Use Of Phosphodiesterase Inhibitors Research Articles

Finasteride-Associated Suicide and Depression in Men Treated for Hypogonadism and Impotence

ABSTRACT Introduction Recent studies have investigated the use of finasteride in the management of alopecia and benign prostatic hyperplasia (BPH). Finding suggest significant increased reporting odds ratios (ROR) of suicidality and psychological adverse events in patients younger than 45. As alopecia and BPH are side effects of testosterone therapy, we sought to evaluate the ratio of adverse events in patients who were medically treated for hypogonadism and sexual dysfunction. Objective The purpose of this study is to evaluate the ratio of adverse events in patients on finasteride who were also medically treated for hypogonadism and sexual dysfunction. Methods We surveyed VigiBase, the World Health Organization's global database of individual case safety reports to detect adverse reactions of interest reported with finasteride. These findings were stratified by patients also treated with testosterone, phosphodiesterase 5 inhibitors (PDE5i), and a combination of the two. Reported adverse events were reported as anxiety disorder and symptoms, depressed mood disorders and disturbance, and suicidal and self injurious behaviors. The strength of association between these events and medications were demonstrated by ROR. Patients stratified by indication (BPH and alopecia) and age (<45 and >45 years). Case data were obtained in June of 2021 and analyzed from reporting year, age, sex, and indication. Results The VigiBase contained 611 reports of suicidality, 2352 reports of anxiety disorders and symptoms, and 2392 reports of depressed mood disorders and disturbances in finasteride users 3994 male [96.9%]; 844 of 3426 [24.6%] with data available aged 18-44 years. A significant disproportionality signal towards suicidality was increased in finasteride alone (ROR, 1.89; 95% CI, 1.74-2.04). This signal was decreased when evaluated for the combination of finasteride and PDE5i (ROR, 0.22; 95% CI 0.12-0.39) and finasteride and testosterone (ROR 0.80; 95% CI 0.35-1.78). Combination finasteride with PDE5i demonstrated a decreased ROR in anxiety disorders (ROR 0.21; 95% CI 0.16-0.27) and in depressed mood disorders (ROR 0.25; 95% CI 0.19-0.33). Combination finasteride with testosterone also demonstrated a decreased ROR in anxiety disorders (ROR 1.25; 95% CI 0.89-1.76) and in depressed mood disorders (ROR 1.23; 95% CI 0.88-1.72). Conclusions RORs of suicidality and psychological adverse events were not elevated in patients with concomitant use of finasteride with testosterone. Moreover, RORs were decreased in patients with use of finasteride and PDE5i. This analysis suggests that treatment of a patient's underlying hypogonadism or sexual dysfunction may be protective in the use of finasteride for alopecia or BPH. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Abbie, American Medical Systems, Augmenta LLC, Clarus Therapeutics, Endo Pharmaceuticals, Lipocine, Vault Health

ASSOCIATIONS BETWEEN PHYSICAL ACTIVITY AND RISK FACTORS FOR TYPE II DIABETES IN PREDIABETIC ADULTS

Diabetes is a national healthcare crisis related to both macrovascular and microvascular complications. We hypothesized that higher levels of physical activity are associated with lower total and visceral fat mass, lower systolic blood pressure, and increased insulin sensitivity. Participant inclusion criteria: 21-50 years old, BMI ≥ 30 kg/m2, hemoglobin A1C 5.7-6.4, fasting glucose 100-125 mg/dL, and HOMA IR ≥ 2.5. Exclusion criteria: history of diabetes, hypertension, HIV, renal disease, hearing loss, alcoholic intake over four drinks daily, use of organic nitrates or PDE5 inhibitors, and decreased cardiac function. Total physical activity was measured using accelerometers, body composition using DXA, and insulin resistance via fsIVGTT. Clinical and biochemical cardiometabolic risk factors, blood pressure and heart rate obtained using a calibrated sphygmomanometer. Anthropometric measures, fasting glucose, insulin, lipid profile, C-reactive protein, and BMP analyzed using standard procedures. Within our study, we found correlations between levels of physical activity in a heterogenous group of prediabetic adults. Patients with more physical activity had a higher degree of insulin sensitivity, lower blood pressure, total visceral adipose tissue, and overall lower total mass. Total physical activity levels showed small, but significant correlations with systolic blood pressure, visceral fat, lean mass and insulin sensitivity. After normalizing for race, age, and gender using multiple regression, these associations were no longer significant considering our small sample size. More research into prediabetes will decrease the population of diabetics overall. In the future we could increase sample size and conduct cross sectional and longitudinal studies in various populations with prediabetes.

