Ahmet Adil Esen

Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE)

BACKGROUND Incontinence has a greater detrimental effect on quality of life than other symptoms of overactive bladder (OAB) and is often difficult to treat with antimuscarinic monotherapy. OBJECTIVE To evaluate the efficacy and the safety and tolerability of combination (solifenacin 5mg and mirabegron 50mg) versus solifenacin 5 or 10mg in OAB patients remaining incontinent after 4 wk of solifenacin 5mg. DESIGN, SETTING, AND PARTICIPANTS OAB patients remaining incontinent despite daily solifenacin 5mg during 4-wk single-blind run-in were randomised 1:1:1 to double-blind daily combination or solifenacin 5 or 10mg for 12 wk. Patients receiving the combination were initiated on mirabegron 25mg increasing to 50mg after week 4. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was a change from baseline to end of treatment (EOT) in the mean number of incontinence episodes per 24h (stratified rank analysis of covariance [ANCOVA]). Key secondary end points were a change from baseline to EOT in the mean number of micturitions per 24h (ANCOVA) and number of incontinence episodes noted in a 3-d diary at EOT (mixed-effects Poisson regression). A trial (BESIDE) comparing combination treatment (solifenacin plus mirabegron) with one treatment alone (solifenacin) tested the superiority of combination versus solifenacin 5mg, noninferiority (and potential superiority) of combination versus solifenacin 10mg (key secondary end points), and the safety and tolerability of combination therapy versus solifenacin monotherapy. RESULTS AND LIMITATIONS A total of 2174 patients were randomised to combination (n=727), solifenacin 5mg (n=728), or solifenacin 10mg (n=719). At EOT, combination was superior to solifenacin 5mg, with significant improvements in daily incontinence (p=0.001), daily micturitions (p<0.001), and incontinence noted in a 3-d diary (p=0.014). Combination was noninferior to solifenacin 10mg for key secondary end points and superior to solifenacin 10mg for improving daily micturitions. All treatments were well tolerated. CONCLUSIONS Adding mirabegron 50mg to solifenacin 5mg further improved OAB symptoms versus solifenacin 5 or 10mg, and it was well tolerated in OAB patients remaining incontinent after initial solifenacin 5mg. PATIENT SUMMARY In this 12-wk study, overactive bladder patients who remained incontinent despite initial solifenacin 5mg treatment received additional treatment with mirabegron 50mg. Combining mirabegron 50mg with solifenacin 5mg was superior to solifenacin 5mg alone in improving symptoms of incontinence and frequent urination, and it was well tolerated. TRIAL REGISTRATION ClinicalTrials.gov NCT01908829.

The Relationship Between Premature Ejaculation and Hyperthyroidism

PURPOSE We determine the prevalence of premature ejaculation in patients with hyperthyroidism and observed intravaginal ejaculation latency time alterations before and after hyperthyroidism treatment. MATERIALS AND METHODS Between January 2004 and June 2007, 49 patients with hyperthyroidism and no history of hyperthyroidism treatment were enrolled in the study. After obtaining a detailed sexual anamnesis an erectile function questionnaire was completed and a patient self-reported outcome measure of difficult control over ejaculation was examined. We assessed stopwatch measurements of intravaginal ejaculation latency time performed by the patient or partner. Patient anxiety status was also evaluated. Changes in the mentioned measurements induced by hyperthyroidism treatment were examined 8 weeks after the achievement of euthyroidism. RESULTS In the 43 eligible patients mean +/- SD age was 48.0 +/- 8.8 years. Premature ejaculation was observed in 31 of the 43 patients (72.1%). Mean intravaginal ejaculation latency time in patients with hyperthyroidism was 72.8 +/- 83.3 seconds. Of the 43 patients 30 (69.8%) were considered to have definite premature ejaculation according to stopwatch measurements. In patients with hyperthyroidism who had definite premature ejaculation anxiety scores were determined to be higher. A positive correlation was noted between serum thyroid stimulating hormone and intravaginal ejaculation latency time in the patients. In 24 patients who completed the followup visits we noted statistically significant improvement in intravaginal ejaculation latency time after the achievement of euthyroidism. CONCLUSIONS Excess thyroid hormone and premature ejaculation are clinically interrelated conditions. Hyperthyroidism should be considered a novel and reversible etiological risk factor for premature ejaculation.

