J.C. Angulo

Efficacy and Tolerability of Mirabegron, a β3-Adrenoceptor Agonist, in Patients with Overactive Bladder: Results from a Randomised European–Australian Phase 3 Trial

BACKGROUND Mirabegron, a β(3)-adrenoceptor agonist, has been developed for the treatment of overactive bladder (OAB). OBJECTIVE To assess the efficacy and tolerability of mirabegron versus placebo. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomised double-blind, parallel-group placebo- and tolterodine-controlled phase 3 trial conducted in 27 countries in Europe and Australia in patients ≥ 18 yr of age with symptoms of OAB for ≥ 3 mo. INTERVENTION After a 2-wk single-blind placebo run-in period, patients were randomised to receive placebo, mirabegron 50mg, mirabegron 100mg, or tolterodine extended release 4 mg orally once daily for 12 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Patients completed a micturition diary and quality-of-life (QoL) assessments. Co-primary efficacy end points were change from baseline to final visit in the mean number of incontinence episodes and micturitions per 24h. The primary comparison was between mirabegron and placebo with a secondary comparison between tolterodine and placebo. Safety parameters included adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, and postvoid residual volume. RESULTS AND LIMITATIONS A total of 1978 patients were randomised and received the study drug. Mirabegron 50-mg and 100-mg groups demonstrated statistically significant improvements (adjusted mean change from baseline [95% confidence intervals]) at the final visit in the number of incontinence episodes per 24h (-1.57 [-1.79 to -1.35] and -1.46 [-1.68 to -1.23], respectively, vs placebo -1.17 [-1.39 to -0.95]) and number of micturitions per 24h (-1.93 [-2.15 to -1.72] and -1.77 [-1.99 to -1.56], respectively, vs placebo -1.34 [-1.55 to -1.12]; p<0.05 for all comparisons). Statistically significant improvements were also observed in other key efficacy end points and QoL outcomes. The incidence of treatment-emergent AEs was similar across treatment groups. The main limitation of this study was the short (12-wk) duration of treatment. CONCLUSIONS Mirabegron represents a new class of treatment for OAB with proven efficacy and good tolerability. TRIAL IDENTIFICATION: This study is registered at ClinicalTrials.gov, identifier NCT00689104.

Oxidative stress and vascular inflammation in aging

Vascular aging, a determinant factor for cardiovascular disease and health status in the elderly, is now viewed as a modifiable risk factor. Impaired endothelial vasodilation is a early hallmark of arterial aging that precedes the clinical manifestations of vascular dysfunction, the first step to cardiovascular disease and influencing vascular outcomes in the elderly. Accordingly, the preservation of endothelial function is thought to be an essential determinant of healthy aging. With special attention on the effects of aging on the endothelial function, this review is focused on the two main mechanisms of aging-related endothelial dysfunction: oxidative stress and inflammation. Aging vasculature generates an excess of the reactive oxygen species (ROS), superoxide and hydrogen peroxide, that compromise the vasodilatory activity of nitric oxide (NO) and facilitate the formation of the deleterious radical, peroxynitrite. Main sources of ROS are mitochondrial respiratory chain and NADPH oxidases, although NOS uncoupling could also account for ROS generation. In addition, reduced antioxidant response mediated by erythroid-2-related factor-2 (Nrf2) and downregulation of mitochondrial manganese superoxide dismutase (SOD2) contributes to the establishment of chronic oxidative stress in aged vessels. This is accompanied by a chronic low-grade inflammatory phenotype that participates in defective endothelial vasodilation. The redox-sensitive transcription factor, nuclear factor-κB (NF-κB), is upregulated in vascular cells from old subjects and drives a proinflammatory shift that feedbacks oxidative stress. This chronic NF-κB activation is contributed by increased angiotensin-II signaling and downregulated sirtuins and precludes adequate cellular response to acute ROS generation. Interventions targeted to recover endogenous antioxidant capacity and cellular stress response rather than exogenous antioxidants could reverse oxidative stress-inflammation vicious cycle in vascular aging. Lifestyle attitudes such as caloric restriction and exercise training appear as effective ways to overcome defective antioxidant response and inflammation, favoring successful vascular aging and decreasing the risk for cardiovascular disease.