A Real-Time, Plate-Based BRET Assay for Detection of cGMP in Primary Cells.

Cyclic guanosine monophosphate (cGMP) is a second messenger involved in the regulation of numerous physiological processes. The modulation of cGMP is important in many diseases, but reliably assaying cGMP in live cells in a plate-based format with temporal resolution is challenging. The Förster/fluorescence resonance energy transfer (FRET)-based biosensor cGES-DE5 has a high temporal resolution and high selectivity for cGMP over cAMP, so we converted it to use bioluminescence resonance energy transfer (BRET), which is more compatible with plate-based assays. This BRET variant, called CYGYEL (cyclic GMP sensor using YFP-PDE5-Rluc8), was cloned into a lentiviral vector for use across different mammalian cell types. CYGYEL was characterised in HEK293T cells using the nitric oxide donor diethylamine NONOate (DEA), where it was shown to be dynamic, reversible, and able to detect cGMP with or without the use of phosphodiesterase inhibitors. In human primary vascular endothelial and smooth muscle cells, CYGYEL successfully detected cGMP mediated through either soluble or particulate guanylate cyclase using DEA or C-type natriuretic peptide, respectively. Notably, CYGYEL detected differences in kinetics and strength of signal both between ligands and between cell types. CYGYEL remained selective for cGMP over cAMP, but this selectivity was reduced compared to cGES-DE5. CYGYEL streamlines the process of cGMP detection in plate-based assays and can be used to detect cGMP activity across a range of cell types.

Use of Phosphodiesterase-5 Inhibitors and the Risk of Melanoma

Use of Phosphodiesterase-5 Inhibitors and the Risk of Melanoma

Advances in the Treatment of Systemic Sclerosis

Although systemic sclerosis (SSc) is currently incurable, there have been recent advances in treatment. This review article begins by providing a brief background to SSc in terms of disease subtyping and autoantibodies, because both predict disease trajectory and help clinicians to select appropriate monitoring and treatment protocols. Broad principles of management are then described: ‘disease-modifying’ therapies and therapies directed at reducing disease burden and/or progression of SSc-related digital vascular disease and of internal organ involvement. Next, advances in the management of digital vasculopathy, pulmonary arterial hypertension (PAH), interstitial lung disease (ILD) and early diffuse cutaneous SSc are discussed in turn, for example: (a) increased use of phosphodiesterase inhibitors and endothelin receptor antagonists for digital vasculopathy; (b) early recognition and treatment of PAH, including with combination therapies; (c) increased use of mycophenolate mofetil and of nintedanib in ILD; and (d) immunosuppression now as standard practice in early diffuse cutaneous SSc, and autologous haematopoietic stem cell transplantation for highly selected patients with progressive diffuse disease. Finally, future challenges are discussed, including ensuring that all patients with SSc are monitored and treated according to best practice guidelines, and whenever possible giving patients the opportunity to participate in clinical trials.

Postimplant Phosphodiesterase-5 Inhibitor Use in Centrifugal Flow Left Ventricular Assist Devices

ObjectivesThis study examined the association between phosphodiesterase-5 inhibitor (PDE-5i) use and outcomes in patients with contemporary centrifugal flow left ventricular assist devices (LVADs). BackgroundPDE-5i use may affect outcomes in patients with continuous flow LVADs. MethodsPatients enrolled in INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support), with HeartMate 3 (n = 4,628) or HeartWare Ventricular Assist Device (HVAD) (n = 2,601) implant were included in the analysis. The mean duration of follow-up was 11.94 ± 8.65 months. PDE-5is were used in 2,173 patients. The primary endpoint was the composite of all-cause mortality, ischemic stroke, and pump thrombosis. Propensity matching and stabilized inverse probability of treatment weights were used to adjust for baseline differences between patients receiving and not receiving PDE-5i. Adjusted Cox proportional hazards analysis was performed for each outcome. ResultsThe primary endpoint was lower in the PDE-5i group (adjusted HR: 0.77; 95% CI: 0.69-0.86; P < 0.0001; HeartMate 3: adjusted HR: 0.77; 95% CI: 0.64-0.92; P = 0.0044; HVAD: adjusted HR: 0.76; 95% CI: 0.66-0.88; P = 0.0002). All-cause mortality was lower with PDE-5is (adjusted HR: 0.75; 95% CI: 0.65-0.86; P < 0.0001; HeartMate 3: adjusted HR: 0.70; 95% CI: 0.57-0.86; P = 0.0007; HVAD: adjusted HR: 0.78; 95% CI: 0.65-0.94; P = 0.0098) and fewer ischemic strokes with PDE-5is were observed (adjusted HR: 0.71; 95% CI: 0.56-0.89; P = 0.003; HeartMate 3: adjusted HR: 0.67; 95% CI: 0.45-0.99; P = 0.045; HVAD: adjusted HR: 0.73; 95% CI: 0.56-0.97; P = 0.03). LVAD thrombosis was unchanged with PDE-5is, with overall low event rates observed. ConclusionsPostimplant PDE-5i use was associated with lower mortality and ischemic strokes in patients with centrifugal flow LVADs.

