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PubMed2001

Evidence for the efficacy and safety of tolterodine in the treatment of overactive bladder.

Overactive bladder (OAB) is a chronic and prevalent condition, the symptoms of which (urinary frequency and urgency, with or without urge incontinence) can exert a profound negative effect on a person's daily life activities. Tolterodine (Detrol in North America and Detrusitol in the rest of the world, Pharmacia), a competitive muscarinic antagonist, is the first agent of this class to be specifically developed for the treatment of OAB. This agent displays in vivo functional selectivity for the bladder over other tissues that contain muscarinic receptors (e.g., salivary glands, eye), which translates into good efficacy and tolerability in patients with OAB (including the elderly). Comparative, randomised, double-blind studies show that tolterodine (administered as immediate-release [IR] tablets 2 mg b.i.d.) is as effective as oxybutynin (5 mg t.i.d.) in improving all of the troublesome symptoms of OAB but with a significantly lower incidence and severity of dry mouth. The advent of a new extended-release (ER) capsule formulation of tolterodine (4 mg) for convenient once-daily treatment builds upon these findings, with significantly improved efficacy for reducing urge incontinence episodes and a lower frequency of dry mouth relative to the existing IR tablet (2 mg b.i.d.). Tolterodine can therefore be considered a valuable, well-tolerated treatment option for patients with OAB, providing improvements in symptoms that are both clinically meaningful to patients and sustained during long-term treatment.

Animals↗
PubMed2004

The perspective of a neurologist on treatment-related research in fecal and urinary incontinence.

Afferent innervation is important in sensing the degree of bladder fullness and in forming the input limb to involuntary detrusor contractions in neurogenic and probably also non-neurogenic detrusor overactivity. It is likely that homologous mechanisms are involved in control of the bowel. Accumulating evidence now suggests that in conditions of bladder hypersensitivity as well as non-neurogenic detrusor overactivity, there is up-regulation of unmyelinated nerve fibers expressing both the vanilloid receptor and purinergic receptors. The development of a selective neurotoxin that could successfully "deafferent" the bladder would have major therapeutic consequences. Women who respond best to neuromodulation through sacral nerve stimulation are those with a primary disorder of sphincter relaxation and a very large capacity without sensations of urgency or a hyperactive sphincter. For these women, neuromodulation may counteract the inhibitory effects of overactive sphincter afferents on the detrusor, and determination of the central nervous system level at which this response occurs may provide an explanation for the paradoxical finding that both urge incontinence and urinary retention are responsive to this intervention. Experimental evidence suggests that the "procontinence" reaction consists of an inhibitory effect on the detrusor and presumably the lower rectum resulting from contraction of the pelvic floor and the anal or urethral sphincter. Development of methods of enhancing the inhibitory reflex effect could lead to improved voluntary control of micturition and defecation for patients with neurogenic bladder overactivity or spinal cord lesions.

Fecal Incontinence↗
PubMed2004

Voiding dysfunction and urodynamic abnormalities in elderly patients.

Lower urinary tract dysfunction is a major cause of morbidity and decreased quality of life in elderly men and women. With the progressive aging of the population, it is important to understand common micturitional disorders that may occur in this population. Most urinary problems in the elderly are multifactorial in origin, demanding a comprehensive assessment of the lower urinary tract organs, functional impairments, and concurrent medical diseases. Urodynamics is a highly valuable tool in the investigation of elderly patients with lower urinary tract symptoms. Urodynamic tests are not always necessary, being indicated after excluding potentially reversible conditions outside the urinary tract that may be causing or contributing to the symptoms. Although urodynamic tests may reveal common diagnoses such as bladder outlet obstruction and stress urinary incontinence in the elderly population, findings such as detrusor overactivity and impaired detrusor contractility are common and have important prognostic and therapeutic implications. The purpose of this article is to describe common urologic problems in the elderly and review the indications for and clinical aspects of urodynamic studies in these conditions.

Age Factors↗
PubMed2002

M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland.

