Phosphodiesterase-5 Inhibitors Research Articles

The new quinazoline derivative (N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine) vasodilates isolated mesenteric arteries through endothelium-independent mechanisms and has acute hypotensive effects in Wistar rats

During the screening of new N2,N4-disubstituted quinazoline 2,4-diamines as phosphodiesterase-5 inhibitors and pulmonary artery vasodilators, one N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine (compound 8) presented a greater selectivity for systemic than pulmonary vasculature. The present study aimed to characterize its vasorelaxant and hypotensive effects in Wistar rats. Vasorelaxant effects of compound 8 and underlying mechanisms were evaluated on isolated mesenteric arteries. Acute hypotensive effect was evaluated in anesthetized rats. Additionally, cell viability and cytochrome P450 (CYP) activities were studied in rat isolated hepatocytes. Nifedipine was used as a comparator. Compound 8 induced a strong vasorelaxant effect, similar to nifedipine. This was unaffected by endothelium removal but was decreased by inhibitors of guanylate cyclase (ODQ) and KCa channel (iberiotoxin). Compound 8 enhanced sodium nitroprusside-induced relaxation, but inhibited vasoconstriction evoked by α1-adrenergic receptor activation and extracellular Ca2+ influx via receptor-operated Ca2+ channels. Acute intravenous infusion of compound 8 (0.05 and 0.1 mg/kg) produced hypotension. It showed similar potency to nifedipine for lowering diastolic and mean arterial blood pressure, but less so for the effect on systolic blood pressure. Compound 8 had no effect on hepatocyte viability and CYP activities except at high concentration (10 μM) at which a weak inhibitory effect on CYP1A and 3A was observed. In conclusion, this study identified a N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine with a potent vasodilator effect on resistance vessels, leading to an acute hypotensive effect and a low risk of liver toxicity or drug-drug interactions. These vascular effects were mediated mainly through sGC/cGMP pathway, opening of KCa channels, and inhibition of calcium entry.

Close Relationship between Systemic Arterial and Portal Venous Pressure in an Animal Model with Healthy Liver.

It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between mean arterial (MAP) and portal venous pressure (PVP) in rats with healthy livers. In a rat model with healthy livers, we investigated the effect of manipulation of MAP on PVP. Interventions consisted of 0.9% NaCl (group 1), 0.1 mg/kg body weight (bw) Sildenafil (low dose), an inhibitor of phosphodiesterase-5 (group 2), and 1.0 mg/kg bw Sildenafil (high dose, group 3) in 600 µL saline injected intravenously. Norepinephrine was used to increase MAP in animals with circulatory failure while PVP was monitored. Injection of the fluids induced a transient drop in MAP and PVP, probably due to a reversible cardiac decompensation. The drop in MAP and drop in PVP are significantly correlated. The time lag between change in MAP and change in PVP by 24 s in all groups suggests a cause-and-effect relationship. Ten minutes after the injection of the fluid, cardiac function was normalized. Thereafter, MAP gradually decreased. In the NaCl group, PVP decreases by 0.485% for a 1% drop of MAP, by 0.550% in the low-dose sildenafil group, and by 0.651% in the high-dose sildenafil group (p < 0.05 for difference group two vs. group one, group three vs. group one, and group three vs. group two). These data suggest that Sildenafil has an inherent effect on portal pressure that exceeds the effect of MAP. Injection of norepinephrine led to a sudden increase in MAP followed by an increase in PVP after a time lag. These data show a close relationship between portal venous pressure and systemic arterial pressure in this animal model with healthy livers. A change in MAP is consequently followed by a change in PVP after a distinct time lag. This study, furthermore, suggests that Sildenafil influences portal pressure. Further studies should be performed in a model with cirrhotic livers, as these may be important in the evaluation of vasoactive drugs (e.g., PDE-5-inhibitors) for therapy of portal hypertension.

A novel technique for unilateral dissection of the penile neurovascular bundle to prevent loss of penile sensation during treatment of Peyronie's disease-Initial results of a pilot study.

