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Phosphodiesterase Inhibitor

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261. Tissue turnover of collagen type I, III and elastin is elevated in the PCLS model of IPF and can be restored back to vehicle levels using a phosphodiesterase inhibitor. Full Text available with Trip Pro

Tissue turnover of collagen type I, III and elastin is elevated in the PCLS model of IPF and can be restored back to vehicle levels using a phosphodiesterase inhibitor. The aim of this study was to develop and validate a model for pulmonary fibrosis, using ex vivo tissue cultures of lungs from bleomycin treated animals, enabling the investigation of fibrosis remodeling using novel biomarkers for the detection of ECM protein fragments. The combination of in vivo and ex vivo models together (...) either two doses of BLM (n = 7) or saline (n = 3) I.T., two days apart. The rats were euthanized fourteen days after the last dose. PCLS were made and cultured for 48 h in: medium, medium + 100 μM IBMX (PDE inhibitor), or medium + 10 μM GM6001 (MMP inhibitor). Turnover of type I collagen (P1NP, C1M), type III collagen (iP3NP, C3M) and elastin degradation (ELM7) was measured in the supernatant of the cultured PCLS.P1NP, C1M, iP3NP, C3M and ELM7 were significantly increased in supernatants from BLM

2016 Respiratory research

262. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Full Text available with Trip Pro

Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks.We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792).Two identically designed, vehicle

2016 Journal of American Academy of Dermatology Controlled trial quality: predicted high

263. A novel inhaled phosphodiesterase 4 inhibitor (CHF6001) reduces the allergen challenge response in asthmatic patients. Full Text available with Trip Pro

A novel inhaled phosphodiesterase 4 inhibitor (CHF6001) reduces the allergen challenge response in asthmatic patients. CHF6001 is an inhaled phosphodiesterase 4 (PDE4) inhibitor in development for the treatment of obstructive lung diseases. The efficacy and safety of CHF6001 were investigated in a double blind, placebo controlled, 3-way cross-over study using the allergen challenge model. Thirty-six atopic asthmatics who were not taking inhaled corticosteroids and who demonstrated a late (...) reductions of 19.7% (p = 0.015) and 28.2% (p < 0.001) respectively of the weighted FEV1 AUC4-10h compared with placebo. The difference between the CHF6001 doses was not statistically significant (p = 0.223). Compared with placebo, CHF6001 caused greater reduction in sputum eosinophil counts, although these changes were not statistically significant. CHF6001 was well tolerated, with similar numbers of adverse events in each treatment period. This inhaled PDE4 inhibitor has the potential to provide

2016 Pulmonary Pharmacology & Therapeutics Controlled trial quality: predicted high

264. Latest Evidence on the Use of Phosphodiesterase Type 5 Inhibitors for the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. (Abstract)

Latest Evidence on the Use of Phosphodiesterase Type 5 Inhibitors for the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. Several preclinical reports, randomized controlled trials, systematic reviews, and posthoc analyses corroborate the role of phosphodiesterase type 5 inhibitors (PDE5-Is) in the treatment of men with lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE).Update of the latest evidence on the mechanisms (...) reviewed recent literature on phosphodiesterase type 5 inhibitors in men with lower urinary tract symptoms associated with prostatic enlargement. We found evidence to confirm that phosphodiesterase type 5 inhibitors are a valid treatment option for men affected by bothersome urinary symptoms with or without erectile dysfunction.Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

2016 European Urology

265. Use of sildenafil or other phosphodiesterase inhibitors and risk of melanoma. Full Text available with Trip Pro

Use of sildenafil or other phosphodiesterase inhibitors and risk of melanoma. Phosphodiesterase 5A inhibitors (PDEIs), a common treatment for erectile dysfunction, were recently linked to an increased risk of melanoma.We conducted two parallel case-control studies, using the Danish Nationwide Health Registries (DNHR) and the Kaiser Permanente Northern California (KPNC) electronic health records. Identifying men with histologically verified melanoma (cases) matched on birth year to 10 cancer

2016 British Journal of Cancer

266. Therapeutic synergy and complementarity for ischemia/reperfusion injury: β<sub>1</sub>-adrenergic blockade and phosphodiesterase-3 inhibition. (Abstract)