The antimuscarinic profile of the experimental drug solifenacin/YM905 [(+)-(1 S,3' R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate] for the treatment of overactive bladder was compared with the commonly prescribed agent oxybutynin. In radioligand binding assays, p K(i) values of solifenacin for M(1), M(2), and M(3) receptors were 7.6, 6.9, and 8.0, respectively. These values for oxybutynin were 8.6 (M(1)), 7.7 (M(2)), and 8.9 (M(3)). Solifenacin and oxybutynin antagonized the contractile effect of carbachol (CCh) on isolated guinea pig urinary bladder smooth muscle (detrusor), displaying the negative logarithm of antagonist apparent affinity constant (p K(b) value) of 7.1 for solifenacin and 7.4 for oxybutynin. To study the tissue selectivity between bladders and salivary glands, guinea pig detrusor and mouse submandibular gland cells were stimulated with CCh and monitored for intracellular Ca2+, as determined by Fura 2 fluorescence. Ca2+ mobilization of detrusor cells was inhibited equipotently by solifenacin (p K(i)=8.4) and oxybutynin (p K(i)=8.6), whereas that of the gland cells was antagonized less potently by solifenacin (p K(b)=7.4) than by oxybutynin (p K(b)=8.8), although the M(3) subtype mediated both cell responses. In anesthetized rats, solifenacin (63-2100 nmol kg(-1) or 0.03-1 mg kg(-1)) dose-dependently inhibited CCh-stimulated increases in urinary bladder pressure, while its inhibitory effects on salivation and bradycardia were apparent only at a dose of 2100 nmol kg(-1). In contrast, oxybutynin within a dose range of 77-770 nmol kg(-1) (0.03-0.3 mg kg(-1)) inhibited responses of the bladder and salivary gland slightly more potently than that of the heart. In addition, inhibitory effects of darifenacin indicated a major role of M(3) receptors in the bladder and salivary gland. Therefore, M(3) receptor antagonism by solifenacin could be bladder-selective. This selectivity remains to be elucidated and may provide new approaches to the pharmacotherapy of overactive bladder.

Animals↗
PubMed2004

Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents.

OBJECTIVES: To investigate the urodynamic changes after detrusor injection of botulinum A toxin in patients with detrusor overactivity refractory to treatment with anticholinergic agents. METHODS: Thirty patients with detrusor overactivity refractory to anticholinergic agents were treated with detrusor injection of botulinum A toxin (Botox) 200 U at 40 sites. Urodynamic parameters and symptom scores were assessed at baseline and 2 weeks and 3 months after the injections. Patients' responses were classified as excellent, improved, or failed. RESULTS: The 12 female and 18 male patients were aged 7 to 83 years (mean 67 +/- 17). Of the 30 patients, 12 had neurogenic detrusor overactivity, 8 had idiopathic detrusor overactivity, and 10 had previous bladder outlet obstruction or had undergone previous transurethral prostatectomy. After detrusor botulinum A toxin injection, 8 patients regained urinary continence (26.7%), 14 patients had improvement in frequency, urgency, and incontinence (46.7%), and treatment failed 8 patients (26.7%). The total success rate was 73.3%. Four patients experienced transient urinary retention and six had difficulty urinating after treatment. The urodynamic results showed increased cystometric capacity, decreased voiding pressure, increased postvoid residual urinary volume, decreased voiding efficiency, and increased bladder neck opening time at 2 weeks. The voiding pressure remained low and bladder neck opening time remained increased at 3 months, although the postvoid residual volume and voiding efficiency had returned to baseline levels. The therapeutic effects lasted for 3 to 9 months (mean 5.3). CONCLUSIONS: Detrusor injection of 200 U of botulinum A toxin is effective in the treatment of detrusor overactivity that is refractory to anticholinergic agents. Patients with detrusor overactivity and inadequate contractility should be carefully selected for this procedure because the postvoid residual urine volume may increase after treatment.

Adolescent↗
PubMed2001

Myosin isoforms in female human detrusor.