Plaque incision/excision and grafting are surgical techniques used to treat patients with Peyronie's disease who are refractory to less invasive interventions, have severe penile curvature, or have an hourglass deformity. However, the procedure carries the risk of penile sensory loss because of the need for dissection of the neurovascular bundle (NVB). The aim of this study was to assess the feasibility of a novel technique for unilateral NVB dissection and its ability to preserve penile sensitivity while maintaining adequate correction of the penile curvature. Charts of patients who underwent unilateral NVB dissection during Peyronie's plaque incision/excision and grafting were retrospectively reviewed. All patients received preprocedural intracavernosal injections of TriMix, and the curvature was measured to be >70 degrees. In 3 cases, an incision and minimal excision of the plaque were performed at the point of maximum curvature on the concave side of the curvature. In 3 cases, Tutoplast allografts (Coloplast US, Minneapolis, MN) were used, whereas autografts were used in 2 other cases. All patients were examined at 1, 3, and 6 months after the procedure when curvature and penile sensation were assessed. Five patients underwent this procedure. The mean age of patients was 55 years (45-70 years). All plaques were dorsally located. The mean preoperative curvature was 78 degrees (75-90 degrees). At the 6-month follow-up, all patients had <15 degrees residual curvature and were satisfied with their cosmetic results. Only 1 patient continued with phosphodiesterase-5 inhibitors to improve potency at the 6-month follow-up. All patients reported normal penile glans sensation. Four patients experienced decreased sensation at the site of NVB dissection, but this was only detected when compared with the contralateral side. Only 2 patients reported a difference after 6 months, and only a minor area of involvement was noted. Unilateral NVB dissection is a feasible technique that does not compromise surgical success in curvature correction and helps avoid sensory injury to the penile glans.

The effects of sildenafil citrate on intrauterine growth restriction: a systematic review and meta-analysis

BackgroundAn increase in vascular resistance of uterine vessels is associated with intrauterine growth restriction (IUGR). Sildenafil citrate, a phosphodiesterase-5 inhibitor that stabilizes cyclic guanosine monophosphate (cGMP) and increases nitric oxide levels, improves placental perfusion by dilation of spiral arteries and is beneficial in managing IUGR. This study aims to determine the effectiveness of sildenafil citrate in improving perinatal outcomes in IUGR pregnancies.MethodsMeta-analysis was performed on data extracted from all studies specific to sildenafil citrate in IUGR management, searching relevant articles on PubMed, Medline, Google Scholar, Embase, and Cochrane databases. Publications identified by the manual search, based on references in reviews, were also included. Dichotomous results were presented as risk ratio (95% confidence interval), while continuous results were expressed as mean difference (MD); samples represented by the random effects model.ResultsNine trials were included where the sildenafil citrate effect was compared with a placebo or no intervention. A significant increase in birth weight [SMD (95% CI), 0.69 (0.31, 1.07)] was seen in IUGR pregnancies managed with sildenafil. However, gestational age (SMD (95% CI), 0.44 (-0.05, 0.94], fetal death rate [RR (95% CI), 0.56 (0.17, 1.79)] in IUGR pregnancies was not changed by sildenafil. Neonatal death [RR (95% CI), 0.93 (0.47, 1.86)] and neonatal intensive care unit (NICU) admissions [RR (95% CI), 0.76 (0.50, 1.17)] were not significantly different between sildenafil and control groups.ConclusionSildenafil citrate increases birth weight and prolonged pregnancies but did not affect stillbirth rate, neonatal death, and NICU admission.Trial registrationThe study was registered in PROSPERO on September 18, 2021 (CRD42021271992).

Carotid artery intima media thickness can predict the response to phosphodiesterase 5 inhibitors in patients with moderate erectile dysfunction.

Increased carotid artery intima-media thickness (CIMT) has been shown to be associated with erectile dysfunction (ED), but studies evaluating the efficacy of CIMT in predicting drug response are lacking in the literature. We aimed to evaluate the efficacy of CIMT in predicting the response to phosphodiesterase-5 inhibitors (PDE5-I). A total of 274 subjects were divided into two groups: ED patients (n = 150) and controls (n = 124). The patients in the ED group were further divided into the subgroups of severe, moderate, mild-moderate, and mild ED. Blood tests, carotid ultrasonography, and the International Index of Erectile Function-5 (IIEF-5) diagnostic tool were applied to all subjects. Tadalafil was administered to each patient. The patients were re-evaluated using the IIEF-5 questionnaire after 2 months of treatment. According to their response to medication, the patients were evaluated as responders or nonresponders. Increased CIMT was significantly associated with the failure of PDE5-I therapy, especially in patients with moderate/mild-moderate ED. Fasting blood glucose, body mass index, and CIMT were significantly higher in the ED group compared to the control group (P =.021, P = .006, and P < .001, respectively). The IIEF-5 score was significantly lower in the ED group (P < .001). CIMT was significantly correlated with the IIEF-5 score. When the total patient group was evaluated, the CIMT value of the responders was significantly lower than that of the nonresponders (P = .001). CIMT was significantly higher among the nonresponders with moderate/mild-moderate ED compared to the responders (P = .004 and .008, respectively), while there was no significant difference in CIMT between the responders and nonresponders with severe or mild ED. A receiver operating characteristic (ROC) analysis of CIMT was performed for discrimination between nonresponders and responders with moderate/mild-moderate ED. The area under the ROC curve was 0.801 (0.682-0.921) (P = .001), and the cutoff value was determined to be 0.825mm, at which CIMT predicted the response to treatment with 65% sensitivity and 89% specificity. Using a validated CIMT cutoff value can help the physician inform the patient about the possibility of drug failure and avoid attempting second-line therapy too soon. There are three main limitations to our study. First, the number of participants was low. Second, ultrasound is a relatively subjective method, and third, all measurements were made by the same radiologist. CIMT can be used as a predictor of response to PDE5-I therapies in patients with moderate/mild-moderate ED.

