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International Journal of Molecular... Jan 2021The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still...
BACKGROUND
The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins.
METHODS
Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10 M) and bicalutamide (BCT) (10 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-β (ERβ), respectively.
RESULTS
TAD increased early AR nuclear translocation ( < 0.05, after 15 min of exposure), and increased AR transcriptional activity ( < 0.05) and protein expression ( < 0.05) after 24 h. Moreover, after 24 h this treatment upregulated Cyp19a1 and ERβ mRNA ( < 0.05 and < 0.005 respectively) and led to an increase in protein expression of both after 48 h ( < 0.05). Interestingly, TAD counteracted Cyp19a1 stimulation induced by BCT ( < 0.05) but did not alter the effect induced by BCT on the AR protein expression.
CONCLUSION
We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERβ expression in PCa cells, suggesting a specific effect of these proteins. In addition, TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa.
Topics: Biomarkers; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hormones; Humans; Male; Phosphodiesterase 5 Inhibitors; Prostatic Neoplasms; Protein Transport; Receptors, Androgen; Signal Transduction; Steroids; Tadalafil
PubMed: 33451122
DOI: 10.3390/ijms22020754 -
ESC Heart Failure Aug 2021Therapy with phosphodiesterase-5 inhibitors (PDE5Is) after left ventricular assist device (LVAD) implantation has been associated with lower mortality and device...
AIMS
Therapy with phosphodiesterase-5 inhibitors (PDE5Is) after left ventricular assist device (LVAD) implantation has been associated with lower mortality and device thrombosis but increased risk for post-operative and gastrointestinal bleeding. We aimed to evaluate the impact of long-term PDE5Is on the overall bleeding risk after LVAD implantation.
METHODS AND RESULTS
We retrospectively included patients who received a continuous-flow LVAD at our site and were prescribed with long-term oral PDE5Is after discharge from the index hospitalization. The primary endpoint was the occurrence of bleeding at 12 month follow-up. Secondary endpoints were all-cause death and the combination of bleeding and all-cause death. Our analysis included 109 patients of whom 75 (69%) received long-term PDE5Is. Mean age was 56 years, and 85% were male. At 12 months, 19 (17%) patients experienced at least one bleeding event. Patients on PDE5Is had higher bleeding rates (23% vs. 6%, P = 0.03) and more bleeding events per patient-year (0.32 vs. 0.06, P = 0.03) compared with patients not on PDE5Is. While overall bleeding incidence was excessively higher in the PDE5I group, there were no significant differences in the incidence of major bleeding (19% vs. 6%, P = 0.08) and gastrointestinal bleeding (11% vs. 3%, P = 0.18). Kaplan-Meier analysis revealed higher cumulative incidence of bleeding for the PDE5I group (log rank = 0.04) with no difference on all-cause death (log rank = 0.67) and the combination of bleeding and all-cause death (log rank = 0.13). Hospitalizations for bleeding and their duration were numerically higher in the PDE5I group (0.28 vs. 0.03, P = 0.07 and 2.4 vs. 0.2, P = 0.07, respectively).
CONCLUSIONS
Phosphodiesterase-5 inhibitor treatment after LVAD implantation is associated with increased bleeding risk after LVAD implantation. The safety of long-term PDE5Is in LVAD patients remains unclear and needs to be further clarified in prospective studies with randomized study design.