The aim of this study was to document the relative proportions of two isoforms of myosin heavy chain in detrusor smooth muscle of women with detrusor overactivity and in asymptomatic controls. Women aged 35-65 with documented detrusor overactivity and without a history of neurologic disease, prior incontinence surgery, elevated post-void residual urine volume, or indwelling urinary catheter were eligible for the study. Full-thickness biopsies of extraperitoneal bladder dome were obtained at the time of laparotomy in six patients with documented detrusor overactivity and in a control group of eight continent patients. Biopsies were frozen in liquid nitrogen, crushed with a frozen mortar and pestle at -80 degrees C, and homogenized in buffer, and the extracts were electrophoresed on 6% polyacrylamide sodium dodecyl sulfate gels and stained with Coomassie blue. The gels were de-stained and then the protein bands were scanned with a densitometer. The mean patient age was 48 years (range, 36-59). Seven patients were Caucasian and seven patients were African American. Detrusor smooth muscle contains a mean of 34% (range, 27-43%) SM1 and 66% (range, 57-73%) SM2 isoforms. There was no difference in isoform composition when patients were compared according to urogynecologic diagnosis or according to race. In detrusor biopsies from women, approximately 34% of myosin is of the SM1 isoform and approximately 66% is of the SM2 isoform. This ratio is relatively constant in the two races studied and unchanged in women with detrusor overactivity. Animal models utilizing outlet obstruction of the bladder to provoke detrusor instability and detrusor hypertrophy are known to alter myosin isoform distribution and may not be appropriate models of detrusor instability in human females.

Adult↗
PubMedDate not supplied

Urinary incontinence: economic burden and new choices in pharmaceutical treatment.

In the year 2000, an estimated 17 million community-dwelling adults in the United States had daily urinary incontinence (UI), and an additional 33 million suffered from the overlapping condition, overactive bladder. Estimates of the total annual cost of these conditions range up to 32 billion US dollar; the largest components are management costs and the expenses associated with nursing home admissions attributable to UI. In most cases, patients with UI can be treated with pharmaceutical agents, in addition to behavioral therapy. Until recently, pharmaceutical therapy for UI has been limited, especially because the adverse effects of available agents resulted in poor adherence to treatment regimens. Recent innovations in molecular design and new dosage forms of UI medications offer the promise of fewer and less severe adverse effects and, thus, better treatment outcomes for patients. Additionally, the availability of multiple agents within a therapeutic class offers health care providers a spectrum of choices with which to personalize treatment for each individual patient. New pharmacologic treatment options for UI have the potential to allow greater independence for older persons who reside at home and to delay or avoid the costs of admission to long-term care facilities. Alternate dosage forms, which include patches and sustained-release formulations, may benefit patients who have difficulty chewing, swallowing, or remembering to take medications. Although these newer products are generally more expensive than older forms of therapy, they typically have more favorable cost-effectiveness ratios. Access to these new medications for patients enrolled in public and private health care plans may help to reduce the economic and social burden of UI care.

Adult↗
PubMed2004

The male sling for stress urinary incontinence: urodynamic and subjective assessment.