Immunomodulatory, apoptotic and anti-proliferative potentials of sildenafil in Ehrlich ascites carcinoma murine model: In vivo and in silico insights.

Sildenafil is a potent phosphodiesterase-5 (PDE5) inhibitor that effectively inhibits cGMP and increases the strength of nitric oxide. PDE5 was overexpressed in several carcinomas, including breast cancer, which inhibited tumor growth and cell division. The current research aims to investigate the in vivo sildenafil's immunomodulatory and antineoplastic potentials against Ehrlich Ascites Carcinoma. This study looked at the effects of sildenafil mono-treatment and co-treatment with cisplatin; tumor cell count, viability and the inhibition rate were determined. Apoptosis, cell cycle distribution, alterations in tumor cells and splenocytes proliferation, changes in splenocytes immunophenotyping using flowcytometry, plasma levels of malondialdehyde (MDA), reduced glutathione (GSH), interferone (IFN)-γ, granzyme B, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and hematological alterations were detected. Additionally, docking study was conducted to get further insights on how Sildenafil exerts its activity. Sildenafil mono-treatment and co-treatment with cisplatin markedly reduced tumor cell count, viability, growth rate and proliferative capability accompanied by apoptosis enhancement and G0/G1 and sub G1 cells cycle arrest. Fortunately, sildenafil evoked efficient cellular immune response by increasing plasma levels of granzyme B and IFN-γ, proportion of splenic T cytotoxic (CD3+CD8+) and T helper (CD3+CD4+), accompanied by decrease in the proportion of splenic regulatory T cells. . Moreover, in silico data suggest LcK and MAPKs as the potential targets of sildenafil. Furthermore, sildenafil rebalanced the oxidant-antioxidant status by decreasing MDA and increasing GSH plasma levels. Sildenafil successfully retrieved various hematological values besides renal and hepatic functions in EAC-bearing animals. In conclusion, our results suggest that sildenafil could be potential safe anti-tumor agent with immuno-modulatory properties against Ehrlich ascites carcinoma.

A Non-Systemic Phosphodiesterase-5 Inhibitor Suppresses Colon Proliferation in Mice.

Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing for colon cancer prevention. A drawback to conventional PDE5i are their side-effects and drug-drug interactions. We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity, and measured its entry into the circulation and effects on colon epithelium. This modification did not affect pharmacology as malonyl-sildenafil had a similar IC50 to sildenafil but exhibited an almost 20-fold reduced EC50 for increasing cellular cGMP. Using an LC-MS/MS approach, malonyl-sildenafil was negligible in mouse plasma after oral administration but was detected at high levels in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. The treatment of mice with malonyl-sildenafil in the drinking water resulted in a suppression of proliferation in the colon epithelium that is consistent with results previously published for mice treated with PDE5i. A carboxylic-acid-containing analog of sildenafil prohibits the systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generating a first-in-class drug for colon cancer chemoprevention.

(164) Real-World Practice in Peyronie’s Disease Management: Results from a National Survey of Urologists

Abstract Introduction There are many treatment options for men with Peyronie's disease, some which have been shown in randomized controlled trials to be more effective than placebo in reducing curvature and plaque size and others which do not have strong evidence of efficacy for use. It is unclear which of the many Peyronie's disease treatment choices are preferred by practicing urologists. Objective To survey practicing urologists on their preferred methods for diagnosing and treating Peyronie's disease. Methods A 34-item survey was distributed via REDCap to urologists in all American Urological Association (AUA) sections. Questions elicited demographic information as well as practices in diagnosis and treatment of Peyronie’s disease. Comparisons were made with Pearson’s chi-squared test. Results A total of 145 respondents completed the survey, of whom 19% were fellowship trained in andrology/sexual medicine, 36% practiced in an academic setting, and 50% had at least 20 years in practice. Only 60% of respondents reporting performing in-office curvature assessment prior to commencing intralesional injection or surgical treatment, with higher prevalence in andrology/sexual medicine fellowship-trained vs. non-fellowship trained urologists (85% vs. 54%, p=0.003). The most popular treatment modalities were collagenase clostridium histolyticum (CCH) (61% of respondents), phosphodiesterase-5 (PDE-5) inhibitors (54%), and penile traction (53%). Twenty-one percent of respondents reported currently using a treatment that is explicitly discouraged by the AUA guidelines (extracorporeal shockwave therapy for curvature, L-carnitine, omega-3 fatty acids, procarbazine, tamoxifen, or vitamin E). Conclusions We found reported use of a variety of Peyronie's disease treatments, despite poor evidence of efficacy for several of these therapies. PDE-5 inhibitors, penile traction, and CCH were among the most popular non-surgical treatments, with a significant proportion of urologists reporting “off-label” use of CCH. Efforts are needed to identify optimal regimens for Peyronie's disease treatment and to better educate urologists on the up-to-date evidence and guidelines in Peyronie's disease management. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Roman Health