Description of Surgical Technique and Oncologic and Functional Outcomes of the Precision Prostatectomy Procedure (IDEAL Stage 1–2b Study)

BackgroundThe existing treatment options for men with intermediate- or high-volume low-risk prostate cancer (PCa) are associated with a substantial risk of over- or undertreatment. The development of risk-adjusted therapies is an unmet need for these patients. ObjectiveTo describe our novel technique of precision prostatectomy, a form of surgical focal therapy that allows radical excision of the index PCa lesion along with >90% prostatic tissue extirpation while preserving the prostatic capsule and seminal vesicle/vas deferens complex on the side contralateral to the dominant cancer lesion, and to report on medium-term functional and oncologic outcomes in the first 88 consecutive men who underwent this procedure between December 2016 and January 2020. Design, setting, and participantsMen with (1) prostate-specific antigen (PSA) ≤20 ng/ml, (2) clinical T stage ≤cT2, (3) a dominant unilateral lesion with Gleason ≤ 4 + 3 disease with any number or percentage of cores involved ipsilaterally on prostate biopsy, (4) no primary Gleason ≥4 lesion contralaterally, and (5) a preoperative Sexual Health Inventory of Men (SHIM) score of ≥17 (out of 25) with/without phosphodiesterase type-5 inhibitor use who consented to undergo precision prostatectomy were included in this single-arm, single-center, IDEAL stage 2b prospective development study. InterventionRobotic precision prostatectomy. Outcome measurements and statistical analysisThe safety and urinary, sexual, and oncologic outcomes of the precision prostatectomy technique were studied. Descriptive statistics and Kaplan-Meier analyses were used to assess 12-mo urinary continence (0–1 pad), 12-mo sexual potency (SHIM score ≥17), 36-mo freedom from clinically significant PCa (grade group ≥2), secondary treatments, metastatic disease, and mortality. Results and limitationsAt study entry, the median age, PSA, and SHIM score were 60.0 yr (interquartile range [IQR] 54.2–65.9), 5.7 ng/ml (IQR 4.2–7.1), and 22 points (IQR 19–24), respectively. The median follow-up was 25 mo (IQR 14–38). At 12 mo, all patients were continent (0–1 pads), with 90.9% of patients using 0 pads. The median time to urinary continence was 1 mo (IQR 1–4). At 12 mo, 85% of all-comers and 90.2% of the preoperatively potent men were potent. The median time to sexual potency was 4 mo (IQR 4–12). From an oncologic standpoint, at 36 mo an estimated 93.4% of the patients were free from clinically significant residual PCa and 91.7% had not undergone any additional treatment. All patients were alive and free of metastatic disease at 36 mo. ConclusionsPrecision prostatectomy is technically safe and reproducible and offers excellent postoperative functional results. At 36-mo follow-up, the oncologic outcomes and secondary treatment rates appear to be superior to existing ablative focal therapy results. Pending long-term data, a risk-stratified surgical approach to PCa may avoid whole-gland therapy and preserve functional quality of life in men with localized PCa. Patient summaryPrecision prostatectomy is a new form of focal therapy for intermediate-risk prostate cancer in which a 5–10-mm rim of prostate capsule is left on the opposite side of the gland to where the dominant cancer is located. The technique appears to be safe and efficacious and adds to the growing armamentarium of risk-adapted therapies for treatment of localized prostate cancer that avoid the adverse effects on urinary and erectile function of whole-gland treatments.

