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Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Oct 2021Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a... (Review)
Review
Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.
Topics: Animals; Colitis; Inflammatory Bowel Diseases; Phosphodiesterase 4 Inhibitors
PubMed: 34986542
DOI: 10.3724/zdxbyxb-2021-0170 -
Cancer Epidemiology, Biomarkers &... Feb 2021Phosphodiesterase 5 (PDE5) inhibitors have been hypothesized to have chemoprotective effects in colorectal cancer. Current population-based epidemiologic evidence is,...
BACKGROUND
Phosphodiesterase 5 (PDE5) inhibitors have been hypothesized to have chemoprotective effects in colorectal cancer. Current population-based epidemiologic evidence is, however, limited and inconsistent.
METHODS
Among 18,123 men in the Health Professionals Follow-up Study who had at least one lower gastrointestinal endoscopy, we evaluated the association between PDE5 inhibitor use and risk of conventional adenoma and serrated lesion between 2000 and 2010, adjusted for repeated observations and multiple risk factors. We stratified by erectile dysfunction to account for potential "confounding by indication."
RESULTS
We documented 2,595 conventional adenomas and 1,395 serrated lesion polyps during the follow-up period. Using people without erectile dysfunction as reference group, recent PDE5 inhibitor use at baseline was not associated with lower risk of conventional adenoma [erectile dysfunction with PDE5 inhibitors: OR = 1.08; 95% confidence interval (CI) = 0.92-1.26; erectile dysfunction without PDE5 inhibitors: OR = 0.95; 95% CI, 0.85-1.06], serrated lesions (erectile dysfunction with PDE5 inhibitors: OR = 1.19; 95% CI = 0.97-1.45; erectile dysfunction without PDE5 inhibitors: OR = 1.03; 95% CI = 0.89-1.19), or advanced conventional adenomas (erectile dysfunction with PDE5 inhibitors: OR = 1.20; 95% CI = 0.94-1.53; erectile dysfunction without PDE5 inhibitors: OR = 0.95; 95% CI = 0.79-1.14). No association was found for PDE5 inhibitor use ever before as well.
CONCLUSIONS
We found no evidence of an association between PDE5 inhibitor use and risk of conventional and serrated precursors of colorectal cancer.
IMPACT
We show that PDE5 inhibitor use is not associated with precursors of colorectal cancer adjusted for medical and lifestyle risk factors among a large population of men with 10 years of follow-up.
Topics: Adenoma; Adult; Colonic Polyps; Endoscopy, Gastrointestinal; Humans; Male; Middle Aged; Negative Results; Phosphodiesterase 5 Inhibitors; Precancerous Conditions
PubMed: 33355205
DOI: 10.1158/1055-9965.EPI-20-1126 -
Journal of Translational Medicine Sep 2023Non-union formation represents a major complication in trauma and orthopedic surgery. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been shown to exert...
Non-union formation represents a major complication in trauma and orthopedic surgery. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been shown to exert pro-angiogenic and pro-osteogenic effects in vitro and in vivo. Therefore, the aim of the present study was to analyze the impact of sildenafil in an atrophic non-union model in mice. After creation of a 1.8 mm segmental defect, mice femora were stabilized by pin-clip fixation. Bone regeneration was analyzed by means of X-ray, biomechanics, photoacoustic and micro-computed tomography (µCT) imaging as well as histological, immunohistochemical and Western blot analyses at 2, 5 and 10 weeks after surgery. The animals were treated daily with either 5 mg/kg body weight sildenafil (n = 35) or saline (control; n = 35) per os. Bone formation was markedly improved in defects of sildenafil-treated mice when compared to controls. This was associated with a higher bending stiffness as well as an increased number of CD31-positive microvessels and a higher oxygen saturation within the callus tissue. Moreover, the bone defects of sildenafil-treated animals contained more tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and CD68-positive macrophages and exhibited a higher expression of the pro-angiogenic and pro-osteogenic markers cysteine rich protein (CYR)61 and vascular endothelial growth factor (VEGF) when compared to controls. These findings demonstrate that sildenafil acts as a potent stimulator of angiogenesis and bone regeneration in atrophic non-unions.
Topics: Animals; Mice; Sildenafil Citrate; Phosphodiesterase 5 Inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 5; Vascular Endothelial Growth Factor A; X-Ray Microtomography; Bone Regeneration; Atrophy
PubMed: 37684656
DOI: 10.1186/s12967-023-04441-8 -
JACC. Heart Failure Feb 2022
Topics: Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Failure; Heart-Assist Devices; Humans; Phosphodiesterase 5 Inhibitors; Stroke
PubMed: 35115083
DOI: 10.1016/j.jchf.2021.10.014 -
Andrology Feb 2023Phosphodiesterase 5 inhibitors (PDE5i), since their introduction in the late 1990s, have proven their efficacy in treating several conditions, predominantly pulmonary... (Review)
Review
BACKGROUND
Phosphodiesterase 5 inhibitors (PDE5i), since their introduction in the late 1990s, have proven their efficacy in treating several conditions, predominantly pulmonary hypertension and erectile dysfunction where they remain the first-line therapeutic option. However, in the recent years, growing evidence from both animal and human studies has emerged to suggest the additional benefits of PDE5i in cardiovascular and metabolic disorders. This is of specific interest to the diabetes population where prevalent cardiovascular disease and metabolic dysregulation significantly contribute to the increased morbidity and mortality.