PURPOSE: We prospectively examined whether the fixed urethral resistance of the perineal male sling for the treatment of stress incontinence causes significant bladder outlet obstruction or de novo voiding dysfunction. MATERIALS AND METHODS: A total of 22 patients (average age 67 years old) were evaluated before and after surgery with videourodynamics, the self-administered UCLA Prostate Cancer Index incontinence section and pad score. RESULTS: Mean followup was 25 months (range 6 to 42). All patients complained of a moderate to severe problem before surgery. After surgery 16 (73%) reported a very small problem/no problem, 3 (14%) a moderate problem and 3 (14%) reported a big problem. Average pad use +/- SD decreased from 4.6 +/- 2.5 to 0.74 +/- 1.0 pads (p <0.01). Median UCLA Prostate Cancer Index incontinence score increased from 82 to 313, p <0.001. Mean retrograde leak point pressure (RLPP) increased from 30.4 +/- 15.9 to 59.9 +/- 9.7 cm water. Bladder outlet obstruction did not develop in any patients after surgery. Average maximum flow rate did not change significantly (17.7 +/- 6.5 vs 19.2 +/- 9.7 ml per second, p = 0.6). Nor was there a significant change in detrusor pressure at maximum flow rate (40.3 +/- 9.2 vs 45.8 +/- 14.7 cm water, p = 0.3). While de novo urgency or urge incontinence did not develop in any patients, 2 of 5 patients with a moderate/big leakage problem demonstrated postoperative detrusor overactivity on cystometry. Both individuals requiring more than 3 pads daily had a postoperative RLPP of less than 50 cm water. CONCLUSIONS: Pad use, leak point pressure and urinary incontinence scores are significantly improved after sling surgery. Fixed resistance does not lead to bladder outlet obstruction. Postoperative RLPP less than 50 cm water and urodynamic detrusor overactivity are associated with increased pad use and bother.

Adult↗
PubMed2006

Animal models in urological disease and sexual dysfunction.

There are several conditions associated with dysfunction of the lower urinary tract or which result in a reduction in the ability to engage in satisfactory sexual function and result in significant bother to sufferers, partners and/or carers. This review describes some of the animal models that may be used to discover safe and effective medicines with which to treat them. While alpha adrenoceptor antagonists and 5-alpha-reductase inhibitors deliver improvement in symptom relief in benign prostatic hyperplasia sufferers, the availability of efficacious and well-tolerated medicines to treat incontinence is less well served. Stress urinary incontinence (SUI) has no approved medical therapy in the United States and overactive bladder (OAB) therapy is limited to treatment with muscarinic antagonists (anti-muscarinics). SUI and OAB are characterised by high prevalence, a growing ageing population and a strong desire from sufferers and physicians for more effective treatment options. High patient numbers with low presentation rates characterizes sexual dysfunction in men and women. The introduction of Viagra in 1998 for treating male erectile dysfunction and the success of the phosphodiesterase type 5 inhibitor class (PDE5 inhibitor) have indicated the willingness of sufferers to seek treatment when an effective alternative to injections and devices is available. The main value of preclinical models in discovering new medicines is to predict clinical outcomes. This translation can be established relatively easily in areas of medicine where there are a large number of drugs with different underlying pharmacological mechanisms in clinical usage. However, apart from, for example, the use of PDE5 inhibitors to treat male erectile dysfunction and the use of anti-muscarinics to treat OAB, this clinical information is limited. Therefore, current confidence in existing preclinical models is based on our understanding of the biochemical, physiological, pathophysiological and psychological mechanisms underlying the conditions in humans and how they are reflected in preclinical models. Confidence in both the models used and the pharmacological data generated is reinforced if different models of related aspects of the same disorder generate confirmatory data. However, these models will only be fully validated in retrospect once the pharmacological agents they have helped identify are tested in humans.

Animals↗
PubMedDate not supplied

Behavioral and functional abnormalities linked with recurrent urinary tract infections in girls.

BACKGROUND: Most girls with recurrent urinary tract infections do not have major urinary tract abnormalities. Recent studies focus on predisposing behavioral and functional abnormalities: infrequent voiding, inadequate fluid intake, stool retention, poor genital hygiene and voiding dysfunction. METHODS: Complete history, bladder and bowel questionnaire, physical examination, voiding-drinking diary, sonography and uroflowmetry were used to assess infrequent voiding, functional stool retention, poor fluid intake, inadequate hygiene, or voiding dysfunction in girls referred for evaluation of three or more symptomatic urinary tract infections (with a first infection at the age of more than 36 months). RESULTS: A total of 141 girls aged 3.9 to 18 years were evaluated between 1996 and 1999; 212 abnormalities were noted in 120 patients: infrequent voiding (isolated, 16; combined with other abnormalities, 47), poor fluid intake (isolated, 10; combined, 50), functional stool retention (isolated, 5; combined, 25), inadequate hygiene or toilet habits (isolated, 3; combined, 24), dysfunctional voiding (isolated, 15; combined, 10), bladder overactivity (isolated, 5; combined, 2). CONCLUSIONS: Most girls referred for evaluation of three or more urinary tract infections have host-mediated predisposing abnormalities: infrequent voiding, poor fluid intake, functional stool retention or voiding dysfunction. Poor genital hygiene and toilet habits were almost always combined with other abnormalities, suggesting that infections are not necessarily related to poor genital hygiene or toilet habits. Two or more indications of predisposing behavior often concur in the same patient.

