Metabolic Recruitment in Brain Tissue.

Information processing imposes urgent metabolic demands on neurons, which have negligible energy stores and restricted access to fuel. Here, we discuss metabolic recruitment, the tissue-level phenomenon whereby active neurons harvest resources from their surroundings. The primary event is the neuronal release of K+ that mirrors workload. Astrocytes sense K+ in exquisite fashion thanks to their unique coexpression of NBCe1 and α2ß2 Na+/K+ ATPase, and within seconds switch to Crabtree metabolism, involving GLUT1, aerobic glycolysis, transient suppression of mitochondrial respiration, and lactate export. The lactate surge serves as a secondary recruiter by inhibiting glucose consumption in distant cells. Additional recruiters are glutamate, nitric oxide, and ammonium, which signal over different spatiotemporal domains. The net outcome of these events is that more glucose, lactate, and oxygen are made available. Metabolic recruitment works alongside neurovascular coupling and various averaging strategies to support the inordinate dynamic range of individual neurons.

[The third version of COPSOQ-Istas21. An updated international instrument for the workplace.] / La tercera versión de COPSOQ-Istas21. Un instrumento internacional actualizado para la prevención de riesgos psicosociales en el trabajo.

OBJECTIVE: The Copenhagen Psychosocial Questio-nnaire (COPSOQ) is one of the most widely used in research and psychosocial risk assessment in the workplace. The adaptation of the third international COPSOQ version to Spain is described and the evidence of its validity and reliability presented. METHODS: Most of the items were already part of the previous versions I and II. The translation of the new items was done by means of translation/reverse translation. The questionnaire was included in the Psychosocial Risk Survey 2016, a cross-sectional study of a representative sample of the wage-earning population in Spain (N=1,807). Descriptive statistics, internal consistency, floor and ceiling effects and factor structure were analysed. Prevalence Ratios adjusted by age, sex and occupational class (aPR) to mental health, general health and job satisfaction were calculated. Finally, population reference values were calculated for all dimensions of the instrument. RESULTS: The questionnaire showed an excellent factorial structure. All scales, except one, showed α of Cronbach >0.70. Comparing the COPSOQ-Istas21 III scales with their international references, Cronbach's α were higher and the ceiling and floor effects were lower; i.e. Organisational Justice: α=0.85 vs 0.74, ceiling and floor 1.6 and 9.4 vs 3.3 and 12.8. The aPR between all the psychosocial dimensions and the Mental Health, General Health and Job Satisfaction were in the expected direction and showed an association gradient. CONCLUSIONS: COPSOQ-Istas21 version III presents psychometric properties analogous or better than the original in English language, and good indicators of validity and reliability, to be used in research and psychosocial risk assessment at the workplace in Spain.

OBJETIVO: El Copenhagen Psychosocial Questionnaire (COPSOQ) es uno de los más utilizados en investigación y evaluación de riesgos psicosociales en el trabajo. En este artículo se describió la adaptación de la tercera versión internacional a España y se presentaron las pruebas de su validez y fiabilidad. METODOS: La mayoría de los ítems ya formaban parte de las versiones anteriores I y II. La traducción de los nuevos ítems fue realizada mediante traducción/traducción inversa. El cuestionario se incluyó en la Encuesta de Riesgos Psicosociales de 2016, estudio transversal de una muestra representativa de la población asalariada en España (N=1.807). Se analizaron los estadísticos descriptivos, consistencia interna, efectos suelo y techo y estructura factorial. Se calcularon las Razones de Prevalencia ajustadas por edad, sexo y clase ocupacional (aRP) con salud mental, salud general y satisfacción laboral. Finalmente, se calcularon los valores de referencia poblacionales para todas las dimensiones del instrumento. RESULTADOS: El cuestionario mostró una excelente estructura factorial. Todas las escalas, excepto una, mostraron α de Cronbach >0,70. Comparando las escalas de COPSOQ-Istas21 III con sus referentes internacionales, las α de Cronbach fueron más altas y los efectos techo y suelo menores (por ejemplo, Justicia organizacional: α=0,85 vs 0,74, techo y suelo 1,6 y 9,4 vs 3,3 y 12,8). Las aRP entre todas las dimensiones psicosociales y las dimensiones de Salud mental, Salud general y Satisfacción, fueron en la dirección esperada y mostraron un gradiente de asociación. CONCLUSIONES: COPSOQ-Istas21 versión III presenta propiedades psicométricas análogas o mejores al original en lengua inglesa y buenos indicadores de validez y fiabilidad para ser usado en investigación y evaluación de riesgos psicosociales laborales en España.