Therapeutic synergy and complementarity for ischemia/reperfusion injury: β1-adrenergic blockade and phosphodiesterase-3 inhibition. The β1-blocker when administered before reperfusion activates myocyte prosurvival signaling via β2-adrenergic receptor (β2-AR) and protein kinase A (PKA)-dependent mechanism during ischemia/reperfusion (I/R). The heart is endowed with powerful self-protective ability executed by endogenous β2-adrenopeptide receptor activation. I/R triggers cardiac (...) mechanisms involved in I/R injury protection. While β2-adrenopeptide-mediated cardioprotection is important, age-related β2-adrenopeptide receptor decoupling can result in their ineffectiveness in response to the receptor-specific therapies. Accordingly, direct activation of receptor-coupled upstream PKA-dependent signaling may serve as a therapeutic alternative to achieve cardioprotection bypassing adrenopeptidergic receptor decoupling accompanied with aging. Phosphodiesterase-3 (PDE3) inhibitor reduces

2016 International journal of cardiology

267. Phosphodiesterase 4 inhibitors have wide-ranging activity in B cell malignancies. Full Text available with Trip Pro

Phosphodiesterase 4 inhibitors have wide-ranging activity in B cell malignancies. Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of 3',5'-cyclic adenosine monophosphate in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases spleen tyrosine kinase and phosphatidylinositol 3-kinase and inhibits vascular endothelial growth factor A secretion by tumor cells, inducing cancer cell apoptosis and blocking (...) angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets.

2016 Blood

268. OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II randomized, double-blind, placebo-controlled study. Full Text available with Trip Pro

OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II randomized, double-blind, placebo-controlled study. Peripheral leukocytes in patients with atopic dermatitis (AD) have elevated phosphodiesterase-4 activity, which is associated with production of proinflammatory mediators. OPA-15406 is a phosphodiesterase-4 inhibitor with high selectivity (...) for phosphodiesterase-4-B.We sought to assess effectiveness and tolerability of topical OPA-15406 in patients with AD.This was a randomized, double-blind, vehicle-controlled, phase-II study. Patients 10 to 70 years of age with mild or moderate AD received topical OPA-15406 0.3% (n = 41), OPA-15406 1% (n = 43), or vehicle (n = 37) twice daily for 8 weeks.The primary end point, Investigator Global Assessment of Disease Severity score of 0 or 1 with greater than or equal to 2-grade reduction, was met at week 4

2016 Journal of the American Academy of Dermatology Controlled trial quality: predicted high

269. A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition. Full Text available with Trip Pro

A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition. The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction.To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin

2016 Journal of Clinical Endocrinology and Metabolism Controlled trial quality: predicted high

270. Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy. Full Text available with Trip Pro

Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy. Diabetic nephropathy (DN) is the leading cause of ESRD worldwide. Reduced bioavailability or uncoupling of nitric oxide in the kidney, leading to decreased intracellular levels of the nitric oxide pathway effector molecule cyclic guanosine monophosphate (cGMP), has been implicated in the progression of DN. Preclinical studies suggest that elevating the cGMP intracellular pool through inhibition (...) of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5) might exert renoprotective effects in DN. To test this hypothesis, the novel, highly specific, and long-acting PDE5 inhibitor, PF-00489791, was assessed in a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group trial of subjects with type 2 diabetes mellitus and overt nephropathy receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker background therapy. In total, 256 subjects

2016 Journal of the American Society of Nephrology Controlled trial quality: predicted high

271. Psychotherapy and phosphodiesterase-5 inhibitor in early rehabilitation after radical prostatectomy: a prospective randomised controlled trial. (Abstract)

Psychotherapy and phosphodiesterase-5 inhibitor in early rehabilitation after radical prostatectomy: a prospective randomised controlled trial. The aim of this study was to evaluate the impact of group psychotherapy and the use of a phosphodiesterase-5 inhibitor (PDE-5i) in the early rehabilitation stage of patients with prostate cancer undergoing radical prostatectomy (RP). Fifty-six patients undergoing RP for prostate cancer were randomised into four groups, and 53 completed the protocol

2016 Andrologia Controlled trial quality: uncertain

272. A Phase I Randomized Trial to Assess the Effect on skin infiltrate thickness and Tolerability of Topical Phosphodiesterase Inhibitors in the Treatment of Psoriasis Vulgaris Using a Modified Psoriasis Plaque Test. (Abstract)