(203) Phosphodiesterase-5 Inhibitor Use and Progression to Heart Failure in Men with Coronary Artery Disease and Erectile Dysfunction

Abstract Introduction Erectile dysfunction (ED) is defined as an inability to reach or sustain an erection for satisfactory intercourse, and this condition affects more than 10 million men in the United States alone. Coronary artery disease (CAD) and ED often co-occur due to shared vascular risk factors for this condition. Phosphodiesterase-5-inhibitors (PDE5i) such as sildenafil and tadalafil are approved as first line treatments for ED, when early trials have demonstrated marked improvements in erectile function. PDE5i such as tadalafil have also been associated with decreased risk of death and cardiovascular disease, as it may alter endothelial function to improve myocardial perfusion and cardiac contractility. To date, information specific to the type of PDE5i used in relation to their perceived cardiac benefits has been limited. Objective We investigated whether the choice of PDE5i may impact progression to heart failure and other major adverse cardiac events (MACE) among men with both CAD and ED. We hypothesized that tadalafil, with its high affinity to PDE5 receptors compared with sildenafil, may provide greater clinical benefits in reducing MACE. Methods A retrospective, propensity-matched, cohort study was performed using the TriNetX Research Network. Patients with an ICD-10 diagnosis of CAD and ED but without pulmonary hypertension were captured from January 2011 to December 2016, with follow up restricted to 5 years. Patients were subdivided and analyzed via pairwise fashion according to known prescriptions for tadalafil, sildenafil, or no treatment (NT). Propensity matching was performed using baseline comorbidities of hypertension, ischemic heart disease, cerebral infarction, diabetes, and hyperlipidemia. Outcomes of interest included 5-year rates of heart failure (HF), acute myocardial infarction (MI), and mortality. Results Prior to propensity score matching, significant differences in baseline comorbidities were noted, with the highest rates of hypertension (9,653 [79.0%]), ischemic heart disease (9,109 [74.6%]), hyperlipidemia (8,541 [69.9%]), and cerebral infarction (690 [5.6%]) in the sildenafil group, and diabetes in the NT group (8,521 [38.2%]). Following propensity score matching, no significant differences were noted (Table 1). When compared with NT, both tadalafil and sildenafil were associated with reduced progression to HF, MI, and overall mortality. Most importantly, compared with sildenafil, tadalafil demonstrated lower progression to HF (HR: 0.85 [0.77-0.94]), MI (HR: 0.86 [0.76-0.97]) and mortality (HR: 0.85 [0.76-0.95]) (Table 2, Figure 1). Conclusions Tadalafil use was associated with a significant reduction in progression to HF, MI, and mortality, compared with sildenafil or no treatment. These preliminary results may signal meaningful clinical differences in drug choice for men suffering from CAD and ED, and therefore require further inquiry. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Endo.

Phosphodiesterase 5 (PDE-5) inhibitors (sildenafil, tadalafil, and vardenafil) effects on esophageal motility: a systematic review

BackgroundEsophageal motility disorders are a group of disorders associated with dysfunctional swallowing resulting from impaired neuromuscular coordination. Phosphodiesterase 5 (PDE-5) inhibitors induce smooth relaxation and are proposed as a treatment option for esophageal motility disorders such as achalasia.MethodsThis study is conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We systematically searched MEDLINE/ PubMed, Scopus, EMBASE, and Web of Science databases for esophageal outcomes of individuals treated with PDE5 inhibitors. A random effect meta-analysis was conducted.ResultsA total of 14 studies were included. They were conducted in different countries, with Korea and Italy having the highest number of articles. The main drug assessed was sildenafil. PDE-5 inhibitors resulted in a significant reduction in lower esophageal sphincter pressure (SMD − 1.69, 95% CI: -2.39 to -0.99) and the amplitude of contractions (SMD − 2.04, 95% CI: -2.97 to -1.11). Residual pressure was not significantly different between the placebo and sildenafil groups (SMD − 0.24, 95% CI: -1.20 to 0.72). Furthermore, a recent study reported contractile integral, stating that ingestion of sildenafil leads to a significant reduction in distal contractile integral and a significant increase in proximal contractile integral.ConclusionPDE-5 inhibitors significantly reduce LES resting pressure and esophageal peristaltic vigor, decreasing esophageal body contractility and contraction reserve. Therefore, using these drugs in patients affected by esophageal motility disorders may potentially improve their condition regarding symptom relief and prevention of further associated complications. Future reports investigating larger sample size is necessary in order to establish definite evidence regarding the efficacy of these drugs.

