PDE5 Inhibitors Research Articles

(187) Efficiency and Safety of Combining Long-Acting and Short-Acting PDE5 Inhibitors

Abstract Introduction Erectile dysfunction is a condition that affects many men worldwide, significantly impacting their quality of life. PDE5 inhibitors (PDE5i) are commonly prescribed medications for treating this condition, but some patients do not adequately respond to these treatments Objective This study aims to evaluate the efficacy and safety of a combination of long-acting and short-acting PDE5 inhibitors in non-responding patients Methods The study was conducted on 40 men with erectile dysfunction refractory to PDE5 inhibitors. Participants were evaluated using questionnaires, clinical examinations, and paraclinical tests. All patients received a combination treatment of daily 5 mg tadalafil and 100 mg sildenafil on-demand, one hour before sexual intercourse. Patients were followed up for 12 weeks, and the results were assessed using questionnaires and recording of side effects. Results The average age of the participants was 47.4 years. The main etiologies of erectile dysfunction were vascular, psychogenic, age-related, or neurological. After 6 weeks of treatment, a statistically significant improvement was observed in erectile function scores (SHIM) and erectile rigidity scores (EHS). This improvement was maintained until the 12th week, although not significantly. Side effects were generally minor and well-tolerated. Conclusions The combination of long-acting and short-acting PDE5 inhibitors proved to be effective and safe in non-responding patients to PDE5 inhibitors. This therapeutic approach offers a promising alternative before resorting to other more invasive options, such as prostaglandins or penile prosthesis. The combined use of these two types of inhibitors improves erectile function while minimizing undesirable side effects. Further studies could explore the addition of vacuum devices, shockwave therapy, or platelet-rich plasma injections to optimize outcomes. Overall, this study provides valuable insights for urologists in the treatment of non-responding patients to a single type of PDE5 inhibitor, opening up new therapeutic perspectives. Disclosure No.

(138) Efficacy and Patient Satisfaction of Low-Intensity Shockwave Treatment for Erectile Dysfunction in a Retrospective Real-World Study in Japan

Abstract Introduction In Japan, the treatment options for erectile dysfunction (ED) are very restricted, if phosphodiesterase type 5 inhibitors (PDE5Is) are not effective. In this situation, low-intensity extracorporeal shockwave therapy (LiESWT) has gained increased attention as a new option for ED treatment in Japan. Objective To clarify the efficacy of low-intensity extracorporeal shockwave therapy for patients with erectile dysfunction, compare the efficacy between two types of lithotripters (ED1000 [focused type] and Renova [linear type]), and detect factors indicative of therapeutic gain with the treatment. Methods This retrospective study included 76 patients (52.8 +/- 11.7 years) treated by ED1000 (12 times over 9 weeks) and 484 patients (52.5 +/- 11.6 years) treated by Renova (4 times over 4 weeks). Age, sexual symptoms scores, and blood examinations were assessed. Efficacy was judged by improvement of the scores and patient satisfaction and compared between patients at 1 month after treatment with the lithotripters. Independent factors influencing efficacy by Renova were also assessed. Results Sexual symptom scores were improved significantly by both lithotripters, although the changes in the scores did not differ significantly between them. Efficacy rate as judged by patient satisfaction was 65.8% with the ED1000 and 71.1% with Renova, also without significant difference. Among several factors including age, sexual symptoms scores, endocrinological factors, metabolic factors, and the rate of phosphodiesterase type 5 inhibitor use, only age was found to be an independent factor influencing the efficacy of Renova. Conclusions We clearly showed the high efficacy of both lithotripters. Although the efficacy rate did not differ between them, we speculated that the fewer treatment sessions needed with the Renova versus the ED1000 would be a great advantage for patients. We also suggest that Renova should be recommended for patients younger than 70 years of age. Disclosure No.

(063) Effect of Phosphodiesterase Type 4 Inhibitor on Erectile Function Recovery and Nerve Regeneration After Cavernous Nerve Injury in Rats

Abstract Introduction There is no consensus on the best treatment regimen for recovery of erectile function (EF) after radical prostatectomy (RP). Although many pharmacological interventions can improve EF in rats, there is still a lack of studies evaluating strategies that promote nerve regeneration of the cavernous nerve (CN). Phosphodiesterase type 4 inhibitors (PDE4Is), such as rolipram, have shown a neuroprotective effect after spinal cord injury in mice, facilitating functional recovery. It has also been suggested that the neuroprotective property of sildenafil is probably attributed to its effect on phosphodiesterase type 4. Objective Our aim was to evaluate the role of rolipram and its association with tadalafil in EF recovery and nerve regeneration after bilateral CN crush injury (BCNI) in rats. Methods Thirty-five male Wistar rats were randomly divided into four groups: (i) sham (no CN lesion); (ii) control (no treatment after BCNI); (iii) BCNI + tadalafil; (iv) BCNI + rolipram and (v) BCNI + tadalafil + rolipram. The initial laparotomy was performed and the CN were crushed with a hemostatic clamp. The animals in groups (iii) and (iv) received tadalafil (5mg/kg/d) or rolipram (1mg/kg/d) orally for 14 days, respectively. The animals in group (v) received tadalafil + rolipram at the same doses. Then, the animals were submitted to CN stimulation at frequencies 4, 8 and 16 Hz, with recording of mean arterial pressure (MAP) and intracavernosal pressure (ICP). EF was represented by the measurement of maximum ICP normalized to MAP (ICP/MAP ratio) and total normalized area under the curve (AUC) of ICP. The penises and CN of the animals were sent for structural evaluation with the immunohistochemical markers S100 and Ki-67. Results In the functional analysis, BCNI resulted in worse EF when compared to sham. This was observed when considering the maximum ICP/MAP and when analyzing normalized AUC of ICP for 4Hz and 8Hz. The different treatments were able to increase the ICP/MAP ratio after stimulation with 4Hz (p = 0.04) and 8Hz (p = 0.01). When considering normalized AUC of ICP, the different drugs (tadalafil, rolipram or tadalafil + rolipram) showed a significant improvement in EF in two of the three frequencies analyzed (4Hz and 8Hz) (figure 1). For 16hz, although it did not reach a statistical difference, a trend of improvement was observed after the different treatments (p = 0.08). With regard to immunohistochemical analysis, the tadalafil group had a higher expression of S100 in the dorsal penile nerve compared to the control group (p = 0.01). The rolipram group had a lower expression of Ki-67 in the CN compared to the control group (p = 0.03). Conclusions The combination of tadalafil and rolipram was associated with a functional improvement in EF in the experimental model with rats. The present study also suggests that rolipram may have a neuroprotective effect according to the structural evaluation of the CN. Disclosure No.

