Hydro-Jet Dissection of the Cavernous Nerves Preserves Erection Function in a Radical Prostatectomy Animal Model.

BACKGROUND: Postoperative erectile dysfunction (ED) remains a prevalent consequence of radical prostatectomy (RP) that significantly impacts patient quality of life. Water-jet technology is widely used for dissection in neurosurgical procedures but novel to urologic surgery. AIM: To establish the impact of hydro-jet dissection (HJD) of the cavernous nerves (CN) on postoperative erectile function in an animal model of RP-induced ED. METHODS: 32 male Sprague-Dawley rats were randomized to 4 groups: Sham surgery (n = 8), bilateral HJD of CN (n = 8), blunt CN injury (n = 8), or stretch CN injury (n = 8). After 4 weeks, erectile function was assessed by measuring intracavernous pressure (ICP), and penile tissues were harvested for immunohistologic studies. MAIN OUTCOME MEASURE: The peak ICP and the area under the curve were calculated for each group. Immunohistologic studies were performed for α-smooth muscle actin and neuronal nitric oxide synthase on cross-sections of penile tissue. RESULTS: Rats in the HJD group demonstrate a significantly higher mean peak ICP and area under the curve compared with both CN injury groups (P = .001). Postoperative erectile function in the HJD group returned to baseline function. Preservation of α-smooth muscle actin and neuronal nitric oxide synthase was observed in the HJD group compared with the other surgical trauma groups. CLINICAL IMPLICATIONS: Hydro-jet dissection used in an RP animal model maintains erectile function and offers a potential benefit that warrants further human studies. STRENGTHS & LIMITATIONS: This is a novel animal study comparing a new technology to established CN dissection techniques. This study uses an animal model, which may not completely translate to post-RP ED in humans. CONCLUSION: Hydro-jet dissection of the CN during RP in an animal model is associated with significantly better postoperative erectile function when compared with other CN injury. Clinical studies are needed to further investigate the putative benefit of HJD on erectile function in patients undergoing RP. Campbell JD, Alenezi H, DeYoung LX, et al. Hydrojet Dissection of the Cavernous Nerves Preserves Erection Function in a Radical Prostatectomy Animal Model. Sex Med 2019;7:104-110.

Multi-institutional Prospective Analysis of Intralesional Injection of Collagenase Clostridium Histolyticum, Tunical Plication, and Partial Plaque Excision and Grafting for the Management of Peyronie's Disease.

OBJECTIVE: To compare in a prospective nonrandomized fashion, the outcomes of collagenase clostridium histolyticum (CCH) and surgical interventions (tunical plication [TP] and partial plaque excision and grafting [PEG]) in patients with Peyronie's disease (PD). Intralesional injection of CCH is the only Food and Drug Administration-approved nonsurgical intervention for PD. MATERIALS AND METHODS: Between June 2015 and January 2017, 57 patients with PD and dorsal, dorsolateral, and/or lateral penile curvatures 30°-90° were included in this study. Patients with ventral curvature, hourglass deformity, and previous surgery for PD were excluded. All patients completed questionnaires and underwent penile measurements and penile vascular studies prior to and after completion of treatment, and were followed for at least 6 months. RESULTS: CCH was administered to 18 patients, TP performed in 14, and PEG in 25. The median follow-up for the whole cohort was 12 months (6-28). Mean changes in curvature after treatment were 23.3° (34.4%) for CCH, 72.0° (92.2%) for TP, and 71.8 ° (94.9%) for PEG, P<.001. Mean changes in International Index of Erectile Function-5 scores were +5.7 for CCH, +4.9 for TP, and +2.2 for PEG, P = .395. Mean penile length changes were -0.2 cm for CCH, -1.0 cm for TP, and +0.9 cm for PEG, P<.001. Three patients in the CCH group had bothersome residual curvature and underwent uneventful TP. CONCLUSION: Surgical options are associated with superior curvature correction. CCH is an effective and safe option for motivated patients who prefer to avoid surgery. PEG is associated with a small stretched penile length gain.

Early experimental results of using a novel delivery carrier, hyaluronan-phosphatidylethanolamine (HA-PE), which may allow simple bladder instillation of botulinum toxin A as effectively as direct detrusor muscle injection.

