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The Canadian Journal of Cardiology Feb 2006Cilostazol is a phosphodiesterase III inhibitor with pharmacological effects that include vasodilation, inhibition of platelet activation and aggregation, inhibition of... (Review)
Review
Cilostazol is a phosphodiesterase III inhibitor with pharmacological effects that include vasodilation, inhibition of platelet activation and aggregation, inhibition of thrombosis, increased blood flow to the limbs, improvement in serum lipids with lowering of triglycerides and elevation of high density lipoprotein cholesterol, and inhibition of vascular smooth muscle cell growth. Cilostazol has been shown in multiple randomized clinical trials to result in decreased claudication and improved ability to walk in patients with peripheral arterial disease. In addition, cilostazol has been shown in multiple randomized clinical trials to decrease restenosis in the setting of coronary stent implantation. The purpose of the present paper was to review the vascular effects of cilostazol and to present results of the major clinical trials of the use of cilostazol in peripheral arterial disease and percutaneous coronary intervention with stent implantation.
Topics: Animals; Cell Proliferation; Cilostazol; Coronary Restenosis; Endothelium, Vascular; Humans; Lipids; Peripheral Vascular Diseases; Phosphodiesterase Inhibitors; Platelet Aggregation Inhibitors; Tetrazoles; Tunica Intima
PubMed: 16498513
DOI: 10.1016/s0828-282x(06)70987-4 -
Clinical Cardiology Apr 2004The mechanism of action of the phosphodiesterase type 5 (PDE5) inhibitors (i.e., sildenafil, tadalafil, and vardenafil) involves inhibition of the PDE5 isoenzyme located... (Review)
Review
The mechanism of action of the phosphodiesterase type 5 (PDE5) inhibitors (i.e., sildenafil, tadalafil, and vardenafil) involves inhibition of the PDE5 isoenzyme located in penile vascular smooth muscle cells. Sexual stimulation triggers the release of nitric oxide (NO), stimulating the release of guanylyl cyclase, leading to an increase in intracellular cyclic guanosine monophosphate (cGMP) concentrations, a decrease in intracellular calcium, and ultimately relaxation of the vascular smooth muscle in the corpus cavernosum and penile erection. The PDE5 inhibitors have no effect on the penis in the absence of sexual stimulation. Although the various PDE5 inhibitors differ with respect to selectivity and pharmacokinetic profiles, efficacy and safety of these agents are comparable in broad populations of men with erectile dysfunction (ED), including those with diabetes or those taking multiple antihypertensive agents. The most frequently reported adverse events of the PDE5 inhibitors are related to their mild vasodilatory effects and include headache, flushing, dyspepsia, and nasal congestion or rhinitis. Side effects are generally reversible and tend to diminish during continued treatment. Differences in pharmacokinetic properties among the PDE5 inhibitors include the fact that sildenafil and vardenafil have a shorter duration of action (approximately 4 h) compared with the longer period of responsiveness observed with tadalafil (up to 36 h). In addition, in the presence of high-fat food, absorption of sildenafil and vardenafil may be delayed; however, the rate and extent of tadalafil absorption are unaffected by high-fat food.
Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cardiovascular Diseases; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Complications; Humans; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Spermatogenesis; Vision Disorders
PubMed: 15115191
DOI: 10.1002/clc.4960271305 -
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 -
The Cochrane Database of Systematic... Nov 2014Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants. BPD is associated with poor long-term respiratory and neurodevelopmental outcome and... (Review)
Review
BACKGROUND
Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants. BPD is associated with poor long-term respiratory and neurodevelopmental outcome and increased mortality. The prophylactic use of agents that modulate inflammation such as pentoxifylline, a synthetic methylxanthine and phosphodiesterase inhibitor, may reduce the incidence of BPD.
OBJECTIVES
The primary objective of this review was to determine the effect of pentoxifylline on the incidence of BPD, death prior to 36 weeks postmenstrual age (PMA), and BPD or death prior to 36 weeks PMA in preterm neonates.
SEARCH METHODS
We searched the Cochrane Neonatal Review Group Specialized Register, CENTRAL (The Cochrane Library Issue 9, 2012), EMBASE (January 1974 to September 2012), PubMed (January 1966 to September 2012), and CINAHL (January 1982 to September 2012) in September 2012. We checked references and cross-references from identified studies. We handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings (from January 1990 to September 2012). We placed no restrictions on language.
