RESUMO
BACKGROUND: Tadalafil is being investigated for the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH-LUTS). OBJECTIVE: To assess efficacy, including onset, and safety of tadalafil on BPH-LUTS and the subject's and clinician's perception of changes in urinary symptoms. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled, 12-week trial enrolled men ≥45 yr of age with BPH-LUTS for >6 mo, International Prostate Symptom Score (IPSS) ≥13, and maximum urine flow rate (Q(max)) ≥4 to ≤15 ml/s. INTERVENTION: Tadalafil 5mg (n=161) or placebo (n=164), once daily. MEASUREMENTS: Analysis of covariance (ANCOVA) modeling evaluated change from baseline in continuous efficacy variables. Categoric efficacy variables were analyzed with the Cochran-Mantel-Haenszel test, and between-group differences in treatment-emergent adverse events (TEAEs) were assessed using the Fisher exact test. RESULTS AND LIMITATION: Tadalafil significantly improved IPSS results, from baseline to endpoint, compared to placebo (-5.6 vs -3.6; p=0.004). Reduction in IPSS results was apparent after 1 wk and significant after 4 wk (tadalafil -5.3 vs placebo -3.5; p=0.003). The BPH Impact Index (BII) was not assessed at week 1; however, BII improvement was apparent at 4 wk (tadalafil -1.8 vs placebo -1.2; p=0.029) and continued at 12 wk (tadalafil -1.8 vs placebo -1.3; p=0.057). Tadalafil significantly improved the International Index of Erectile Function-Erectile Function score in sexually active men with erectile dysfunction (ED; 6.7 vs 2.0; p<0.001) at 12 wk (not assessed at week 1). Few subjects reported one TEAE or more (p=0.44). For tadalafil, the most common TEAEs were headache (3.7%) and back pain (3.1%). Tadalafil did not significantly improve Q(max) or reduce postvoid residual volume. CONCLUSIONS: Tadalafil 5mg once daily for 12 wk resulted in a clinically meaningful reduction in total IPSS results as early as 1 wk and achieved statistical significance at 4 wk in men with BPH-LUTS. The adverse event profile was consistent with that previously reported in men with ED. TRIAL REGISTRATION: This clinical trial is registered on the clinicaltrials.gov website (http://www.clinicaltrials.gov). The registration number is NCT00827242.
Assuntos
Carbolinas/administração & dosagem , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Hiperplasia Prostática/tratamento farmacológico , Idoso , Análise de Variância , Argentina , Carbolinas/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Europa (Continente) , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/fisiopatologia , Masculino , México , Pessoa de Meia-Idade , Ereção Peniana/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/efeitos adversos , Placebos , Hiperplasia Prostática/complicações , Hiperplasia Prostática/fisiopatologia , Tadalafila , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Micção/efeitos dos fármacos , Urodinâmica/efeitos dos fármacosRESUMO
INTRODUCTION AND AIM: This study evaluated the possible differences between an angiotensin converting enzyme (ACE) inhibitor and a beta-blocker concerning their potential protective role on female external genitalia in spontaneously hypertensive rats (SHR). MAIN OUTCOME MEASURES: Morphological changes in the clitoris after antihypertensive treatments. METHODS: For 6 months, SHR received no treatment; SHR + ramipril (RAM), SHR + atenolol (AT), and control Wistar Kyoto (WKY) rats received no treatment. Clitorises were processed for immunohistochemistry using anti-alpha-smooth muscle actin (alpha-SMA), anti-collagen I and III, anti-transforming growth factor beta(1) (TGFbeta(1)), and anti-endothelial nitric oxide synthase (eNOS) antibodies. RESULTS: SHR + RAM and SHR + AT presented significantly lower blood pressure in both groups vs. untreated SHR. Compared with WKY, alpha-SMA was increased in the arteries and in the cavernous spaces of the clitoris together with a marked increase in wall/lumen ratio in clitoral vessels in untreated SHR. All these alterations were diminished in SHR + AT (P < 0.01). SHR + RAM presented differences with respect to SHR + AT in the reduction of these variables. TGFbeta(1) expression in the vessel wall from the clitoris and collagen I and III deposition in the interstitium from the clitoris in untreated SHR were significantly more (P < 0.01) than in WKY. While SHR + AT showed a mild decrease in these variables, SHR + RAM presented a significant reduction (P < 0.01) in TGFbeta(1) expression interstitial fibrosis and in both types of collagens. Positive immunostaining of eNOS in the sinusoidal endothelium from the clitoris was less (P < 0.01) in untreated SHR (3.4 +/- 1.3%) and SHR + AT (5.1 +/- 1.2%) than in SHR + RAM (17.2 +/- 1.6%) and WKY (15.9 +/- 1.7%). Untreated SHR and SHR + AT presented more surrounding connective tissue at the perineurium in the clitoris (P < 0.01) than SHR + RAM. CONCLUSION: ACE inhibition provided a considerable protective role on the female external genitalia structures in SHR by a mechanism that may be, at least in part, independent of the degree of blood pressure lowering.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Clitóris/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Antagonistas Adrenérgicos beta/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Imuno-Histoquímica/métodos , Ratos , Ratos Endogâmicos WKYRESUMO
OBJECTIVE: The present study reviews the mechanism involved in the initiation and maintenance of penile erection. METHOD: The study reviews the literature on the basic concepts supporting either "magically" or scientifically the erectile mechanism. An anatomo-physiological update is also included (i.e., the main neurological, muscular, and vasculoendothelial phenomena). RESULTS: Present studies based on the vasoactive action of different drugs have increased the knowledge on the neurological, muscular, and vasculoendothelial phenomena. The cavernous muscular relaxation may start and finish due to the equilibrium between the contractile adrenergic and the relaxing non adrenergic-non cholinergic stimulus through intracellular nitric oxide synthesis. This is an essential phenomenon involved in the entry and "trapping" of blood within the sinus spaces. CONCLUSIONS: Our knowledge on the erectile mechanisms through neuromediators is increasing. The role of the endothelium in intracellular nitric oxide synthesis and its relaxing effect, will improve our understanding of both physiological and therapeutic phenomena.