INTRODUCTION: Botulinum toxin A (BTX-A) is a neurotoxin that inhibits acetylcholine release by cleaving cytosolic synaptosome-associated protein 25 (SNAP-25) and results in bladder relaxation. A BTX-A intravesical injection has been established as an effective option for treating detrusor overactivity. STUDY DESIGN: Sixty female Sprague Dawley rats were equally divided into control and experimental groups. Control Groups 1 to 3 received: BTX-A 10 units + saline instillation; hyaluronan-phosphatidylethanolamine (HA-PE) 0.5 g + saline instillation; and BTX-A 5 Uintra-detrusor injections, respectively. Treatment Groups 4 to 6 received: Alexa®594-labeled BTX-A 10 U + HA-PE 0.5 g + saline instillation; BTX-A 5 U + HA-PE 0.2-0.5 g instilled for 60 min; and BTX-A 10 U + HA-PE 0.2-0.5 g instilled for 30 min, respectively. All procedures were performed under isoflurane general anesthesia. The primary outcome of this study was the degree of SNAP-25 staining in control and experimental groups compared to Group 3 (detrusor muscle injection). Urodynamic studies were performed at baseline and at day 14 after 1% acetic acid (AA) instillation, to evaluate the maximum pressure during filling (MP) and inter-contraction intervals (ICI). Group 4 rats were examined for Alexa®594 fluorescence to demonstrate physical translocation of BTX-A-HA-PE complex. Standard histology was performed to assess the effect of HA-PE on bladder mucosa and detrusor muscle. RESULTS: Group 3 showed the least SNAP-25 staining (7.3 ± 5.0%) compared with all groups except Group 5A (12.4 ± 12.27%, P = 1.0). Group 6A, which had high HA-PE dose but a shorter instillation time, showed fairly extensive SNAP-25 staining (22.9 ± 10%). Confocal microscopy of Group 4 confirmed the presence of Alexa®594 fluorescence across the urothelium. Urodynamic parameters were not significantly different at baseline (P = 1.0). After acetic acid instillation, Group 5A showed minimal change in ICI, which was comparable to ICI in Group 3 rats. DISCUSSION: SNAP-25 staining in Group 5A was comparable to Group 3, suggesting that adequate HA-PE and instillation time allows the efficacy of this carrier mechanism to be comparable to standard intra-detrusor injections. All other groups showed significantly higher SNAP-25 staining compared to Group 3. A dose response effect was demonstrated; higher dose of HA-PE (Group 5A vs Group 5B) and longer instillation time (Group 5 vs Group 6) led to lower SNAP-25 staining. CONCLUSION: This novel method of BTX-A delivery to the bladder using a carrier (HA-PE) is promising and requires further investigation. Using a larger animal model, identifying an optimal dose of HA-PE and instillation time, and reproducing the current results are further required to validate this carrier.

The effects of combined free radical scavenger and sildenafil therapy on age-associated erectile dysfunction: An animal model.

INTRODUCTION: Aging results in erectile dysfunction that is partially attributed to decreased nitric oxide (NO) and increased free radical generation. Vitamin E enhances endothelial cell function and acts as a free radical scavenger; however, its benefits on erectile function in the elderly are unknown. AIMS: The aim of the following study is to determine if Vitamin E alone, or in combination with the phosphodiesterase 5 inhibitor sildenafil, may improve erectile function and the NO signaling in a cohort of aged (13-15 month old) rats. MATERIALS AND METHODS: Male Sprague-Dawley rats (n = 28) were divided based upon age into young (4-5 months old, n = 7) and aged (13-15 months old, n = 21) cohorts. Aged rats were treated with Vitamin E, sildenafil or a combination of both. Penile cavernosal and dorsal nerve tissues were evaluated for neuronal nitric oxide synthase (nNOS) and caveolin-1 expression. Erectile function was assessed through intra-cavernous pressure (ICP) recordings. RESULTS: nNOS and cavoelin-1 were significantly decreased in aged rats compared with young controls. In aged rats, both Vitamin E and sildenafil partially recovered nNOS expression but when combined, a synergistic elevation in nNOS was observed. The significant decreases in ICP recorded in aged rats were improved with sildenafil; however, Vitamin E did not yield any additional improvements in ICP. CONCLUSIONS: Diminished levels of nNOS and caveolin-1 are found in aged rats. When combined with sildenafil, Vitamin E synergistically increased nNOS expression. Since biochemical gains were not realized physiologically, other contributing factors likely exist.