Topics: Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Failure; Heart-Assist Devices; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Retrospective Studies
PubMed: 33821578
DOI: 10.1002/ehf2.13322 -
International Journal of Molecular... Feb 2024Atherosclerotic cardiovascular disease (ASCVD) stands as the leading global cause of mortality. Addressing this vital and pervasive condition requires a multifaceted... (Meta-Analysis)
Meta-Analysis Review
Atherosclerotic cardiovascular disease (ASCVD) stands as the leading global cause of mortality. Addressing this vital and pervasive condition requires a multifaceted approach, in which antiplatelet intervention plays a pivotal role, together with antihypertensive, antidiabetic, and lipid-lowering therapies. Among the antiplatelet agents available currently, cilostazol, a phosphodiesterase-3 inhibitor, offers a spectrum of pharmacological effects. These encompass vasodilation, the impediment of platelet activation and aggregation, thrombosis inhibition, limb blood flow augmentation, lipid profile enhancement through triglyceride reduction and high-density lipoprotein cholesterol elevation, and the suppression of vascular smooth muscle cell proliferation. However, the role of cilostazol has not been clearly documented in many guidelines for ASCVD. We comprehensively reviewed the cardiovascular effects of cilostazol within randomized clinical trials that compared it to control or active agents and involved individuals with previous coronary artery disease or stroke, as well as those with no previous history of such conditions. Our approach demonstrated that the administration of cilostazol effectively reduced adverse cardiovascular events, although there was less evidence regarding its impact on myocardial infarction. Most studies have consistently reported its favorable effects in reducing intermittent claudication and enhancing ambulatory capacity in patients with peripheral arterial disease. Furthermore, cilostazol has shown promise in mitigating restenosis following coronary stent implantation in patients with acute coronary syndrome. While research from more diverse regions is still needed, our findings shed light on the broader implications of cilostazol in the context of atherosclerosis and vascular biology, particularly for individuals at high risk of ASCVD.
Topics: Humans; Cilostazol; Phosphodiesterase 3 Inhibitors; Atherosclerosis; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Cholesterol, HDL; Phosphoric Diester Hydrolases; Biology; Tetrazoles; Drug Therapy, Combination
PubMed: 38473840
DOI: 10.3390/ijms25052593 -
Journal of the American Heart... Nov 2022Background Pharmacologic treatment for pulmonary arterial hypertension (PAH) improves exercise capacity, functional class, and hemodynamic indexes. However, monthly...
Background Pharmacologic treatment for pulmonary arterial hypertension (PAH) improves exercise capacity, functional class, and hemodynamic indexes. However, monthly prescription costs often exceed $4000. We examined associations between (1) medication copayment and (2) annual household income with adherence to pulmonary vasodilator therapy among individuals with PAH. Methods and Results We used administrative claims data from an insured population in the United States to identify individuals diagnosed with PAH between 2015 and 2020. All individuals had ≥1 medication claim for endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, prostanoids or prostacyclin receptor agonists, or the soluble guanylate cyclase stimulator riociguat. We defined copayments as low, medium, or high, as determined by their distributions for each medication class. Annual household income was categorized as <$40 000, $40 000 to $74 999, and ≥$75 000. The primary outcome was medication adherence, defined by proportion of days covered ≥80%. We studied 4025 adults (aged 65.9±13.3 years; 71.2% women). Compared with those with annual household income ≥$75 000, individuals in the <$40 000 and $40 000 to $74 999 categories had no significant differences in medication adherence. Compared with those with low copayments, individuals with high copayments had decreased adherence to prostanoids (odds ratio [OR], 0.36 [95% CI, 0.20-0.65]; <0.001) and combination therapy with endothelin receptor antagonist and phosphodiesterase type-5 inhibitor (OR, 0.61 [95% CI, 0.38-0.97]; =0.03). Conclusions We identified associations between copayment and adherence to prostanoids and combination therapy among individuals with PAH. Copayment may be a structural barrier to medication adherence and merits inclusion in studies examining access to pharmacotherapy among individuals with PAH.
Topics: Female; Humans; Male; Endothelin Receptor Antagonists; Phosphodiesterase 5 Inhibitors; Prostaglandins; Pulmonary Arterial Hypertension; United States; Middle Aged; Aged; Medication Adherence; Health Expenditures; Income
PubMed: 36370005
DOI: 10.1161/JAHA.122.026620 -
Journal of the American Academy of... Mar 2024Orismilast is a novel oral phosphodiesterase-4 (PDE4) B/D inhibitor being investigated as a potential treatment for moderate-to-severe psoriasis. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Orismilast is a novel oral phosphodiesterase-4 (PDE4) B/D inhibitor being investigated as a potential treatment for moderate-to-severe psoriasis.
