Gregory Lowe

10‐Year Analysis of Adverse Event Reports to the Food and Drug Administration for Phosphodiesterase Type‐5 Inhibitors

INTRODUCTION To ensure public safety all Food and Drug Administration (FDA)-approved medications undergo postapproval safety analysis. Phosphodiesterase type-5 inhibitors (PDE5-i) are generally regarded as safe and effective. AIM We performed a nonindustry-sponsored analysis of FDA reports for sildenafil, tadalafil, and vardenafil to evaluate the reported cardiovascular and mortality events over the past 10 years. METHODS Summarized reports of adverse events (AEs) for each PDE5-i were requested from the Center for Drug Evaluation and Research within the FDA. These data are available under the Freedom of Information Act and document industry and nonindustry reports of AEs entered into the computerized system maintained by the Office of Surveillance and Epidemiology. MAIN OUTCOME MEASURE The data were analyzed for the number of AE reports, number of objective cardiovascular events, and reported deaths. RESULTS Overall, 14,818 AEs were reported for sildenafil. There were 1,824 (12.3%) reported deaths, and reports of cardiovascular AEs numbered 2,406 (16.2%). Tadalafil was associated with 5,548 AEs and 236 deaths were reported. Vardenafil was associated with 6,085 AEs and 121 reports of deaths. The percentage of reported severe cardiovascular disorders has stabilized at 10% to 15% of all AE reports for sildenafil and tadalafil and 5% to 10% for vardenafil. Only 10% of AE reports sent to the FDA for PDE5-i were from pharmaceutical manufacturers. CONCLUSION Reports of deaths associated with PDE5-i remain around 5% of total reported events. Despite inherent limitations from evaluating FDA reports of AEs, it is important that these reports be reviewed outside pharmaceutical industry support in order to provide due diligence and transparency. Lowe G and Costabile RA. 10-year analysis of adverse event reports to the Food and Drug Administration for phosphodiesterase type-5 inhibitors. J Sex Med 2012;9:265-270.

Ultrasonic, Pneumatic and Combination Intracorporeal Lithotripsy for Percutaneous Nephrolithotomy

INTRODUCTION Refinements in ultrasonic and pneumatic lithotriptors, as well as the development of new dual-modality lithotriptors, have increased the options available for the endourologist. Studies comparing the efficiency of the devices in both bench and clinical models help provide the endourologist with guidance in selecting the most appropriate lithotrite. METHODS A review of the literature was performed reviewing the current status of pneumatic, ultrasonic, and dual-modality lithotriptors. RESULTS Performance characteristics of currently available lithotriptors differ. Dual-modality lithotriptors offer superior efficiency compared to separate ultrasonic and pneumatic lithotriptors but durability may be a concern with some models. CONCLUSIONS Ultrasonic and pneumatic devices are the lithotriptors of choice for PCNL. Dual-modality lithotriptors have been shown to be the most efficient in both bench and limited clinical trials.

Laparoscopic reconstructive options for obstruction in children with duplex renal anomalies.

To present our initial experience of laparoscopic reconstructive surgery in children with upper urinary tract obstruction associated with duplex anomalies, as although there is much information on ablative procedures such as laparoscopic heminephrectomy, there is little available about minimally invasive reconstructive options for duplex renal anomalies in children.

Prostate-specific antigen response after definitive radiotherapy for Skene's gland adenocarcinoma resembling prostate adenocarcinoma

OBJECTIVES To assess prostate-specific antigen response after definitive radiotherapy in a patient with localized Skenes gland adenocarcinoma resembling prostate adenocarcinoma. MATERIALS AND METHODS A 71-year-old patient was evaluated for a 2 year history of painless hematuria and found to have a localized Skenes gland adenocarcinoma resembling prostate adenocarcinoma with a pre-therapy PSA of 54.52 ng/ul. She elected to undergo definitive radiotherapy holding radical surgery for salvage. She received 73.8 Gy of intensity modulated radiotherapy in 41 fractions. Serum PSA, imaging, and cystoscopy were followed at 6 month intervals for 2.5 years. RESULTS The PSA decreased to 0.65 ng/ul 32 months after treatment, her clinical symptoms resolved, and on imaging and exam she has no evidence of residual disease. The PSA half life was 6.16 months (r(2) = 0.97). CONCLUSIONS For this rare tumor we show that PSA is a reliable marker for disease response and also show that definitive radiotherapy can be an option for organ and functional preservation in patients with localized disease. Cases of periurethral adenocarcinomas should be pathologically screened to assess if they are of Skenes gland origin, as our results suggest a radiotherapy treatment paradigm may be appropriate management in a select subgroup of women with periurethral adenocarcinoma.

