Efficacy and safety of a hexanic extract of Serenoa repens (Permixon® ) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies.

OBJECTIVES: To comprehensively evaluate the efficacy and safety of the hexanic extract of Serenoa repens (HESr, Permixon® ; Pierre Fabre Médicament, Castres, France), at a dose of 320 mg daily, as monotherapy for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) and prospective observational studies in patients with LUTS/BPH identified through searches in Medline, Web of Knowledge (Institute for Scientific Information), Scopus, the Cochrane Library, and bibliographic references up to March 2017. Articles studying S. repens extracts other than Permixon were excluded. Data were collected on International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ), nocturia, quality of life, prostate volume, sexual function, and adverse drug reactions (ADRs). Data obtained from RCTs and observational studies were analysed jointly and separately using a random effects model. A sub-group analysis was performed of studies that included patients on longer-term treatment (≥1 year). RESULTS: Data from 27 studies (15 RCTs and 12 observational studies) were included for meta-analysis (total N = 5 800). Compared with placebo, the HESr was associated with 0.64 (95% confidence interval [CI] -0.98 to -0.31) fewer voids/night (P < 0.001) and an additional mean increase in Qmax of 2.75 mL/s (95% CI 0.57 to 4.93; P = 0.01). When compared with α-blockers, the HESr showed similar improvements on IPSS (weighted mean difference [WMD] 0.57, 95% CI -0.27 to 1.42; P = 0.18) and a comparable increase in Qmax to tamsulosin (WMD -0.02, 95% CI -0.71 to 0.66; P = 0.95). Efficacy assessed using the IPSS was similar after 6 months of treatment between the HESr and 5α-reductase inhibitors (5ARIs). Analysis of all available published data for the HESr showed a mean improvement in IPSS from baseline of -5.73 points (95% CI -6.91 to -4.54; P < 0.001). HESr did not negatively affect sexual function and no clinically relevant effect was observed on prostate-specific antigen. Prostate volume decreased slightly. Similar efficacy results were seen in patients treated for ≥1 year (n = 447). The HESr had a favourable safety profile, with gastrointestinal disorders being the most frequent ADR (mean incidence of 3.8%). CONCLUSION: The present meta-analysis, which includes all available RCTs and observational studies, shows that the HESr (Permixon) reduced nocturia and improved Qmax compared with placebo and had a similar efficacy to tamsulosin and short-term 5-ARI in relieving LUTS. HESr (Permixon) appears to be an efficacious and well-tolerated therapeutic option for the long-term medical treatment of LUTS/BPH.

Halothane-anesthetized rabbit: a new experimental model to test the effects of besipirdine and duloxetine on lower urinary tract function.

INTRODUCTION: The effects of besipirdine and its main metabolite, HP-748, as well as duloxetine and tomoxetine in the lower urinary tract (LUT) were studied using in vitro and in vivo techniques. MATERIALS AND METHODS: For in vivo studies, besipirdine or duloxetine effects on cystometric parameters and striated sphincter electromyographic (SS-EMG) activity were investigated. On the isolated urethra, norepinephrine (NE) concentration-response curves (CRC) were performed in the presence of besipirdine, duloxetine or tomoxetine. Moreover, CRC to HP-748 were constructed in the absence or presence of prazosin. Potency (pEC(50)) and maximal responses (E(max)) were determined. RESULTS: Besipirdine at 1, 3 and 5 mg/kg intravenously (i.v.) induced a significant increase in SS-EMG activity (250, 273 and 241%, respectively), bladder capacity (172, 197, and 235%, respectively), intercontraction interval (ICI; 208, 242, and 400%, respectively), and residual volume (181, 191, and 236%, respectively). Duloxetine at 2 mg/kg i.v. increased significantly SS-EMG activity (219%), micturition volume (222%), and ICI (205%). In the isolated urethra, besipirdine, tomoxetine and duloxetine significantly displaced to the left the NE CRC. In addition, HP-748 induced contraction of the isolated urethra with a pEC(50) of 5.89 and an E(max) of 37%. CONCLUSIONS: These data support the potential of besipirdine as a new drug for LUT dysfunctions such as stress and mixed urinary incontinence.