(206) Strategies of Nitric Oxide Augmentation for PDE5 Inhibitors

Abstract Introduction Erectile function and endothelial functions are closely related entities. Nitric oxide NO regulates circulation and microcirculation involved in erection.NO concentration is reduced with aging, diabetes, environment pollution smoking, obesity, inflammation, high prolactin, low testosterone oxidative stress and atherosclerosis. Many of erectile dysfunction patients are PDE5 inhibitor resistant. Strategies to enhance NO expression, can be employed to convert treatment resistant patient into responder. Objective Employ every possible mechanism to augment nitric oxide expression. Greater base line nitric oxide better would be PDE5 inhibitor respose. Methods Internet search was made on various website including pub med, science direct, google scholars using key words like erection, erectile dysfunction, nitric oxide, l arginine, oxidative stress, antioxidant, NOS, endothelial dysfunction, atherosclerosis and etc. This was followed by literature study on given topic. Results Efficacy of PDE 5 inhibitor in ED treatment is 70%. NO concentration decline to 50% by age of 40 and is only 15% at age 60. Humming can increase nasal NO level up to 15 time. Conclusions NO regulates endothelial function, vasodilatation, platelet aggregation inhibition, free radical scavenging, testosterone synthesis and neuronal protection. Study of mechanism of NO production provides, strategies for its enhancement. L arginine, L citrulline, serve as substrate and vitamin C, tetrahydrobiopterin (BH4) act as co factors in production of NO. Endothelial nitric oxide synthase e NOS, neuronal nitric oxide synthase n NOS are major enzymes act involved in synthesis. Oxygen is required for NO synthesis process. Supplementation of substrate and cofactors help increase NO levels. Oxygen availability can be increased through exercise and raising hemoglobin level. Reactive oxygen species ROS convert NO into bioinactive peroxynitrite which itself is ROS. Oxidative stress can cause endothelial nitric oxide synthase uncoupling. Consequently eNOS start producing ROS. This causes oxidation of NOS and as well as of cofactor like BH4 and vitamin C. ROS also increase level of methylarginines. Antioxidant used to neutralize ROS include Co Q10, alpha lipoic acid, flavonoids, bioflavonoids poly phenols, pycnogenol, resveterol, fulvic acid and etc. Second mechanism NO production is from dietary nitrates. Nutritional nitrates are converted into nitrite by oral anaerobic bacteria’s. Nitrate rich foods like beet root or spinach are added to enhance nitrate based NO. Nitric oxide thus produced is used for vasodilatation of penile vessels as well sinuses of corpus cavernousm. Apart from that it inhibits uncoupling of NOS. This support L arginine based mechanism of NO production. Nitroglycerin or minoxidal act as NO donors. These agents can be used locally at glans penis to augment NO availability. Bee breathing is maneuver in which humming sound vibrates nasal sinus increasing NO production up to 15 folds. Inhaled NO act as bronchodilator which increase lung capacity leading to higher blood oxygen concentration. Various NO enhancement strategies thus applied, may convert non responder PDE5 inhibitor to responders. Disclosure No.

(065) A Randomized, Single-Dose, Bioavailability and Safety Study on Novel SDS-089 Nasal Vardenafil 4mg Spray Solution in Comparison to Oral Vardenafil Tablet 10 mg in Healthy Volunteers

Abstract Introduction Oral phosphodiesterase type 5 inhibitor (PDE5i) is recognized as an effective first-line medical therapy for males with erectile dysfunction. However, oral PDE5i drug adherence and satisfaction rates were not high due to the need for oral ingestion, lack of sexual spontaneity, and delay in time to clinical effect. Hence, a nasal delivery of PDE5i drug may circumvent these limitations. Objective To assess the bioavailability and safety profile of SDS-089 nasal Vardenafil spray compared to oral Vardenafil 10mg tablet. Methods Following approval from Institutional Review Board and Biosafety Committee (FB18/IRB/099), 13 subjects out of the 32 healthy volunteers met the study criteria and were randomized to receive SDS-089 nasal Vardenafil spray (4 mg) or oral Vardenafil tablet (10 mg). The vardenafil HCl formulation SDS-089 was prepared with the active pharmaceutical ingredient meeting the United States Pharmacopeia (USP) standard (batch 1704002361). Blood tests were conducted on the subjects to evaluate Vardenafil drug bioavailability and treatment-related adverse events (TRAEs) data was collected. Results All 13 subjects completed the study. Based on the drug pharmacokinetics data, SDS-089 nasal spray was shown to have a faster onset and achieve optimal dose with a lower amount of drug compared to oral formulation. Of the 42 recorded TRAEs, 33 TRAEs were associated with the nasal spray, and 9 TRAEs were related to oral drugs. Transient headache is the most common TRAE in the nasal group and was very tolerable. The reported headaches showed no relationship with Cmax (peak concentration) and AUC0-inf (the total drug exposure across time) based on the Vardenafil drug levels. Conclusions SDS-089 nasal spray formulation Vardenafil HCl at 4 mg successfully achieved a similar Cmax with that of oral Vardenafil 10 mg tablet, and while it appeared to have more TRAEs, these were transient and well-tolerated by the subjects. Disclosure Yes, this is sponsored by industry/sponsor: LTR Pharma. Clarification: Industry funding only - investigator initiated and executed study.