(169) Characteristics of Telehealth Platforms Offering Erectile Dysfunction Treatment

Abstract Introduction Telehealth platforms are becoming more prevalent in the field of medicine, including men’s sexual health. Due to the sensitivity and potential embarrassment of discussing erectile dysfunction (ED) issues in-person, men may seek alternative methods to obtain ED treatment without leaving their homes. Objective We sought to compare the offerings of telehealth platforms for ED treatment with respect to consultation, price, services provided, and privacy policy. Methods Google was queried in June 2022 to identify online telehealth platforms offering ED treatment. Two reviewers identified and analyzed the top 50 results using the keywords “telehealth erectile dysfunction,” “telemedicine erectile dysfunction,” and “online erectile dysfunction.” Inclusion criteria are as follows: platforms must serve a majority of US states, exist online-only, provide both the consultation and prescription for phosphodiesterase 5 inhibitors (PDE5i), and deliver the prescription to the patient. Descriptive analysis of pricing information, physician access, and HIPAA compliance was performed. Results Fifteen online platforms met inclusion criteria. Ten provided “free” consultations; however, patients were expected to pay monthly or quarterly fees for prescriptions. Four bundled the consultation fee with the first month of the prescription; one of these functioned as a subscription service with a $10 monthly charge plus monthly refill fee. Fourteen (93%) platforms began the consult with an online form and ten (67%) platforms advertised review by the prescriber within two business days. Four (33%) platforms explicitly advertised physician-only consults, five (27%) used the vague term “provider,” and the remaining six (40%) advertised either physicians or other prescribers on staff. Direct contact with the prescriber (digital/audio/video) would only occur if needed or if required by state law at eight (53%) platforms. The ability to directly purchase sildenafil and tadalafil was advertised on all platforms. Pricing information varied depending on pill strength and quantity ordered on eight platforms. Six platforms only offered pricing per dose without specifying medication strength. Minimum prices of sildenafil ranged from $0.99-35/pill (mean $5.37/pill, median $2.50/pill) while tadalafil ranged from $0.90-44/pill (mean $8.48/pill, median $6/pill). In addition to ED therapy, thirteen (86%) platforms offered treatment for other men’s health issues such as premature ejaculation or hair loss. All platforms included a privacy policy, but only ten (66%) mentioned HIPAA compliance with two of these claiming to not be “covered entities.” Conclusions Telehealth platforms are changing the face of healthcare to offer evaluation and treatment of health conditions, including ED, privately from the patient’s own home. Although platforms are transparent with PDE5i medication and subscription pricing information, very few offer direct contact with a physician to further discuss issues related to ED after completion of the online intake form. For patients seeking a more comprehensive evaluation for their ED in a HIPAA compliant setting, a formal in-person or telemedicine visit should be arranged with their physician. Disclosure No

(529) Etiology of Erectile Dysfunction in Patients who Underwent Endourological Procedures for Prostate vs. Robotic and Open Radical Prostatectomy.