Short-term outcomes of phosphodiesterase type 5 inhibitors for fetal growth restriction: a study protocol for a systematic review with individual participant data meta-analysis, aggregate meta-analysis, and trial sequential analysis

BackgroundEarly onset fetal growth restriction secondary to placental insufficiency can lead to severe maternal and neonatal morbidity and mortality. Pre-clinical studies and a few small randomised clinical trials have suggested that phosphodiesterase type 5 (PDE-5) inhibitors may have protective effects against placental insufficiency in this context; however, robust evidence is lacking. The STRIDER Consortium conducted four randomised trials to investigate the use of a PDE-5 inhibitor, sildenafil, for the treatment of early onset fetal growth restriction. We present a protocol for the pre-planned systematic review with individual participant data meta-analysis, aggregate meta-analysis, and trial sequential analysis of these and other eligible trials. The main objective of this study will be to evaluate the effects of PDE-5 inhibitors on neonatal morbidity compared with placebo or no intervention among pregnancies with fetal growth restriction.MethodsWe will search the following electronic databases with no language or date restrictions: OVID MEDLINE, OVID EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and the clinical trial registers Clinicaltrials.gov and World Health Organisation International Clinical Trials Registry Platform (ICTRP). We will identify randomised trials of PDE-5 inhibitors in singleton pregnancies with growth restriction. Two reviewers will independently screen all citations, full-text articles, and abstract data. Our primary outcome will be infant survival without evidence of serious adverse neonatal outcome. Secondary outcomes will include gestational age at birth and birth weight z-scores. We will assess bias using the Cochrane Risk of Bias 2 tool. We will conduct aggregate meta-analysis using fixed and random effects models, Trial Sequential Analysis, and individual participant data meta-analysis using one- and two-stage approaches. The certainty of evidence will be assessed with GRADE.DiscussionThis pre-defined protocol will minimise bias during analysis and interpretation of results, toward the goal of providing robust evidence regarding the use of PDE-5 inhibitors for the treatment of early onset fetal growth restriction.Systematic review registrationPROSPERO (CRD42017069688).

Usage and risk with phosphodiesterase type 5 inhibitors in male patients with chronic ischemic heart disease on oral organic nitrates

Abstract Background Combining oral organic nitrates (OON) with phosphodiesterase type 5 (PDE5) inhibitors is contraindicated. Growing and liberal use of PDE5 inhibitors for erectile dysfunction among patients with ischemic heart disease (IHD) could pose serious health consequences especially among patients with IHD on OON. Purpose We hypothesize that concomitant prescription of OON and PDE5 inhibitors is prevalent and has increased in recent years, and further that possible co-exposure could be associated with an increased risk of ischemic stroke, myocardial infarction (MI) or acute coronary angiography (CAG). Methods During 2000–2018, we included all male patients with history of IHD between 18 and 85 years of age from nationwide Danish health registers. Patients with a history of pulmonary hypertension were excluded and not followed up afterwards if they developed the condition during follow-up. From this cohort, we identified an OON treated subgroup defined by two consecutively redeemed prescriptions of OON within 180 days from each other. Further, to become a case or control, patients had to redeem a prescription of OON within 180 days prior to the event or corresponding date among controls. Temporal trends during 2001–2018 of PDE5 inhibitor use were calculated among all male patients with IHD and the subgroup on OON. Among OON treated patients, we examined associations between PDE5 inhibitor use and risk of ischemic stroke, MI or CAG using a case-crossover design where each individual serves as his/her own control thereby controlling for time-invariant confounding. The case-crossover design compares an individual's exposure in an index period just before the event occurred to a reference period prior to the index period. We investigated periods of varying length (7, 14, 21 and 28 days). To account for possible temporal trends in the use of PDE5 inhibitors, we also conducted a case-time-control analysis using a control group matched on age and calendar year. Results We identified 249,541 male patients with IHD (median age 65 years [IQR 56–73]), and a subgroup of 42,073 (17%) on OON treatment (median age 70 years [IQR 62–77]). From 2001 to 2018, the use of PDE5 inhibitors saw a 6-fold increase among all male IHD patients and a 10-fold rise in the subgroup on OON (Figure 1). The risk of ischemic stroke, MI or CAG following exposure to PDE5 inhibitors was not increased in the OON subgroup in neither the case-crossover nor the case-time-control analyses (Figure 2). Conclusions The use of PDE5 inhibitors has increased 6-fold since 2001 among male patients with IHD, and 10-fold among patients on OON–notwithstanding an established absolute contraindication. However, we did not find any evidence of an increased risk of ischemic stroke, MI or acute CAG following exposure to PDE5 inhibitors in the OON subgroup. This suggests that patients on OON are adequately informed and comply with the recommended pause in OON medication prior to PDE5 inhibitor use. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Ib Mogens Kristiansens Almene FondandHelsefonden