[Hematuria of papillary or medullar origin: a difficult diagnosis entity]. / Hematuria de origen papilar o medular: entidad de difícil diagnóstico.

OBJECTIVES: Renal haemangiomas of renal papillary or medullar origin are a difficult diagnosis entity, being one of the most frequent processes of chronic episodes of hematuria, secondary to benign disease, mainly in young patients. The objective of this paper is to show the difficulty of this diagnosis and the need to suspect it in cases with clinical history similar to the ones described in these cases. METHODS: We report 4 cases of spontaneous hematuria of renal origin, with clinical presentation as renal colic, from the historical case series of the Fundacion Jimenez Díaz-Capio, the last two from the years 2005-6. We present the diagnostic and therapeutic methodology employed, including angio-CT and flexible ureterorenoscopy (URS) as well as various treatment options. RESULTS: Hematuria was identified as "essential" when any relation with tumor or lithiasic pathologies was ruled out, and of renal origin when the source was clearly pointed. We interpreted it was related to angiomas or microangiomas of papillary or medullar origin. In one case, the vascular malformation was interpreted as an arterial venous fistula (AVF) at that level. Hematuria stopped spontaneously in two cases after exploratory URS. The eldest historical case required surgical expiration of the caliceal structures. CONCLUSION: Years ago, following the professional development of Urology as speciality, conventional surgery was carried out in all these cases, of very difficult diagnosis, with a very small number of cases undergoing a conservative approach based on the examination of renal cavities trying to observe and find the bleeding point. Most cases underwent complete or partial nephrectomy. Currently, the possibility of exploration of all renal cavities with the flexible ureterorenoscope enables a better diagnosis of the lesions and a more conservative treatment. The ultimate diagnosis of renal papillary angioma is the pathologic diagnosis, without pathognomonic data in the imaging tests. This pathology is thought of at the end of the diagnostic workup, and when the papillary area is identified as the source of bleeding. The historical case series, with the pathologic findings from nephrectomy specimens, permits us to point out this entity as papillary angioma, in patients with similar clinical presentation.

Receptor activator of nuclear factor-kappaB ligand (RANKL) as a novel prognostic marker in prostate carcinoma.

Combined immunodetection of parathyroid hormone-related protein (PTHrP) and receptor activator of NF-kappaB ligand (RANKL) has shown to successfully distinguish poorly- and well-differentiated prostate carcinoma (PCa). In the present study, we aimed to assess whether immunohistochemical evaluation of these factors, and also osteoprotegerin (OPG) and Ki67, in radical prostatectomy specimens can predict biochemical recurrence. Fifty nine PCa cases undergoing radical prostatectomy between 1995 and 1998, without history of neoadjuvant hormonal therapy, were studied. Preoperative serum prostate-specific antigen (PSA), Gleason-sum score, pathologic stage, perineural invasion, seminal vesicle involvement, and positive surgical margins were assessed in these patients. Biochemical recurrence, defined by PSA > 0.4 ng/mL at 90 days or later after prostatectomy, occurred in 32/59 patients. In these patients, positivity for OPG and RANKL in the tumoral epithelium was higher than in those patients with no biochemical recurrence. Using univariate analysis, Gleason-sum score, surgical margins, and seminal vesicle involvement, as well as OPG and RANKL immunostaining (using a score value corresponding to moderate staining as cut-off) were significant predictors of biochemical recurrence (p<0.05). Using the multivariate Cox model, among the evaluated factors only RANKL expression (hazard ratio 11.6; p <0.001) was an independent prognostic indicator. Our findings suggest that immunohistochemical evaluation of RANKL in the primary tumor is a potential risk factor in PCa patients.

[Infections of the urinary tract caused by permanent catheterization. Natural history, infective mechanisms and prevention strategies. An overall review based on our clinical experience and research]. / Infecciones del aparato urinario motivadas por la sonda permanente. Historia natural, mecanismos infectivos y estrategias de prevención. Una revisión de conjunto basada en nuestra experiencia clínica e investigaciones.