Intraoperative and postoperative complications of penile implant surgery. Diagnosis and treatment. / Complicaciones intraoperatorias y postoperatorias de la cirugía de prótesis de pene. Diagnóstico y tratamiento.

We describe the most frequent complications associated with penile implant surgery, paying special attention to their practical management. We have analyzed preoperative complications and postoperative complications separately. The intraoperative include perforation of the corpora cavernosa during dilation, cylinder cross-over or cross-placement and urethral injury during implantation. The most frequent postoperative complications are mechanical failure, cylinder erosion and prosthesis infection. We emphasize on rescue surgery and reimplantation techniques in cavernous tissue fibrosis.

Complicaciones intraoperatorias y Postoperatorias de la cirugía de Prótesis de Pene. Diagnóstico y Tratamiento / Intraoperative and postoperative complications of penile implant surgery. Diagnosis and treatment

Describimos las complicaciones más frecuentes de la cirugía de implante de prótesis de pene haciendo hincapié en su manejo práctico. Hemos dividido las complicaciones en intraoperatorias y postoperatorias. Entre las complicaciones intraoperatorias destacan: la perforación de los cuerpos a cavernosos durante la dilñatación, el cross-ver de los cilindros o colocación cruzada y la lesión uretral durante el implante. Las complicaciones más frecuentes postoperatorias son el fallo mecánico de la prótesis, la erosión de cilindros y la infección las prótesis haciendo énfasis en la cirugía de rescate y en las técnicas de reimplante en fibrosis de tejido cavernoso

We describe the most frequent complications associated with penile implant surgery, paying special attention to their practical management. We have analyzed preoperative complications and postoperative complications separately. The intraoperative include perforation of the corpora cavernosa during dilation, cylinder cross-over or cross-placement and urethral injury during implantation. The most frequent postoperative complications are mechanical failure, cylinder erosion and prosthesis infection. We emphasize on rescue surgery and reimplantation techniques in cavernous tissue fibrosis

Combination therapy for erectile dysfunction involving a PDE5 inhibitor and alprostadil.

The phosphodiesterase-5 inhibitors (PDE5Is) are the first-line treatment option for men with erectile dysfunction (ED), with alprostadil considered a second-line choice. Consideration has to be given to patients who fail these treatments and what their options are. This review evaluates the data on the combination of a PDE5I with alprostadil in patients who have previously failed therapy with either drug. A PubMed search was conducted and identified nine publications relating to combination treatment with alprostadil as intracavernosal, intraurethral or topical application. The results indicate that with all three formulations the combination therapy resulted in an improved outcome compared with either of the drugs as monotherapy. This was demonstrated by the increased total International Index of Erectile Function (IIEF) scores as well as IIEF erectile function domain scores. This finding was also valid for patients with post-prostatectomy ED. The associated side effects of the combined treatment did not result in treatment discontinuation. These findings suggest that combination therapy with a PDE5I and alprostadil might be considered a treatment option in patients who have previously had a poor response to either drug.

Psychosocial outcomes after initial treatment of erectile dysfunction with tadalafil once daily, tadalafil on demand or sildenafil citrate on demand: results from a randomized, open-label study.

