Osamu Yamaguchi

β3-adrenoceptors in human detrusor muscle ☆

The detrusor muscle contains beta-adrenoceptors (beta-AR), and 2 subtypes-beta1-AR and beta2-AR-have been identified in most species. Although beta2-AR has an important role in muscle relaxation via activation of adenylate cyclase, evidence suggests that a third subtype, beta3-AR, which is implicated in metabolic functions of endogenous catecholamines, mediates relaxation of human detrusor muscle. There is a predominant expression of beta3-AR messenger RNA (mRNA) in human bladder tissue, with 97% of total beta-AR mRNA being represented by the beta3-AR subtype and only 1.5% and 1.4% by the beta1-AR and beta2-AR subtypes, respectively. Functionally, selective beta3-AR agonists relax human isolated detrusor, whereas selective beta1-AR/beta2-AR agonists do not. Isoproterenol-induced relaxation is inhibited by selective beta3-AR antagonists but not by selective beta1-AR or beta2-AR antagonists. In animal models, beta3-AR agonists increase bladder capacity and have only weak cardiovascular side effects. Although this evidence points toward the clinical utility of beta3-AR agonists as therapy for overactive bladder, clinical trials of beta3-AR agonists identified in animal models as antiobesity agents indicate side effects of tremor and tachycardia. Development of compounds with high selectivity for the human beta3-AR, identified by screening techniques using cell lines transfected with the human beta1-AR, beta2-AR, and beta3-AR genes, may mitigate such problems. Together with the preliminary finding that 49% (21 of 43) of patients with idiopathic detrusor instability have a tryptophan 64 arginine mutation of the beta3-AR gene, which may be a useful genetic marker, evidence points toward beta3-AR being a therapeutic target for treatment of overactive bladder disorder.

Clinical guidelines for overactive bladder

Department of Urology, Fukushima Medical University, Fukushima, Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Department of Urology, University of Yamanashi Interdisciplinary Graduate School of Medicine and Engineering, Chuo, Yamanashi, Department of Urology, University of Fukui Faculty of Medicine, Fukui, Department of Urology, University of Tokyo Faculty of Medicine, Tokyo, Department of Urology, Asahikawa Medical College, Asahikawa, Hokkaido, Department of Urology, Niigata University School of Medicine, Niigata, Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka, Department of Urology, Graduate School of medical Science, Kumamoto University, Kumamoto, Japan

Randomized, double‐blind, placebo‐ and propiverine‐controlled trial of the once‐daily antimuscarinic agent solifenacin in Japanese patients with overactive bladder

To compare solifenacin succinate (5 and 10u2003mg once‐daily) to placebo and propiverine hydrochloride (20u2003mg once‐daily), respectively, in Japanese patients with overactive bladder syndrome (OAB).

ESTIMATE CRITERIA FOR EFFICACY OF TREATMENT IN BENIGN PROSTATIC HYPERPLASIA

Background: Various treatment modalities for benign prostatic hyperplasia (BPH) have emerged and are now in use or await evaluation of clinical usefulness. It is difficult, however, to compare their efficacies on a single scale, because standardized criteria for therapeutic efficacy of BPH treatments have not been established.

The effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat†‡

To develop a rat model of atherosclerosis‐induced chronic bladder ischemia and investigate the effect of chronic bladder ischemia on voiding behavior and bladder function.

Solifenacin as add-on therapy for overactive bladder symptoms in men treated for lower urinary tract symptoms--ASSIST, randomized controlled study.

OBJECTIVESnTo assess the efficacy and safety of solifenacin add-on therapy to tamsulosin in lower urinary tract symptoms (LUTS) men with residual overactive bladder (OAB) symptoms despite tamsulosin monotherapy.nnnMETHODSnIn this randomized, multicenter, double-blind study, male LUTS patients aged≥50 years with urgency episodes/24 hours≥2 and micturitions/24 hours≥8 were randomized to 3 groups: 12-weeks tamsulosin plus placebo (TAM+PBO), tamsulosin plus solifenacin 2.5 mg (TAM+SOL), and tamsulosin plus solifenacin 5 mg (TAM+SOL). Changes from baseline to end of treatment in the number of urgency episodes/24 hours (primary endpoint), micturitions, nocturia, urgency incontinence episodes, International Prostate Symptom Scores (IPSS), and Overactive Bladder Symptom Score (OABSS) were compared between the TAM+SOL groups and TAM+PBO. Safety was assessed on adverse events, postvoid residual volume, and maximal urinary flow rate (Qmax.).nnnRESULTSnSix-hundred thirty-eight men were randomized. Urgency was reduced by 2.2 and 2.4 episodes in the TAM+SOL 2.5 and 5 mg groups, respectively. The TAM+SOL 5 mg group showed significant improvement compared with TAM+PBO (-2.4 vs -1.9, P=.049). The number of micturitions in both TAM+SOL groups were significantly reduced compared with TAM+PBO (both P<.001). IPSS storage symptom score and OABSS significantly improved in both TAM+SOL groups compared with TAM+PBO. Changes in IPSS voiding symptom score and Qmax. were similar in all groups. Four patients (1.9%) in the TAM+SOL 5 mg group had urinary retention, but all recovered after catheterization.nnnCONCLUSIONSnIn male LUTS patients with residual OAB symptoms despite tamsulosin monotherapy, TAM+SOL showed efficacy on urgency, which represents OAB symptoms and was well tolerated.