Penile Vascular Impairment in Erectile Dysfunction Patients with Metabolic Syndrome: Penile Doppler Ultrasound Findings

Background: The constellation of truncal obesity, glucose intolerance, dyslipidemia (high triglycerides, low HDL cholesterol), and hypertension has been recognized as metabolic syndrome. However, the pathophysiological association between metabolic syndrome and erectile dysfunction (ED) has not yet been clearly determined. This study aimed to evaluate the penile Doppler ultrasound (PDU) findings of ED patients with metabolic syndrome. Patients and Methods: Sixty-one age-matched ED patients with or without metabolic syndrome were included in the study. Patients were investigated by grouping according to risk factors of metabolic syndrome with PDU parameters (5th, 10th and 20th minute peak systolic velocity and end-diastolic velocity). PDU parameters of patients with and without metabolic syndrome were compared. Results: The mean age of the patients were 54.9 ± 8.3 and 54.9 ± 7.6 years for the groups of with (n = 27) and without (n = 34) metabolic syndrome, respectively. When the mean peak flow velocities were compared with presence of metabolic syndrome, we observed differences between at the 5th, 10th and 20th minute peak systolic velocities (p = 0.083, p = 0.022 and p = 0.080, respectively). Conclusion: Metabolic syndrome seems to be the potential risk factor for ED, which may exert its effect by decreased arterial inflow due to endothelial dysfunction.

Effect of doxazosin with and without rho-kinase inhibitor on human corpus cavernosum smooth muscle in the presence of bladder outlet obstruction.

PURPOSE We investigated the relationship of adrenergic responses in corpus cavernosum tissues in the presence of BOO using the alpha1-adrenergic receptor antagonist doxazosin (Pfizer, New York, New York) and the rho-kinase inhibitor Y-27632 (Calbiochem, San Diego, California). MATERIALS AND METHODS CCSM tissue was obtained from patients who underwent penile prosthesis implantation. Patients were divided into 2 groups according to the presence of BOO. The submaximal (EC80) concentration of phenylephrine (Sigma Chemical Co., St. Louis, Missouri) was calculated by evaluating adrenergic activity responses with cumulatively applied phenylephrine. After achieving a stable contraction plateau test compounds were put in an organ bath. The relaxant potencies of doxazosin and Y-27632 were expressed as the percent of inhibition of the contraction plateau induced EC80 concentration of phenylephrine. Relaxation responses in the 2 groups were compared. RESULTS At the highest dose of increasing concentrations phenylephrine generated 70% more contraction response in the BOO positive group than in the BOO negative group. Doxazosin and Y-27632 caused concentration dependent relaxation in CCSM precontracted by phenylephrine. With doxazosin significantly higher relaxation responses were attained in the BOO positive group in terms of log IC50 and the maximal relaxation response (p = 0.0353 and 0.0003, respectively). Maximum relaxation responses following Y-27632 administration were significantly higher in the BOO positive group. CONCLUSIONS The contractility of human corpus cavernosum is increased in the presence of BOO. Doxazosin and Y-27632 generate effective CCSM relaxation in the presence of BOO. Doxazosin and Y-27632 may be the alternatives for the treatment of erectile dysfunction associated with BPH.

The Effect of Extracorporeal Electromagnetic Shock Waves on the Morphology and Contractility of Rabbit Ureter

PURPOSE Although extracorporeal shock wave lithotripsy (ESWL) is known to cause pathologic changes in various organs, little is known about its effects on the ureter, the target organ in ESWL of ureteral stones in situ. In this study, we sought to determine the short-term effects of ESWL on the ureter. MATERIALS AND METHODS Left lower ureteral segments of 21 rabbits were removed to serve as the control group and 2000 shocks were applied to the right lower ureters. Groups of 7 rabbits were sacrificed 1, 3 and 5 days after shock wave exposure. While histomorphological alterations were examined under light and transmission electron microscopy, contractility of all ureters was determined in organ baths. RESULTS The epithelial cells disclosed no change after shock wave application. Histologically the muscular layer was the most affected part of the ureter. There was interstitial and intracellular edema on light microscopy and marked chromatin and mitochondrial changes at the subcellular level. The adventitial layer was also edematous. These changes were prominent on days 1 and 3 and returned to normal on day 5. The contractility of the ureters on day 1 was significantly reduced (p < 0.05). However, the contractility of the samples on days 3 and 5 were not significantly different from controls. CONCLUSION Our findings demonstrate that electromagnetic shock waves produce reversible morphological and functional changes in rabbit ureteric muscle.