Abstract Introduction Erectile dysfunction continues to be a concern for patients and physicians after surgical treatment of prostate pathology. Objective To analyze doppler diagnosis on patients who underwent prostate surgery for benign or malignant pathology of the prostate. Methods We retrospectively analyzed all patients who underwent either robotic assisted prostatectomy (RALP), open retropubic prostatectomy (RRP), endoscopic procedures such as greenlight procedure, laser resection of the prostate or transurethral resection of the prostate (TURP); and High Intensity Focused Ultrasound (HIFU) treatment for prostate pathology and who underwent intracavernous injection followed by Color Doppler Duplex Ultrasound (CDDU) at our institution between 2005 and 2019. CDDU findings were recorded following injection of low dose alprostadil (10-20 mcg) and again after a period of privacy and visual sexual stimulation. CCDU findings including peak systolic velocities (PSV), and resistive indices (RIs) were recorded. Arterial insufficiency (AI) was defined as either a post-stimulation PSV &amp;lt; 25 with any RI or a PSV 25-34.9 with RI≥0.9. Cavernous Venous Occlusion Disease (CVOD) was defined as post-stimulation PSV ≥35 with RI &amp;lt; 0.9. Mixed was defined as post-stimulation PSV 25-34.9 with RI &amp;lt; 0.9. Vascular normal was defined as post-stim PSV ≥ 35 with RI ≥ 0.9. Results 380/1917 (19.8%) patients had a past surgical history of prostate surgery. 111/380 (29.2%) underwent RRP, 168/380 (44.2%) patients underwent RALP, 85/380 (22.3%) underwent endourological resection of the prostate and 2/380 (0.5%) patients underwent HIFU. Median age for the RALP group was 60.5 (IQR 23.7-82.8), RRP group was 64.2 (29.7-87.7), endourological resection of the prostate 64.6 (30.8 – 85.6) and HIFU 65.0 (46.9-79.4). 87.1% of patients who had an endoscopic procedure were using phosphodiesterase-5 inhibitors at the time of CDDU. CVOD was the most common etiology of ED in patients who underwent RRP (28.8%) and Endourological procedures of the prostate (32.9%); In patient who underwent RALP the most common etiology of ED was noted to be AI (28.6%), however none of these values were statistically significant (p=0.428). Conclusions There is no difference in etiology of ED in patients who underwent open, robotic or endoscopic manipulation of the prostate as shown by CDDU. Disclosure No

(022) Men with History of Depression Are More Likely to Continue Use of Antidepressants If Erectile Dysfunction is Treated with Testosterone or Phosphodiesterase-5 Inhibitors

Abstract Introduction Erectile dysfunction (ED) affects an estimated 30 million men in the United States with an estimated 82% of men with erectile dysfunction experiencing depressive symptoms. Prior literature has shown that initiation of therapy for ED is associated with a decrease in depressive symptoms; however, the rates of antidepressant continuation following initiation of erectile dysfunction has not been analyzed. Objective Our goal was to analyze the rate of antidepressant continuation for depression after prescribing testosterone or PDE-5 inhibitors for erectile dysfunction. Methods We queried the TriNetX Diamond network database, a health research network including 212 million patients, including healthcare encounters, insurance claims data, and prescription data between 2009-2021. We identified men with a diagnosis of depression (ICD-10: F32-33), 12 consecutive prior months of antidepressant prescriptions (VA Formulary: CN609), and a diagnosis of erectile dysfunction (ICD-10: N52). We then compared rates of antidepressants continuation over the following year in men who were prescribed PDE5i or testosterone for their erectile dysfunction versus men who had never been prescribed testosterone or PDE5i for their erectile dysfunction. The two cohorts were matched on age, race, and ethnicity. Rates of antidepressant discontinuation were compared with risk ratios (RR) and 95% confidence interval (95% CI). Results We identified 31,306 men that were prescribed a PDE-5 inhibitor without testosterone and an equal number of men that weren't prescribed testosterone nor PDE5i. We found that 54% of men receiving PDE5i continued using antidepressants after 12 months; while, 49% of men that weren't prescribed testosterone nor PDE5i continued using antidepressants (RR: 1.11, 95% CI: 1.10-1.13). We identified 4,468 patients who were prescribed testosterone without a PDE5i and an equal number of men that weren't prescribed testosterone nor PDE5i prescriptions. We found that 61% of men receiving testosterone prescriptions continued the use of antidepressants over subsequent 12 months; while 49% of men that weren't prescribed testosterone nor PDE5i continued using antidepressants (RR: 1.24, 95% CI: 1.20-1.29). Conclusions We conclude that patients who were prescribed PDE-5 inhibitors or testosterone were more likely to continue usage of antidepressants after 1 year despite the potential negative sexual dysfunction side effects that they may cause. The patient's psychiatric conditions and comorbidities should be considered when prescribing medications for sexual wellbeing in order to more holistically treat patients. Disclosure No