A Phase I Randomized Trial to Assess the Effect on skin infiltrate thickness and Tolerability of Topical Phosphodiesterase Inhibitors in the Treatment of Psoriasis Vulgaris Using a Modified Psoriasis Plaque Test. Oral phosphodiesterase (PDE)4 inhibitors have shown efficacy in chronic obstructive pulmonary disease and psoriasis.To assess the effectiveness, local safety and tolerability, and systemic pharmacokinetics of two topical PDE4 inhibitors, roflumilast and TAK-084, in plaque psoriasis.An (...) on psoriasis plaques for 3 weeks.The primary end point of (mean) change from baseline in skin infiltrate thickness after 3 weeks of treatment showed statistically significant improvements for all treatments: betamethasone valerate cream (-286·9 μm), the selective PDE4 inhibitors roflumilast 0·5% (-237·1 μm) and TAK-084 (0·5% cream, -153·6 μm; 5% cream, -216·7 μm) and calcipotriol 0·005% (-187·7 μm) when compared with vehicle cream control (all P < 0·001). Both the TAK-084 5% and roflumilast 0·5

2016 The British journal of dermatology Controlled trial quality: uncertain

273. Efficacy of a novel phosphodiesterase inhibitor, E6005, in patients with atopic dermatitis: An investigator-blinded, vehicle-controlled study. (Abstract)

Efficacy of a novel phosphodiesterase inhibitor, E6005, in patients with atopic dermatitis: An investigator-blinded, vehicle-controlled study. Phosphodiesterase type 4 (PDE4) inhibition is a well-known anti-inflammatory mechanism. However, the clinical use of PDE4 inhibitors has been compromised by the occurrence of mechanism-associated adverse reactions, which often limit the maximum tolerated dose. To minimize systemic exposure, a topically active PDE4 inhibitor with low transdermal (...) bioavailability could be clinically useful. The purpose of this study was to evaluate the efficacy of a novel topical PDE4 inhibitor, E6005, in patients with atopic dermatitis.This randomized, investigator-blinded, vehicle-controlled, multiple ascending dose study included 40 adult male patients with atopic dermatitis, who were randomly assigned to 10 days of treatment with either E6005 ointment (0.01, 0.03, 0.1 or 0.2%) or vehicle ointment.Of 81 patients screened, 40 who had typical lesions

2016 The Journal of dermatological treatment Controlled trial quality: uncertain

274. The Association Between Phosphodiesterase Type-5 Inhibitors and Prostate Cancer: Results from the REDUCE Study. Full Text available with Trip Pro

The Association Between Phosphodiesterase Type-5 Inhibitors and Prostate Cancer: Results from the REDUCE Study. Despite routine use of phosphodiesterase type 5 inhibitor to treat erectile dysfunction the role in prostate cancer chemoprevention remains unclear. Only a few studies have explored the link between phosphodiesterase type 5 inhibitor use and prostate cancer. We tested the association between phosphodiesterase type 5 inhibitor and prostate cancer risk in the REDUCE (Reduction (...) by Dutasteride of Prostate Cancer Events) trial.REDUCE was a 4-year multicenter study testing the effect of daily dutasteride on prostate cancer risk in men with prostate specific antigen 2.5 to 10.0 ng/ml and negative biopsy who underwent study mandated biopsies at 2 and 4 years. The association of phosphodiesterase type 5 inhibitor with overall prostate cancer risk and disease grade (Gleason 2-6 and 7-10) was examined using adjusted logistic and multinomial regression analysis. Secondary analysis

2016 Journal of Urology Controlled trial quality: uncertain

275. Apremilast, an oral phosphodiesterase-4 inhibitor, in the treatment of palmoplantar psoriasis: Results of a pooled analysis from phase II PSOR-005 and phase III Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) clinical Full Text available with Trip Pro

Apremilast, an oral phosphodiesterase-4 inhibitor, in the treatment of palmoplantar psoriasis: Results of a pooled analysis from phase II PSOR-005 and phase III Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) clinical Difficult-to-treat palmoplantar psoriasis has a disproportionately negative impact on quality of life.We evaluated the efficacy and safety of apremilast in palmoplantar psoriasis.A post hoc analysis of data pooled from phase IIb (PSOR-005

2016 Journal of the American Academy of Dermatology

276. Additive anti-inflammatory effects of corticosteroids and phosphodiesterase-4 inhibitors in COPD CD8 cells. Full Text available with Trip Pro