(202) Comparative Study of the Efficacy of Avanafil and Atorvastatin Daily Dose in Management of Vasculogenic Erectile Dysfunction

Abstract Introduction Erectile dysfunction (ED) is defined as the “consistent inability to attain or maintain a penile erection, or both, sufficient for adequate sexual relations”. ED is not only a medical problem but affects the marital relations and patient's self-esteem and causes the quality of life to decrease. which in turn causes the patient to go into depression or develop anxiety. In the past, erectile dysfunction was considered, in most cases, to be a purely psychogenic disorder, but current evidence suggests that more than 80% of cases have an organic aetiology. Causes of organic erectile dysfunction can now be broadly divided into nonendocrine and endocrine. Of the nonendocrine aetiologies, vasculogenic (affecting blood supply) is the most common and can involve arterial inflow disorders and abnormalities of venous outflow (corporeal veno-occlusion). Avanafil is a second-generation phosphodiesterase type 5 inhibitor approved for erectile dysfunction by the FDA on 2012 and by EMA in 2013. With a high selectivity for phosphodiesterase type 5 isoform AND faster onset of action compared with other PDE5 inhibitors, it offers more tolerability and less adverse events. Atorvastatin is 3-hydroxy-methylglutaryl (HMG)-CoA reductase inhibitor act on the rate-limiting step in cholesterol biosynthesis (the conversion of HMG-CoA to mevalonate) and are effective in treating dyslipidemia. statins reverse endothelial dysfunction by decreasing the action of oxidized low-density lipoprotein (LDL) on endothelial cells, resulting in an increase of NO activity. Objective is to evaluate and compare the efficacy of avanafil and atorvastatin daily dose in management of patients with vasculogenic erectile dysfunction. Methods A 60 adult heterosexual males complaining of vasculogenic erectile dysfunction proven by penile duplex were collected from outpatient andrology clinics of Al-Azhar University Hospitals. The patients were divided into two treatment groups: (Group A): 30 patients received daily dose of 100 mg avanafil. (Group B): 30 patients received daily dose of 40 mg atorvastatin, The main outcome measures and the difference in penile duplex ultrasound results and IIEF-EF scores between the two groups are evaluated and compared at the end of the study, Age of patients between 20 and 50 years, established diagnoses of Vasculogenic erectile dysfunction, Normal lipid profile, Normal Total and Free testosterone levels and No contraindications to the study medications were included criteria. However patients who failed to fulfill any of the inclusion criteria, psychogenic or neurogenic erectile dysfunction, dyslipidemia Patients with Renal or Hepatic insufficiency and Patients with advanced cardiovascular diseases such as heart failure and coronary artery disease on antianginal drugs especially nitrates were excluded. Results Our study revealed statistically significant improvement in Penile Doppler ultrasonography parameters (PSV, EDV& RI) and IIEF-EF scores in avanafil group compared to atorvastatin group. Conclusions avanafil 100 mg daily dose leads to significant improvement in men with vasculogenic erectile, while atorvastatin 40 mg caused no significant differences, neither positively nor adversely. In summary, avanafil at dose of 100 mg can be a therapeutic appropriate choice in cases of vasculogenic ED. Disclosure No.

(274) BMP2 Restores Erectile Dysfunction Through Neurovascular Regeneration and Fibrosis Reduction in Diabetic Mice

Abstract Introduction The odds of erectile dysfunction (ED) are thrice more prevalent in diabetes. Severe peripheral vascular and neural damage in diabetic patients responds poorly to PDE5 inhibitors. However, bone morphogenetic protein 2 (BMP2) is known to be involved in angiogenesis. Objective To assess the efficacy of BMP2 stimulating angiogenesis and augmenting nerve regeneration in a mouse model of diabetic-induced erectile dysfunction. Methods The induction of diabetes mellitus was done by streptozotocin (STZ, 50 mg/kg daily) administered intraperitoneally for five successive days to male C57BL/6 mice that were 8 weeks old. Eight weeks post inductions, animals were allocated to one of five groups: a control group, an STZ-induced diabetic mouse group receiving two intra-cavernous 20 μL PBS injections, or one of three BMP2 groups administered two injections of BMP2 protein (1μg, 5 μg, or 10 μg) diluted in 20 μL of PBS with three days interval between the first and second injection. The erectile functions were assessed two weeks after PBS or BMP2 protein injections by recording the ICP (intracavernous pressure) through cavernous nerve electrical stimulation. Angiogenic activities also nerve regenerating effects of BMP2 were determined in penile tissues, aorta, vena cava, the main pelvic ganglions, the dorsal roots, and from the primary cultured MCECs (mouse cavernous endothelial cells). Moreover, fibrosis-related factors protein expressions were evaluated by western blot. Results Erectile function recovery to 81% of the control value in diabetic mice was found with intra-cavernous BMP2 injection (5 μg/20 μL). Pericytes and also endothelial cells were extensively restored. It was confirmed that angiogenesis was promoted in the corpus cavernosum of diabetic mice treated with BMP2 through increased ex vivo sprouting of aortic rings, vena cava and penile tissues, and migration and tube formation of MCECs. BMP2 protein enhanced cell proliferation and reduced apoptosis in MCECs and penile tissues, and promoted neurite outgrowth in major pelvic ganglia and dorsal root ganglia under high-glucose conditions. Furthermore, BMP2 suppressed fibrosis by reducing MCEC fibronectin, collagen 1, and collagen 4 levels under high-glucose conditions. Conclusions BMP2 modulates neurovascular regeneration and inhibits fibrosis to revive the mice's erection function in diabetic conditions. Our findings propose that the BMP2 protein represents a novel and promising approach to treating diabetes-related erectile dysfunction (ED). Disclosure No.

(276) Light Emitting Diodes (LED) as a Potential Therapy for Erectile Function: A Preclinical Study in a Cavernous Nerve Injury Model

