François Giuliano

Tadalafil, a long‐acting phosphodiesterase type 5 inhibitor, is approved for treating signs and symptoms of benign prostatic hyperplasia (BPH) and erectile dysfunction (ED); tamsulosin, an alpha‐blocker, is approved for treating signs and symptoms of BPH. To determine the effects of tadalafil or tamsulosin on sexual function, including ejaculation and orgasm, satisfaction, and erectile function, in sexually active men with ED and lower urinary tract symptoms suggestive of BPH (LUTS/BPH). A randomized, double‐blind, placebo‐controlled study of tadalafil 5 mg once daily for 12 weeks in men with LUTS/BPH; tamsulosin 0.4 mg once daily was an active control. The International Index of Erectile Function (IIEF) questionnaire was administered at baseline and 4, 8, and 12 weeks. Analysis of orgasm and ejaculation was post hoc based on the IIEF‐Orgasmic Function (OF) domain (IIEF‐Q9 [ejaculatory frequency] and Q10 [orgasmic frequency]). Other measures included IIEF‐Intercourse Satisfaction (IS), Overall Satisfaction (OS), and Erectile Function (EF) domains. Changes from baseline to 12 weeks (or last observation) vs. placebo were analyzed using analysis of covariance. Higher IIEF scores indicate better functioning. Of 511 study participants, 310 (60.7%) had ED and were sexually active. The IIEF‐OF increased significantly through 12 weeks with tadalafil vs. placebo (P = 0.048), as did IIEF‐Q9 (P = 0.045) but not IIEF‐Q10 (P = 0.100). Compared with placebo, IIEF‐OF, Q9, and Q10 decreased significantly with tamsulosin (all P < 0.05). The IIEF‐IS and OS increased significantly at end point with tadalafil (both P < 0.001); for tamsulosin, change was not significant for IS, while OS decreased significantly (P = 0.009). The IIEF‐EF domain increased significantly vs. placebo with tadalafil (P < 0.001) but not tamsulosin (P = 0.699). Tadalafil 5 mg once daily significantly improved ejaculation and orgasm, intercourse and overall satisfaction, and erectile function. Men receiving tamsulosin 0.4 mg once daily experienced a decrease in both ejaculatory/orgasmic frequency and overall satisfaction vs. placebo, with no significant effect on erectile function.

To evaluate erectile function among men who had undergone laparoscopic radical prostatectomy and received postoperative medical therapy for erectile dysfunction. We performed a prospective study in men who underwent laparoscopic radical prostatectomy between September 2003 and November 2005 at our center and who received penile rehabilitation after surgery. All patients had antegrade interfascial dissection. They received 10 mg tadalafil on the fifth postoperative day and continued to receive it every other day, regardless of erectile function. Intracavernous injection of alprostadil was initiated at 3 or 6 months depending on response to treatment with tadalafil. Follow up evaluations were done at 3, 6, 12, 18 and 24 months. Oncologic and functional outcomes and compliance were assessed. Patients filled in International Index of Erectile Function-5 (IIEF-5) questionnaires. Of 1078 men who underwent laparoscopic radical prostatectomy during this time, 586 patients met inclusion criteria, complied with the study medication, and had complete data for 24 months. The patients had a median preoperative baseline IIEF-5 score of 22. A total of 150 patients (26%) underwent unilateral nerve-sparing surgery, while 436 patients (74%) had bilateral nerve-sparing surgery. At 24 months, 35% of patients who underwent unilateral nerve-sparing surgery and 68% of patients who underwent bilateral nerve-sparing surgery reported having sufficient erectile function for intercourse without using intracavernous injection of alprostadil. At 24 months after surgery, the median IIEF-5 score was 13 (1-25) for the whole cohort, 5 (1-25) for patients who had undergone unilateral nerve-sparing surgery, and 15 (1-25) for patients who had undergone bilateral nerve-sparing surgery. The findings suggest that adequate patient selection and postoperative medical intervention allows the preservation or recovery of erectile function after laparoscopic radical prostatectomy. Inaccurate selection of patients and postoperative assessment might explain inferior erectile function results following this surgery.