OBJECTIVE
To evaluate efficacy and safety of orismilast modified-release formulation in moderate-to-severe psoriasis.
METHODS
This multicenter, randomized (1:1:1:1 to 20, 30, 40 mg orismilast or placebo, twice daily), double-blinded, placebo-controlled, parallel-group, phase 2b, 16-week, dose-ranging study evaluated orismilast in adults with moderate-to-severe plaque psoriasis (NCT05190419). Efficacy end points were analyzed using multiple imputation.
RESULTS
Of 202 randomized patients, baseline characteristics were balanced across arms, except greater severe disease proportions for orismilast vs placebo. Orismilast showed significant improvements in the primary end point, percentage change in Psoriasis Area and Severity Index (PASI), from baseline to week 16 (orismilast -52.6% to -63.7% and placebo, -17.3%; all P <.001). Greater proportions receiving orismilast achieved PASI75 (39.5%-49.0%; P <.05) and PASI90 (22.0%-28.3%; P <.05 for 20 and 40 mg) vs placebo (PASI75, 16.5% and PASI90, 8.3%) at week 16. Safety findings were as expected with PDE4 inhibition; dose-dependent tolerability effects observed.
LIMITATIONS
Small sample size, disease severity imbalance between groups, limited duration and diversity in study population.
CONCLUSION
Orismilast demonstrated greater efficacy vs placebo and a safety profile in line with PDE4 inhibition.
Topics: Adult; Humans; Treatment Outcome; Severity of Illness Index; Double-Blind Method; Psoriasis; Phosphodiesterase 4 Inhibitors
PubMed: 37951245
DOI: 10.1016/j.jaad.2023.11.005 -
Biomedicine & Pharmacotherapy =... Feb 2022The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge... (Review)
Review
INTRODUCTION
The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge to improve respiratory function and help patients to survive the most challenging period. Drugs used in targeted therapy of pulmonary arterial hypertension (PAH) appears to be suitable for this task and this article describes their potential for treatment of severe cases of COVID-19.
METHODS
The authors reviewed the following databases for randomized controlled trials, reviews and meta-analyses published up to July 2020: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. The authors included every study contributory to the assessment of the potential of drugs used in targeted PAH therapy in treatment of COVID-19.
RESULTS
Endothelin receptor antagonists, phosphodiesterase 5 inhibitors, riociguat and prostacyclin have proven ani-inflammatory effect and reduce pulmonary artery blood pressure, lung oedema and remodelling. Bosentan shows antiviral properties and sildenafil, as well as epoprostenol, inhibits apoptosis of lung epithelial cells. Among patients with lung lesions the decrease of pulmonary blood pressure can lead to increase of ventilation/perfusion mismatch and decrease of blood oxygenation.
CONCLUSIONS
Among all assessed drugs bosentan, sildenafil and epoprostenol appear to be most promising and a combination of these drugs should be considered due to synergism. The targeted PAH therapy in treatment of COVID-19 associated ARDS could be a useful tool saving lives of patients with severe SARS-CoV-2 infection, however, its introduction should be investigated and monitored very carefully as it can lead to transient deterioration of patient condition.