Abstract Introduction Erectile dysfunction (ED) induced by nerve injury including prostatectomy poorly responds to PDE5 inhibitor and requires invasive treatment. Light emitting diodes (LED) in some spectral range, is able to irradiate cells without overheating for its low energy consumption and to enhance mitochondrial metabolism, intracellular energy transfer, and thereby cell proliferation and tissue regeneration in some organs. We, herein, investigated whether and how LED therapy may improve penile erection in mouse cavernous nerve injury (CNI) - induced ED model Objective To identify the optimal LED parameters using molecular, histological, and erectile function analysis in cavernous nerve injury. Methods Eight week old male mice (n=120) were divided into 5 age-matched groups, a sham operation group receiving heat treatment, a CNI group receiving heat treatment, a CNI group receiving red light of LED (wavelength; 660 ±3% nm), a CNI group receiving near infrared light of LED (wavelength; 830 ±2% nm), and a CNI group receiving combination of both LED light. Mice were exposed to LED light for 30 minutes on the ventral side including penis for 5 consecutive days after CNI operation. Molecular study, histopathological analysis of the penis and erectile function test were done 2 weeks following the treatment in each subject. Results CNI group with heat treatment had much lower maximum and total ICP than sham control group. In contrast, three groups with LED light irradiation exhibited considerably improved maximum and total ICP, and the group with both LED treatments had the best erectile performance, reaching 90% of the sham surgery group. Histologically, mice treated with RED, NIR, or LED irradiation had more cavernous pericytes and endothelial cells than CNI mice after sham operation. In addition, all three CNI groups with various LED lengths improved neuroprotection and brain regeneration in CNI mice. All groups treated with LED showed increased expression of βIII-tubulin, neurofilament-1, and nNOS in cavernous tissue and dorsal nerve bundle. Additionally, LED treatment in three groups, particularly the combination group, significantly increased βIII-tubulin, S100, and myelin basic protein levels, indicating axonal integrity or expansion in the dorsal root and major pelvic ganglions. Molecular analysis of downstream signals of neural regeneration or angiogenesis showed that 3 groups with LED treatment increased phosphorylated PI3K, neurotrophic factors like BDNF, NGF, and NT-3, and angiogenic factors like angiopoietin1 and vascular endothelial growth factor in cavernous tissue and llpopolysaccharide-treated PC-12 cells. The TUNEL assay and BrdU staining of these tissue and cells showed lower cell apotosis and proliferation in LED-treated groups. Conclusions The results show that LED therapy with RED, NIR, preferably combination of each wavelength improves penile erection by neural progection or regeneration in cavernous nerve injury induced-ED. This noninvasive therapy may be useful in near future for ED refractory to PDE5 inhibitor. As far as we are aware, this is the first research to demonstrate the advantage of LED therapy, low level in sexual dyfunction field. Disclosure No.

(152) Efficiency Improvement Veno-Occlusive Surgeries for Treatment of Venous Leak with Autologous Stem Cell, VEGF and PRP

Abstract Introduction The venous leakage is one of the most often reason of erectile dysfunction (ED) in young and middle age men. The main reason of venous leakage or veno-occlusive Erectile Dysfunction (VOED) is the insufficiency venous obstruction under tunica albuginea of corpora cavernosa. Accordingly all types of veno-occlusive operations have particular and short term effect up to renovation of venous leakage in half year. Conservative treatment of VOED with PDE-5 has a low or mild effectiveness. Evermore young patients deny penile prosthesis implantation for psychological reason. Objective We want to stimulate growth of endothelial valves under tunica albuginea with injections autological mesenchymal stem cells (ASC) and autological VEGF (Vascular endothelial growth factor) and combine it with veno-occlusive surgeries. Methods 2012–2022 we treated 178 patients with VOED. The average patient age is 36.5 +4.1 years. Patients with prostatitis or depression/anxiety were excluded from the investigation or treated previously. We embolizated deep dorsal and Santorini plexus veins for patients with distal form of VOED–47 patients -Group 1. We ligated deep dorsal and penile veins for proximal form of VOED – 68 patients – Group 2. And we made both methods together for 65 patients –Group 3 with combination of proximal and distal leak. Patients with only surgical methods created subgroup A – 105 men. For improving of veno-occlusive mechanism for 73 patients (subgroup B) we injected to each corpus cavernosa 1 mln of autological stem cells 6 times (2 times before, during surgery and 3 times after surgery) each month and we performed 15 microinjections of VEGF each 10 days. Then we compared short (2 months) and long term (10 months) results. Results The efficacy of surgical treatment according to subjective data (questionnaires on IIEF-5) in 2 months was almost equal (16.7+3.1 and 16.9+3.0), but in 10 months significantly higher in SubGroup B(14.3+3.2 and 19.6+3.4). According to Doppler Penile Ultrasound in 10 months adding microinjections ASC and VEGF to surgery significantly improves Erectile function (absence of venous leakage) 56.4% - subgroup A and 87.4% - subgroup B. Only 6.8% patients subgroup B (opposite to 35.9% subgroup A) have to take PDE-5 inhibitors for maintain erectile function. Conclusions Half year injections of ASC and VEGF improve of veno-occlusive mechanism and increases effectiveness and long term result of veno-occlusive operations for treatment of VOED. Combine occlusive method (embolisation and ligation of veins) has the highest effectiveness and should be used in different types of leakage. Disclosure No.

Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and the Risk of Alzheimer Disease: A Cohort Study.

Repurposing phosphodiesterase type 5 inhibitors (PDE5Is) as drugs for Alzheimer disease (AD) risk reduction has shown promise based on animal studies. However, evidence in humans remains inconclusive. Therefore, we conducted a cohort study to evaluate the association between PDE5I initiation compared with nonuse and the risk of developing AD in men with erectile dysfunction (ED). Using electronic health records from IQVIA Medical Research Data UK (formerly known as the THIN database), we identified men aged ≥40 years with a new diagnosis of ED between 2000 and 2017. Individuals with a previous diagnosis of dementia, cognitive impairment, confusion, or prescription for dementia symptoms were excluded. The occurrence of incident AD was identified using diagnostic read codes. To minimize immortal-time bias, PDE5I initiation was treated as a time-varying exposure variable. Potential confounders were adjusted using inverse probability of treatment weighting based on propensity scores. Cox proportional hazard models were used to estimate the adjusted hazard ratio (HR) with 95% CIs. A secondary analysis explored the association between AD and the cumulative number of PDE5I prescriptions. Sensitivity analyses included lag (delay) periods of 1 and 3 years after cohort entry to address the prodromal stage of AD. The study included 269,725 men, with 1,119 newly diagnosed with AD during a median follow-up of 5.1 (interquartile range 2.9-8.9) years. The adjusted HR in PDE5I initiators compared with nonuse was 0.82 (95% CI 0.72-0.93). The associated risk of AD decreased in individuals issued >20 prescriptions: HR 0.56 (95% CI 0.43-0.73) for 21-50 prescriptions and HR 0.65 (95% CI 0.49-0.87) for >50 prescriptions. Sensitivity analysis with a 1-year lag period supported the primary findings (HR 0.82, 95% CI 0.72-0.94), but the results differed with the inclusion of a 3-year lag period (HR 0.93, 95% CI 0.80-1.08). PDE5I initiation in men with ED was associated with a lower risk of AD, particularly in those most frequently issued prescriptions. The differences between primary and sensitivity analyses highlight the need to explore the optimal lag period. To enhance the generalizability of our findings, a randomized controlled trial including both sexes and exploring various PDE5I doses would be beneficial to confirm the association between PDE5I and AD.