SELECTION CRITERIA
Randomised or quasi-randomised clinical trials of systemic or nebulised pentoxifylline in preterm neonates less than 32 weeks gestational age or less than 1500 g birth weight, reporting on at least one outcome of interest, were eligible for inclusion in the review.
DATA COLLECTION AND ANALYSIS
We used the standard methods of the Cochrane Neonatal Review Group and The Cochrane Collaboration. Two review authors (SMS and SK) independently searched the literature as described above and selected studies. Any disagreements were resolved by discussion involving all review authors.
MAIN RESULTS
We identified one randomised clinical trial eligible for inclusion in this review. This study compared the use of nebulised pentoxifylline versus placebo for prevention of BPD in 100 preterm infants and was at high risk of bias due to lack of blinding of intervention and outcome assessors, and incomplete outcome data. There was no statistically significant effect of nebulised pentoxifylline versus placebo on individual outcomes of BPD at 36 weeks PMA or on death prior to 36 weeks PMA. There was no significant effect of nebulised pentoxifylline on intraventricular haemorrhage, periventricular leukomalacia, sepsis, or patent ductus arteriosus (PDA) requiring ligation. The study did not report any of the other secondary outcomes considered for this review. Reporting of adverse events was very limited and did not allow for reliable judgement on the incidence of such events. No long-term outcomes were reported.
AUTHORS' CONCLUSIONS
There is insufficient evidence to determine the safety and efficacy of pentoxifylline for prevention of BPD in preterm neonates. We encourage researchers to conduct clinical trials to confirm or refute the role of pentoxifylline for prevention of BPD in preterm neonates. These trials should report on clinically important outcomes and, ideally, on long-term neurodevelopmental outcome.
Topics: Bronchopulmonary Dysplasia; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Pentoxifylline; Phosphodiesterase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 25418278
DOI: 10.1002/14651858.CD010018.pub2 -
Journal of Cardiac Failure Jan 2017Pediatric heart failure (HF) patients have a suboptimal response to traditional HF medications, although phosphodiesterase-3 inhibition (PDE3i) has been used with...
BACKGROUND
Pediatric heart failure (HF) patients have a suboptimal response to traditional HF medications, although phosphodiesterase-3 inhibition (PDE3i) has been used with greater success than in the adult HF population. We hypothesized that molecular alterations specific to children with HF and HF etiology may affect response to treatment.
METHODS AND RESULTS
Adenylyl cyclase (AC) and phosphodiesterase (PDE) isoforms were quantified by means of quantitative real-time polymerase chain reaction in explanted myocardium from adults with dilated cardiomyopathy (DCM), children with DCM, and children with single-ventricle congenital heart disease of right ventricular morphology (SRV). AC and PDE expression profiles were uniquely regulated in each subject group and demonstratde distinct changes in response to chronic PDE3i. There was unique up-regulation of AC5 in adult DCM with PDE3i (fold change 2.415; P = .043), AC2 in pediatric DCM (fold change 2.396; P = .0067), and PDE1C in pediatric SRV (fold change 1.836; P = .032). Remarkably, PDE5A expression was consistently increased across all age and disease groups.
CONCLUSIONS
Unique regulation of AC and PDE isoforms supports a differential molecular adaptation to HF in children compared with adults, and may help identify mechanisms specific to the pathogenesis of pediatric HF. Greater understanding of these differences will help optimize medical therapies based on age and disease process.
Topics: Adenylyl Cyclases; Age Factors; Child; Child, Preschool; Female; Gene Expression Regulation; Heart Failure; Humans; Male; Middle Aged; Myocardium; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; RNA; Real-Time Polymerase Chain Reaction
PubMed: 27427220
DOI: 10.1016/j.cardfail.2016.07.429 -
Pharmacology Research & Perspectives Aug 2020We propose a new hypothesis that the established drug pentoxifylline deserves attention as a potential repurposed therapeutic for COVID-19. Pentoxifylline is an... (Review)
Review
We propose a new hypothesis that the established drug pentoxifylline deserves attention as a potential repurposed therapeutic for COVID-19. Pentoxifylline is an immunomodulator with anti-inflammatory properties. It is a nonselective phosphodiesterase inhibitor and through Adenosine A2A Receptor-mediated pathways reduces tumor necrosis factor alpha, interleukin 1, interleukin 6, and interferon gamma and may act to reduce tissue damage during the cytokine storm host response to SARS-CoV-2 infection. This agent has been used clinically for many years and has a favorable profile of safety and tolerability. Pre-clinical data support pentoxifylline as effective in cytokine-driven lung damage. Clinical studies of pentoxifylline in radiation and cytokine-induced lung damage in humans are positive and consistent with anti-inflammatory efficacy. Pentoxifylline is a readily available, off-patent and inexpensive drug, suitable for large-scale use including in resource-limited countries. Current trials of therapeutics are largely focused on the inhibition of viral processes. We advocate urgent randomized trials of pentoxifylline for COVID-19 as a complementary approach to target the host responses.