Adolescent↗
PubMed2003

[Pathophysiology of the overactive bladder and its pharmacological treatment].

This paper reviews the possible mechanisms underlying bladder overactivity and discusses the targets for pharmacological treatment of this disorder. Damage to the brain (cerebrovascular disease, etc.) induces bladder overactivity by reducing suprapontine inhibition. Currently, attention has focused on C-fiber bladder afferents that may concern the mechanisms for bladder overactivity resulting from various etiologies such as spinal cord lesions, bladder outlet obstruction and bladder hypersensitivity disorders. With regard to the pathophysiology of idiopathic overactive bladder, both myogenic and neurogenic mechanisms may be involved in involuntary detrusor contraction. Since an intravesical capsaicin or resiniferatoxin was shown to have favorable therapeutic effects, afferent C-fiber neurons become a new target for pharmacological treatment. C-fiber neurons are known to contain tachykinins and other peptides as neurotransmitters. When released, tachykinins can influence via NK receptors bladder activity. In addition, evidences suggest that ATP receptors (P2X3) and prostaglandin receptors in afferent C-fiber neurons may play a role in mediating bladder overactivity. Thus, NK-antagonist, P2X3-antagonist and PG receptor-antagonist may be potential therapeutic drugs in the near future. beta 3-Adrenoceptor agonist is an another candidate drug for the treatment of the overactive bladder. Finally, it is important to notice that in any etiology including an idiopathic one, antimuscarinic drugs can improve bladder overactivity, although dry mouth and constipation are inevitable side-effects.

Humans↗
PubMed2006

Short- and long-term efficacy of solifenacin treatment in patients with symptoms of mixed urinary incontinence.

OBJECTIVE: To evaluate urinary symptom relief in women with mixed urinary incontinence (MUI) treated for up to 52 weeks with solifenacin succinate for overactive bladder (OAB), as MUI is a complex and distressing condition reported by about a third of incontinent women, and with confirmed efficacy in OAB-related urge incontinence, anticholinergic agents are a reasonable therapeutic option for such women. PATIENTS AND METHODS: Patients with OAB (mean of > or = 8 voids/24 h, plus > or = 1 incontinence episode or > or = 1 urgency episode/24 h) were pooled from four studies. A subgroup of 1041 patients reporting MUI at baseline were evaluated over 12 weeks in a double-blind, placebo-controlled study, and up to a further 40 weeks in 433 in an open-label solifenacin treatment (5 mg and 10 mg). Voiding frequency, episodes of incontinence and urgency, and volume voided per void, were collected from voiding diaries completed during the 3 days before each study visit. RESULTS: Patients with a history of MUI treated with solifenacin for up to 12 weeks had statistically significant reductions in voiding frequency and episodes of incontinence and urgency vs placebo. In all, 43% and 49% (at 5 mg and 10 mg, respectively) of patients with a history of MUI regained continence after 12 weeks, vs 33% with placebo. Among patients in the open-label study with mixed symptoms, 52% reported regaining continence, and 34% reported resolution of symptomatic urgency based on diary reporting at study end. Sustained improvements in quality of life and high satisfaction ratings accompanied symptom improvements. CONCLUSIONS: Significant reductions in OAB-related frequency, incontinence and urgency were reported after 12 weeks of solifenacin treatment in patients with a history of MUI. Symptom improvement in this subgroup was maintained during long-term treatment. These findings support the therapeutic potential of solifenacin for treating symptoms of MUI and the need to re-evaluate classically defined MUI.