Design, synthesis, and biological evaluation of some new 2-phenyl-3,6-pyridazinedione derivatives as PDE-5 inhibitors

Various 2-phenyl-3,6-pyridazinedione derivatives 4a-j, 5a-c, 6a,b, 7a-c, 8, 9, 10a-d, and 11a-d, were effectivelysynthesized, and tested for their potential inhibition of phosphodiesterase enzyme at 10 µM. Then fourteen compounds exhibiting the highest inhibition 4b, 4d, 4e, 4g, 4h, 4i, 5a, 6a,b, 7c, 10a,b, 11a, and 11d were selected for screening their PDE-5 inhibition, where compounds 4b,g,h, and 11a revealed promising PDE-5 inhibition having IC50 values = 25, 53, 22, and 42 nM, respectively in comparison with Sildenafil (IC50 = 16 nM). Additionally, these four most active compounds were safe to normal fibroblast cell line WI-38. Moreover, 4f, 4h, 4j, 10d, and 11d had almost the same anti-proliferative effect against the aortic cell line as Sildenafil. Furthermore, molecular docking illustrated that the binding of the target compounds with the key amino acids in the binding site of PDE-5 (PDB 2H42) was like to that of the cocrystallized ligand Sildenafil. Additionally, molecular dynamics simulation for the most active compound 4h revealed high stability of the 4h -PDE5 complex explaining its promising activity as a PDE-5 inhibitor. Therefore, the 2-phenyl-3,6-pyridazinedione scaffold can be considered an important core for designing more promising PDE-5 inhibitors.

(160) Improving Symptoms in Young Men with Erectile Dysfunction: Testosterone Therapy With or Without PDE5 Inhibitors

Abstract Introduction While erectile dysfunction (ED) in young men has traditionally been viewed as primarily psychogenic in etiology, a growing body of evidence supports a higher prevalence of organic etiology. Objective The aim of this study was to further characterize the etiology and treatment outcomes of ED in men under 40 years at a single institution. Methods A retrospective chart review of men presenting with ED from 2010-2022 was undertaken. Men initially presenting under the age of 40 years were included and analyzed for hypogonadism, ED etiology, and treatment outcomes. Results Of our cohort, a total of 74 men under the age of 40 years presented with complaint of ED (mean age 31.6 years). Twenty-three (31.1%) men were eugonadal without organic etiology of ED. Of these men, 22 (95.7%) were started on phosphodiesterase-5 inhibitors (PDE5i) and one (4.3%) reported symptom resolution without treatment. The remaining 51 (68.9%) men presented with ED of likely organic origin. Forty-two (82.4%) of these men were hypogonadal and were started on testosterone, human chorionic gonadotropin, clomid and/or a PDE5i. Of those who followed up, 32 (91.9%) men reported improvement in symptoms after therapy. The organic etiologies of ED in the nine (17.6%) eugonadal men included history of urologic surgery (4), Peyronie’s disease (2), prior genitourinary trauma (1), spinal cord tumor (1), and prolactinoma (1). Within this group, four (44.4%) progressed to intra-cavernosal injection, two (22.2%) improved with PDE5i, and three (33.3%) were lost to follow-up. Conclusions It appears that the majority of young patients who present with ED are hypogonadal. Treating this population of men with medication to raise natural testosterone with or without the addition of a PDE5i has been shown to improve their symptoms. Young eugonadal men with no discernable organic etiology of ED respond well to oral PDE5i alone but tended to not follow-up, suggesting possible ED resolution without a need for prolonged treatment. In all, clinicians should check serum testosterone levels and conduct a thorough urological history to identify potential organic etiologies of ED in younger men before assuming a psychogenic basis. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Consultant for AbbVie, Marius, Tolmar, Endo, Petros, Boston Scientific, Coloplast Investor: Sprout.

(248) Evaluation of Androgen Receptor Signaling and Saturation in Erectile Dysfunction

Abstract Introduction Testosterone (T) is a steroid hormone responsible for the development and maintenance of male secondary sex characteristics. T exerts this physiologic function throughout by binding to the androgen receptor (AR). It is unclear how AR function varies as a function of serum T. Objective We hypothesized that there is a saturation value for the AR above which excess serum T does not lead to increased binding or downstream signaling. This study evaluated whether varied serum T levels were associated with AR signaling in the penile tissue of men with erectile dysfunction (ED). Methods The mean age of participants was 61 (IQR 8.5) years. The mean serum T level was 300.2 (IQR 231.3). The results of the western blot showed that HO and PDE-5 signaling was decreased in men with serum T less than 200 ng/dL compared to those with serum T above 200, while AR and iNOS expression was decreased in men with serum T less than 300 ng/dL compared to those with serum T above 300. Results Within a wide range of serum T values, AR signaling was similar in penile tissue above 200-300 ng/dL. These findings provide a possible explanation for why PDE5 inhibitors are most effective in men with serum testosterone levels greater than 200 ng/dL, as our western blot results indicate that PDE-5 signaling is diminished in men with lower serum testosterone levels. This suggests that maintaining eugonadal levels of serum androgens is essential for optimal functioning of PDE-5 inhibitors. Conclusions Our findings suggest that there is a limit to the effect of serum testosterone levels on AR signaling, as the downstream activity appears to plateau beyond a certain point of receptor activation. Disclosure No.