Topics: Animals; COVID-19; Endothelin Receptor Antagonists; Humans; Phosphodiesterase Inhibitors; Prostaglandins; Pulmonary Artery; Pyrazoles; Pyrimidines; Respiratory Distress Syndrome; COVID-19 Drug Treatment
PubMed: 35062063
DOI: 10.1016/j.biopha.2021.112592 -
Clinical and Translational Science May 2021LY2775240 is a highly selective, potent and orally-administered inhibitor of phosphodiesterase 4 (PDE4), and is being investigated as a treatment option for inflammatory... (Randomized Controlled Trial)
Randomized Controlled Trial
LY2775240 is a highly selective, potent and orally-administered inhibitor of phosphodiesterase 4 (PDE4), and is being investigated as a treatment option for inflammatory disorders, such as psoriasis. LY2775240 was investigated in rodent and rhesus monkey nonclinical models. Treatment with LY2775240 led to significant reductions in TNFα production, a marker of PDE4 engagement upon immune activation, in both nonclinical models. In the first part of a 2-part first-in-human randomized study, a wide dose range of LY2775240 was safely evaluated and found to be well-tolerated with common adverse events (AEs) of nausea, diarrhea, and headache. No serious AEs were reported. The pharmacokinetic profile of LY2775240 was well-characterized, with a half-life that can support once-a-day dosing. An ex vivo pharmacodynamic (PD) assay demonstrated dose-dependent PDE4 target engagement as assessed by reduction in TNFα production. A 20 mg dose of LY2775240 led to near-maximal TNFα inhibition in this PD assay in the first part of the study and was selected for comparison with the clinical dose of apremilast (30 mg) in the crossover, second part of this study. The 20 mg dose of LY2775240 demonstrated sustained maximal (50%-80%) inhibition of TNFα over all timepoints over the 24-h duration. The comparator apremilast achieved peak inhibition of ~ 50% at only 4 h postdose with a return to about 10% inhibition within 12 h of dosing. In summary, the nonclinical data and safety, tolerability, and PK/PD data in healthy subjects supports further investigation of LY2775240 in inflammatory indications. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Phosphodiesterase 4 (PDE4) inhibitors, such as apremilast, are currently approved to treat autoimmune disorders, such as psoriasis. LY2775240 is an oral PDE4 inhibitor being developed for treatment of a variety of inflammatory disorders. The degree of enzymatic inhibition achieved by PDE4 inhibitors clinically is poorly understood. WHAT QUESTION DID THIS STUDY ADDRESS? This study investigated single ascending doses of LY2775240, a highly selective oral PDE4 inhibitor, in healthy subjects. LY2775240 was well-tolerated over the dose range evaluated, and pharmacokinetic/pharmacodynamic (PD) profiles were well-characterized. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study evaluated different doses of LY2775240 and subsequently compared a selected LY2775240 dose with the clinical dose of apremilast with an ex vivo assay. This information builds a connection between target engagement and clinical efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This is the first report of an ex vivo PD assay that has been systematically implemented in a PDE4 inhibitor Phase 1 study. Early investigation of exposure-response relationships versus a comparator can support evaluation of clinically meaningful doses of investigational agents.
Topics: Administration, Oral; Adult; Animals; Cross-Over Studies; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Evaluation, Preclinical; Drugs, Investigational; Enzyme Assays; Female; Healthy Volunteers; Humans; Macaca mulatta; Male; Mice; Middle Aged; Phosphodiesterase 4 Inhibitors; Psoriasis; Thalidomide
PubMed: 33382916
DOI: 10.1111/cts.12968 -
Archivio Italiano Di Urologia,... Jun 2022Priapism is a persistent penile erection lasting longer than 4 hours, that needs emergency management. This disorder can induce irreversible erectile dysfunction. There... (Review)
Review
Priapism is a persistent penile erection lasting longer than 4 hours, that needs emergency management. This disorder can induce irreversible erectile dysfunction. There are three subtypes of priapism: ischemic, non-ischemic, and stuttering priapism. If the patient has ischemic priapism (IP) of less than 24-hours (h) duration, the initial management should be a corporal blood aspiration followed by instillation of phenylephrine into the corpus cavernosum. If sympathomimetic fails or the patient has IP from 24 to 48h, surgical shunts should be performed. It is recommended that distal shunts should be attempted first. If distal shunt failed, proximal, venous shunt, or T-shunt with tunneling could be performed. If the patient had IP for 48 to 72h, proximal and venous shunt or T-shunt with tunneling is indicated, if those therapies failed, a penile prosthesis should be inserted. Non-ischemic priapism (NIP) is not a medical emergency and many patients will recover spontaneously. If the NIP does not resolve spontaneously within six months or the patient requests therapy, selective arterial embolization is indicated. The goal of the management of a patient with stuttering priapism (SP) is the prevention of future episodes. Phosphodiesterase type 5 (PDE5) inhibitor therapy is considered an effective tool to prevent stuttering episodes but it is not validated yet. The management of priapism should follow the guidelines as the future erectile function is dependent on its quick resolution. This review briefly discusses the types, pathophysiology, and diagnosis of priapism. It will discuss an updated approach to treat each type of priapism.
