fMLP-induced O2- production in a concentration-dependent manner (IC50 = 0.3 microM). In contrast, neither siguazodan, a PDE III inhibitor, nor zaprinast, a PDE V inhibitor, had an appreciable effect. R-rolipram (30 microM) also reduced by 25 to 40% the adhesion of eosinophils to HUVECs stimulated with phorbol myristate acetate or tumor necrosis factor-alpha, particularly under conditions in which both cell types were simultaneously exposed to the PDE IV inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphodiesterase IV inhibitors as therapy for eosinophil-induced lung injury in asthma. 770 12

Narrowing of the airway lumen as a result of plasma exudation could augment airflow obstruction after allergen-induced bronchoconstriction. Because leukotrienes are putative mediators of bronchial asthma, the effects of a lipoxygenase inhibitor, VZ564 (N-hydroxy-N-(6-methoxy-3,4-dihydro-2- naphthylmethyl) urea. CAS 147495-99-6), on increased pulmonary permeability and bronchoconstriction during anaphylactic reaction were studied in guinea pigs and compared to the effects of the phosphodiesterase inhibitor theophylline. An anaphylactic reaction was induced by ovalbumin challenge (0.2 mg/kg i.v.) in passively sensitized and antihistamine (mepyramine)-pretreated guinea pigs; bronchoconstriction was measured as increased intratracheal pressure; lung vascular permeability was evaluated as extravasation of Evans blue dye up to 10 min after antigenic challenge. Ovalbumin challenge induced an increase in intratracheal pressure by 31 +/- 3 mmHg; the pulmonary permeability index was higher in ovalbumin-challenged versus saline (sham)-challenged guinea pigs (1.49 +/- 0.17 vs 0.56 +/- 0.04, p < 0.05). VZ564 and theophylline dose-dependently reduced increased pulmonary permeability and bronchoconstriction. VZ564 (10 and 46.4 mg/kg p.o., given 1 h before ovalbumin challenge) inhibited increased lung permeability by 42% and 95% and reduced bronchoconstriction by 61% at the higher dose. Theophylline (1 and 10 mg/kg i.v., given 10 min before ovalbumin challenge) diminished increased pulmonary permeability by 88% and reduced bronchoconstriction by 63% at the higher dose. In conclusion, the novel lipoxygenase inhibitor VZ564 inhibits after oral application important symptoms of asthma, namely bronchoconstriction and alveolar exudation of plasma in anaphylactic guinea pigs. The acute effects of VZ564 in this experimental model are comparable with the effects of the well known antiasthmatic substance theophylline.
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PMID:Effect of the lipoxygenase inhibitor N-hydroxy-N-(6-methoxy-3,4-dihydro-2-naphthylmethyl)urea on bronchoconstriction and lung vascular permeability in anaphylactic guinea pigs. 771 Apr 38

Asthma is now recognized as an inflammatory disease associated with eosinophil infiltration into the pulmonary tissue. It has appeared in recent years that phosphodiesterase type IV inhibitors presented all the necessary characteristics to be used as new anti-asthmatic drugs. Indeed, in addition to their bronchodilator properties, they have inhibitory activities on inflammatory cell infiltration into the lung and on inflammatory mediator release. However, the mechanism of action of phosphodiesterase inhibitors, theoretically linked to the increase in intracellular cAMP, is now largely open for discussion.
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PMID:Asthma and airway inflammation: potential anti-inflammatory activities of phosphodiesterase inhibitors. 771 Jun 53

Cyclic nucleotide phosphodiesterase (PDE) isoenzymes (I-V) have been demonstrated in airways smooth muscle of several species including man. Theophylline is a non-selective inhibitor of PDE and is a potent relaxant of airways smooth muscle but its use is limited by its toxicity. Consequently, research into new, isoenzyme-selective PDE inhibitors is seen as important. The potential airways smooth muscle relaxant effects of these drugs is discussed in this review. Cyclic AMP PDE (types III and IV) inhibition produces greater relaxation than cyclic GMP PDE (types I and V) inhibition. No PDE II-selective inhibitors have been described. Airways smooth muscle relaxation in vitro, is greater with PDE IV than PDE III inhibitors in guinea-pig and bovine airways whereas PDE III is more important in porcine airways. Both cyclic AMP PDEs are important in human airways. PDE III or IV inhibition can produce additive effects and can augment isoprenaline actions. PDE V inhibition augments sodium nitroprusside-induced effects. There are no reported interactions between cyclic AMP and cyclic GMP PDE inhibitors. In vivo, cyclic AMP PDE inhibitors are more potent bronchodilators than cyclic GMP PDE inhibitors. PDE IV inhibitors have less cardiovascular side-effects. Topical administration may further increase efficacy and selectivity. Clinically PDE III inhibition improves lung function but also affects cardiovascular parameters. Inhaled PDE III/IV inhibitors produce bronchodilation without marked side effects. Potent, selective PDE IV inhibitors are currently being evaluated. In conclusion, isoenzyme-selective PDE inhibitors, especially PDE IV, may be useful airways smooth muscle relaxants in the treatment of lung disorders such as asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isoenzyme-selective cyclic nucleotide phosphodiesterase inhibitors: effects on airways smooth muscle. 775 80


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