Investigation of the Neural Target Level of Hyperthyroidism in Premature Ejaculation in a Rat Model of Pharmacologically Induced Ejaculation

INTRODUCTION Association between hyperthyroidism and premature ejaculation was demonstrated in clinical studies. AIM The aim of this study is to determine the target level of changes on ejaculatory physiology under hyperthyroid states. METHODS p-Chloroamphetamine (PCA)-induced pharmacologic ejaculation model with 24 male Wistar rats was used in the study. Subcutaneous injection of L-thyroxine for 14 days was performed to induce hyperthyroidism. At the end of the injection period, thyroid hormone status was evaluated by serum thyroid-stimulating hormone measurements in all rats. At the beginning of the operations, complete spinal transections (tx) at the T8-T9 level were performed to half of the L-thyroxine-injected and control group rats. Thus, experimental groups were constructed as follows: Group 1--control-spinal intact (n=6), group 2-control-spinal tx (n=6), group 3-hyperthyroid-spinal intact (n=6), and group 4-hyperthyroid-spinal tx (n=6). Ejaculatory responses were recorded before and 30 minutes after intraperitoneal administration of 5 mg/kg PCA. MAIN OUTCOME MEASURES During the operations, seminal vesicle (SV) catheterization and bulbospongiosus (BS) muscle dissections were performed in all rats to demonstrate SV pressure (SVP) BS electromyographic (EMG) activity changes. RESULTS Following PCA administration SVP tonic amplitude, SV phasic contraction (SVPC) frequency, SVPC maximal amplitude, and BS EMG area under curve values were higher in hyperthyroid intact rats than in control intact rats. The time interval between PCA administration and first ejaculation of hyperthyroid intact rats were significantly shorter than control intact rats (261 ± 7.30 seconds vs. 426 ± 49.6 seconds, P=0.008). All of the changes in the ejaculatory parameters that were induced by hyperthyroidism were completely resolved after spinal transections at the T8-T9 level in group 4. CONCLUSION In this study, we confirmed the recent data that hyperthyroidism affects both the emission and expulsion phases of ejaculation. The changes that were induced by hyperthyroidism on ejaculatory physiology probably take place in the supraspinal centers above T8 level.

An Experimental Approach to the Interrelationship Between Hyperthyroidism and Ejaculation Latency Time in Male Rats

PURPOSE We investigated the effects of experimentally induced hyperthyroidism on seminal vesicle pressure measurements and bulbospongiosus muscle contractile activity in a para-chloroamphetamine (Sigma-Aldrich) induced ejaculation model in rats. MATERIALS AND METHODS Male Wistar rats were used in the study. Daily injection of 25 microg/100 gm body weight L-thyroxine (T4, Sigma-Aldrich) for 14 days was performed in 14 rats to induce hyperthyroidism. Seven L-thyroxine injected rats were in the hyperthyroid group. The remaining 7 rats (recovery group) underwent operation after a 28-day washout period to determine spontaneous recovery from hyperthyroidism. At each operation seminal vesicle catheterization was done to measure intraluminal pressure and bulbospongiosus muscle dissection was performed for electromyography. After intraperitoneal administration of 5 mg/kg para-chloroamphetamine physiological parameters related to the ejaculatory process were measured. RESULTS The interval between para-chloroamphetamine administration and first ejaculation was significantly decreased in the hyperthyroid rat group compared with that in the control group (mean +/- SD 202.8 +/- 22.3 vs 465.4 +/- 104.6 seconds, p = 0.001). Seminal vesicle phasic contraction frequency was significantly higher than control group values in hyperthyroid rats (for 30 minutes 32.3 +/- 13.9, p = 0.047). The mean AUC of bulbospongiosus muscle electromyography activity was also significantly increased in this group (11.1 +/- 4.1 V per second x 10(-4), p = 0.0001). All parameters in recovery and control group rats were not significantly differed from each other. CONCLUSIONS Hyperthyroidism leads to enhanced seminal vesicle contraction frequency and bulbospongiosus muscle contractile activity in rats. Hyperthyroidism affects the emission and expulsion phases of ejaculation in reversible fashion.