Muscularis mucosa differentiates two populations with different prognosis in Stage T1 bladder cancer

OBJECTIVES Contrary to previous belief, the existence of a muscularis mucosa in the human urinary bladder has now been well described. Although the degree of development of this structure seems variable, it can frequently be used to differentiate two levels within the subepithelial connective tissue: the lamina propria and the submucosa. The present study evaluates whether this morphologic feature is potentially useful for the identification of two populations with Stage T1 bladder cancer: those with tumor invasion confined to the lamina propria (pT1A) and those with tumors infiltrating into the submucosa (pT1B). METHODS A series of 170 Stage T1 papillary bladder tumors was analyzed pathologically to identify the level of subepithelial connective tissue invasion. Both the reproducibility of such a differentiation and its prognostic implication were evaluated using Kaplan-Meier survival estimates and the Cox regression model. RESULTS In specimens from transurethral resection, categorization into T1A or T1B could be performed in 98 of 170 cases (58% of specimens). Such differentiation proved to be of prognostic value with significantly different 5-year survivals between the two subcategories (pT1A [n = 50] vs pT1B [n = 49]) (log-rank, P < 0.02). Coxs regression analysis of pT1 subcategory and grade was performed in the 99 cases in which the differentiation between pT1A/pT1B could be made. This demonstrated that the depth of subepithelial connective tissue invasion was an independent prognostic factor (P < 0.05). CONCLUSIONS The depth of tumor infiltration can be assessed in a considerable proportion of Stage T1 bladder neoplasms. The present study validates the prognostic significance of such a distinction both by Mantel-Haenszel life table method and Coxs regression analysis.

Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies.

To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results.

Mechanisms involved in the aging-induced vascular dysfunction.

Vascular aging is a key process determining health status of aged population. Aging is an independent cardiovascular risk factor associated to an impairment of endothelial function, which is a very early and important event leading to cardiovascular disease. Vascular aging, formerly being considered an immutable and inexorable risk factor, is now viewed as a target process for intervention in order to achieve a healthier old age. A further knowledge of the mechanisms underlying the age-related vascular dysfunction is required to design an adequate therapeutic strategy to prevent or restore this impairment of vascular functionality. Among the proposed mechanisms that contribute to age-dependent endothelial dysfunction, this review is focused on the following aspects occurring into the vascular wall: (1) the reduction of nitric oxide (NO) bioavailability, caused by diminished NO synthesis and/or by augmented NO scavenging due to oxidative stress, leading to peroxynitrite formation (ONOO−); (2) the possible sources involved in the enhancement of oxidative stress; (3) the increased activity of vasoconstrictor factors; and (4) the development of a low-grade pro-inflammatory environment. Synergisms and interactions between all these pathways are also analyzed. Finally, a brief summary of some cellular mechanisms related to endothelial cell senescence (including telomere and telomerase, stress-induced senescence, as well as sirtuins) are implemented, as they are likely involved in the age-dependent endothelial dysfunction, as well as in the lower vascular repairing capacity observed in the elderly. Prevention or reversion of those mechanisms leading to endothelial dysfunction through life style modifications or pharmacological interventions could markedly improve cardiovascular health in older people.