Use of sildenafil and other phosphodiesterase type 5 inhibitors among pregnant women in Scandinavia

For phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, the only approved indication in women is for pulmonary arterial hypertension. These drugs are increasingly being proposed and tested for treatment of female infertility and complications in pregnancy. However, the extent of use of PDE5 inhibitors in the general pregnant population over the last decades is unknown. Therefore, we conducted a descriptive cohort study using data from the population health registers in the Scandinavian countries. By linking the Medical Birth Registers and the Prescribed Drug Registers in Denmark (1997-2017), Norway (2004-2017), and Sweden (2006-2016), women with filled prescriptions of PDE5 inhibitors in outpatient settings in the 90days before the date of last menstrual period and/or during pregnancies were identified. With additional linkage to the National Patient Registers, information on maternal, pregnancy, and infant characteristics, co-morbidities, and co-medication was collected and described. Among over 3million singleton pregnancies, only 77 were pregnancies in women who had at least one filled prescription of a PDE5 inhibitor within the 90days before the start of pregnancy to delivery. Prescription fills most often occurred before the last menstrual period and in the first trimester, with very few occurring later in pregnancy. Sildenafil was the most used PDE5 inhibitor. Among pregnant women using PDE5 inhibitors, 44% were 35years of age or older, eight had a cardiovascular diagnosis, and three specifically had a diagnosis of pulmonary arterial hypertension. Among the infants born to mothers using PDE5 inhibitors, nine were born preterm, six were small-for-gestational age, five had an Apgar score at 5minutes below 8, 18 were admitted to the Neonatal Intensive Care Unit, and eight had respiratory and cardiovascular conditions. Few women used PDE5 inhibitors in outpatient settings before or during pregnancy in the Scandinavian countries in the last decades. Only a small proportion had a diagnosis for pulmonary arterial hypertension, suggesting off-label use in the remaining users. Use was predominantly in mothers over age 35years. The safety of fetal exposure to sildenafil and other PDE5 inhibitors in pregnancy has not been established. As maternal age continues to increase and additional uses of PDE5 inhibitors are investigated, the safety of these drugs in pregnancy should be thoroughly evaluated.

CAMP Modulators before In Vitro Maturation Decrease DNA Damage and Boost Developmental Potential of Sheep Oocytes.

Simple SummaryOocyte in vitro maturation has massive potential for the generation of great numbers of embryos for research and for the application of assisted reproductive technologies, such as in vitro embryo production. However, the developmental ability of in vitro matured oocytes is lower than those matured in vivo. Here, incubating the oocytes with cAMP modulating agents for two hours before in vitro maturation decreased oocyte DNA damage and increased the number of embryos generated after in vitro fertilization. The present findings could help to develop new methods to improve the quality and developmental potential of in vitro matured oocytes.To date, the underlying mechanisms by which cAMP modulators act during in vitro maturation to improve oocyte developmental competence are poorly understood. Here, we sought to fill this knowledge gap by evaluating the use of phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) and adenylyl cyclase activator forskolin during a culture period of 2 h before in vitro maturation (pre-IVM) on the nuclear and cytoplasmic maturation features in essential organelles, cumulus cells activity, and in vitro developmental potential of sheep oocytes. Results showed that pre-IVM treatment significantly decreased (p < 0.05) the DNA damage of mature oocytes (pre-IVM = 2.08% ± 3.51% vs. control = 20.58% ± 3.51%) and increased (p ≤ 0.05) expanded blastocyst rates compared to the control (from the total of oocytes: pre-IVM = 23.89% ± 1.47% vs. control = 18.22% ± 1.47%, and from the cleaved embryos: pre-IVM = 45.16% ± 1.73% vs. control = 32.88% ± 1.73%). Considering that oocytes are highly vulnerable to the accumulation of DNA damage because of exposure to in vitro culture conditions, our results suggest that the modulation of intra-oocyte cAMP levels with forskolin and IBMX before IVM might afford oocytes a more effective DNA repair mechanism to overcome damage obstacles and ultimately improve developmental competence. This previously unappreciated action of cAMP modulators could help to develop improved methods for assisted reproduction technologies in animal and clinical research.