(162) Evaluating the Effectiveness of Testosterone Therapy Combined with PDE5 Inhibitors in Enhancing Erectile Function in Eugonadal Men

Abstract Introduction Historically, testosterone therapy (TTh) is not indicated in eugonadal men with erectile dysfunction (ED). Moreover, the 2018 AUA Guidelines state that TTh is not indicated as monotherapy for men suffering from ED but should be considered as combination therapy with PDE5i, as TTh may increase the efficacy of PDE5i therapy. Objective We investigated the benefits of providing TTh in combination with PDE5i therapy in marginally eugonadal men to determine its efficacy in improving erectile function. Methods A retrospective chart review was performed on men presenting with ED to an academic institution’s Men’s Health Clinic from 2010 to 2022. Objective data was gathered on key variables that affected patient-reported outcomes of ED, including age at presentation and comorbidities, as well as use of TTh and use of oral PDE5i. 177 eugonadal men were selected with the criteria of testosterone levels >300 ng/dL on initial presentation. Results were then statistically analyzed using a two-tailed student’s T test in R and p-values to determine the significance between variables and outcomes in ED. Results Out of our cohort of 179 eugonadal men presenting with ED, 42 patients were continued or started on concurrent TTh with oral PDE5i therapy added, and 83 were started on PDE5i monotherapy. Men in the dual-therapy group excluding those already on TTh began with a pre-therapy testosterone mean of 412.3 ng/dL compared to 443.0 ng/dL which was insignificant (p=0.22). There were no significant differences in presenting age (p=0.61) or comorbidities including hypertension (p=0.89) and diabetes (p=0.63) between the two groups. Additionally, there were no significant differences in lab values of HgA1c (p=0.34), cholesterol (p=0.80), triglycerides (p=0.27), or LDL (p=0.89). However, there was a lower initial HDL in the combination group of 45.1 mg/dL compared to 55.8 mg/dL (p = 0.036). Men in the dual-therapy group were more likely to report subjective improvement in ED symptoms compared to men taking PDE5is alone. This was supported by 33/42 (78.6%) of men in the dual therapy group reporting improved erectile function compared to 49/83 (59.0%) of men in the PDE5i only group (p = 0.029). Conclusions In conclusion, these results demonstrate that treatment of eugonadal men with concurrent TTh and PDE5i therapy demonstrated a significant improvement in erectile function as compared to PDE5i therapy alone. These findings suggest consideration of testosterone therapy in addition to PDE5i in clinical practice when treating marginally eugonadal men presenting with ED. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Consultant for AbbVie, Marius, Tolmar, Endo, Petros, Boston Scientific, Coloplast Investor: Sprout.

(229) A Pilot Study of a Novel PRP Protocol to Increase Penile Length, Girth, and Function

Abstract Introduction A study of a novel PRP protocol to increase penile length, girth, and function Intro: Various solutions have been utilized to increase penis size, including fillers, fat transfers, traction devices, suspensory ligament ligation, and silicon augmentation. None of these improve length, girth, function and are completely safe. PRP is an autologous source of growth factors. The RestoreX is a well-studied traction device. Vacuum erection devices provide a stimulus for circumferential penile growth. Nitric Oxide boosters improve blood flow and nighttime erections. Objective The P-Long Study aims to find a safe and reproducible way to increase the length, girth, and function of a normal male penis. Methods The study is IRB approved and patient consented. Inclusion criteria: healthy men aged 20 to 55 with normal erectile function (SHIM greater than 22) and no Peyronie’s Disease, previous penile interventions, or congenital penile issues. Measurement of penile length and girth were performed by the patient on an erect penis during self-stimulation at full tumescence with standard protocol and measuring instruments (transparent rigid ruler and flexible tape measure) and documented with digital images. No PDE-5 inhibitors or Trimix were used. Measurements were taken at baseline and once a month for six months. PRP was administered in the right and left corpora under ultrasound guidance once a month for six months using PureSpin double spin system (60cc blood drawn) Centrifuge technical data show an average platelet recovery of 84% and average concentration of 6.6 times that of the whole blood sample. Using this data, the injection of 10cc of PRP, assuming a starting platelet count of 250K/microliter, would contain approximately 1.65 billion platelets. Traction with RestoreX 20 minutes bid and suction with Joel Kaplan penis pump (pressure 5-10 for 12 minutes bid (1 minute x 2 and 5 minutes x 2.) Nitric Oxide boosting supplement (trade name AFFIRM) with a dose of 3 gm L-Citrulline and 1 gm beet extract (nitrate). Results 29 men have completed treatment. The mean age was 32 and mean baseline erect penile length was 5.70 and girth was 5.25. Erect penis length was 0.805 inch greater after six months from baseline (N=29, paired t-test t=13.641 p value=0.000). Circumference was 0.469 inch greater (N=29, paired t-test t=13.498 p value=0.000). Using a Likert scale, all participants reported better erectile function. Conclusions The P-Long Protocol is potentially a safe way to improve erect penile length 0.81 inches and girth 0.47 inches over a period of six months and subjectively improve function in a healthy penis. The P-Long Protocol does not require any synthetic injectables or foreign bodies or extensive penile traction. The P-Long Protocol ultrasound-guided PRP injection can be taught to urologists and sexual medicine practitioners. It does not preclude additional augmentation procedures and is potentially an acceptable first option for men interested in penile enhancement. This study provides a guide for expectations for growth for men using the protocol. The slope of the growth curve indicates possible continued growth with additional treatments. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: AFFIRM Science.

(127) Sexual Health Implications Associated with Psychotropic Medication Use Among Adolescents During the COVID-19 Pandemic