Increased bladder activity is associated with elevated oxidative stress markers and proinflammatory cytokines in a rat model of atherosclerosis-induced chronic bladder ischemia.

To further characterize, in a rat model, the effects of atherosclerosis‐induced chronic bladder ischemia on bladder function and associated changes in oxidative stress markers and proinflammatory cytokines.

Assessment of overactive bladder symptoms: comparison of 3-day bladder diary and the overactive bladder symptoms score.

OBJECTIVESnTo compare the Overactive Bladder Symptom Score (OABSS) and a bladder diary as a tool for assessing symptoms of overactive bladder (OAB).nnnMETHODSnTreatment-naive OAB patients received an antimuscarinic agent, solifenacin. At baseline and 12 weeks after treatment, patients completed a 3-day bladder diary and the OABSS. Relationships between the 2 methods were evaluated by comparison of changes after treatment, agreement between variables and correlation between changes.nnnRESULTSnIn total, 79 patients (42 male and 37 female, mean age 71.1 years) were included in the analysis. Statistically significant improvements were noted for all the OABSS and the corresponding diary variables. The effect size (ES) was largest for the OABSS urgency score (2.00), followed by the OABSS total score (1.54), and then by the diary urgency score (0.92). All of the ESs for the OABSS, except daytime frequency, were larger than those of the corresponding diary variables. The standard response means followed a similar pattern to the ESs. A fairly good agreement between OABSS items and the corresponding diary variables was found at baseline and 12 weeks (kappa coefficient, 0.33-0.80). High correlations (Spearmans rho, ≥ 0.5) between changes in OABSS items and the corresponding diary variables were found for urgency incontinence and night-time frequency.nnnCONCLUSIONSnThe OABSS is highly sensitive to treatment-related changes of OAB symptoms. Because of its simplicity and dependability, the OABSS can be an alternative to a bladder diary for symptom and efficacy assessment in daily clinical practice.

Antimuscarinics and overactive bladder: other mechanism of action.

Antimuscarinics are considered first‐line treatment for patients with overactive bladder (OAB). However, the mechanism by which antimuscarinics improve the symptoms of OAB remains to be elucidated. Animal studies suggest that antimuscarinics may exert an inhibitory effect on afferent nerves without an effect on detrusor contraction. A release of acetylcholine from the urothelium has been demonstrated in isolated human bladder. In addition, muscarinic receptors (MRs) were found in the urothelium and suburothelial myofibroblasts, suggesting a role for MR mechanisms in urothelial sensory function. Acetylcholine released during the storage phase could be expected to enhance the myogenic contractile activity of the detrusor, which can generate afferent signals. It is suggested that antimuscarinics may decrease bladder afferent activity by blocking MR in the above sites, thereby improving OAB symptoms. Neurourol. Urodynam. 29: 112–115, 2010.

Association of the Outcome of Renal Transplantation with Antibody Response to Cytomegalovirus Strain—Specific Glycoprotein H Epitopes

BACKGROUNDnCytomegalovirus (CMV) is the most important pathogen affecting the outcome of renal transplantation. The combination of CMV-seronegative transplant recipients with CMV-seropositive transplant donors places recipients at the highest risk of CMV disease. In cases of congenital CMV infection, existing immunity only partially protected mothers from reinfection with a different genotypic strain. The effect of differences in infected CMV strains between CMV-seropositive transplant donors and CMV seropositive transplant recipients on the outcome of transplantation remains unclear.nnnMETHODSnIn this prospective multicenter study, the presence of antibodies against strain-specific glycoprotein H epitopes in 84 CMV-seropositive transplant donor/CMV-seropositive transplant recipient renal transplantation cases were determined, and their relationships to acute transplant rejection, CMV infection, degree of antigenemia, and CMV disease were evaluated.nnnRESULTSnAmong the 84 donor/recipient pairs, 45 and 32 had matched and mismatched strain-specific glycoprotein H antibodies, respectively. Acute transplant rejection in the mismatched group was more frequent than it was in the matched group (63% vs. 22%; P=.005). CMV disease was also more frequently observed in the mismatched group (28% vs. 9%; P=.026). The mismatched group had a higher level of antigenemia (P=.019).nnnCONCLUSIONSnOur results illustrate more adverse events in the cases with a CMV-seropositive transplant donor and a CMV-seropositive transplant recipient in which the glycoprotein H antibodies are mismatched, suggesting that reinfection with a different CMV strain results in more complications.