(206) Erectile Dysfunction and Hypogonadism in Men with Spina Bifida

Abstract Introduction Spina Bifida is a congenital neurological defect associated with genitourinary anomalies, requiring comprehensive urological care from pediatrics to adulthood. For men with spina bifida, a significant focus is on urinary tract surveillance to maintain continence, preserve kidney and bladder health, and optimize fertility and sexual function. While men with SB have an increasing interest in exploring their sexuality and sexual health, these concerns may be under-discussed and undertreated depending on their burden of illness. ED is associated with diminished body image and low self-confidence resulting in poor sexual health. Additionally, it creates barriers to maintaining intimate relationships. Current data tackling the prevalence of erectile dysfunction demonstrates variations in value, yet low quantifications of treatment for SB patients. Prior studies have shown a positive response to phosphodiesterase-5 (PDE5) inhibitor therapy (80%). Concurrently, the impact of hypogonadism on the SB is unknown. Hypogonadism is associated with increased insulin resistance in young males, hyperlipidemia, and other adverse vascular effects. These risk factors play a role in the vascular etiology of erectile dysfunction and can be a burden on sexual health. With a scarcity of men’s sexual health data focused on the adult SB male population, there is a need to illustrate the prevalence of ED and HG in men with SB while investigating treatment utilization. We hypothesize that men with SB will experience a higher rate of diagnosis of ED and HG compared to the general adult male population, and lower treatment utilization rates. Objective To calculate the estimated prevalence of erectile dysfunction and hypogonadism in adult men with spina bifida Methods This retrospective claims study used the MarketScan® databases from 2008 to 2017 to derive prevalence estimates for erectile dysfunction and hypogonadism in men with spina bifida, to compare these estimates to those in men without spina bifida, and to describe treatment patterns in this cohort. All men in aged 18 years and older with a diagnosis of SB were included for analysis. Patients with congenital hormonal disorders were excluded. To analyze treatment utilization, the National Drug Codes for pharmacotherapies for ED or HG and Current Procedural Terminology (CPT) codes for penile prosthesis were used. Results The estimated prevalence of erectile dysfunction and hypogonadism in men with spina bifida was 7.83% and 7.71%, respectively. Men with spina bifida in the sample exhibited high rates of smoking and metabolic comorbidities, but were diagnosed less frequently with erectile dysfunction when controlling for age and metabolic comorbidities than men without spina bifida. Most men with spina bifida and ED (66.6%) or hypogonadism (77.4%) do not receive treatment. However, a diagnosis of spina bifida did not appear to affect the likelihood of treatment for either condition on multivariate analysis. Conclusions Based on the results, claims data suggest that HG and ED are diagnosed less frequently than expected. While there are some limitations to the population being examined in this database, improving health care delivery of sexual health concerns during the surveillance of men with spina bifida will enhance their quality of life and optimize their sexual and metabolic function. Disclosure No

Phosphodiesterase-5 Inhibitors as Therapeutics for Cardiovascular Diseases: A Brief Review.

Three selective and most used inhibitors of PDE-5-sildenafil, vardenafil and tadalafil- have been successfully used for the treatment of erectile dysfunction. Erectile dysfunction and cardiovascular diseases might be considered as two dissimilar clinical signs of the identical systemic disease. PDE-5 inhibitors can through different models and mechanisms induce vasodilation, decrease apoptosis and cell proliferation, and they are widely present in various tissues that make them promising targets in a range of cardiovascular diseases. PubMed was explored to identify papers published from 1990-2019, presenting data for the most used PDE-5 inhibitors (sildenafil, tadalafil or vardenafil) in treatment of cardiovascular diseases. This article analyses the therapeutic potentials of PDE-5 inhibitors in cardiovascular diseases and discusses mechanisms, possible risks and limitations. Comparable to earlier studies, newer studies suggest cardioprotective effects of PDE-5 inhibitors, which include different models and mechanisms and do not indicate an increased rate of significant cardiovascular adverse reactions. Dissimilarity in the pharmacokinetics and pharmacodynamics of PDE-5 inhibitors are significant to their risk- benefit profile and clinical use. Some of the studies suggesting infarct size reduction after PDE-5 inhibition described the especially close dose-effect relation, other studies dosage adaptation in drug- drug interactions. PDE-5 inhibitors indicate the encouraging useful effects by ischemia/reperfusion injury, myocar-dial infarction, cardiac hypertrophy, cardiomyopathy and systolic and diastolic congestive heart failure. Therefore, this and similar reviews can help for additional clinical targeting in the therapy of cardiovascular diseases.

85 - Major Adverse Cardiovascular Events (MACE) related to phosphodiesterase 5 inhibitors (PDE5I): Analysis of real-life data from Eudra-Vigilance (EV) database

85 - Major Adverse Cardiovascular Events (MACE) related to phosphodiesterase 5 inhibitors (PDE5I): Analysis of real-life data from Eudra-Vigilance (EV) database

Using Big Data to Uncover Association Between Sildenafil Use and Reduced Risk of Alzheimer's Disease.

Alzheimer's disease is a chronic neurodegenerative disease with multiple pathogenesis pathways. Sildenafil, one of the phosphodiesterase-5 inhibitors, was proven to have effective benefits in transgenic Alzheimer's disease mice. The purpose of the study was to investigate the relationship between sildenafil use and the risk of Alzheimer's disease based on the IBM® MarketScan® Database covering over 30 million employees and family members per year. Sildenafil and non-sildenafil-matched cohorts were generated using propensity-score matching with the greedy nearest-neighbor algorithm. The propensity score stratified univariate analysis and the Cox regression model showed that sildenafil use was significantly associated with a 60% risk reduction of developing Alzheimer's disease (HR=0.40; 95%CI:0.38-0.44; P<.0001) compared to the cohort of individuals who did not take sildenafil. Sex-stratified analyses revealed that sildenafil was related to a lower risk of Alzheimer's disease in subgroups of both males and females. Our findings demonstrated a significant association between sildenafil use and a lower risk of Alzheimer's disease.