Abstract Introduction The use of psychotropic medications has a notable effect on sexual well-being. Prolonged use is closely linked to dyspareunia, reduced sexual desire, hypogonadism, and erectile dysfunction. We hypothesized that there was an increase in the prescription rates of psychotropic medications among adolescent patients during the COVID-19 pandemic due to the unprecedented stress experienced by isolated youth. Objective We examined the prescription rates of psychotropic medications and the simultaneous usage of PDE5 inhibitors in adolescent patients during the COVID-19 pandemic in order to compare usage of these medications prior to the pandemic. Methods To conduct our retrospective matched cohort study, we utilized data obtained from the TriNetX Research Network. The study focused on adolescent patients aged 10-19 presenting for outpatient evaluation, and were placed into two cohorts: 1) those evaluated before the COVID-19 pandemic, and 2) those evaluated during the pandemic. Patients with previous psychiatric diagnoses or prior use of psychotropic medications were excluded from the study. Our primary interest was to examine new prescription patterns within 90 days of the outpatient evaluation. To ensure balanced cohorts, propensity score matching was conducted using logistic regression, resulting in cohorts of equal size. Results A total of 1,612,283 adolescents pre-COVID-19 and 1,008,161 adolescents presenting during the COVID-19 pandemic for outpatient evaluations were identified. After propensity matching, a total of 1,005,408 adolescents were included in each cohort each with an average age of 14.7 ± 2.84 and 52% female and 48% male. Prescribing of antipsychotics and benzodiazepines were more frequent during the pandemic for adolescents (RR: 1.58, 95% CI 1.01-2.2). However, they were less likely to receive antidepressants (Risk Ratio (RR): 0.6, 95% Confidence Interval (CI) 0.57-0.63), anxiolytics (RR: 0.78, 95% CI 0.75-0.81), stimulants (RR: 0.26, 95% CI 0.25-0.27), as well as mood stabilizers (RR: 0.44, 95% CI 0.39-0.49). Erectile dysfunction requiring oral PDE5i in this cohort was more frequent during the pandemic for adolescents (RR: 1.53, 95% CI 1.05-2.01). Conclusions During the global COVID-19 pandemic, there was a notable rise in the prescription rates of antipsychotic and benzodiazepine medications compared to previous years. Interestingly, this increase aligned with a statistically significant rise in the prescription of PDE5 inhibitors (PDE5i) for treating erectile dysfunction. These findings indicate that clinicians need to be aware of the potential increased risk of medication-related sexual dysfunction among adolescents. Disclosure Yes, this is sponsored by industry/sponsor: NIH health grant RO1 DK130991 and Clinician Scientist Development Grant from the American Cancer Society. Clarification: Industry funding only - investigator initiated and executed study.

(287) A Patient's Journey with Erectile Dysfunction: Prediction Progression to Penile Implant

Abstract Introduction Inflatable penile prosthesis (IPP) is seen as the gold standard for surgical treatment for ED, specifically for patients that are not amenable to lifestyle changes or oral medications. Objective This study aims to explore which patients progress to seeking treatment with an IPP along their journey with erectile dysfunction. Methods This retrospective study identified patients with ED as a chief complaint during the primary visit or follow-up from 2009-2022. If patients eventually progressed to treatment with IPP, data was collected to find common features and analyzed. Results Of our cohort of 361 men presenting with erectile dysfunction (ED), 21 men progressed to the placement of an inflatable penile prosthesis (IPP). 20 men classified as non-Hispanic, with 13 white, 6 African American/black, and 1 Asian males. Only 1 man was Hispanic. 5 men had either hypertension (n = 11), hyperlipidemia (n = 10), or DM (n = 3), with 6 having both hypertension and hyperlipemia, 1 with hypertension and diabetes, and 1 with hypertension, hyperlipidemia, and diabetes. Median age of the group at surgery was 76 years (IQR: 71 – 82), with median time from initial presentation to surgery of 12 (IQR = 11.5-27.5) months. N = 10 men had trialed oral phosphodiesterase inhibitor type 5 (PDE-5i) therapy, and 7 men failed intracavernosal injection (ICI) therapy. 8 men had been treated for hypogonadal symptoms with testosterone replacement therapy (TRT). Of patients who had data available on their reason for IPP placement, indications included were Peyronie’s disease inhibiting intercourse (8/21), longstanding ED refractory to medical therapy (4/21), post-prostatectomy ED (4/21), history of priapism requiring surgical intervention (1/21), and history of spinal cord tumor (1/21). Among those treated with IPP, the median patient waited almost 1 year from initial presentation following failure with PDE5i, ICI, and TRT. 17/21 men reported satisfaction after IPP treatment. In those who progressed to IPP, the majority of indications were organic forms of ED (Peyronie’s disease, neurogenic, surgery). Conclusions Only 5.8% of men in this cohort went on to proceed with an IPP. In summary, our results indicate that IPP is best suited for those presenting with organic ED who have failed more conservative management techniques. Further studies are needed to assess why so few men go on to proceed with an IPP and wait an average of 2 years. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Consultant for AbbVie, Marius, Tolmar, Endo, Petros, Boston Scientific, Coloplast Investor: Sprout.

(012) Incidence of Peyronie’s Disease After Radical Prostatectomy Among Patients Undergoing Penile Rehabilitation Regimen

Abstract Introduction Radical prostatectomy remains one of the gold standard treatments for localized prostate cancer, the most prevalent solid organ cancer in men. Surgical management of prostate cancer has been theorized to increase the risk of developing Peyronie’s Disease (PD). In 2010, Drs. Tal and Mulhall’s team characterized the incidence of PD in a cohort of 1011 men after radical prostatectomy to be 13.7% at 2 years and 15.9% at 3 years of follow-up. These numbers, significantly higher than estimates in the general population, which range from 0.5 to 7.1% (Sharma et al., Sex Med Rev 2020;8:314–23), suggest radical prostatectomy is a risk factor for developing PD. Objective Our aim was to evaluate the incidence of PD among post-prostatectomy patients who undergo a formal multi-modal penile rehabilitation program that includes mechanical and pharmacologic interventions to promote penile smooth muscle activation after surgery. Methods In this retrospective, descriptive study we reviewed the charts of 581 patients who were diagnosed with prostate cancer, treated with robot-assisted laparoscopic radical prostatectomy (RALP), and were engaged in a penile rehabilitation program from January 2016 through January 2019. At our institution, patients scheduled for prostatectomy are referred preoperatively to an academic Men’s Health clinic to start a multi-modal program and follow up regularly for evaluation of sexual health. The program includes daily tadalafil, L-citrulline, and VED use (Table 1). Patients refractory to these therapies had the option to increase tadalafil dosing or undergo further treatment with intracavernosal injections at ~3 months post-op. We excluded patients who had PD pre-operatively or who did not have post-operative follow-up with the providers at this institution. The primary outcome of interest was the incidence of PD among this cohort. Secondary outcome included time to development or diagnosis of PD. Results 581 patients with prostate cancer treated with RALP engaged in penile rehabilitation and were included in this analysis. The median age of men was 62.6 y with additional demographics listed in Table 2. The incidence of PD in this cohort was 2.9% (17 patients) with a median follow-up of 21.4 mo (IQR 2.8 – 55.8 mo). The diagnosis of PD was made at a median of 28.7 mo (IQR 20 – 36 mo) after prostatectomy. The 17 patients with PD had a median follow-up of 38.9 mo (IQR 23.2 – 55.8 mo). Conclusions In this cohort of prostate cancer patients treated with RALP and undergoing a consistent, multi-modal penile rehabilitation program, the incidence of PD was 2.9%, and median time to diagnosis was 28.7 months. This is the first study to assess PD incidence in men who engage in mechanical and pharmacologic penile rehabilitation at time of RALP. Furthermore, diagnosis of PD was made more than two years after surgery; this warrants further evaluation on whether penile rehabilitation prevents PD. This retrospective analysis is a hypothesis-generating study that should inspire further research on the role of regular mechanical stimulation or daily PDE-5 inhibitors in delaying or preventing PD after pelvic surgery. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Endo Scientific.