Initiation of ED treatment with a particular PDE5I may influence treatment-adherence and other outcomes. In this multicenter, open-label study, men with ED, naïve to PDE5I, were randomized to tadalafil 5 mg once-a-day (OaD; N=257), 10 mg on demand (PRN; N = 252) or sildenafil-citrate (sildenafil) 50 mg PRN (N = 261) for 8 weeks (dose adjustments allowed), followed by 16 weeks of pragmatic treatment (switching between PDE5I allowed). Primary outcomes (treatment-adherence) were reported previously. Here, we report effects on: Psychological and Interpersonal Relationship Scales, Self-Esteem and Relationship (SEAR) questionnaire, ED Inventory of Treatment Satisfaction (EDITS), International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP) and Global Assessment Questions (GAQ). Mixed-model for repeated measures and analysis of covariance were used to analyze changes from baseline; GAQ-responses were evaluated by logistic regression. Analyses were adjusted for treatment, country, ED-severity, baseline and baseline-by-treatment interaction. Patients randomized to tadalafil OaD or PRN reported greater improvement (least-square mean (s.e.) change) in Sexual Self-Confidence (OaD +0.90 (0.048), PRN +0.93 (0.050), vs +0.73 (0.049); P=0.006 and P=0.001) and Spontaneity (OaD +0.11 (0.035), PRN +0.13 (0.035), vs +0.02 (0.035); P = 0.044 and P = 0.010) compared with sildenafil. Improvements in GAQ and SEP responses, IIEF-EF, orgasmic function, sexual desire, overall satisfaction domains, SEAR and EDITS scores did not differ significantly between treatment groups.

Small is fast: astrocytic glucose and lactate metabolism at cellular resolution.

Brain tissue is highly dynamic in terms of electrical activity and energy demand. Relevant energy metabolites have turnover times ranging from milliseconds to seconds and are rapidly exchanged between cells and within cells. Until recently these fast metabolic events were inaccessible, because standard isotopic techniques require use of populations of cells and/or involve integration times of tens of minutes. Thanks to fluorescent probes and recently available genetically-encoded optical nanosensors, this Technology Report shows how it is now possible to monitor the concentration of metabolites in real-time and in single cells. In combination with ad hoc inhibitor-stop protocols, these probes have revealed a key role for K(+) in the acute stimulation of astrocytic glycolysis by synaptic activity. They have also permitted detection of the Warburg effect in single cancer cells. Genetically-encoded nanosensors currently exist for glucose, lactate, NADH and ATP, and it is envisaged that other metabolite nanosensors will soon be available. These optical tools together with improved expression systems and in vivo imaging, herald an exciting era of single-cell metabolic analysis.

Acute feedback control of astrocytic glycolysis by lactate.

Neuronal activity is accompanied by a rapid increase in interstitial lactate, which is hypothesized to serve as a fuel for neurons and a signal for local vasodilation. Using FRET microscopy, we report here that the rate of glycolysis in cultured mice astrocytes can be acutely modulated by physiological changes in extracellular lactate. Glycolytic inhibition by lactate was not accompanied by detectable variations in intracellular pH or intracellular ATP and was not dependent of mitochondrial function. Pyruvate was also inhibitory, suggesting that the effect of lactate is not mediated by the NADH/NAD(+) ratio. We propose that lactate serves as a fast negative feedback signal limiting its own production by astrocytes and therefore the amplitude of the lactate surge. The inhibition of glucose usage by lactate was much stronger in resting astrocytes than in K(+)-stimulated astrocytes, which suggests that lactate may also help diverting glucose from resting to active zones.

Current benign prostatic hyperplasia treatment: impact on sexual function and management of related sexual adverse events.

