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      Advances in targeting cyclic nucleotide phosphodiesterases

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          Abstract

          Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants.

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          The future of peptide-based drugs.

          The suite of currently used drugs can be divided into two categories - traditional 'small molecule' drugs with typical molecular weights of 5000 Da that are not orally bioavailable and need to be delivered via injection. Due to their small size, conventional small molecule drugs may suffer from reduced target selectivity that often ultimately manifests in human side-effects, whereas protein therapeutics tend to be exquisitely specific for their targets due to many more interactions with them, but this comes at a cost of low bioavailability, poor membrane permeability, and metabolic instability. The time has now come to reinvestigate new drug leads that fit between these two molecular weight extremes, with the goal of combining advantages of small molecules (cost, conformational restriction, membrane permeability, metabolic stability, oral bioavailability) with those of proteins (natural components, target specificity, high potency). This article uses selected examples of peptides to highlight the importance of peptide drugs, some potential new opportunities for their exploitation, and some difficult challenges ahead in this field. © 2012 John Wiley & Sons A/S.
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            Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.

            Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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              Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.

              Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo. Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.
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                Author and article information

                Journal
                Nature Reviews Drug Discovery
                Nat Rev Drug Discov
                Springer Science and Business Media LLC
                1474-1776
                1474-1784
                April 2014
                April 1 2014
                April 2014
                : 13
                : 4
                : 290-314
                Article
                10.1038/nrd4228
                24687066
                92c4748a-9c8b-426b-9965-91f085f150a6
                © 2014

                http://www.springer.com/tdm

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