(222) Simultaneous Inflatable Penile Prosthesis and Adjustable Male Sling: A Step-by-Step Surgical Technique

Abstract Introduction Erectile dysfunction (ED) and urinary incontinence (UI) are common complications following radical prostatectomy (1). At twenty-four months post-surgery, approximately 43% of men experience some degree of ED, while UI affects around 15% of patients between twelve to twenty-four months (2, 3). Notably, nearly 20% of patients experience both ED and UI complications (4). Initial conservative management strategies include the use of PDE-5 inhibitors, intercavernosal injections, or a vacuum erectile device for ED and pelvic floor muscle training for UI (5). However, symptoms that persist or worsen beyond six months can be considered for surgical intervention (6). Surgical options include penile prosthesis implantation for ED and diverse techniques such as the Artificial Urinary Sphincter (AUS) or adjustable male urethral sling, depending on symptom severity, for UI management. Limited evidence suggests that a simultaneous surgical approach addressing both conditions can be a cost-effective and a safe alternative to separate surgeries (7, 8). Objective In this context, the objective of this video presentation is to illustrate a detailed, step-by-step technique for the simultaneous implantation of an inflatable penile prosthesis (IPP) and an adjustable male sling (AMS), while also discussing its feasibility, safety, and functional outcomes. Methods The combined IPP and AMS surgery is a safe, viable, and cost-effective option for patients who need to address both ED and UI. Rhee (2005) initially described the concurrent placement of a penile prosthesis (PP) and male sling (MS) in a series of four post-prostatectomy patients. Results The results demonstrated successful restoration of erections and complete continence in all patients, with no postoperative complications. Our previous systematic review, comparing the outcomes of simultaneous surgical placement of PP and MS versus PP and artificial urethral sphincter (AUS), found no clinically significant differences in outcomes between the two groups (Raheem 2021). Therefore, the simultaneous placement of IPP and AMS should be considered an option for patients, as it shows comparable effectiveness to other concurrent surgical interventions. Dual implantation of PP and male sling have also demonstrated cost savings of approximately $9,000 for patients, further enhancing its advantages in managing both ED and UI (Gorbatiy 2010). Ultimately, a collaborative discussion between patients and their urologist is crucial in determining the most suitable approach for patient individual needs. Conclusions The simultaneous surgical placement of an inflatable penile prosthesis (IPP) and adjustable male sling (AMS) presents a favorable and viable solution for managing erectile dysfunction (ED) and urinary incontinence (UI) in patients who exhibit an inadequate response to conservative management following prostatectomy. Disclosure No.

(230) Investigating the Efficacy, Satisfaction, and Predictors of Response to Low-Intensity Shockwave Therapy for Erectile Dysfunction

Abstract Introduction Erectile dysfunction (ED) affects 52% of men in the US, with treatment modalities varying significantly in their degree of invasiveness. Low-intensity shockwave therapy (LI-SWT) is an emerging non-invasive therapy that uses acoustic waves to improve cavernosal arterial flow by inducing microtrauma and subsequent angiogenesis, in addition to enhancing tissue regeneration and reducing local inflammation. Objective Our objective is to investigate the efficacy of LI-SWT, identify factors predictive of response, and explore patient satisfaction and attitudes towards the therapy. Methods An IRB-approved retrospective chart review and survey study was conducted, examining 102 men who underwent LI-SWT for ED between 2009-2022 at a single tertiary referral center. Univariate and multivariate analyses were performed in JMP. Results Out of 102 men, 50 (49.0%) subjects responded to the survey. 22 (44.0%) men reported clinical responses to LI-SWT, with an average improvement of 1.46 on the validated Erection Hardness Score (EHS; scale 0-5). Clinical responders noticed their first response after a mean of 3.53 treatments. 48 of the respondents (96.0%) had previously trialed PDE5 inhibitors, while 18 (36.0%) men previously trialed intracavernosal injections (ICI). On univariate analysis, alcohol use (OR 0.23, 95% CI 0.07-0.77, p =0.015) and prior ICI (OR 0.23, 95% CI 0.05-0.95, p=0.036) use were both associated with lower odds of response to LI-SWT. Interestingly, history of radical prostatectomy (RP) did not correlate with LI-SWT response (p=0.117). These results were redemonstrated on multivariate logistic regression, with alcohol use (OR 0.23, p=0.039) and prior ICI use (OR 0.17, p=0.047) again predicting lower odds of LI-SWT response. Of 28 men who did not benefit from LI-SWT, 5 (18%) progressed to ICI, and 3 (11%) progressed to inflatable penile prosthesis (IPP). Out of all respondents, only 2 men (4%) experienced side effects, which consisted of mild transient pain/paresthesia. No hematomas or bruising were reported, including 8 men on anticoagulants. Clinical responders demonstrated a higher mean satisfaction score of 7.1 on the 10-point Likert scale (somewhat satisfied) compared to non-responders who scored an average satisfaction score of 2.3 (somewhat dissatisfied). Surprisingly, the majority (66%) of the survey respondents were willing to try LI-SWT again, including 54% of first time non-responders. Conclusions Patients with a history of alcohol use and/or prior ICI use were associated with a lower likelihood of response to LI-SWT. LI-SWT demonstrated promising results as a non-invasive option for ED treatment, including treatment refractory ED as well as post-prostatectomy ED, with minimal adverse events. Responders viewed LI-SWT favorably as a modality for treating ED, and the majority of patients who had undergone LI-SWT were willing to try it again. These findings support the use of LI-SWT before resorting to more invasive ED therapies, including surgery. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Mohit Khera - consultant for Endo, Petros, AbbVie, Tolmar, Marius, Halozyme, Boston Scientific.