Topics: Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Pandemics; Pentoxifylline; Phosphodiesterase Inhibitors; Pneumonia, Viral; Research Design; SARS-CoV-2; Tumor Necrosis Factor-alpha; COVID-19 Drug Treatment
PubMed: 32715661
DOI: 10.1002/prp2.631 -
The Korean Journal of Internal Medicine Jun 2012
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Hypoxia; Kidney Tubules; Male; Pentoxifylline; Phosphodiesterase Inhibitors
PubMed: 22707885
DOI: 10.3904/kjim.2012.27.2.151 -
Drug Design, Development and Therapy Jul 2010In April 2010, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of roflumilast, a selective phosphodiesterase 4... (Review)
Review
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.
Topics: Adult; Aminopyridines; Animals; Benzamides; Cyclopropanes; Humans; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Severity of Illness Index
PubMed: 20689641
DOI: 10.2147/dddt.s7667 -
British Journal of Pharmacology Jul 2009Phosphodiesterase (PDE)4, and to a lesser extent, PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for diseases including chronic... (Review)
Review
Phosphodiesterase (PDE)4, and to a lesser extent, PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for diseases including chronic obstructive pulmonary disease. Indeed, ibudilast and theophylline are utilized clinically, and roflumilast is in late-stage clinical development. Unfortunately, however many PDE4 and dual PDE3/4 inhibitors have failed in early development due to low therapeutic ratios. The majority of these compounds are however orally administered and non-selective for either PDE3(A, B) or PDE4(A, B, C, D) subtypes. Developing an inhaled dual PDE3/4 inhibitor with subtype specificity may represent one strategy to improve the therapeutic index. Indeed combined inhibition of PDE3 and PDE4 inhibitor has additive and synergistic anti-inflammatory and bronchodilatory effects versus inhibition of either PDE3 or PDE4 alone. Given that synergy has been seen in terms of efficacy end points, an obvious concern is that synergy may also be observed in side effects. Interestingly, however, no synergy or additive effects with a combination of a PDE3 and PDE4 inhibitor in a cardiomyocyte assay were observed. This review will summarize the rationale for developing an inhaled dual PDE3/4 inhibitor, as a treatment for chronic obstructive pulmonary disease together with recent advances in trying to understand the pathogenesis of PDE inhibitor-induced mesenteric vasculitis (a key potential dose-limiting side effect of these agents), highlighting potential early and sensitive predictive biomarkers.
Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Combinations; Drug Synergism; Humans; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive
PubMed: 19508401
DOI: 10.1111/j.1476-5381.2009.00170.x -
Expert Opinion on Therapeutic Patents Sep 2011Inhibitors of topoisomerase I (Top1) that result in stalled Top1 cleavage complexes (Top1cc) are commonly employed against cancer. Combination chemotherapy with DNA... (Review)
Review
Inhibitors of topoisomerase I (Top1) that result in stalled Top1 cleavage complexes (Top1cc) are commonly employed against cancer. Combination chemotherapy with DNA repair inhibitors can potentially improve response to these widely used chemotherapeutics. One line of inquiry focuses on inhibitors of tyrosyl-DNA phosphodiesterase 1 (Tdp1), a repair enzyme for Top1cc. Tdp1 catalyzes the hydrolysis of DNA adducts covalently linked to the 3'-phosphate of DNA, including Top1-derived peptides and also 3'-phosphoglycolates. Tdp1 inhibitors should synergize not only with Top1-targeting drugs (camptothecins, indenoisoquinolines), but also with bleomycin, topoisomerase II (Top2) inhibitors (etoposide, doxorubicin) and DNA alkylating agents. Here, we summarize the structure-activity relationship obtained from the reported Tdp1 inhibitors. Better understanding of Top1cc repair in vivo coupled with detailed structural studies on Tdp1-inhibitor interaction will be crucial in guiding the rational design of Tdp1 inhibitors.
Topics: Animals; Benzamidines; Biomimetics; DNA Adducts; Humans; Models, Molecular; Patents as Topic; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Ribosomes; Tetracyclines; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors
PubMed: 21843105
DOI: 10.1517/13543776.2011.604314