Clinical outcomes and patient satisfaction rates among elderly male aged ≥75 years with inflatable penile prosthesis implant for medically refractory erectile dysfunction.

PURPOSE: The purpose of the study is to assess the clinical outcomes and patient satisfaction rate between men aged under and over 75 years who underwent inflatable penile prosthesis (IPP) implantation. METHODS AND MATERIALS: A retrospective review of clinical database and follow-up independent telephone survey was undertaken in all men who underwent first-time IPP implantation between January 2006 and November 2010. Patient demographics, surgical outcomes, and patient satisfaction rate using Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) scores were recorded. RESULTS: A total of 216 first-time IPP were implanted. Of these, 30 patients were aged ≥75 years. In men aged ≥75 years, 3 patients had IPP revision surgery for mechanical malfunction (average 18.6 months; 12-24 months). While the 2-year Kaplan-Meier estimates of mechanical survival showed better outcome in men aged ≥75 years than men aged <75 years (95 vs. 92%; p = 0.38), there was no difference in the IPP mechanical survival between the 2 groups at 3 years follow-up. There were no statistically significant differences in the ease of IPP use, and EDITS scores among the two groups. The majority of men were satisfied and would recommend the IPP surgery to other men. CONCLUSIONS: Men aged ≥75 years reported satisfactory outcome with IPP surgery with no statistical significant difference identified across device survival and satisfaction rates compared to men aged <75 years.

Comparison between AMS 700™ CX and Coloplast™ Titan inflatable penile prosthesis for Peyronie's disease treatment and remodeling: clinical outcomes and patient satisfaction.

INTRODUCTION: The implantation of inflatable penile prosthesis (IPP) with simultaneous manual penile remodeling allows for men to undergo a single procedure aimed at correcting both the penile deformity/curvature and erectile dysfunction (ED). AIM: To evaluate the clinical outcomes and patient satisfaction in men with Peyronie's disease (PD) and ED who underwent AMS 700™ CX and the newer Coloplast™ Titan inflatable penile prosthesis (IPP) implant. MAIN OUTCOME MEASURES: Patient demographics, type of IPP, clinical outcomes, post-implant sexual characteristics, and overall patient satisfaction. METHODS: A single-center retrospective review of clinical database and prospective telephone survey were conducted in all men with PD who underwent IPP between January 2006 and November 2010. RESULTS: A total of 138 patients with an average age of 57.7 (32 to 80) underwent AMS 700 CX (88 patients) and Coloplast Titans (50 patients) IPP implantation during the 5-year period. The majority of patients (91%) had only one IPP implantation. The IPP clinical outcomes include eight (6%) revision surgery for device malfunction and three (2%) device explantation for prosthesis infection. While there was no statistically significance in device survival between the two devices, the trend favored AMS 700 CX over Titan (5-year Kaplan-Meier estimates of mechanical survival were 91% vs. 87%, P>0.05) and both IPPs provided similar penile straightening without the need for revision surgery. Most men (79%) reported great satisfaction following CX or Titan implants with greater than two thirds of men reported greater self-confidence and 82% of patients would undergo the same operation again. CONCLUSIONS: AMS 700™ CX and Coloplast™ Titan IPP implantation and penile remodeling appeared to provide permanent penile straightening and high patient satisfaction without an increase risk of revision surgery.

Daily use of sildenafil improves endothelial function in men with type 2 diabetes.

Diminished vascular endothelial function results in decreased vasodilator capacity and is associated with erectile dysfunction (ED) in patients afflicted with type 2 diabetes. The current study was designed to evaluate whether daily use of sildenafil could alter endothelial function and improve penile rigidity in a group of patients with diabetic ED. A double-blind, placebo-controlled, prospective trial was conducted with 24 men with type 2 diabetes who were randomized into 2 groups: one receiving daily sildenafil (50 mg, n = 12) and the other placebo (n = 12) for 10 weeks. Erectile function was captured subjectively using the International Index of Erectile Function (IIEF-5), and endothelial function was objectively monitored via brachial artery flow-mediated dilation. Among the placebo and sildenafil groups, there were no significant differences in average patient age, time from type 2 diabetes diagnosis, duration of ED, or baseline IIEF-5 scores. Past medical histories, including smoking, alcohol consumption, hypertension, and hyperlipidemia, were also similar. At the conclusion of the 10-week trial, patients who received daily sildenafil had significantly improved erectile rigidity as captured by IIEF-5 (P < .001) and increased endothelial function via brachial artery flow-mediated dilation (P < .01). Endothelial function in men with type 2 diabetes was enhanced with daily sildenafil. Improved erectile rigidity and enhanced vascular circulation was noted after 10 weeks of daily sildenafil use.