Renal Echinococcosis: Clinical Study of 34 Cases

PURPOSE Hydatid disease, a cyclo-zoonotic parasitic infestation caused by the larval stage of the cestode Echinococcus granulosus, is prevalent worldwide. We reviewed the clinical findings of a large series of renal hydatidosis treated in an endemic area with special emphasis on diagnostic pitfalls. MATERIALS AND METHODS A retrospective 15-year review in a rural area of central Spain (600,000 population), with a global incidence of hydatidosis of 10 new cases per 100,000 population per year, revealed 34 with renal echinococcosis treated surgically (3 to 4% of officially confirmed cases of hydatidosis). Clinical, radiological and laboratory data were analyzed. RESULTS Renal hydatid disease mimicked other diseases. The combination of clinical history, imaging studies, and serological and urine investigation yielded a reliable pretreatment diagnosis in only 50% of cases and a presumptive diagnosis in 71%. Among imaging studies computerized tomography was the most valuable diagnostic examination. Moderate eosinophilia was found in half of the cases, while a third had scoleces in the urine. A diagnostic and therapeutic algorithm is presented. CONCLUSIONS Preoperative diagnosis of renal hydatid disease is difficult even in an endemic zone. Imaging studies are suggestive but usually inconclusive, and the differential diagnosis with a renal tumor or complicated cyst may not be made without surgery. Renal sparing surgery is possible in a significant proportion of cases, particularly when preoperative diagnosis has been considered. Significant surgical morbidity can be expected, and the risk of anaphylaxis and hydatid seeding, although low, should not be overlooked.

Diabetes Exacerbates the Functional Deficiency of NO/cGMP Pathway Associated with Erectile Dysfunction in Human Corpus Cavernosum and Penile Arteries

INTRODUCTION Diabetic men with erectile dysfunction (ED) are less responsive to therapy with type 5 phosphodiesterase (PDE5) inhibitors. Although an impairment of the nitric oxide (NO)/cyclic guanosin-monophosphate (cGMP) pathway has been shown in diabetic ED vs. non-diabetic ED, the functionality of NO/cGMP pathway in non-diabetic and diabetic ED patients with respect to non-ED patients has not been established. AIM The aim of this study is to evaluate the function of NO/cGMP signalling in human erectile tissues from ED patients exploring the added impact of diabetes. METHODS Corpus cavernosum strips (human corpus cavernosum [HCC]) and penile resistance arteries (HPRA) were collected from penile specimens from organ donors (OD) and from diabetic and non-diabetic men with ED undergoing penile prosthesis implantation. MAIN OUTCOME MEASURES Relaxations to acetylcholine, electrical field stimulation, sodium nitroprusside, and sildenafil were evaluated in phenylephrine-contracted HCC and norepinephrine-contracted HPRA. cGMP content in HCC was also determined. RESULTS The impairment of endothelium-dependent relaxation in HCC and HPRA from ED patients was exacerbated by diabetes (E(max) 76.1, 62.9, and 49.3% in HCC and 73.1, 59.8, and 46.0% in HPRA from OD, non-diabetic and diabetic ED, respectively). Hypertension, hypercholesterolemia, or aging did not exert a further impairment of endothelial relaxation among ED patients. Diabetes also causes a further impairment of neurogenic relaxation in HCC and HPRA. The basal and stimulated content of cGMP in HCC was significantly decreased in patients with ED, but specially reduced in diabetic patients. Diabetes clearly impaired PDE5 inhibitor-induced vasodilation of HPRA from ED patients. CONCLUSIONS ED is related to impaired vasodilation, reduced relaxant capacity, and diminished cGMP content in penile tissue. These alterations are more severe in diabetes and accompany reduced relaxant efficacy of PDE5 inhibition. Thus, an exacerbated reduction of nitric oxide/cGMP signaling could be responsible for ED in diabetic men and would explain their reduced response to treatment.

Differential effects of serotonin reuptake inhibitors on erectile responses, NO-production, and neuronal NO synthase expression in rat corpus cavernosum tissue

Increased incidence of impotence is associated with some selective serotonin‐reuptake‐inhibitors (SSRIs), but the pathophysiological mechanism is unknown. Paroxetine and citalopram are extensively used SSRIs, but only paroxetine has been shown to inhibit nitric oxide synthase (NOS) activity. NO is a key mediator of penile erection. Thus, the aim of this study was to determine the effects of paroxetine and citalopram on erectile function and NO production, in a rat model. Application of cavernosal nerve electrical stimulation produced frequency‐related intracavernosal pressure (ICP) increases, which were inhibited by the NOS inhibitor, NG‐nitro‐L‐arginine (0.3 mg kg−1). Acute or chronic (2 weeks) paroxetine‐treatment (10 mg kg−1) reduced ICP‐responses, while citalopram did not. Paroxetine, but not citalopram, significantly reduced nitrite+nitrate plasma levels by 61.4% and inhibited penile neuronal NOS (nNOS) protein expression by 31.2% after chronic treatment. The results show that paroxetine inhibits erectile responses in rats. We propose that this effect is due to reduced NO production and nNOS expression.

