Normal lower urinary tract function consists of voiding and storage. During voiding, the pontine micturition reflex center orders the sacral parasympathetic nucleus to increase parasympathetic activity, resulting in urinary bladder detrusor contraction via activation of post-synaptic muscarinic receptors (M_2/3), and the relaxation of both urethral and prostatic smooth muscle by NO. In addition, the rhabdosphincter relaxes by inhibition of pudendal nucleus at the sacral portion. During the storage phase, an increase in sympathetic activity relaxes urinary bladder via activation of post-synaptic β₃ receptors, and both the urethral and prostatic smooth muscles are contracted via α₁-adrenoceptor. Many factors influence voiding function, including lower urinary tract disorders (benign prostatic hyperplasia in males, urethral stricture), and neurological disorders (central and peripheral). Theories of action of pharmacotherapy for voiding dysfunction are: 1) increase detrusor contractility, and 2) decrease urethral resistance. The former includes agonists for muscarinic receptors, and choline-esterase inhibitor, and the latter includes α₁-adrenoceptor antagonists, nitric oxide donors, Benzodiazepines, Baclofen, Dantrolene, and Boturinum toxin.

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Overactive bladder (OAB) syndrome, which is characterized by a complex of storage symptoms (urinary urgency, frequency, nocturia and urgency incontinence) is highly prevalent in the general population; it causes significant distress to patients in terms of their psychosocial and physical functioning. Muscarinic receptors of bladder smooth muscles are involved in both normal and involuntary detrusor contraction (detrusor overactivity). Up-regulation of the muscarinic receptor function may contribute to the pathophysiology of OAB. In addition, several reports have suggested that various stimulations release many substances (ATP, prostaglandins, nitric oxide and acetylcholine) from bladder urothelium, which contribute to the pathophysiology of the increased bladder sensation, OAB symptoms and detrusor overactivity. The bladder urothelium also prossesses the non-neuronal cholinergic system and high density of muscarinic receptors. The roles and functions of the non-neuronal cholinergic system in OAB are currently under evaluation. Furthermore, new action sites of anticholinergic drugs have also been proposed. In this review, in addition to the pathophysiology of detrusor overactivity and OAB, the pharmacotherapy for OAB is discussed.

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In lifestyle-related diseases, such as cerebrovascular diseases, diabetes mellitus, and hypertension, all have lower urinary tract symptoms. In cerebrovascular diseases, the symptoms of overactive bladder such as urinary frequency, urinary urgency, and urge incontinence are prominent. In diabetes mellitus, half of the patients with diabetes have an overactive bladder. However, advanced peripheral neuropathy shows an underactive bladder such as presence of residual urine without the urge to urinate. Hypertension is not a specific disease showing lower urinary tract symptoms in itself. However, it has a negative influence on both urine voiding and collecting symptoms. Hypertension caused by increased concentrations of noradrenaline and dopamine during the daytime increase renal arterial resistance, decrease renal blood flow, and lead to insufficient daytime urine production. When catecholamines decrease at night, renal arterial resistance decreases and renal blood flow increases, allowing urine production to increase at night in order to excrete water stored during the daytime. It is also possible that an increase of the plasma catecholamine levels is not only related to nocturnal polyuria but also to diminished bladder capacity. The increase of plasma catecholamine levels influences the ascending limb of the micturition reflex in the spinal cord and induces the urge to urinate at lower bladder volumes. Furthermore, the increased plasma catecholamines act on the smooth muscle in the prostate gland, and narrow the prostatic urethra. If there is an obstructive bladder state, such as benign prostatic hyperplasia, the obstructive bladder state worsens to the high plasma catecholamine level. Obstructive bladder leads to overactive bladder.

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Overactive bladder (OAB) is characterized by symptoms of urgency and urinary frequency with or without urge incontinence; it is a common disease that is most often observed in the elderly population. Pharmacological treatment with muscarinic receptor antagonists has been the most widely used treatment modality for OAB. Solifenacin shows the highest affinity for the muscarinic M₃ receptor, which mediates urinary bladder contraction, and is utilized worldwide in the treatment of OAB. In our in vitro and in vivo studies, solifenacin exhibited a high bladder-selectivity profile compared with other antimuscarinic agents. It also increased bladder capacity without affecting micturition pressure and residual urine in an OAB model of rats. Recently, urgency is considered to be the result of overactivation of afferent nerves from the urinary bladder. It has been reported that afferent nerves are located adjacent to the urothelium and stimulation of the muscarinic receptors expressed on the urothelium may contribute to the activation of afferent nerves. In preclinical studies, solifenacin has been reported to produce an inhibitory effect on bladder afferent activity. It has been reported that solifenacin ameliorates all symptoms in OAB patients with good tolerability, and in particular it results in significant reduction of urgency episodes, which is the principal symptom of OAB. In addition, solifenacin significantly increases the warning time (the period from first sensation of urgency to voiding). Therefore, the pharmacological profile of solifenacin is considered contributory to its benefits of high efficacy against OAB symptoms with few adverse effects.