Clinical outcomes of intracavernosal injection in postprostatectomy patients: a single-center experience.

OBJECTIVE: To evaluate the clinical outcomes of intracavernosal injection (ICI) use in an undifferentiated group of men with erectile dysfunction at various stages after radical prostatectomy. METHODS: Retrospective charts, mailed questionnaires, and a telephone survey of patients after radical prostatectomy prescribed ICI by a single urologist from January 2006 to January 2008. The patient demographics and prostate cancer profiles, current ICI use patterns, adverse outcome, and clinical efficacy were collected. RESULTS: A total of 117 patients completed the questionnaire. The mean age was 65±6.2 years, and the patients had undergone radical prostatectomy 4.1±2.7 years earlier. Most patients had hypertension (38%) and dyslipidemia (26%); 51% of the patients actively used ICI, with a median of 3 attempts monthly. Sixty-eight percent of all patients were sexually active (98% of ICI users vs 36% of ICI nonusers, P<.001). In the sexually active patients, ICI was associated with significantly greater International Index of Erectile Function scores (20.8±4.1 vs 16.0±6.9, P=.008). ICI was most frequently discontinued because of patient-perceived ineffectiveness (48%), pain (21%), and prolonged erections (11%). Twenty-eight percent of patients had erections lasting longer than they had wished at some point in their treatment, with 10% incidence of priapism. CONCLUSION: ICI use among patients after prostatectomy can be highly effective but has a significant attrition rate (49%). The identification of reasons for discontinued use can aid healthcare providers to support patients in the early period after adoption of ICI and to direct their counseling more effectively.

The role of PDE5 inhibitors in penile septal scar remodeling: assessment of clinical and radiological outcomes.

INTRODUCTION: Effective oral medication for use in men with Peyronie's disease (PD) has been an area of interest of the medical community and lay public for decades. Isolated septal scars (ISS) without evidence of penile deformity is a relatively new clinical entity, and at present, there is paucity in the published literature regarding its treatment. Current research into the use of phosphodiesterase type 5 (PDE5) inhibitors in regulating penile erectile response has revealed an alternative role for PDE5 inhibitors in decreasing oxidative stress-associated inflammatory change as seen in PD. AIM: To examine the presence of ISS and assess the efficacy of PDE5 inhibitor use in septal scar remodeling. METHODS: Retrospective review of prospective database on all men who underwent penile Doppler ultrasound between December 2007 and December 2009. MAIN OUTCOME MEASURES: Of the 65 men with ultrasonographic-confirmed ISS, 35 men received tadalafil 2.5 mg daily over a 6-month period. The clinical outcomes between the two groups were compared using International Index of Erectile Function (IIEF)-5 score and 6 months penile Doppler ultrasound follow up. RESULTS: The mean age for the tadalafil group was 43.2 (20-65) years, similar to the control group at 44.2 (34-72) years. The length of time from onset to presentation was 22 (6 to 40) months. The majority of ultrasonographic-proven ISS was not clinically palpable and complaint of decreased penile rigidity (66%) was the predominant feature. Treatment with low-dose daily tadalafil did not result in any significant side effects (such as headache and flushing) or discontinuation. The tadalafil group reported higher IIEF-5 score (pretreatment 11/25 to post-treatment 18/25) (P < 0.01) and resolution of septal scar were recorded in 24 patients (69%) compared to three patients (10%) in the control group. CONCLUSION: Low-dose daily tadalafil is a safe and effective treatment option in septal scar remodeling.

Daily administration of phosphodiesterase type 5 inhibitors for urological and nonurological indications.