Benign prostatic hyperplasia (BPH) is a common disease in older men that can lead to lower urinary tract symptoms (LUTS). Male sexual dysfunction is also an age-related condition. Epidemiological studies have confirmed an association between BPH/LUTS and sexual dysfunction in ageing men that is independent of the effects of age, other co-morbidities and lifestyle factors. Proposed pathophysiological mechanisms for BPH/LUTS-associated sexual dysfunction include the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway, rho-kinase and endothelin-1 activity, autonomic nervous system overactivity and the metabolic syndrome, and pelvic organ atherosclerosis. Both BPH/LUTS and sexual dysfunction can have a substantial negative impact on a man's quality of life. However, urologists and primary care physicians appear to under-recognise sexual dysfunction in men with BPH/LUTS. Current guidelines recommend alpha-blockers and 5-alpha reductase inhibitors, either alone or in combination, among appropriate medical treatment options for BPH/LUTS. Randomised, controlled trials demonstrate that these therapies can be associated with sexual adverse effects (AEs) such as loss of libido, erectile dysfunction and ejaculatory disorders. Sexual dysfunction should be fully evaluated in men requiring treatment for BPH/LUTS using validated questionnaires. Management of sexual dysfunction in men treated for BPH/LUTS should involve assessment of co-morbidities and concomitant medications, consideration of lifestyle interventions such as weight loss and increased physical activity to improve risk factors and, if necessary, introduction of pharmacotherapies. In addition, physicians should provide patients with proper counselling on the possible sexual AEs of medical therapies for BPH/LUTS and their impact on sexual satisfaction, while being aware of the possibility that counselling in itself is likely to influence reported rates of sexual dysfunction.

Evaluación de la autoestima en varones con disfunción eréctil tratados con sildenafilo. Análisis de un grupo de pacientes españoles procedentes de un estudio multicéntrico internacional / Evaluation of self-esteem in males with erectile dysfunction treated with viagra. Analysis of a Spanish patients group selected from a multicenter, international study

Introducción y objetivos: La disfunción eréctil (DE) provoca alteraciones psicológicas, principalmente ansiedad y pérdida de la autoestima. Intentamos conocer los cambios emocionales, basados en la autoestima y las relaciones, en un grupo de varones españoles con DE tras el tratamiento con sildenafilo, utilizando para ello el cuestionario SEAR (Self-Esteem And Resationship). Material y método: De un estudio internacional multicéntrico, randomizado, grupos paralelos, doble ciego y controlado por placebo de sildenafilo diseñado para evaluar la autoestima y relaciones en varones con DE, seleccionamos los pacientes reclutados en España. Se compararon los cambios en los diferentes dominios del cuestionario SEAR (autoestima, actividad sexual, autoconfianza y relaciones generales) que se administró antes y después del tratamiento, así como los diferentes dominios del IIEF. También se calculó la correlación entre el cambio en el dominio autoestima del cuestionario SEAR y el dominio función eréctil del IIEF. El estudio estadístico se basó en un análisis de la covarianza del cambio en las puntuaciones y en un estudio de correlación. Resultados: El grupo español de investigadores incluyó 119 pacientes. La puntuación del dominio función eréctil mostró una mejoría significativamente mayor para el grupo de sildenafilo. La diferencia de cambio en la media de la puntuación total del SEAR tras el tratamiento fue de 16,9 (IC 95%: 8,9; 24,8) a favor de sildenafilo respecto al placebo (p=0,0001), con una mejoría en la puntuación significativamente superior en todos los dominios del SEAR a favor de sildenafilo. Se observó una correlación significativa entre los cambios en el dominio de autoestima del SEAR y el dominio función eréctil del IIEF para ambos grupos de tratamiento. Conclusiones: Se confirma una mejoría emocional en los pacientes tratados con sildenafilo en base a la mejora en la autoestima, autoconfianza y las relaciones. Variaciones en el dominio función eréctil del IIEF muestran correlación con las del dominio autoestima del SEAR (AU)