Covid-19-induced pulmonary hypertension in children, and the use of phosphodiesterase-5 inhibitors

Respiratory tract infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first occurred in Wuhan, China, in December 2019 and was declared as a pandemic by WHO. The interaction between the 2019 coronavirus disease (COVID-19) and pulmonary hypertension (PH) in children is not widely known. Phosphodiesterase-5 inhibitors (PDEI), one class of drugs used to treat PH, including sildenafil, can suppress angiotensin type I (AT-1) receptor expression. Furthermore, it reduces proinflammatory cytokines and infiltrates the alveolar, inhibits endothelial and smooth muscle transition, mesenchymal cells in the pulmonary artery, and prevents clotting and thrombosis complications. Sildenafil has shown positive effects by diverting the blood flow to the lungs in such a way that ventilation is adequate and can also be anti-inflammatory.

This Month in Adult Urology

This Month in Adult Urology

Safety of Phosphodiesterase-5 Inhibitors in Valvular Heart Disease.

Erectile dysfunction is a common entity in clinical practice. Primary erectile dysfunction, not related to vasculopathy or psychiatric disorder, can be readily treated with phosphodiesterase inhibitors. These drugs have many physiologic effects that can alter a patient's hemodynamic profile considerably, especially in the presence of concomitant structural heart disease, specifically valvular heart disease. Although some contraindications to the use of PDE5 inhibitors in patients with cardiovascular disease are defined, the effect of these drugs in the presence of valvular heart disease is not well documented. The purpose of this review is to analyze the data regarding the safety of PDE5 inhibitors in patients with valvular heart disease.

In Vitro Fertilization Entails a High Prevalence of Erectile and Male Sexual Dysfunction: A Prospective Case-Control Study.

We evaluated the effect of in vitro fertilization (IVF) on sexual function in men, particularly for erectile dysfunction. A prospective case-control study at a tertiary medical center. The study group comprised men of infertile couples that required IVF to conceive. The control group comprised men of couples who conceived spontaneously. The effects of IVF on sexual and erectile function were assessed based on the International Index of Erectile Function (IIEF-15) and the Self-Esteem and Relationship (SEAR) questionnaires. Participants were followed up to 1 year postpartum. Compared to the control group (378), for the IVF group (356), mean IIEF-15 scores were significantly lower: prior to pregnancy (31.7±4.5 vs 64.4±7.2, p <0.0001), at mid-pregnancy (37.3±5.1 vs 66.4±5.5, p <0.0001) and up to one year postpartum (42.3±4.9 vs 68.6±4.3, p <0.0001). Compared to the control group, in the IVF group, mean SEAR scores were significantly lower at these 3 respective time points (29.9±6.3 vs 66.5±8.3; 34.1±5.8 vs 66.9±7.2; and 40.9±6.7 vs 67.3±5.6; p <0.0001). At the 3 time points, for the IVF compared to the control group, the median monthly sexual intercourse rate was lower; and both the use of phosphodiesterase-5 inhibitor and psychologist/sexologist care were higher. The prevalence of erectile dysfunction among men participating in IVF in order to conceive is significantly higher compared to couples that conceived spontaneously, thus leading to an extremely high rate of phosphodiesterase-5 inhibitor use.

Low-intensity extracorporeal shock wave therapy for Peyronie's disease: a single-center experience.