Additive anti-inflammatory effects of corticosteroids and phosphodiesterase-4 inhibitors in COPD CD8 cells. CD8 lymphocytes play an important role in the pathogenesis of COPD. Corticosteroids and phosphodiesterase 4 (PDE4) inhibitors are anti-inflammatory drugs used for COPD treatment. Little is known of the combined effect of these drugs on COPD CD8 cells. We studied the effect of corticosteroid combined with PDE4 inhibitors on cytokine release form circulating and pulmonary CD8 cells (...) , and on glucocorticoid (GR) nuclear translocation.The effect of dexamethasone alone and in combination with the PDE4 inhibitors roflumilast and GSK256066 on cytokine release from circulating and pulmonary CD8 cells was measured. The effect of the compounds on nuclear translocation of GR and cyclic AMP-responsive element-binding protein (CREB) was studied using immunofluorescence.Dexamethasone inhibited cytokine release from COPD CD8 cells in a concentration dependent manner. PDE4 inhibitors enhanced this anti

2016 Respiratory research

277. Dual Strategy With Oral Phosphodiesterase Type 5 Inhibition and Intracavernosal Implantation of Mesenchymal Stem Cells Is Superior to Individual Approaches in the Recovery of Erectile and Cavernosal Functions After Cavernous Nerve Injury in Rats. (Abstract)

Dual Strategy With Oral Phosphodiesterase Type 5 Inhibition and Intracavernosal Implantation of Mesenchymal Stem Cells Is Superior to Individual Approaches in the Recovery of Erectile and Cavernosal Functions After Cavernous Nerve Injury in Rats. Novel effective therapeutic strategies are necessary for treating erectile dysfunction secondary to cavernous nerve injury (CNI).To functionally evaluate the benefits of long-term oral treatment with a phosphodiesterase type 5 inhibitor (...) on the potential capacity of intracavernosal cell therapy to recover erectile function after CNI.Bilateral crush CNI (BCNI) was produced in anesthetized male rats. After BCNI, rats were treated with the phosphodiesterase type 5 inhibitor tadalafil (TAD; 5 mg/kg/d orally; BCNI + TAD), a single intracavernosal injection of bone marrow-derived mesenchymal stem cells (BMSCs; BCNI + BMSC), or dual therapy (BCNI + BMSC + TAD). Ex vivo function of the corpus cavernosum (CC) and in vivo intracavernosal pressure

2016 Journal Of Sexual Medicine

278. Phosphodiesterase-5 Inhibitor Use: An Under-reported Cause of Profuse Nasal Bleeding. (Abstract)

Phosphodiesterase-5 Inhibitor Use: An Under-reported Cause of Profuse Nasal Bleeding. Phosphodiesterase-5 (PDE-5) inhibitors enhance penile erection and have gained popularity not only for erectile dysfunction, but also in recreational settings. Nevertheless, adverse effects have been associated with their use, with nasal bleeding among them. PDE-5 inhibitor action is materialized through the inhibition of the cyclic guanosine monophosphate (cGMP) enzyme. cGMP is present at several sites (...) of the human body in addition to the corpus cavernosum, leading to the adverse effects associated with its nonselective inhibition.Two male patients with severe epistaxis who were taking PDE-5 inhibitors for erectile dysfunction or recreational purposes are discussed. Surgical intervention was required in both patients to control the nasal hemorrhage. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Nasal bleeding in patients who are taking PDE-5 inhibitors might represent an under-reported cause

2016 Journal of Emergency Medicine

279. Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). Full Text available with Trip Pro

Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). Juvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival (...) and quality of life of afflicted children. Cyclic adenosine monophosphate (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival. Here we investigated whether 3 phosphodiesterase-4 (PDE4) inhibitors (rolipram, roflumilast, and PF-06266047) could mitigate behavioral deficits and cell-specific pathology in the Cln3Δex7/8 mouse model of JNCL.In a randomized, blinded study, wild-type (WT) and Cln3Δex7/8 mice received PDE4 inhibitors daily beginning

2016 Annals of Neurology

280. Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase-5A inhibitor vardenafil in rats with type 2 diabetes. Full Text available with Trip Pro

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase-5A inhibitor vardenafil in rats with type 2 diabetes. Heart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including (...) diabetic cardiomyopathy. We investigated the effect of long-term preventive application of the phosphodiesterase-5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy-associated HFpEF.Zucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure-volume analysis and echocardiography at week 32

2016 European Journal of Heart Failure

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