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α₁-Adrenoceptors, in particular the α_1A-subtype, show a pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, especially in elderly men with an enlarged prostate. On the other hand, the α_1B-subtype is reported to help maintain vascular smooth muscle tone. Therefore, α_1A-subtype-selective antagonist was suggested to be useful for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).
Silodosin can selectively bind to α_1A-subtype with sub-nanomolar affinity. Clinical studies have clearly indicated that silodosin achieves significant improvement in LUTS associated with BPH, as well as quality of life. The improvements were observed in both voiding and storage symptoms. This higher selectivity for the α_1A-subtype contributing to inhibition of sympathetic nerve stimulation resulted in significant relaxation of the muscle tone of lower urinary tract tissues. In addition, the clinical effects were observed in the earlier treatment phase, and not only in the mild cases, but also in severe symptoms.
This article reviews the therapeutic usefulness of silodosin for LUTS associated with BPH from the preclinical and clinical points of view, which are supported by its higher affinity and selectivity for the α_1A-subtype.

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The in vivo characterization of drug-receptor binding facilitates integrated analysis of pharmacokinetics and pharmacodynamics of drugs. α₁-Adrenergic antagonists and antimuscarinic agents are clinically useful in the treatment of lower urinary tract symptoms due to benign prostatic hypertrophy and overactive bladder (OAB). For anticholinergic therapy for OAB, side effects of dry mouth and cognitive impairment are concerns. Currently, novel agents have been developed to minimize these side effects. We have characterized in vivo muscarinic receptor (mAChR) binding of anticholinergic agents in the bladder, salivary gland and brain. Transdermal oxybutynin (Oxy) showed little long-lasting binding of mAChR in the submaxillary gland of rats after oral Oxy. Orally administered tolterodine and solifenacin bound mAChR in the bladder with a slower onset and longer duration than oral Oxy. In an autoradiographic study, there was a dose-dependent binding of mAChR in rat brain regions after intravenous injection of anticholinergic agents. The dose ratios for brain mAChR occupancy (RO₅₀) to inhibition of carbachol-induced increase in intavesical pressure (ID₅₀), which reflects in vivo bladder selectivity to brain, were significantly greater for solifenacin and tolterodine than Oxy. In a positron emission tomography study using conscious rhesus monkeys, brain mAChR occupancy was 40-60% at 1-4hr after oral Oxy at pharmacologically relevant doses. Our data shows that novel antimuscarinic agents are advantageous in the target organ selectivity of receptor occupancy after systemic administration. The in vivo receptor binding characteristics of these drugs were closely related to their pharmacological specificities.

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In recent years, the use of the EDC system in clinical trials has expanded rapidly. Many medical institutions have accepted the installation of the EDC system for clinical trials. However, a few systems reflect a paticular opinion on the data entry side in former system development.
Therefore, we undertook an investigation which focused on the problems of the system and based on the results we considered means of improvement for enhanced usability of the EDC system.
A questionnaire survey was sent to CRCs which are the clinical trial implementation hospitals of national organizations and university hospitals (in total 131 facilities), the 61 member companies of Japanese SMO society, and the attendees of luncheon seminars 1 and 2 of CRC meeting 2008 in Kanazawa.
A total of 811 questionnaire survey responses were obtained. Of the respondents 93.6% had prior experience using the EDC system, and 69.5% implementing EDC system with English entry. The items with the most frequent responses were training program (38%), inconsistent entry form (36%), the limitation of the usable system (34%), data entry using English language (31%) and management of identification number and password (28%).
The EDC system has rapidly become popular, and it is expected that use of the EDC system with English entry will increase in the future. In this investigation, problems such as system improvement in the design process and interface were extracted. These problems have been extracted for system improvement, and based on the addressing these problems there is hope for the realization of correct and quick data acquisition.

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