Introduction and objectives: Erectile dysfunction (ED) leads to psychological disturbances, especially anxiety and loss of self-esteem. We try to understand the emotional changes, based on self-esteem and relationships in a group of Spanish men with ED after sildenafil treatment, with the use of the SEAR questionnaire (Self-Esteem And Relationship). Materials and methods: The patients recruited in Spain, where selected from an international, multicenter, randomized, parallel-group, double-blind, placebo-controlled, sildenafil study designed to assess self-esteem and relationships in men with ED. We compared the changes in the different domains of the SEAR questionnaire (Self-steem, sexual activity, self-confidence and general relationships) that was administered before and after treatment; the different domains of the IIEF was evaluated aswell. We also calculated the correlation between changes in self-esteem domain of the SEAR questionnaire. The statistical study was based on an analysis of covariance of change in scores and a correlation analysis. Results: The Spanish group of researchers included 119 patients. The erectile function domain score showed significantly greater improvement for the group of sildenafil. The difference in change in total mean score of the SEAR after treatment was 16.9 (95% CI 8.9, 24.8) for sildenafil over placebo (p=0.0001), with a significantly higher score improvement in all the domains of the SEAR for Sildenafil. There was a significant correlation between the changes in the domain of self-esteem of the SEAR and the IIEF erectile function domain for both treatment groups. Conclusions: Emotional improvement was confirmed in patients treated with sildenafil based on improved self-esteem, self-confidence and relationships. Changes in the IIEF erectile function domain correlate with the SEAR self-esteem domain (AU)

[Evaluation of self-esteem in males with erectile dysfunction treated with viagra. Analysis of a Spanish patients group selected from a multicenter, international study]. / Evaluación de la autoestima en varones con disfunción eréctil tratados con sildenafilo. Análisis de un grupo de pacientes españoles procedentes de un estudio multicéntrico internacional.

INTRODUCTION AND OBJECTIVES: Erectile dysfunction (ED) leads to psychological disturbances, especially anxiety and loss of self-esteem. We try to understand the emotional changes, based on self-esteem and relationships in a group of Spanish men with ED after sildenafil treatment, with the use of the the SEAR questionnaire (Self-Esteem And Relationship). MATERIALS AND METHODS: The patients recruited in Spain, where selected from an international, multicenter, randomized, parallel-group, double-blind, placebo-controlled, sildenafil study designed to assess self-esteem and relationships in men with ED. We compared the changes in the different domains of the SEAR questionnaire (Self-steem, sexual activity, self-confidence and general relationships) that was administered before and after treatment; the different domains of the IIEF was evaluated as well. We also calculated the correlation between changes in self-esteem domain of the SEAR questionnaire. The statistical study was based on an analysis of covariance of change in scores and a correlation analysis. RESULTS: The Spanish group of researchers included 119 patients. The erectile function domain score showed significantly greater improvement for the group of sildenafil. The difference in change in total mean score of the SEAR after treatment was 16.9 (95% CI 8.9, 24.8) for sildenafil over placebo (p=0.0001), with a significantly higher score improvement in all the domains of the SEAR for Sildenafil. There was a significant correlation between the changes in the domain of self-esteem of the SEAR and the IIEF erectile function domain for both treatment groups. CONCLUSIONS: Emotional improvement was confirmed in patients treated with sildenafil based on improved self-esteem, self-confidence and relationships. Changes in the IIEF erectile function domain correlate with the SEAR self-esteem domain.

Cambios morfométricos peneanos tras prostatectomía radical: revisión de la evidencia / Penile morphometric changes after radical prostatectomy: Evidence-based