Feasibility and Adequacy of Robot-Assisted Lymphadenectomy for Renal-Cell Carcinoma

BACKGROUND AND PURPOSE The role of lymph node dissection (LND) for renal-cell carcinoma (RCC) is evolving. When clinically negative, nodal disease is rare, but LND remains important in selected patients. Earlier identification of micrometastasis may become beneficial with emerging systemic agents. The ability to perform an adequate LND laparoscopically is uncertain. Open surgical data suggest a minimum of 12 nodes needed to identify most nodal metastases. Robotics may improve adequacy of laparoscopic LND. We report our results with the first reported robot-assisted LND series for RCC. PATIENTS AND METHODS Robot-assisted LND was performed in 36 patients with RCC by a single surgeon. For right-sided tumors, LND included paracaval, retrocaval, and interaortocaval nodes, and left-sided tumors included interaortocaval and periaortic nodes. RESULTS Mean patient age was 58 years (22-79) with a mean body mass index of 32 kg/m(2) (20-54). Mean tumor size was 7.3 cm with 16 T(3) tumors, including 4 vena caval tumor thrombi. Mean time for LND was 31 minutes, and mean estimated blood loss was 74 mL with no transfusions. Discharge was postoperative day (POD) 1 in 94% and POD 2 in 6%. A mean of 13.9 nodes was obtained with 1 pN+ (2.8%) patient. Mean nodal yield from the first to second half of cases rose from 11 to 16.8 nodes (P=0.02) with 77% having a minimum of 12 nodes in the second half. CONCLUSIONS Robot-assisted LND for RCC is feasible with adequate nodal yield. Increased yield in later cases may reflect a learning curve. The positivity rate was low as expected, but higher yield was obtained than in the limited laparoscopic literature.

Non-invasive management of primary phosphodiesterase type 5 inhibitor failure in patients with erectile dysfunction

Phosphodiesterase type 5 inhibitors (PDE5-i) have become first line therapy for the treatment of erectile dysfunction. Most initial prescriptions for PDE5-i are by primary care practitioners. Urologists must now routinely manage the patient who has failed initial therapy with PDE5-i. Lifestyle modifications can be of benefit to patients. Patient education and optimization of the PDE5-i can result in a successful response. Interestingly, there are reports of up to 60% salvage after changing the PDE5-i utilized. Daily PDE5-i have shown benefit, and treatment of hypogonadism can enhance response to PDE5-i. We review the management of PDE5-i failures with emphasis on noninvasive approaches to gaining improved erectile response to these medications. An algorithm based on the reviewed strategies is proposed to guide clinicians in the treatment of erectile dysfunction.

Rethinking the value of sending vasectomy specimens for histologic examination: an analysis of arterial vasculature and failure to transect the vas deferens.

OBJECTIVES The testicular, deferential, and cremasteric arteries and their branches surround the vas deferens (VD), leaving them susceptible to injury during vasectomy. Literature describing the caliber of arteries seen in vasectomy specimens is lacking, making it difficult to categorize the significance of an observed artery. We aimed to establish reference values for arterial size typically encountered in vasectomy specimens and assess our institutional experience with failure to transect the VD. METHODS The luminal diameter of the largest artery in 231 consecutive VD specimens from 116 patients was measured microscopically. For comparison, the diameter of the largest artery within 10 spermatic cord cross-sections from inguinal orchiectomies was obtained. The immediate vasectomy failure rate based on histologic assessment was calculated using specimens from 2008 to 2012. RESULTS The luminal diameter of the largest artery encountered in a vasectomy specimen was 1.00 mm or less in 96.5% of cases. Artery sizes greater than or equal to 2.50 mm were only seen in spermatic cord resections. From 2008 to 2012, three (0.36%) of 837 patients undergoing vasectomy had specimens that showed failure to transect both VD. CONCLUSIONS Although the American Urologic Association and European Association of Urology state that histologic evaluation of vasectomy specimens is not required, we encourage the surgeon to send VD specimens for histologic examination. Doing so allows early identification of the failure to transect the VD and the resection of surrounding vasculature, providing quality control feedback to the surgeon.