OBJECTIVES
To examine the available data on the non-standard, pleiotropic effects of PDE5i in patients with diabetes mellitus.
MATERIALS AND METHODS
The review of the published background research, preclinical studies and clinical trials.
RESULTS
In human studies, PDE5 inhibition appeared to be associated with reduced cardiovascular mortality and overall improved clinical outcomes in those with established cardiovascular disease. PDE5i were also consistently found to reduce albuminuria in subjects with diabetic nephropathy. Furthermore, animal data suggest a plausible effect of this group of medication on sensory function and neuropathic symptoms in diabetic neuropathy as well as improved wound healing. A decrease in insulin resistance and augmentation of beta cell function seen in preclinical studies has not been consistently demonstrated in human trials.
DISCUSSION AND CONCLUSION
In animal models, PDE5 inhibition appears to decrease oxidative stress and reduce some of the micro- and macrovascular complications associated with diabetes. However, data from human trials are limited and largely inconsistent, highlighting the need for adequately powered, randomised-controlled trials in diabetic cohorts in order to fully assess the benefits of PDE5i in this group of patients.
Topics: Animals; Humans; Male; Cardiovascular Diseases; Diabetes Mellitus; Phosphodiesterase 5 Inhibitors; Diabetes Complications; Metabolic Syndrome
PubMed: 36367281
DOI: 10.1111/andr.13328 -
PloS One 2023Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer's disease and related dementias (ADRD), but two recent cohort studies have...
A case-control study of phosphodiesterase-5 inhibitor use and Alzheimer's disease and related dementias among male and female patients aged 65 years and older supporting the need for a phase III clinical trial.
BACKGROUND
Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer's disease and related dementias (ADRD), but two recent cohort studies have offered opposing conclusions.
METHODS
We performed an unmatched case-control study using electronic medical records from a large healthcare system to evaluate the association of PDE5i use and ADRD in patients ≥65 years old.
RESULTS
Odds of PDE5i exposure were 64.2%, 55.7%, and 54.0% lower in patients with ADRD than controls among populations with erectile dysfunction, benign prostatic hyperplasia, and pulmonary hypertension, respectively. We observed odds ratios less than unity among males and females and with exposure to the PDE5i sildenafil (Viagra®) and tadalafil (Cialis®). We also evaluated the odds of exposure to two other common treatments for pulmonary hypertension: endothelin receptor antagonists (ERA) and calcium channel blockers (CCB). The odds of ERA exposure were 63.2% lower, but the odds of CCB exposure were 30.7% higher, in patients with ADRD than controls among the population with pulmonary hypertension.
CONCLUSIONS
Our results reconcile the opposing conclusions from the previous observational studies and support further research into using PDE5i for prevention and treatment of ADRD.
Topics: Aged; Female; Humans; Male; Alzheimer Disease; Case-Control Studies; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelin Receptor Antagonists; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil
PubMed: 37851623
DOI: 10.1371/journal.pone.0292863 -
BMC Neuroscience Jul 2023Several phosphodiesterase 4 (PDE4) inhibitors have emerged as potential therapeutics for central nervous system (CNS) diseases. This study investigated the...
BACKGROUND
Several phosphodiesterase 4 (PDE4) inhibitors have emerged as potential therapeutics for central nervous system (CNS) diseases. This study investigated the pharmacological effects of two selective PDE4 inhibitors, roflumilast and zatolmilast, against lipopolysaccharide-induced neuroinflammation.
RESULTS
In BV-2 cells, the PDE4 inhibitor roflumilast reduced the production of nitric oxide and tumor necrosis factor-α (TNF-α) by inhibiting NF-κB phosphorylation. Moreover, mice administered roflumilast had significantly reduced TNF-α, interleukin-1β (IL-1β), and IL-6 levels in plasma and brain tissues. By contrast, zatolmilast, a PDE4D inhibitor, showed no anti-neuroinflammatory effects in vitro or in vivo. Next, in vitro and in vivo pharmacokinetic studies of these compounds in the brain were performed. The apparent permeability coefficients of 3 µM roflumilast and zatolmilast were high (> 23 × 10 cm/s) and moderate (3.72-7.18 × 10 cm/s), respectively, and increased in a concentration-dependent manner in the MDR1-MDCK monolayer. The efflux ratios were < 1.92, suggesting that these compounds are not P-glycoprotein substrates. Following oral administration, both roflumilast and zatolmilast were slowly absorbed and eliminated, with time-to-peak drug concentrations of 2-2.3 h and terminal half-lives of 7-20 h. Assessment of their brain dispositions revealed the unbound brain-to-plasma partition coefficients of roflumilast and zatolmilast to be 0.17 and 0.18, respectively.