The aim of this article is to assess the outcomes of a low-intensity extracorporeal shock wave therapy (LiESWT) protocol for the treatment of Peyronie's disease (PD). Patients treated for PD were prospectively recorded, and data were retrospectively reviewed. Age, characteristics of fibrous plaques, concomitant treatments, International Index of Erectile Function (IIEF-5), Lue score, and pain score on Likert scale were collected. Patients in acute phase of PD and an angulation of <40° were included. The protocol consisted of 6 weekly sessions of 4000 pulses each, applied from different directions, with a maximal power of 20 W and 8 Hz frequency. We included 39 patients (median age: 56.8 years, interquartile range [IQR]: 35.8–62.2 years). The median number of sessions received per patient was 7.2. After treatment, the median Lue score decreased from 6.8 initially to 3.3 (P = 0.003), the median Likert pain score dropped from 1.8 to 0.7 (P = 0.004), the median plaque size was reduced from 2 cm to 1.2 cm (P = 0.08), and the median penile curvature diminished from 31° to 17° (P = 0.07). On univariate and multivariate analysis, the only predictors of success were younger age (odds ratio [OR] = 0.95, P = 0.03 and OR = 0.91, P = 0.04, respectively) and concomitant use of phosphodiesterase-5 inhibitors (PDE5i; OR = 0.92, P = 0.02 and OR = 0.93, P = 0.01, respectively). LiESWT had a favorable impact on Lue score and notably penile pain, curvature, plaque size, and erectile function in patients treated for PD during the early inflammatory phase, with no side effects. Younger age and concomitant use of PDE5i were the only success predictors.

Long-term tolerability of phosphodiesterase-5 inhibitors in pulmonary hypertension of sickle cell disease.

Sickle cell disease-related pulmonary hypertension (SCD-PH) is a complex disorder with multifactorial contributory mechanisms. Previous trials have evaluated the efficacy of pulmonary arterial hypertension (PAH) therapies in SCD-PH with mixed results. We hypothesized that a subset of patients with right heart catheterization (RHC) confirmed disease may benefit from PAH therapy. We performed a retrospective chart review of patients with SCD-PH diagnosed by RHC who were treated with phosphodiesterase 5 inhibitor (PDE5-I) therapy for ≥4months between 2008 and 2019 at two institutions. Thirty-six patients were included in the analysis. The median age (IQR) upon PDE5-I initiation was 47.5years (35-51.5years); 58% were female and twenty-nine (81%) had HbSS disease. Of these, 53% of patients had a history of acute chest syndrome, 42% had a history of venous thromboembolism, and 38% had imaging consistent with chronic thromboembolic PH. Patients were treated for a median duration of 25months (IQR 13-60months). Use of PDE5-I was associated with a significant improvement in symptoms as assessed by NYHA Class (P=.002). In SCD patients with PH defined by RHC, PDE5-I therapy was tolerated long-term and may improve physical activity.

Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

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.

Phosphodiesterase 5 Inhibitor Use and Risk of Conventional and Serrated Precursors of Colorectal Cancer.

Phosphodiesterase 5 (PDE5) inhibitors have been hypothesized to have chemoprotective effects in colorectal cancer. Current population-based epidemiologic evidence is, however, limited and inconsistent. 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." 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. We found no evidence of an association between PDE5 inhibitor use and risk of conventional and serrated precursors of colorectal cancer. 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.

Erectile Dysfunction and Cardiovascular Risk in Men With Rheumatoid Arthritis: A Population-based Cohort Study.

Both erectile dysfunction (ED) and rheumatoid arthritis (RA) are associated with increased cardiovascular (CV) risk. It is unknown if these diagnoses are associated or if their combination confers additional CV risk. We aimed to define the incidence of ED in RA, and to determine if ED correlates with increased CV risk in RA. Medical information concerning RA, ED, and CV diagnoses for men with RA (n = 260) diagnosed in Olmsted County, Minnesota, and age-matched male comparators was extracted from a comprehensive medical record system. ED incidence was similar between the RA cohort and comparators (HR 0.80, 95% CI 0.55-1.16). In men with RA, ED diagnosis was associated with a trend toward an increase in peripheral arterial disease (HR 2.22, 95% CI 0.98-5.03) and a significantly decreased rate of myocardial infarction (HR 0.26, 95% CI 0.07-0.90), heart failure (HR 0.49, 95% CI 0.25-0.94), and death (HR 0.56; 95% CI 0.36-0.87). In men with RA and ED, phosphodiesterase-5 inhibitor use was associated with a decreased risk of death (HR 0.35, 95% CI 0.16-0.79), with a trending decreased risk of some CV diagnoses. Incidence of ED was not statistically increased in RA. Although patients with both RA and ED had a similar overall CV risk to those with RA alone, men with both RA and ED had decreased risk of heart failure, myocardial infarction, and death, as well as an increased risk of peripheral arterial disease. Further studies are needed to clarify these associations and their implications for pathogenesis and therapeutics.