Permanent drainage of the urinary tract by catheters or tubes causes bacteriuria. The potential harmful effects of the indwelling catheter's bacteriuria are related to: time since the insertion of the catheter; location of the catheter (urethra, bladder, kidney); catheter composition (latex, silicone, etc.); type of ineffective bacteria and specific pathogenic mechanisms; health status of the urinary tract being drained (prior radiation therapy, tumors, etc.); patient's health status (diabetes, immunodeficiency) and mobility; incidents and manipulations of the catheter, such as obstruction, irrigation, or retrieval. The evaluation of all mentioned factors enables strategies for prevention of septic episodes in relation with indwelling catheters, strategies that can be individualized for greater efficiency. Despite these preventive measures, infections secondary to the indwelling catheter may cause extremely severe septic episodes. Today, the indwelling catheter bacteriuria constitutes the greater source of nosocomial infection and its prevention and treatment a health care action of the highest importance. The study of mechanisms implied in the formation of biofilms, their pathogenic potential and preventive measures have been an attractive field of clinical and experimental research over the last years. The objective of this review is to make a synthesis of the works performed by our group.

[Male aging in the Middle Ages: commentaries on the book by Arnau de Vilanova "Conservatio juventute preservatio senectute"]. / Envejecimiento masculino en la Edad Media: comentarios al libro de Arnau de Vilanova "Conservatio juventute preservatio senectute.

In the Middle Ages medical texts the notes about personal hygiene are scarce and they are dedicated to the Kings or the aristocracy. In his work Regimen sanitatis ad inclytum regen Aragorum, Amaldo de Vilanova underlines six things that are necessary for cleanliness, among which he includes his well-known proposition Conservatio juventute preservatio senectute. We compared his text with those from other authors with references to the issue and, once examined, Vilanova's work stands out. Doctors in the middle ages were already interested in aging and propositions considered today as modern are found described in various works from that period.

[Chronic prostatitis: critical review of its current nosologic definition, classification and potential carcinogenesis]. / Prostatitis crónica: una revisión crítica de su actual definición nosológica, clasificación y potencial carcinogénesis.

Updated critical review of chronic prostatitis as a nosologic, anatomic-clinical entity of supposed microbiological or inflammatory origin. Scientific reasoning about the role of amicrobial inflammation in both caudal and cranial prostate, after new progresses, to reconsider the convenience of maintaining the current classification of chronic prostatitis, mainly in the section referred to "histological prostatitis". Analysis of scientific evidences relating prostatitis and "pelvic pain", the dominant syndrome in many patients and basement of the current terminological proposal: prostatitis-pelvic pain. The role of inflammation in the genesis of BPH and prostate cancer. Justification and convenience of a new term in logic consensus on prostatitis.

Immunohistochemical analysis of low-grade and high-grade prostate carcinoma: relative changes of parathyroid hormone-related protein and its parathyroid hormone 1 receptor, osteoprotegerin and receptor activator of nuclear factor-kB ligand.

AIM: To investigate multiple bone cytokines produced by prostate carcinoma (PCa) as a novel strategy to differentiate potential aggressiveness in localised PCa using immunohistochemical analysis. METHODS: A total of 47 cases of PCa undergoing radical prostatectomy or transurethral prostatic resection at our institution (Fundación Jiménez Díaz (Grupo Capio), Madrid, Spain) between January 1991 and June 1998 were identified as low-grade (< or =4; n = 22) or high-grade (> or =7, excluding 7 (3+4) cases; n = 25) PCa according to Gleason grade. PCa specimens were immunostained for: parathyroid hormone (PTH)-related protein (PTHrP), the PTH1 receptor, osteoprotegerin and receptor activator of nuclear factor-kappa B ligand (RANKL), as well as Ki67 (a proliferation marker) and CD34 (an angiogenesis marker). RESULTS: PCa samples showed an increased immunostaining for both osteoprotegerin and RANKL, associated with tumour grade and PTHrP positivity, in the tumoral epithelium. Using a score value of 4-corresponding to moderate staining - as cut-off, the best sensitivity value was for PTHrP (with C-terminal antiserum C6; 100 %); wheras the best specificity value was for RANKL (95 %). CONCLUSIONS: All the evaluated factors are overexpressed mainly in the high-grade tumours. Our findings indicate that, in most patients with PCa (with Ki67 values between 1% and 9%), sequential determination of C-terminal PTHrP and RANKL immunoreactivities is a useful approach to discriminate low-grade and high-grade tumours.