Significant intra- and interindividual variability has been observed in response to use of pharmacological agents in treatment of HIV infection. Treatment of HIV infection is limited by high rates of adverse drug reactions and development of resistance in a significant proportion of patients as a result of suboptimal drug concentrations. The efficacy of antiretroviral therapy is challenged by the emergence of resistant HIV-1 mutants with reduced susceptibility to antiretroviral drugs. Moreover, pharmacotherapy of patients infected with HIV is challenging because a great number of comorbidities increase polypharmacy and the risk for drug-drug interactions. Drug-metabolizing enzymes and drug transporters regulate drug access to the systemic circulation, target cells, and sanctuary sites. These factors, which determine drug exposure, along with the emergence of mutations conferring resistance to HIV medications, could explain variability in efficacy and adverse drug reactions associated with antiretroviral drugs. In this review, the major factors affecting the disposition of antiretroviral drugs, including key drug-metabolizing enzymes and membrane drug transporters, are outlined. Genetic polymorphisms affecting the activity and/or the expression of cytochromes P450 or UGT isozymes and membrane drug transport proteins are highlighted and include such examples as the association of neurotoxicity with efavirenz, nephrotoxicity with tenofovir, hepatotoxicity with nevirapine, and hyperbilirubinemia with indinavir and atazanavir. Mechanisms of drug resistance conferred by specific viral mutations are also reviewed, with particular attention to replicative viral fitness and transmitted HIV drug resistance with the objectives of providing a better understanding of mechanisms involved in HIV drug resistance and helping health care providers to better manage interpatient variability in drug efficacy and toxicity.

What's known on the subject? and What does the study add? Lower urinary tract symptoms (LUTS) resulting from benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are common problems in the aging male population. Moreover, several recent studies have shown that ED is closely associated with the presence and severity of LUTS independently of co‐morbidities. However, the pathophysiological mechanisms linking LUTS/BPH and ED remain largely unexplored. The major difficulty in studying such relationships between ED and LUTS/BPH, and of exploring the impact of new therapeutic approaches for both LUTS/BPH and ED, is the lack of experimental model combining ED, prostate enlargement and bladder dysfunction all at once. The present study describes a new model of BPH, the SHR supplemented with testosterone which is the first animal model which displays all at once the key features of BPH: prostate enlargement and an increased sympathetic tone of bladder outlet mimicking the static and the dynamic components of voiding symptoms of BPH, a significant impairment of bladder function which reflects the storage symptoms of BPH and finally, ED. This model could be very relevant to better characterize the close relationship that exists between BPH/LUTS and ED, and to evaluate new therapeutic strategies for BPH together with their side effect profile on sexual function on the same animal, thus allowing a reduction of the number of animals to be used in such studies. Study Type – Aetiology (case control) Level of Evidence 3b OBJECTIVE: To design a new experimental model combining erectile dysfunction, prostate enlargement and urodynamic impairment characteristic of lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH). MATERIALS AND METHODS: Three groups of animals (12‐week‐old; n = 7/group) were considered: Wistar Kyoto (control) rats (WKY), untreated spontaneously hypertensive rats (SHR) and SHR treated with testosterone (SHR‐T, 3 mg/kg/day) for 3 weeks. Cystometry experiments and evaluation of erectile function were performed. Prostate enlargement was evaluated. RESULTS: SHR displayed a significant decrease in the intercontraction interval (ICI) and in the voided volume (VV) whereas non‐voiding contractions (NVC) were increased. SHR‐T exhibited a further decreased ICI and VV and an increased frequency of NVC. Erectile responses to electrical stimulation of the cavernous nerve were significantly impaired in both SHR (−66%) and SHR‐T (−58%). The prostate weight was similar in WKY and SHR, but significantly increased in SHR‐T. CONCLUSIONS: The testosterone‐supplemented SHR represents an experimental model for urodynamic impairment combining both static and dynamic components of voiding symptoms with erectile dysfunction and prostate enlargement. This model is suitable for the assessment of sexual side effects of LUTS/BPH treatments and efficacy of new therapeutic agents in LUTS/BPH and associated erectile dysfunction.

Penile erection and ejaculation are closely associated during sexual intercourse. Erection is a central psychoneuroendocrine and peripheral neuro-vasculo-tissular event, resulting in blood filling the sinusoidal spaces of the corpora cavernosa and corpus spongiosum. Ejaculation represents the climax of the sexual cycle and comprises emission (secretion of semen) and expulsion (propulsion of semen) phases. This article provides an overview of the proposed neurophysiology of erection and ejaculation. Review of the literature. Current data on the neurophysiology of erection and ejaculation. In terms of peripheral innervation, the pelvic plexus represents a junction for efferent nerves to the structures involved in erection and ejaculation. At the spinal level, the spinal cord contains three sets of neurons (thoracolumbar sympathetic, sacral parasympathetic, and somatic) innervating the sexual organs involved in erection and ejaculation. The presence of cerebral descending pathways to spinal erection and ejaculation centers indicates that the brain has an excitatory or inhibitory effect on these processes. Brain structures that modulate spinal command of erection and ejaculation are part of a larger network that is dedicated to regulating sexual responses. Neurophysiological and pharmacological research has elucidated that dopamine and serotonin have central roles in modulating erection and ejaculation. Interestingly, erection is not a prerequisite for ejaculation, and each of these sexual responses can exist without the other. Despite the association between erection and ejaculation during intercourse, these two processes can be considered distinct events from an anatomical, physiological, and pharmacological perspective. Giuliano F. Neurophysiology of erection and ejaculation.