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Introduction
Published in Amritpal Singh Saroya, Reverse Pharmacology, 2018
As far as cosmetic application is concerned, cyclic nucleotide phosphodiesterase 4 (PDE4) was the most promising candidate. The others PDE1, 2, 3, 5 and 6 subtypes were not retained, which clearly indicates for a selectivity for PDE4. Investigatory tests with 6 subtypes of phosphodiesterase demonstrated a significant selectivity for phosphodiesterase 4 subtype. Evaluation of e-viniferin on the secretion of markers of inflammation confirmed the selectivity (Do et al. 2005).
Chronic obstructive pulmonary disease
Published in Louis-Philippe Boulet, Applied Respiratory Pathophysiology, 2017
Julie Milot, Mathieu Morissette
Phosphodiesterase-4 (PDE-4) is expressed in most inflammatory and lung cells. Clinical trials with PDE-4 inhibitor showed a significant reduction of 17% (up to 21% with concomitant treatment with LABA) in moderate-to-severe exacerbation rates in patients with COPD [111,112]. In vivo studies showed a reduction of neutrophils, eosinophils, and concentration of inflammatory mediators in sputum (IL-8 and NE) and in the serum (TNF-α) [113]. In a bronchial biopsy study, a PDE-4 inhibitor reduced the number of CD8+ T-lymphocytes and macrophages (CD68+ cells) [114].
Shock
Published in Brice Antao, S Irish Michael, Anthony Lander, S Rothenberg MD Steven, Succeeding in Paediatric Surgery Examinations, 2017
Robert Baird, Pramod S Puligandla
From the list of options above, choose which medication is best depicted in the following descriptions. Each option may be used once, more than once, or not at all. Produces vasodilatation and increases inotropic activity of the heart. Higher doses may result in toxic metabolites.Selectively inhibits phosphodiesterase type III in cardiac and smooth vascular muscle, resulting in reduced afterload, reduced preload and increased inotropy.Stimulates multiple receptors resulting in renal and mesenteric vasodilatation followed by cardiac stimulation and peripheral vasoconstriction at higher doses.
Novel Insights into the Pathophysiology and Treatment of Sickle Cell Disease
Published in Hemoglobin, 2023
Aderson da Silva Araújo, Ana Cristina Silva Pinto, Clarisse Lopes de Castro Lobo, Maria Stella Figueiredo, Sandra Fátima Menosi Gualandro, Sara Teresinha Olalla Saad, Rodolfo Delfini Cancado
PF‐04447943, a phosphodiesterase 9 A inhibitor, was evaluated in a short randomized phase 1b trial [54]. SCD adult patients, with or without stable HU, received placebo or 5 mg or 25 mg BID of PF‐04447943 for 29 days. Preclinical models with PF-04447943 have shown an accumulation of cGMP in the mouse brain and, in combination with HU, an amelioration of cellular aggregates and adhesion markers in SCD murine blood [54]. The authors found that the number and size of circulating monocyte-platelet and neutrophil-platelet aggregates and the level of circulating soluble E-selectin were significantly reduced from baseline in patients who received PF-04447943 25 mg twice daily, suggesting that PF-04447943 has beneficial effects that may help reduce parameters that contribute to vaso-occlusion in SCD. No apparent synergism with HU was found [54].
The state of the art of fetal hemoglobin-inducing agents
Published in Expert Opinion on Drug Discovery, 2022
Aline Renata Pavan, Juliana Romano Lopes, Jean Leandro Dos Santos
Phosphodiesterases (PDEs) are a class of enzymes responsible for the regulation of intracellular levels of cAMP and cGMP. PDE9 is highly specific for cGMP, with a km of 0.07 to 1.7 µM. Therefore, inhibition of PDE9 can cause accumulation of cGMP in the cells and modulation of γ-globin expression. BAY 73–6691 (Figure 2) is a potent and selective PDE9 inhibitor with an IC50 of 55 nM. When evaluated alone in a recombinant PDE9 cell line, BAY 73–6691 did not significantly alter the levels of cGMP, however, when applied along with sGC stimulators, such as BAY 58–2667 or BAY 41–2272, it caused cGMP accumulation in the cells, and the PDE9 inhibitor was also able to shift the concentration-response curves of the sGC stimulators towards the left. At 10 µM, BAY 73–6691 reduced the EC50 value for intracellular cGMP accumulation of BAY 58–2667 from 340 nM to 30.8 nM, indicating that this compound could enhance the effect of sGC stimulators [94]. In an experiment using K562 cells, the sGC stimulator BAY 41–2272 at 60 nM increased the production of cGMP by three-fold and the expression of γ-globin by two-fold, approximately. The same experiment showed that the PDE9 inhibitor, but not inhibitors of other PDE enzymes, was also able to increase the HBG mRNA to the same extent as BAY 41–2272, suggesting that PDE9 inhibitors might be considered for SCA treatment [95].
Killing all the birds with one drug – is oral roflumilast a novel treatment option for psoriasis?
Published in Journal of Dermatological Treatment, 2022
Mette Gyldenløve, Alexander Egeberg
Phosphodiesterases (PDEs) comprise an intracellular enzyme family. Most immune cells are dominated by PDE-4 which promotes inflammation by hydrolyzing cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP) (1). PDE-4 activity is increased in psoriasis and inhibition results in the down-regulation of key cytokines in psoriasis pathogenesis (2,3). Over the years, numerous PDE-4 blocking compounds have been investigated for inflammatory diseases, but drug development has been challenged by narrow therapeutic windows and dose-limiting side effects (1,4). In 2011, the oral PDE-4 inhibitor, roflumilast was approved first-in-class for the treatment of severe chronic obstructive pulmonary disease (COPD). Three years later, in 2014, apremilast was the first small-molecule drug since acitretin to be indicated for moderate-to-severe plaque psoriasis in adults. Initially, apremilast gained much attention, but gastrointestinal side effects and lower efficacy compared to similarly priced biologic therapies have limited its use in many countries (5).