Comparative effects of clomipramine and duloxetine on detrusor and striated sphincter function in male and female rabbits.

OBJECTIVE: Serotonin and norepinephrine systems are involved in the neural control of lower urinary tract function. The aim of this study was to compare the response on striated anal sphincter electromyographic (SAS-EMG) activity and cystometric parameters, when duloxetine and clomipramine were intravenously administrated. METHODS: The effects of intravenous 1 and 2 mg./Kg. duloxetine or clomipramine on lower urinary tract function were studied in a total of 32 male and 32 female rabbits, under nonirritative conditions (intravesical infusion of saline) and in a model of bladder irritation (i.e., transvesical infusion of 0.5% acetic acid). A transurethral double-lumen catheter in male rabbits, and a subcutaneous cystostomy in female rabbits, were used for liquid infusion and recording of intravesical pressure during a cystometrogram. Simultaneously, SAS-EMG was recorded through electromyography electrodes placed in the perianal striated muscle. RESULTS: Cystometric parameters: Under irritative conditions, 2 mg./Kg. clomipramine in male rabbits and 1 or 2 mg./Kg. in female rabbits, depending on the dose, increased bladder capacity (BC), contraction duration (CD) and intercontraction interval (ICI), and decreased baseline pressure (BP). In male and female rabbits, duloxetine dose-dependently increased BC, CD and ICI. Under nonirritative conditions, clomipramine at 2 mg./Kg. and duloxetine dose-dependently solely increased BC in female rabbits. Electromyographic activity: A marked effect on SAS-EMG activity of duloxetine under irritative conditions was revealed in male and female rabbits. Under these conditions, clomipramine increased SAS-EMG activity only in female rabbits. Under nonirritative conditions, 2 mg./Kg. duloxetine increased SAS-EMG activity only in female rabbits. CONCLUSIONS: The stronger effects on the SAS-EMG activity were produced by duloxetine in female rabbits under irritated bladder conditions. Clomipramine, under irritative conditions, had a relaxing effect on intravesical pressure, which is not the case with duloxetine.

Histopathology reporting of prostate needle biopsies. 2005 update.

This report reviews the diagnostic and prognostic importance of the pathologic findings in prostate needle biopsies. The morphological findings of the needle biopsy may be placed into one of the following five categories: prostate cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, inflammation, and benign prostatic tissue. While the prime goal of the biopsy is to diagnose prostatic adenocarcinoma, once carcinoma is detected, further descriptive information regarding the type, amount of cancer, and grade forms the cornerstone for contemporary management of the patient and for assessment of the potential for local cure and the risk for distant metastasis. The information provided in the needle biopsy report regarding the attributes of carcinoma is used depending on the individual patient's medical condition and preference and on the treating physician's evaluation to determine whether any form of treatment is indicated and, if so, the type of therapy.

2005 update on pathology of prostate biopsies with cancer.

OBJECTIVE: To review the diagnostic and prognostic importance of pathologic findings in prostate biopsies. MATERIALS AND RESULTS: While the primary goal of the biopsy is to diagnose prostatic adenocarcinoma, once carcinoma is detected, information regarding the type, amount, and grade of cancer forms the cornerstone for contemporary management of the patient and for assessment of the potential for local cure and the risk for distant metastasis. CONCLUSIONS: The novelty of this 2005 update is represented by a detailed morphologic and immunohistochemical description of prostatic adenocarcinoma features in biopsies.

The impact of medical therapy on surgery for benign prostatic hyperplasia: a study comparing changes in a decade (1992-2002).

