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Revista Da Associacao Medica Brasileira... Nov 2020
Topics: Cardiovascular Diseases; Cohort Studies; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Phosphodiesterase 5 Inhibitors
PubMed: 33295389
DOI: 10.1590/1806-9282.66.11.1464 -
Journal of the American Heart... Jul 2020
Topics: Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Failure; Heart-Assist Devices; Humans; Phosphodiesterase 5 Inhibitors; Thrombosis
PubMed: 32648504
DOI: 10.1161/JAHA.120.017585 -
Neuropharmacology Jun 2023Apremilast is a phosphodiesterase (PDE) type 4 inhibitor that is nonselective at subtypes PDE4A-D. It modulates ethanol and GABAergic responses via protein kinase A...
Apremilast is a phosphodiesterase (PDE) type 4 inhibitor that is nonselective at subtypes PDE4A-D. It modulates ethanol and GABAergic responses via protein kinase A (PKA) phosphorylation of specific GABA receptor subunits and has opposite effects on ethanol-induced ataxia in wild-type and GABA β3-S408/409A knock-in mice. We hypothesized that these different effects are due to preferential actions at different PDE4 subtypes. To test this hypothesis, we compared effects of selective PDE4 inhibitors on responses to ethanol and GABAergic drugs in male and female C57BL/6J mice. The PDE4B inhibitor A33 accelerated recovery from ataxia induced by ethanol and diazepam but did not alter ataxia induced by propofol. The PDE4D inhibitor D159687 accelerated recovery from diazepam-induced ataxia but prolonged recovery from ethanol- and propofol-induced ataxia. A33 shortened, while D159687 prolonged, the sedative-hypnotic effects of ethanol. Both drugs shortened diazepam's sedative-hypnotic effects. The modulatory effects of A33 and D159687 were completely prevented by the PKA inhibitor H89. Only D159687 prevented development of acute functional tolerance to ethanol-induced ataxia. D159687 transiently reduced two-bottle choice drinking in male and female mice that had consumed ethanol for 3 weeks and transiently reduced two-bottle choice, every-other-day drinking in male mice. A33 did not alter ethanol drinking in either procedure. Neither drug altered binge-like ethanol consumption or blood ethanol clearance. Thus, D159687 produced behavioral effects similar to apremilast, although it produced a more transient and smaller reduction in drinking. These results indicate that PDE4D inhibition contributes to apremilast's ability to reduce ethanol drinking, whereas PDE4B inhibition is not involved.
Topics: Mice; Male; Female; Animals; Ethanol; Propofol; Mice, Inbred C57BL; Cyclic Nucleotide Phosphodiesterases, Type 4; Hypnotics and Sedatives; Phosphodiesterase 4 Inhibitors; Ataxia; Diazepam
PubMed: 36935006
DOI: 10.1016/j.neuropharm.2023.109508 -
Dermatologic Therapy Jul 2020The world is facing a viral pandemic of a new coronavirus called COVID-19. Pentoxifylline is a methyl-xanthine derivative and it inhibits the phosphodiesterase IV (PDE... (Review)
Review
The world is facing a viral pandemic of a new coronavirus called COVID-19. Pentoxifylline is a methyl-xanthine derivative and it inhibits the phosphodiesterase IV (PDE IV). This drug is known for its unique features as an immunomodulatory and anti-inflammatory agent, also it could have antiviral affects. This is a scoping review, in which all related articles on COVID-19 and the probable benefits of Pentoxifylline against COVID-19 pathogenesis, in Medline, Scopus, Web of Sciences, and Google Scholar up to 20 March 2020 with proper keywords including: pentoxifylline, Pentoxil, COVID-19, coronavirus, treatment, anti-inflammatory, immunomodulatory, antifibrosis, oxygenation, circulation, bronchodilator, ARDS, and organ failure. We found many confirmatory data on proper efficacy of pentoxifylline on controlling COVID-19 and its consequences. The antiviral, anti-inflammatory, anti-oxidative, immune-modulatory, bronchodilator and respiratory supportive effects and protective roles in organ failures of PTX, along with its main functions means better circulation-oxygenation properties, low price and safety, make it a promising drug to be considered for COVID-19 treatment, especially as an adjuvant therapy in combination with other drugs.