Introducción: La prostatectomía radical en cualquiera de sus abordajes representa el tratamiento de elección del cáncer localizado de la próstata y especialmente en pacientes jóvenes sexualmente activos con deseo de mantener su vida sexual. Además de la bien conocida y definida disfunción eréctil postoperatoria, el período de silencio eréctil causa en muchos pacientes (9–71%) cambios estructurales, a veces irreversibles, en la estructura peneana. Estos cambios tisulares derivan en una pérdida de longitud y grosor del pene, que preocupa a los pacientes. Objetivo: Revisar de manera sistemática los datos publicados en la literatura médica hasta el momento en relación con los cambios peneanos tras prostatectomía radical. Material y métodos: Realizamos una búsqueda sistemática en PubMed, EMBASE, Cochrane, SCOPUS y Science Citation Index durante el período de enero de 1990 a septiembre de 2009 para los términos «prostatectomy», «organ size», «fibrosis», «sexual activity», «erectile dysfunction», «penile size», «radical prostatectomy», «prostatic neoplasms», «body weights» y «penis measures».Material y métodosSe seleccionaron 7 series de pacientes para su análisis. Resultados: Se exponen los diferentes métodos de medición peneana y sus potenciales sesgos y diferencias. Asimismo, repasamos las principales teorías fisiopatogénicas para explicar este fenómeno. Finalmente, se detallan los resultados de diferentes series de pacientes comunicadas. Conclusiones: Parece un hecho demostrado que el pene sufre cambios importantes en su longitud y grosor tras prostatectomía radical. Diferentes autores han comunicado los datos de sus series así como las diferentes opciones de tratamiento (inhibidores de la 5-PDE, dispositivos de vacío [DV], extensores del pene, etc.). Las estrategias encaminadas a preservar y a proteger el tejido cavernoso y la túnica albugínea tras el procedimiento así como las que aumenten la oxigenación y permitan recuperar la erección en el menor tiempo posible impactarán positivamente en la calidad de nuestros pacientes (AU)

Introduction: Radical prostatectomy in all its approaches is the treatment of choice for localized prostate cancer and especially in young, sexually active patients with a desire to keep their sex life. In addition to the well-known and defined postoperative erectile dysfunction, erectile silent period causes, in many patients (9–1%), structural changes, in the penile structure, sometimes irreversible. These tissue changes, resulting in a loss of length and girth, that concern patients. Objective: To systematically review to date published data in the literature regarding penile changes after radical prostatectomy. Material and methods: We performed a systematic search in: PubMed, EMBASE, Cochrane, SCOPUS, Science Citation Index period January 1990 to September 2009 for the terms “prostatectomy”, “organ size”, “fibrosis”, “sexual activity”, “erectile dysfunction”, “penile size”, “radical prostatectomy”, “prostatic neoplasms”, “body weights” and “penis measures”. Seven series of patients were selected for analysis. Results: We described the different measurement methods and their potential biases and differences. Also, we reviewed main physiopathogenic theories to explain this phenomenon. Finally, we detail the results of different series of patients reported. Conclusions: It seems to be a proven fact that the penis undergoes major changes in its length and girth after radical prostatectomy. Several authors have communicated the data of their series and the different treatment options (5PDE inhibitors, vacuum devices, penile extenders, etc.). Strategies addressed to preserve and protect cavernous tissue and tunica albuginea after the procedure, as well as to increase oxygenation and allow erection to be recovered in the shortest posible time positive will impact on the quality of life of our patients (AU)

[Penile morphometric changes after radical prostatectomy: Evidence-based]. / Cambios morfométricos peneanos tras prostatectomía radical: revisión de la evidencia.

INTRODUCTION: Radical prostatectomy in all its approaches is the treatment of choice for localized prostate cancer and especially in young, sexually active patients with a desire to keep their sex life. In addition to the well-known and defined postoperative erectile dysfunction, erectile silent period causes, in many patients (9-1%), structural changes, in the penile structure, sometimes irreversible. These tissue changes, resulting in a loss of length and girth, that concern patients. OBJECTIVE: To systematically review to date published data in the literature regarding penile changes after radical prostatectomy. MATERIAL AND METHODS: We performed a systematic search in: PubMed, EMBASE, Cochrane, SCOPUS, Science Citation Index period January 1990 to September 2009 for the terms prostatectomy, organ size, fibrosis, sexual activity, erectile dysfunction, penile size, radical prostatectomy, prostatic neoplasms, body weights and penis measures. Seven series of patients were selected for analysis. RESULTS: We described the different measurement methods and their potential biases and differences. Also, we reviewed main physiopathogenic theories to explain this phenomenon. Finally, we detail the results of different series of patients reported. CONCLUSIONS: It seems to be a proven fact that the penis undergoes major changes in its length and girth after radical prostatectomy. Several authors have communicated the data of their series and the different treatment options (5PDE inhibitors, vacuum devices, penile extenders, etc.). Strategies addressed to preserve and protect cavernous tissue and tunica albuginea after the procedure, as well as to increase oxygenation and allow erection to be recovered in the shortest possible time positive will impact on the quality of life of our patients.