OBJECTIVES: To compare the clinical profile (age, comorbidities, symptom severity, and incidence of acute urinary retention, AUR), the type and duration of medical treatment, and indications for surgery of patients undergoing surgery for benign prostatic hyperplasia (BPH) in 1992 and 2002 at one centre. PATIENTS AND METHODS: In this single-centre, retrospective, cross-sectional observational study, the medical history of all patients who had surgery for BPH in the first semester of 1992 (85) and 2002 (70) was reviewed. The preoperative clinical profile was determined by assessing age, main comorbidities, prostatic volume, maximum urinary flow rate and symptom severity. The type and duration of pharmacology for BPH was evaluated from the medical history and telephone contact with the patients. Indications for surgery, the method of operation and the weight of removed tissue (open adenectomy) or the volume of the resected tissue (transurethral resection) were obtained from the patients' records and compared. Surgical complications in both groups were assessed, as was the average stay in hospital. RESULTS: In our institution, surgery for BPH decreased by 17.6% in the decade, with patients having surgery when older, at a mean (sd) of 69.1 (8.57) vs 72.3 (7.59) years, i.e. 3.1 years older (P = 0.028), but with similar comorbidities. Reasons for surgery in 1992/2002, respectively, were AUR in 41/37%, and symptoms worsening in 48/51%. The few cases of haematuria and bladder stone were similarly distributed in both groups. Pharmacology for BPH was prescribed in 46% of patients in 1992, phytotherapy being the most common (89%), whereas in 2002, 82% (P < 0.01) were treated, most of them with alpha-adrenergic antagonists (79%). Open surgery was indicated in 18.8% of patients in 1992 (mean adenoma weight 73.8 g, sd 37.12) and in 28.6% in 2002 (79.8 g, sd 35.41; P = 0.625). The mean (sd) hospital stay was 8.9 (4.06) vs 5.0 (1.22) days in 1992 and 2002, respectively (P < 0.01) for transurethral resection, and 14.1 (5.74) vs 8.7 (4.83) for open adenectomy (P = 0.013). The complication rate was similar for both groups. CONCLUSIONS: Compared with 1992, fewer patients with BPH have surgery, when older and after receiving medical treatment for longer. The indications for surgery are similar. Significantly more patients had open surgery, perhaps because the progressive increase in prostate volume was not affected by the medical therapy used predominantly during this decade.

[Impotence and cardiovascular disease: a new perspective in the health-care compromise of the urologist]. / Impotencia y enfermedad cardiovascular: una nueva perspectiva en el compromiso asistencial del urólogo.

OBJECTIVES: To review the evidence currently available to establish the pathogenic connection between erectile dysfunction (ED) and cardiovascular disease (CVD), and the effects this scientific progress has introduced in the classical impotence urology clinic. METHODS: We reviewed the most recent publications about this disease (2000-2004) and the concept of endothelial dysfunction by appropriate MEDLINE searches, with specific selection of reviews and clinical practice guidelines. RESULTS: The fact that ED and CVD share risk factors is confirmed; the pathogenic unity of both processes having endothelial dysfunction as the underlying problem; anticipation of ED over CVD in time of presentation; notable increase of research about this issue over the last two years; the change of scenario in the impotence urology clinics due to these findings. CONCLUSIONS: The number of cases in which ED is not an organ disease but an early symptom of endothelial dysfunction forces changes in the extent and depth of the diagnostic, prognostic and follow-up strategies in the urology impotence clinics of extraordinary importance from both the individual and health-care politics point of view.

Serenoa repens treatment modifies bax/bcl-2 index expression and caspase-3 activity in prostatic tissue from patients with benign prostatic hyperplasia.

PURPOSE: Permixon is a lipidosterolic extract of Serenoa repens (SR) widely used to treat men with benign prostatic hyperplasia (BPH). We tested the effect of this drug on molecular mechanisms associated with apoptosis, such as the Bax-to-Bcl-2 expression ratio and caspase-3 activity, in prostatic tissue from men with symptomatic BPH treated for 3 months before surgery. MATERIALS AND METHODS: An open, multicenter pilot study of 2 parallel groups of patients with BPH was done. They were randomized to be followed for 3 weeks without any treatment before surgery (control group) or to receive 160 mg SR orally twice daily for a 3-month period preceding the same surgery. Surgery was ultimately performed in 17 controls and 12 patients by transurethral prostate resection or retropubic adenomectomy. Bax and Bcl-2 expression, and caspase-3 activity were determined by Western blot in 15 controls and 10 patients, and reported in blinded fashion. RESULTS: The Bax-to-Bcl-2 ratio, which is used as an apoptotic index, was significantly increased in the prostatic tissue of treated patients. The level of the intact 116 kDa poly (adenosine diphosphate-ribose) polymerase form, an enzyme involved in the cell death apoptotic pathway, was also found to be decreased in prostatic tissue from SR treated patients, suggesting increased caspase 3 activity in the prostate. CONCLUSIONS: Permixon increased molecular markers involved in the apoptotic process, ie the Bax-to-Bcl-2 expression ratio and caspase-3 activity. This could have clinical relevance due to the improvement in symptoms produced by treatment with this drug.