The Use of Patient Reported Outcome Questionnaires in the Diagnosis of Androgen Deficiency

As the proportion of elderly individuals in the population has increased so has awareness of testosterone deficiency syndrome (TDS). Testosterone deficiency is manifested in numerous ways including low libido, sexual dysfunction, impaired fertility, loss of muscle mass, fatigue, hot flashes, mood instability, and increased abdominal fat deposition. Patient reported outcome measures are useful for clinicians, researchers, and patients. For the patient, these outcome measures, often termed instruments, express what the patient is able to do and how they feel over time. Researchers use these instruments to compare similar populations in a reliable and valid manner, while clinicians find them useful for assessing aspects of health not assessed by TDS exam or laboratory testing. Multiple questionnaires have been designed to screen patients for testosterone deficiency and to follow symptom response during treatment. These instruments are reviewed in this chapter. Due to the significant symptom overlap with common comorbidities, testosterone deficiency symptom scales lack specificity. Each of the scales has significant limitations. Therefore, current guidelines do not support their clinical use in identifying patients with low testosterone levels.

Safety, Efficacy, and Patient and Partner Acceptability of Vardenafil Orally Disintegrating Tablets for the Treatment of Erectile Dysfunction

Staxyn (Bayer HealthCare Pharmaceuticals) is an oro-dispersible form of vardenafil. Oro-dispersible vardenafil functions in the same manner as other phosphodiesterase type 5 inhibitors to prevent the breakdown of cyclic guanosine monophosphate (cGMP), promoting greater erectile response and duration. Pharmacodynamic studies reveal a similar profile to vardenafil 10 mg, with greater bioavailability seen in the oro-dispersible form. Time to maximal concentration is slightly longer with orally dissolving vardenafil, although absorption through the oral mucosa decreases first pass metabolism. Few clinical studies exist on this formulation of vardenafil; however, those available reveal a similar effectiveness to film-coated vardenafil. The POTENT I and POTENT II trials are reviewed and provide the basis for most clinical data on this form of vardenafil. Staxyn has a safety profile comparable to other phosphodiesterase inhibitors, and a similar medication compatibility. Vardenafil ODT’s place in erectile dysfunction treatment is currently based largely on patient preference.

Optimal pneumatic settings for the Lithoclast Ultra in a cystolitholapaxy model

The Lithoclast Ultra(R) is a combined ultrasonic and pneumatic lithotrite shown to speed the fragmentation and clearance of renal calculi. We constructed an ex vivo cystolitholapaxy model to investigate the optimal pneumatic frequency for the Lithoclast Ultra(R). Bego and U-30 test stones were used. Ten trials of each stone type were performed at each setting. Each trial consisted of ultrasonic lithotripsy alone, and then in combination with pneumatic lithotripsy at frequencies of 2Hz, 4Hz, 8Hz, and 12 Hz. Ultrasonic lithotripsy alone was the control group. The ultrasound settings remained constant at 100% power and 90% duty. Time to 5mm fragments and time to stone clearance were recorded. Mean time to 5mm fragments for Bego stones using ultrasound alone, and with the pneumatic lithotrite at 2Hz, 4Hz, 8Hz, and 12Hz was 21min, 14min, 10min, 13min, and 14min respectively. Mean time to stone clearance for Bego stones was 29min, 25min, 23min, 22min, and 22min respectively. Mean time to 5mm fragments for U-30 stones was 101s, 89s, 68s, 64s, and 66s respectively. Mean time to stone clearance for U-30 stones was 162s, 148s, 133s, 137s, and 127s respectively. The combination of pneumatic and ultrasonic lithotrites decreases the time to stone fragmentation and clearance compared to ultrasound alone. The optimal pneumatic frequency appears to reach a plateau at 4Hz.