Effect of lamotrigine on sexual function in patients with epilepsy.

OBJECTIVE: To assess the course of sexual function in epilepsy patients treated with lamotrigine. MATERIAL AND METHODS: This open study included 141 patients treated with lamotrigine for a period of 8 months: 79 patients initiated treatment with lamotrigine monotherapy, and 62 were switched to lamotrigine because of lack of efficacy or adverse events to a previous antiepileptic drug (AED). Patients were assessed at baseline and after 4 and 8 months of treatment. In the baseline and final visits the Changes in Sexual Functioning Questionnaire (CSFQ) was applied. Analysis was performed in an intent-to-treat population. RESULTS: In women who started treatment with lamotrigine, a significant improvement was observed, both in total CSFQ score (increase of 5.39 +/- 6.95 points; p < 0.05), and in the five dimensions of the scale (desire/frequency, desire/interest, pleasure, arousal/excitement and orgasm). In men, a significant improvement was only observed in the pleasure dimension. In the group of patients in whom a previous AED was substituted by lamotrigine, significant improvement was recorded in the dimensions of pleasure and orgasm in men and desire/frequency in women, whilst in women the desire/interest dimension showed a decrease. CONCLUSIONS: In this observational study, an improvement in sexual dysfunction was observed in association with lamotrigine. This could have been the result of improvement of the epilepsy, changes in quality of life, elimination of side effects from other AEDs, or a mood-stabilizing effect of lamotrigine.

Core document on erectile dysfunction: key aspects in the care of a patient with erectile dysfunction.

The aim of this Core Document of the Spanish Consensus on Erectile dysfunction (ED) is to offer guidance to the nonspecialist physician in the management of patients with ED. ED is one of the most frequent chronic health problems in men older than 40 y of age and may also act as a sentinel symptom for other important underlying diseases. Its etiology can be classified into organic, psychogenic, or mixed. In most cases, the underlying cause of ED is usually a chronic health problem (such as diabetes, hypertension, atherosclerosis, and so on) or an adverse drug effect. The initial step in the management is to assess erectile function in patients with risk factors for ED. Once ED has been established, a detailed sexual, medical, and social history, including a review of medications used, is the most important aspect of a patient's assessment. Generally, examination should be limited to the cardiovascular, neurological, and urogenital systems. Fasting glucose and blood lipid profile should be performed in every man with ED, and free testosterone levels in men older than 50 y or if hypogonadism is suspected; other diagnostic tests are optional and should be requested on an individualized basis. In many cases, the most likely cause of ED can be identified based on the above information. Therapeutic intervention should be patient-oriented and based on the expectations and wishes of the patient and his partner, who should be included in discussions whenever possible. Basic interventions common to any type of ED include sexual counseling, lifestyle modifications, treatment of associated medical conditions, and switching to alternative drugs with lower risk of ED. In certain cases, an etiologic treatment may be performed (sex therapy, revascularization surgery, and hormonal therapy). Most patients with ED will benefit from symptomatic treatments; first-line therapy may be prescribed by physicians who are not specialists in ED, and includes oral agents such as inhibitors of phosphodiesterase type 5, currently considered the drugs of choice for initial treatment of ED. Intracavernous drugs are the second-line therapy, and surgical treatments, such as implantation of penile prostheses, are reserved for urologists/andrologists who specialize in ED. Referral may be appropriate where indicated by age, clinical findings, or the patient's request.

Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction.

OBJECTIVE: To assess the long-term safety and tolerability of tadalafil for patients with erectile dysfunction (ED). PATIENTS AND METHODS: This was a multicentre, open-label, 24-month extension trial involving 1173 men with ED. The mean age was 57 (range 23-83) years and 74.8% of patients were taking concomitant medications for comorbid conditions, including diabetes mellitus in 30.5% of men and hypertension in 29.5%. These patients had participated in 1 of 5 previous 8-week or 12-week randomised, double-blind, placebo-controlled tadalafil studies. In the present trial, the starting 10mg dose of tadalafil could be increased to 20mg if the patient could not achieve satisfactory intercourse or reduced to 5mg for an adverse event that was persistent, intolerable and judged by the investigator to be related to tadalafil. RESULTS: Four hundred ninety-three (42.0%) men completed 24 months of treatment. In addition, a further 234 (19.9%) completed 18 months of treatment due to a sponsor decision to reduce the study duration. The total tadalafil exposure was 1676.0 patient-years. Tadalafil was safe and well tolerated. Headache (15.8%), dyspepsia (11.8%), nasopharyngitis (11.4%), and back pain (8.2%) were the most common treatment-emergent adverse events. The rate of discontinuations due to adverse events for this 18-24-month study was 6.3% and the rate for any individual event was <1%. Serious adverse events occurred in 8.6% of patients. No consistent pattern of serious adverse events assessed as causally associated with tadalafil administration was observed. None of the four deaths that occurred during the study was assessed as tadalafil related. There were no clinically significant laboratory or electrocardiographic findings or changes in vital signs in mean baseline-to-endpoint analysis attributable to tadalafil. Tadalafil administration was not causally associated with drug-induced hepatotoxicity, neutropenia, thrombocytopenia, or renal dysfunction. CONCLUSION: Tadalafil at doses of 5, 10, or 20mg taken as needed up to once daily for 18 to 24 months was safe and well tolerated. These findings support the long-term use of tadalafil in the clinical management of erectile dysfunction.

The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil.

We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (PDE5) or bovine sources (PDEs 1, 2, 3, 4 and 6). The inhibition of these PDEs and of human recombinant PDEs by vardenafil was determined. The ability to potentiate NO-mediated relaxation and influence cGMP levels in human corpus cavernosum strips was measured in vitro, and erection-inducing activity was demonstrated in conscious rabbits after oral administration together with intravenous doses of sodium nitroprusside (SNP). The effects of vardenafil were compared with those of the well-recognized PDE5 inhibitor, sildenafil (values for sildenafil in brackets). Vardenafil specifically inhibited the hydrolysis of cGMP by PDE5 with an IC50 of 0.7 nM (6.6 nM). In contrast, the IC50 of vardenafil for PDE1 was 180 nM; for PDE6, 11 nM; for PDE2, PDE3 and PDE4, more than 1000 nM. Relative to PDE5, the ratios of the IC50 for PDE1 were 257 (60), for PDE6 16 (7.4). Vardenafil significantly enhanced the SNP-induced relaxation of human trabecular smooth muscle at 3 nM (10 nM). Vardenafil also significantly potentiated both ACh-induced and transmural electrical stimulation-induced relaxation of trabecular smooth muscle. The minimum concentration of vardenafil that significantly potentiated SNP-induced cGMP accumulation was 3 nM (30 nM). In vivo studies in rabbits showed that orally administered vardenafil dose-dependently potentiated erectile responses to intravenously administered SNP. The minimal effective dose that significantly potentiated erection was 0.1 mg/kg (1 mg/kg). The selectivity for PDE5, the potentiation of NO-induced relaxation and cGMP accumulation in human trabecular smooth muscle and the ability to enhance NO-induced erection in vivo indicate that vardenafil has the appropriate properties to be a potential compound for the treatment of erectile dysfunction. Vardenafil was more potent and selective than sildenafil on its inhibitory activity on PDE5.