Topics: Betacoronavirus; COVID-19; Chemotherapy, Adjuvant; Coronavirus Infections; Humans; Pandemics; Pentoxifylline; Phosphodiesterase Inhibitors; Pneumonia, Viral; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32473070
DOI: 10.1111/dth.13733 -
Medicine Nov 2023This retrospective study assessed the efficacy of low-intensity extracorporeal shockwave therapy (Li-ESWT) in the treatment of erectile dysfunction (ED) in patients...
This retrospective study assessed the efficacy of low-intensity extracorporeal shockwave therapy (Li-ESWT) in the treatment of erectile dysfunction (ED) in patients unresponsive to phosphodiesterase inhibitors (PDE5is). Between May 2020 and December 2022, we retrospectively analyzed the records of 126 ED patients who underwent Li-ESWT post unsuccessful PDE5is trials, defined as inadequate response following at least 6 consistent trials with correct dosage (preference given to 20 mg tadalafil). Patients with neurogenic disorders were excluded. Patients' ED severity was determined using the IIEF-5 score and further categorized into 2 groups. The Li-ESWT treatment protocol consisted of 12 weeks. Data was analyzed using descriptive statistics and paired t-tests. In the cohort of 126 patients, the mean age was 50.5 ± 12.4 years, with a BMI of 29.18 ± 3.49. Notably, 74.6% had ED for more than 12 months. Before Li-ESWT, 55.6% used sildenafil and 44.4% used tadalafil. Post 3 months of Li-ESWT, the average IIEF score rose significantly from 10.19 ± 7.71 to 14.29 ± 0.92 (P < .01). Particularly, Group 2 exhibited a significant improvement in their mean IIEF score from 13.78 ± 1.38 pretreatment to 21 ± 2.31 post-treatment. However, Group 1 (with higher diabetes prevalence) showed a marginal rise from 5.8 ± 1.47 to 6.1 ± 3.2 (P = .14). Similarly, the overall EHS score progressed significantly from 1.34 ± 0.8 to 2.3 ± 1.17 post-treatment. Post-treatment, while Group 1 showed no changes in successful vaginal penetration, Group 2 reported a dramatic increase in successes, from 16 before treatment to 68 after. This study demonstrated the efficacy of Li-ESWT for PDE5is-refractory ED, particularly in patients with moderate to mild ED. However, patients with severe ED and comorbidities did not show significant improvement. Further research with larger sample sizes, control groups, longer follow-up periods, and standardized protocols is required to confirm the effectiveness and limitations of Li-ESWT in ED treatment.
Topics: Male; Humans; Adult; Middle Aged; Erectile Dysfunction; Retrospective Studies; Extracorporeal Shockwave Therapy; Phosphodiesterase Inhibitors; Tadalafil; Treatment Outcome
PubMed: 37960801
DOI: 10.1097/MD.0000000000035939 -
Molecular Psychiatry Sep 2021Phosphodiesterases (PDEs) are enzymes involved in the homeostasis of both cAMP and cGMP. They are members of a family of proteins that includes 11 subfamilies with... (Review)
Review
Phosphodiesterases (PDEs) are enzymes involved in the homeostasis of both cAMP and cGMP. They are members of a family of proteins that includes 11 subfamilies with different substrate specificities. Their main function is to catalyze the hydrolysis of cAMP, cGMP, or both. cAMP and cGMP are two key second messengers that modulate a wide array of intracellular processes and neurobehavioral functions, including memory and cognition. Even if these enzymes are present in all tissues, we focused on those PDEs that are expressed in the brain. We took into consideration genetic variants in patients affected by neurodevelopmental disorders, phenotypes of animal models, and pharmacological effects of PDE inhibitors, a class of drugs in rapid evolution and increasing application to brain disorders. Collectively, these data indicate the potential of PDE modulators to treat neurodevelopmental diseases characterized by learning and memory impairment, alteration of behaviors associated with depression, and deficits in social interaction. Indeed, clinical trials are in progress to treat patients with Alzheimer's disease, schizophrenia, depression, and autism spectrum disorders. Among the most recent results, the application of some PDE inhibitors (PDE2A, PDE3, PDE4/4D, and PDE10A) to treat neurodevelopmental diseases, including autism spectrum disorders and intellectual disability, is a significant advance, since no specific therapies are available for these disorders that have a large prevalence. In addition, to highlight the role of several PDEs in normal and pathological neurodevelopment, we focused here on the deregulation of cAMP and/or cGMP in Down Syndrome, Fragile X Syndrome, Rett Syndrome, and intellectual disability associated with the CC2D1A gene.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cyclic AMP; Cyclic GMP; Humans; Neurodevelopmental Disorders; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases
PubMed: 33414502
DOI: 10.1038/s41380-020-00997-9 -
Expert Opinion on Drug Discovery Feb 2021Cyclic nucleotides, cAMP, and cGMP, are important second messengers of intracellular signaling and play crucial roles in cardiovascular biology and diseases. Cyclic... (Review)
Review
INTRODUCTION
Cyclic nucleotides, cAMP, and cGMP, are important second messengers of intracellular signaling and play crucial roles in cardiovascular biology and diseases. Cyclic nucleotide phosphodiesterases (PDEs) control the duration, magnitude, and compartmentalization of cyclic nucleotide signaling by catalyzing the hydrolysis of cyclic nucleotides. Individual PDEs modulate distinct signaling pathways and biological functions in the cell, making it a potential therapeutic target for the treatment of different cardiovascular disorders. The clinical success of several PDE inhibitors has ignited continued interest in PDE inhibitors and in PDE-target therapeutic strategies.
AREAS COVERED
This review concentrates on recent research advances of different PDE isoforms with regard to their expression patterns and biological functions in the heart. The limitations of current research and future directions are then discussed. The current and future development of PDE inhibitors is also covered.
EXPERT OPINION
Despite the therapeutic success of several marketed PDE inhibitors, the use of PDE inhibitors can be limited by their side effects, lack of efficacy, and lack of isoform selectivity. Advances in our understanding of the mechanisms by which cellular functions are changed through PDEs may enable the development of new approaches to achieve effective and specific PDE inhibition for various cardiac therapies.
Topics: Animals; Cardiovascular Diseases; Drug Development; Heart Diseases; Humans; Molecular Targeted Therapy; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Signal Transduction
PubMed: 32957823
DOI: 10.1080/17460441.2020.1821643 -
International Journal of Molecular... Mar 20213'-5' cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes playing a fundamental role in the control of intracellular levels of cAMP and cGMP....
3'-5' cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes playing a fundamental role in the control of intracellular levels of cAMP and cGMP. Emerging evidence suggested an important role of phosphodiesterases in heart formation, but little is known about the expression of phosphodiesterases during cardiac development. In the present study, the pattern of expression and enzymatic activity of phosphodiesterases was investigated at different stages of heart formation. C57BL/6 mice were mated and embryos were collected from 14.5 to 18.5 days of development. Data obtained by qRT-PCR and Western blot analysis showed that seven different isoforms are expressed during heart development, and PDE1C, PDE2A, PDE4D, PDE5A and PDE8A are modulated from E14.5 to E18.5. In heart homogenates, the total cAMP and cGMP hydrolytic activity is constant at the evaluated times, and PDE4 accounts for the majority of the cAMP hydrolyzing ability and PDE2A accounts for cGMP hydrolysis. This study showed that a subset of PDEs is expressed in developing mice heart and some of them are modulated to maintain constant nucleotide phosphodiesterase activity in embryonic and fetal heart.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cyclic AMP; Cyclic GMP; Female; Fetal Heart; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases
PubMed: 33807511
DOI: 10.3390/ijms22052593 -
Neurotherapeutics : the Journal of the... Oct 2023Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in... (Review)
Review
Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244, ClinicalTrials.gov ).
Topics: Humans; Phosphodiesterase 5 Inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 5; Sildenafil Citrate; Cerebrovascular Circulation; Brain Injuries, Traumatic; Biomarkers
PubMed: 37697134
DOI: 10.1007/s13311-023-01430-z -
International Journal of Molecular... Feb 2021Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone... (Review)
Review
Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial-endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.
Topics: Acute Lung Injury; Animals; COVID-19; Cyclic AMP; Disease Models, Animal; Humans; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Respiratory Distress Syndrome; Sepsis; COVID-19 Drug Treatment
PubMed: 33669167
DOI: 10.3390/ijms22041929