OBJECTIVES: Although the discovery of phosphodiesterases (PDEs) was made soon after the identification of cyclic adenosine monophosphate nearly half a century ago, their true importance in medicine has taken many decades to be realised. The recognition of the important role PDE enzymes play and the impact of altering intracellular cyclic nucleotide levels became significant for most urologists and clinicians in the early 1990s with the discovery of sildenafil, a PDE5 inhibitor (PDE5-I). Once approved around the world, on-demand use of PDE5-Is became the gold standard. Recently, the potential beneficial effects of PDE5-Is on the pulmonary, vascular, and other systems has led to examination of alternative dosing regimens. In this review, we have synthesised the available published peer-reviewed literature to provide a critical contemporary view of evolving indications for PDE5-Is and how alternative dosing regimens may impact on sexual and other functions. METHODS: MEDLINE search of all peer-reviewed English literature for the period 1990-2007. RESULTS: The plethora of articles detailing potential uses of PDE5-I in multiple fields of medicine was uncovered. Use of alternative dosing regimens shows great promise across a number of clinical indications, including post-radical retropubic prostatectomy, pulmonary hypertension, endothelial dysfunction, and salvage of on-demand PDE5-I nonresponders. CONCLUSIONS: Use of PDE5-I on a daily basis may evolve into a major form of drug administration both for men with erectile dysfunction and for those with a myriad of other conditions shown to benefit from this approach.

Regulation of intracellular Ca2+ release in corpus cavernosum smooth muscle: synergism between nitric oxide and cGMP.

Tonic contraction of corpus cavernosum smooth muscle cells (SMCs) maintains the flaccid state of the penis, and relaxation is initiated by nitric oxide (NO), leading to erection. Our aim was to investigate the effect of NO on the smooth muscle cellular response to adrenergic stimulation in corpus cavernosum. Fura-2 fluorescence was used to record intracellular Ca(2+) concentration ([Ca(2+)](i)) from freshly isolated SMCs from rat and human. Phenylephrine (PE) transiently elevated [Ca(2+)](i) in the presence and absence of extracellular Ca(2+), indicating release from intracellular stores. Whereas the NO donor S-nitroso-N-acetylpenicillamine (SNAP) with sildenafil citrate (SIL) caused no change in basal [Ca(2+)](i), the PE-induced rise of [Ca(2+)](i) was reversibly inhibited by 27 +/- 7% (n = 21, P < 0.005) in rat and by 55 +/- 15% (n = 9, P < 0.01) in human SMCs. SNAP and SIL also reduced the contractile response to PE. To investigate the mechanism, we applied mediators alone or in combination. The soluble guanylyl cyclase inhibitor ODQ reduced the effect of SNAP and SIL. SIL, cGMP analogs, and NO donors without SIL did not reduce the PE-induced rise of [Ca(2+)](i). However, the combination of 8-bromo-cGMP with SNAP reduced the Ca(2+) peak by 42 +/- 9% (n = 22, P < 0.01). Our results demonstrate that NO and cGMP act synergistically to reduce Ca(2+) release from intracellular stores. Reduction of intracellular Ca(2+) release may contribute to relaxation of the corpus cavernosum, leading to erection.

Ca2+-activated Cl- channels in corpus cavernosum smooth muscle: a novel mechanism for control of penile erection.

Little is known of the excitatory mechanisms that contribute to the tonic contraction of the corpus cavernosum smooth muscle in the flaccid state. We used patch-clamp electrophysiology to investigate a previously unidentified inward current in freshly isolated rat and human corporal myocytes. Phenylephrine (PE) contracted cells and activated whole cell currents. Outward current was identified as large-conductance Ca(2+)-activated K(+) current. The inward current elicited by PE was dependent on the Cl(-) gradient and was inhibited by niflumic acid, indicative of a Ca(2+)-activated Cl(-) (Cl(Ca)) current. Furthermore, spontaneous transient outward and inward currents (STOCs and STICs, respectively) were identified in both rat and human corporal myocytes and derived from large-conductance Ca(2+)-activated K(+) and Cl(Ca) channel activity. STICs and STOCs were inhibited by PE and A-23187, and combined 8-bromoadenosine cAMP and 8-bromoadenosine cGMP decreased their frequency. When studied in vivo, chloride channel blockers transiently increased intracavernosal pressure and prolonged nerve-evoked erections. This report reveals for the first time Cl(Ca) current in rat and human corpus cavernosum smooth muscle cells and demonstrates its key functional role in the regulation of penile erection.