CONCLUSIONS
These findings suggest that roflumilast, but not zatolmilast, has the potential for use as a therapeutic agent against neuroinflammatory diseases.
Topics: Mice; Animals; Phosphodiesterase 4 Inhibitors; Neuroinflammatory Diseases; Lipopolysaccharides; Tumor Necrosis Factor-alpha; Aminopyridines; Cyclopropanes
PubMed: 37525115
DOI: 10.1186/s12868-023-00810-7 -
Giornale Italiano Di Dermatologia E... Aug 2020Psoriatic arthritis (PsA) is a seronegative inflammatory arthritis often observed in patients with skin psoriasis. Treatment of PsA, especially peripheral PsA, has... (Review)
Review
Psoriatic arthritis (PsA) is a seronegative inflammatory arthritis often observed in patients with skin psoriasis. Treatment of PsA, especially peripheral PsA, has typically relied on disease-modifying anti-rheumatic agents (DMARDs); however, these agents have limited efficacy and considerable associated toxicity. More recently, monoclonal antibodies (biologic agents) have revolutionized management of immune-mediated diseases; however, these therapies carry a high cost and require parenteral administration. Apremilast, a novel oral DMARD, was approved by the European Union for psoriatic arthritis in 2015. Apremilast inhibits the function of phosphodiesterase-4, a regulator of cyclic adenosine monophosphate, leading to a broad inhibition of proinflammatory mediators and subsequent reduction in tumour necrosis factor-alpha (TNF-α) response. The PALACE and ACTIVE trials, phase III randomized controlled trials for apremilast, showed that apremilast is effective at improving various clinical and patient-reported outcome measures for psoriatic arthritis in both DMARD-naïve and DMARD-experienced PsA patients. Efficacy was limited in patients with previous biologic DMARD failure and the overall efficacy of apremilast appears to be less than biologics agents, though no head-to-head trials exist comparing apremilast to biologic DMARDs. Apremilast is generally well tolerated, with short-lived gastrointestinal side effects being the most commonly reported adverse events. Guidelines suggest a trial of apremilast in patients who have failed traditional oral DMARDs and for whom, biologics are contraindicated. More studies directly comparing apremilast to conventional DMARDs and biologic DMARDs are needed and will be crucial in informing clinical and economic decisions about apremilast role in management of PsA.
Topics: Antirheumatic Agents; Arthritis, Psoriatic; Biological Products; Humans; Phosphodiesterase 4 Inhibitors; Randomized Controlled Trials as Topic; Thalidomide
PubMed: 33050680
DOI: 10.23736/S0392-0488.20.06640-7 -
International Journal of Environmental... Sep 2022Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per... (Review)
Review
Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.
Topics: Female; Fetal Growth Retardation; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pre-Eclampsia; Pregnancy; Sildenafil Citrate
PubMed: 36141480
DOI: 10.3390/ijerph191811207 -
Aging Cell Mar 2024Pericytes are mesenchymal cells that surround endothelial cells, playing a crucial role in angiogenesis and vessel maturation. Additionally, they are associated with...
Pericytes are mesenchymal cells that surround endothelial cells, playing a crucial role in angiogenesis and vessel maturation. Additionally, they are associated with interstitial fibrosis as a major contributor to renal myofibroblasts. In this study, we aim to investigate whether the phosphodiesterase inhibitor, pentoxifylline (PTX), can ameliorate aging-related functional and histological deterioration in the kidney. We subjected aging C57BL/6 mice, dividing into young, aging, and PTX-treated aging groups. Renal function, albuminuria, and histological changes were assessed. Interstitial pericytes were assessed by immunohistochemistry analysis. We examined changes in pericytes in elderly patients using human kidney tissue obtained from healthy kidney donors for kidney transplantation. In vitro experiments with human pericytes and endothelial cells were performed. Aging mice exhibited declined renal function, increased albuminuria, and aging-related histological changes including mesangial expansion and tubulointerstitial fibrosis. Notably, number of pericytes declined in aging kidneys, and myofibroblasts increased. PTX treatment ameliorated albuminuria, histological alterations, and microvascular rarefaction, as well as modulated angiopoietin expression. In vitro experiments showed PTX reduced cellular senescence and inflammation. Human kidney analysis confirmed similar pericyte changes in aging kidneys. The phosphodiesterase inhibitor, PTX preserved microvascular density and improved renal interstitial fibrosis and inflammation in aging mice kidneys. These protective effects were suggested to be associated with the amelioration of pericytes reduction and the transition to myofibroblasts. Additionally, the upregulation of angiopoietin-1 expression may exert potential impacts. To the best of our knowledge, this is the first report on the changes in renal interstitial pericytes in aging human kidneys.
Topics: Humans; Mice; Animals; Aged; Pericytes; Phosphodiesterase Inhibitors; Endothelial Cells; Albuminuria; Mice, Inbred C57BL; Kidney; Kidney Diseases; Aging; Fibrosis; Inflammation
PubMed: 38155524
DOI: 10.1111/acel.14075