Topics: Algorithms; Humans; Male; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Priapism; Stuttering
PubMed: 35775354
DOI: 10.4081/aiua.2022.2.237 -
Cardiovascular Drugs and Therapy Jun 2020The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) maintain physiological cardiac contractility and... (Review)
Review
The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) maintain physiological cardiac contractility and integrity. Cyclic nucleotide-hydrolysing phosphodiesterases (PDEs) are the prime regulators of cAMP and cGMP signalling in the heart. During heart failure (HF), the expression and activity of multiple PDEs are altered, which disrupt cyclic nucleotide levels and promote cardiac dysfunction. Given that the morbidity and mortality associated with HF are extremely high, novel therapies are urgently needed. Herein, the role of PDEs in HF pathophysiology and their therapeutic potential is reviewed. Attention is given to PDEs 1-5, and other PDEs are briefly considered. After assessing the role of each PDE in cardiac physiology, the evidence from pre-clinical models and patients that altered PDE signalling contributes to the HF phenotype is examined. The potential of pharmacologically harnessing PDEs for therapeutic gain is considered.
Topics: Animals; Heart Failure; Humans; Myocytes, Cardiac; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Signal Transduction
PubMed: 32172427
DOI: 10.1007/s10557-020-06959-1 -
PloS One 2019Current treatments for overactive bladder (OAB) are often discontinued due to side effects or lack of efficacy. The goal of this study was to determine if combining a...
INTRODUCTION
Current treatments for overactive bladder (OAB) are often discontinued due to side effects or lack of efficacy. The goal of this study was to determine if combining a phosphodiesterase type 4 inhibitor (PDE4i); with a type 5 inhibitor (PDE5i); would have a beneficial effect on OAB symptoms and if a reduced dose of PDE4i in combination with PDE5i could also provide a beneficial effect in OAB. We hypothesized that PDE5i and PDE4i combination treatment could be utilized to reduce non-voiding contractions and smooth muscle disruption in a rat model of OAB.
METHODS
Fifty-eight age-matched Sprague-Dawley rats underwent PBOO and daily gavage with PDE4i alone (roflumilast; 1mg/kg), PDE5i alone (tadalafil;10mg/kg), high dose combination (PDE4i 1mg/kg, PDE5i 10mg/kg), low dose combination (PDE4i 0.2mg/kg, PDE5i 10mg/kg), or vehicle for 28 days. Fourteen animals underwent sham PBOO with vehicle. Rats underwent conscious and anesthetized cystometry 28 days after PBOO and were euthanized for qualitative bladder histology. One-way ANOVA on ranks with a Dunn's post hoc test was used to indicate statistically significant differences between groups (p<0.05).
RESULTS
Bladder & urethral weight was significantly increased after PBOO with vehicle, PDE4i alone, and PDE5i alone, but not with either combination treatment. Frequency of non-voiding contractions during both conscious and anesthetized cystometry increased significantly after PBOO with vehicle, but not after PDE4i or high dose combination treatments compared to sham PBOO. Threshold pressure for voiding was significantly decreased with high dose combination compared to vehicle. PBOO treated with PDE4i alone or high dose combination showed less bladder smooth muscle fibrosis than vehicle, PDE5i alone, or low dose combination treatments.
CONCLUSION
A PDE4i and PDE5i combination treatment has potential benefit in reducing OAB symptoms, but future research is needed.
Topics: Animals; Drug Therapy, Combination; Female; Muscle Contraction; Phosphodiesterase 4 Inhibitors; Phosphodiesterase 5 Inhibitors; Rats, Sprague-Dawley; Urinary Bladder; Urinary Bladder, Overactive; Urination
PubMed: 31461445
DOI: 10.1371/journal.pone.0220788