Acute Effects of Hypercholesterolemic Diet on Erectile Responses in Rats

Objective: The aim of this study was to evaluate the acute effects of a high cholesterol diet (HCD) on erectile and endothelial functions in Sprague-Dawley rats. Materials and Methods: Sprague-Dawley rats were divided into 2 groups as control and HCD groups. The control group was fed on a normal diet and the hypercholesterolemia group was fed a 1% cholesterol-enriched diet daily for 2 weeks. Total cholesterol levels were measured at the end of 2 weeks in both groups. To examine the effect of HCD on erectile function, electric cavernous nerve stimulation (CNS) at 20 Hz with a pulse duration of 1 ms for 1 min at 5 V was performed. During CNS, we measured intracavernous pressure (ICP), mean arterial pressure (MAP), detumescence time and area under the curve (AUC). To evaluate the endothelial responses, acetylcholine (Ach) was applied cumulatively (1 nM to 1 µM) to thoracic aorta tissues contracted with 60 mM KCl. Results: In the HCD group total cholesterol levels were significantly higher than in the control group (148.1 ± 18.9 vs. 55.7 ± 8.1 mg/dl, p = 0.002). The detumescence time was significantly decreased after HCD compared to the control diet (19.3 ± 3.6 vs. 78.6 ± 12.8 s, p < 0.001). The decreases in the HCD group were also significant in terms of ICP (53.4 ± 4.5 vs. 35.6 ± 5.5 mm Hg; p < 0.05), ICP/MAP (55.9 ± 3.9 vs. 38.2 ± 5.2%; p < 0.05) and AUC (1,404 ± 197.1 vs. 2,250 ± 253.7, p < 0.05) values. There were no significant changes in maximum relaxation responses of the thoracic aorta to Ach. Conclusion: These results suggest that erectile functions were significantly damaged early in HCD rats. However, endothelial functions, evaluated in the thoracic aorta, were not affected simultaneously with erectile functions in rats fed a low concentration of HCD.

The effect of α-blocker therapy on erectile functions in patients with lower urinary tract symptoms due to benign prostate hyperplasia

In this study we aimed to evaluate the impact of doxazosin treatment on erectile functions in patients with lower urinary tract symptoms (LUTS) and having erectile dysfunction (ED) at baseline. Fifty-three patients with LUTS (IPSS score > 7) whose maximum flow rate (Q(max)) < 15 mL s(-1) and PSA < 4 ng dL(-1) were enrolled in the study. Patients received doxazosin 4 mg once daily for 6 weeks. Subjective efficacy was assessed by IPSS, IPSS-Quality of Life (IPSS-QoL) for LUTS and efficacy was assessed by International Index of Erectile Function (IIEF) for erectile functions at baseline and sixth weeks. The objective efficacy was assessed by Q(max). The patients were classified according to their self reported erectile status: group I had ED and group II did not have ED. At the endpoint, doxazosin significantly improved the total IPSS score (-7.7 +/- 6.1, P = 0.006), IPSS-QoL score (-1.5 +/- 1.5, P = 0.024) and Q(max) (3.2 +/- 4.6 mL s(-1), P = 0.002) over baseline. Mean decrease in IPSS and IPSS-QoL scores after the treatment period were 6.9 +/- 6.4 (P < 0.001) and 0.95 +/- 1.80 (P < 0.05) in group I, whereas 8.2 +/- 5.8 (P < 0.001) and 1.9 +/- 1.1 in group II (P < 0.001), respectively. Mean changes of Q(max) values were 2.3 +/- 3.3 mL s(-1) in group I (P < 0.05) and 3.7 +/- 5.3 mL s(-1) in group II (P < 0.001). The improvement of IIEF-EF scores after the treatment period was only significant for group I. The efficacy of alpha-blocker therapy for LUTS was better by means of symptomatic relief for patients who did not have ED when compared with patients who had ED at baseline. However, slight improvement in erectile functions with alpha-blocker therapy was only seen in LUTS patients with ED.

Factors associated with phosphodiesterase type 5 inhibitor treatment satisfactions: results of patient interrogation

Introduction. Phosphodiesterase type 5 (PDE5) inhibitor therapy is an efficacious means of treatment for erectile dysfunction (ED). PDE5 inhibitors supply penile erection by inhibiting the hydrolysis of cGMP and therefore relaxing the corpus cavernosum. In this study, retrospective evaluation of those patients who were admitted to our clinic with the complaint of ED and who were recommended on PDE5 inhibitor treatment in terms of follow-up results and patient satisfaction were aimed. Method. The patients were called by phone and after informing about the study and taking the informed consent, patient satisfaction with the treatment, purposes of withdrawal, treatment alterations and partner satisfaction were investigated. Results. Interviews were made with 345 patients, who accepted to enroll in the study and the mean patient age was 56 ± 11.2 years. Of the patients 66.4% were learned to be satisfied with the treatment. It was determined that 10.7% of the patients have never used the medication and 50% could not continue because of high drug cost. It was recognised that 50.2% of the patients who are not satisfied with the treatment tried another PDE5 inhibitor. The success rate of the treatment was found to be higher in the followed-up group than those losses to follow-up. Conclusion. Therapy with PDE5 inhibitors is an effective means of ED treatment. The importance of doctor-patient communication should be considered, and the patient should be advised for adaptation to follow-up program. High drug cost is a significant predictor of patient compliance to treatment continuation.