[Upper urinary tract video-urodynamics. Current indications]. / "Vidaus" videourodinamia del aparato urinario superior. Indicaciones actuales.

OBJECTIVES: Upper urinary tract videourodynamic studies were first described in the second half of the 20th century (years 60-70). The antegrade pyelogram with constant pressure and controlled flow received the name of its author, "Vela Navarrete test" (1982), who currently refers to it as video-urodynamic study of the upper urinary tract. It is the simultaneous study of pressure, flow, and dynamic x-ray of the upper urinary tract and it keeps same indications than the original design, in spite of the appearance of new dynamic and static imaging techniques (ultrasound, CT scan, MRI, radioisotope studies). The continued practice of video urodynamic study of the upper urinary tract in the FJD prompted an update of the procedure reviewing its current indications. METHODS: Patient is positioned in the prone decubitus on an x-ray table with video. After punctioning renal cavities with fine needle, video urodynamic tests are performed: pyelomanometry, basal pyelic pressure (basic urodynamics study), pressure changes after induced diuresis, and pressure-flow studies. 10-20 ml of urine are obtained for biochemical tests (creatinine, electrolytes, osmolarity,...), which give information about the functional viability of the renal unit, cytology or microbiological tests. Finally, the study concludes with an antegrade pyelogram, a fluoroscopic study of the radiological anatomy which provides morphologic and dynamic data of the upper urinary tract. In the Urodynamics Unit of the FJD, urologists perform 30-40 studies per year. We analyzed retrospectively all studies performed over the last five years (1999-2005) for various pathological entities of kidney dilation. (Table I). RESULTS: Structural and dynamic data obtained by the studies offered conclusive information in most of them facilitating the decision for surgery or observation (Table II). CONCLUSIONS: The interpretation of the upper urinary tract video-urodynamic study is based on radiological and dynamic findings. Flow-controlled pyelogram enables determining the existence of obstruction, dilation volume, and ureteral peristaltic behaviour. Constant pressure enables quantification of obstruction. The video urodynamic study of the upper urinary tract is easy to perform, well tolerated and may be repeated as many times as required, mainly if nephrostomy tube is placed for more prolonged evaluations. It offers excellent anatomical, dynamic, and etiological information about the upper urinary tract, and furthermore conclusive, with minimal risk.

[Current indications of percutaneous nephrostomy associated with extracorporeal shock wave lithotripsy in the treatment of renoureteral stones]. / Indicaciones actuales de la nefrostomía percutanea asociada a la litotricia extracorpórea por ondas de choque en el tratamiento de la litiasis reno ureteral.

OBJECTIVES: To evaluate the usefulness of PN as urinary diversion in the treatment of urinary stones by ESWL. METHODS: Between April 1996 and June 2003 9554 ESWL were performed at the lithiasis unit of the Fundación Jiménez Diaz; 0.91% required previous insertion of a PN. We performed a retrospective analysis of the 49 patients with the diagnosis of upper urinary tract stones who require treatment by ESWL associated with PN. Indications for PN were: ureteral obstruction by fragments 6%, treatment of residual stones after percutaneous nephrolithectomy 6%, ureteral obstruction by a calcified double J stent 5%, urinary sepsis 75%, and obstructive anuria in a solitary kidney 8%. RESULTS: Overall, 87 sessions were performed in 49 patients. Number of shock waves 3996, Kv 7.69. Results where comparable in terms of stone size and composition. 57% of the patients were stone-free after one session, 24% after 2, and 19% required more than 2 sessions. There were two failures requiring surgery. CONCLUSIONS: Although in-situ ESWL is the treatment of choice for renoureteral lithiasis, the PN is a complementary procedure when ureteral obstruction requires treatment; it is non invasive and may be successfully associated to ESWL.