Regulation of human penile smooth muscle tone byprostanoid receptors

We have characterized the prostanoid receptors involved in the regulation of human penile arterial and trabecular smooth muscle tone. Arachidonic acid induced relaxation of human corpus cavernosum strips (HCCS) that was blocked by the cyclo‐oxygenase inhibitor, indomethacin, and augmented by the thromboxane receptor (TP) antagonist, SQ29548, suggesting that endogenous production of prostanoids regulates penile smooth muscle tone. TP‐receptors mediate contraction of HCCS and penile resistance arteries (HPRA), since the agonist of these receptors, U46619, potently contracted HCCS (EC50 8.3±2.8 nM) and HPRA (EC50 6.2±2.2 nM), and the contractions produced by prostaglandin F2α at high concentrations (EC50 6460±3220 nM in HCCS and 8900±6700 nM in HPRA) were inhibited by the selective TP‐receptor antagonist, SQ29548 (0.02 μM). EP‐receptors are responsible for prostanoid‐induced relaxant effects in HCCS because only prostaglandin E1 (PGE1), prostaglandin E2 and the EP2/EP4‐receptor agonist, butaprost, produced consistent relaxation of this tissue (EC50 93.8±31.5, 16.3±3.8 and 1820±1284 nM, respectively). In HPRA, both prostacyclin and PGE1 (EC50 60.1±18.4 and 109.0±30.9 nM, respectively) as well as the selective IP receptor agonist, cicaprost, and butaprost (EC50 25.2±15.2 and 7050±6020 nM, respectively) caused relaxation, suggesting co‐existence of IP‐ and EP‐receptors (EP2 and/or EP4). In summary, endogenous production of prostanoids may regulate penile smooth muscle contractility by way of specific receptors. TP‐receptors mediate contraction in HCCS and HPRA, while the relaxant effects of prostanoids are mediated by EP2‐ and/or EP4‐receptors in HCCS and by EP‐ and IP‐receptors in HPRA.

ISOLATED RETROVESICAL AND EXTRARENAL RETROPERITONEAL HYDATIDOSIS: CLINICAL STUDY OF 10 CASES AND LITERATURE REVIEW

PURPOSE Isolated extrarenal retroperitoneal echinococcal cyst is a rare manifestation of hydatid disease. We review the clinical findings of a series of isolated retrovesical and retroperitoneal hydatid cysts in an endemic area, with special emphasis on diagnostic pitfalls. MATERIALS AND METHODS A retrospective 15-year review in a rural area of central Spain (600,000 population), with a global incidence of hydatidosis of 10 new cases per 100,000 population per year, revealed 10 patients (0.1 cases per 100,000 per year) with surgically treated primary extrarenal retroperitoneal echinococcosis and absence of other hydatid cysts in any organ. Clinical, radiological and laboratory data are analyzed. The literature of the last 15 years on hydatid disease with a primary retroperitoneal and retrovesical location is reviewed. RESULTS A total of 42 cases of isolated retrovesical (25) and retroperitoneal (17) hydatidosis was compiled. Male predominance of 2.5:1 was noted and age ranged from 8 to 79 years (mean 42.2 +/- 5.4). The most frequent presentation was a palpable mass in 29% of the cases followed by flank pain in 24%, frequency in 17% and urinary retention in 14% of the cases. Hydatiduria of the urinary tract was present in 9.5% of the cases. Different serological investigations were performed in 45% of the cases with positive results in 68%. The lesion had been surgically removed in all cases. Therapy and followup of each patient were analyzed. CONCLUSIONS An isolated retrovesical, retroperitoneal or even retrocrural cyst can be the unique manifestation of hydatid disease. Although difficult, preoperative diagnosis is desirable for the selection of a surgical approach and prevention of allergic reactions and operative spillage. A diagnostic algorithm and several therapeutic guidelines are proposed.