Determination of Phosphodiesterase Type-5 Inhibitors (PDE-5) in Dietary Supplements.

This study proposed a high-performance thin-layer chromatography (HPTLC) screening method to detect phosphodiesterase 5 (PDE-5) inhibitors as possible adulterant agents in various dietary supplements. Chromatographic analysis was performed on silica gel 60F254 plates using a mixture of ethyl acetate:toluene:methanol:ammonia in a volume ratio of 50:30:20:0.5 as a mobile phase. The system provided compact spots and symmetrical peaks of sildenafil and tadalafil with retardation factor values of 0.55 and 0.90, respectively. The analysis of products purchased from the internet or specialized stores demonstrated the presence of sildenafil, tadalafil, or both compounds in 73.3% of products, highlighting inadequacies and inconsistencies in the labeling, as all dietary supplements were declared to be natural. The results were confirmed using ultra-high-performance liquid chromatography coupled with a positive electrospray ionization high-resolution tandem mass spectrometry (UHPLC-HRMS-MS) method. Furthermore, in some samples, vardenafil and various analogs of PDE-5 inhibitors were detected using a non-target HRMS-MS approach. The results of the quantitative analysis revealed similar findings between the two methods, with adulterant quantities found to be similar to or higher than those in approved medicinal products. This study demonstrated that the HPTLC method is a suitable and economical method for screening PDE-5 inhibitors as adulterants in dietary supplements intended for sexual activity enhancement.

Comparison of the efficacy of tadalafil in three different groups; patients on hemodialysis, first kidney transplant recipients, and second kidney transplant recipients

Introduction: The efficacy of phosphodiesterase-5 inhibitors (PDE5Is) on the improvement of erectile dysfunction (ED) in second kidney transplant (KT) recipients has not been studied before. Objectives: We aimed to compare the efficacy of tadalafil in three groups: hemodialysis (HD) patients, first KT recipients (KT1) and second KT recipients (KT2) with bilaterally ligated internal iliac arteries (IIAs). Patients and Methods: Age-matched men with ED were included in the study. Patients divided into three groups; HD, KT1 and KT2. The international index of erectile function 15 (IIEF-15) questionnaire was used to assess the baseline erectile function. Tadalafil was administered in a dose-escalation method for three months. Patients were reevaluated by the questionnaire at three months. The mean score evolution was compared between the study groups by Kruskal-Wallis H test. Results: Total number of 106 patients in three groups was included in the final analysis. There was no significant difference between the study groups in terms of age, body mass index (BMI), blood pressure and frequency of smoking, opium, or alcohol use. Tadalafil was safe and effective in all three groups. The mean IIEF score evolution in HD, KT1 and KT2 groups was 16.4 (58.7% increase from baseline), 19.3 (45.0% increase) and 20.4 (52.7% increase), respectively. Conclusion: Tadalafil is effective and safe in the management of ED even after the second kidney transplantation when the IIAs are cut bilaterally. The response rate is similar to first KT recipients and HD patients. Trial Registration: The trial protocol was approved by the Thai Clinical Trials Registry (https://www.thaiclinicaltrials.org/show/TCTR20220310008, ethical code# IR.SBMU. UNRC.1396.43).

The action of phosphodiesterase-5 inhibitors on β-amyloid pathology and cognition in experimental Alzheimer's disease: A systematic review.

Alzheimer's disease (AD) is the most frequent cause of dementia worldwide. The etiology of AD is partially explained by the deposition of β-amyloid in the brain. Despite extensive research on the pathogenesis of AD, the current treatments are ineffective. Here, we systematically reviewed studies that investigated whether phosphodiesterase 5 inhibitors (PDE5i) are efficient in reducing the β-amyloid load in hippocampi and improving cognitive decline in rodent models with β-amyloid accumulation. We identified ten original studies, which used rodent models with β-amyloid accumulation, were treated with PDE5i, and β-amyloid was measured in the hippocampi. PDE5i was efficient in reducing the β-amyloid levels, except for one study that exclusively used female rodents and the treatment did not affect β-amyloid levels. Interestingly, PDE5i prevented cognitive decline in all studies. This study supports the potential therapeutic use of PDE5i for the reduction of the β-amyloid load in hippocampi and cognitive decline. However, we highlight the importance of conducting additional experimental studies to evaluate the PDE5i-related molecular mechanisms involved in β-amyloid removal in male and female animals.