Adolescent↗
PubMed2005

A critical review of diagnostic criteria for evaluating patients with symptomatic stress urinary incontinence.

The first paper in this section is a review by several highly respected authors of diagnostic criteria for evaluating patients with symptomatic stress urinary incontinence, and is followed by a review of the role of urgency and its measurement in the overactive bladder symptom syndrome, with emphasis on current concepts and future prospects. These are two important papers, which point the reader in the direction of a greater understanding of these conditions. The concept of alpha-blockade before a trial without catheter after acute urinary retention is revisited by authors from the UK, who used tamsulosin in a randomized controlled trial. They found that it is appropriate to recommend tamsulosin for such use in this condition.

Female↗
PubMed1996

The Burch colposuspension for women with and without detrusor overactivity.

OBJECTIVE: To compare the results of the Burch colposuspension in women with stress urinary incontinence and detrusor overactivity with those obtained in women with stress incontinence and stable bladders. Additionally, to analyse the value of two detrusor instability indexes and of standard cystometric parameters in predicting the surgical outcome. DESIGN: Retrospective cohort study. SETTING: Secondary referral centre Urodynamics Unit, San Gerardo Hospital, Monza. SAMPLE: Forty-four women with detrusor overactivity (21 with low compliance bladder and 23 with detrusor instability) and 44 with stable bladders. They were matched for age, parity, dystocia, menopause, body mass index, previous vaginal surgery, heavy work, urethral functional length and maximum urethral closure pressure. RESULTS: At two years follow up, the cure rate of stress incontinence was 95% in the control group (patients with stable bladders) and 75% in detrusor overactivity group (odds ratio 0.1, 95% confidence interval 0.01-0.9, P = 0.02). No significant differences were observed between cured and failed patients according to both detrusor instability indexes. Likewise, mean pre-operative standard cystometric values of cured and failed patients showed no differences. CONCLUSIONS: Although results were better in women with stable bladders, we believe that the success of the Burch colposuspension in cases with mixed incontinence should be considered satisfactory. No pre-operative cystometric parameter consistently predicting the surgical outcome on stress incontinence was identified.

Cohort Studies↗
PubMed1995

Tethered spinal cord: the effect of neurosurgery on the lower urinary tract and male sexual function.

OBJECTIVE: To determine the effect of neurosurgical untethering on the lower urinary tract and male sexual function, in patients with tethered spinal cord. PATIENTS AND METHODS: Thirty-six children with tethered spinal cord due to neurospinal dysraphism were assessed clinically and urodynamically before and after surgical untethering. Sexual function was evaluated in 14 boys before and after neurosurgery. In young boys, the assessment was by parental observation and was considered normal if erections had been observed regularly, or if the child had mentioned having an erection at any time. Older patients were asked if they had achieved voluntary erections and whether or not they were able to ejaculate. RESULTS: The mean follow-up was 91 months and the mean follow-up after neurosurgery was 34 months. A lasting improvement of urinary tract function occurred in only one patient, while another became worse. Seven children had temporary changes of bladder/sphincter function; two developed detrusor overactivity with sphincter dyssynergia and five had signs of bladder denervation. Long-term follow-up showed no permanent changes of lower urinary tract function in 94% of 34 patients. Sexual function was considered normal in 13 boys. One boy apparently gradually lost erectile ability before untethering and regained it after surgery, while another boy had erectile dysfunction post-operatively for almost 6 months. CONCLUSION: Changes in bladder-sphincter function after untethering are usually transient and often the result of partial denervation. Although a small group of children seem to benefit from untethering, others can become worse and the individual outcome cannot be predicted. Erectile dysfunction can occur and parents and patients have to be informed of this possible complication. As pre-operative progression of neurological symptoms and post-operative denervation were observed only in patients with myelomeningocele and lipomyelomeningocele, this group may be distinct from patients with occult forms of spinal dysraphism. The natural history in the latter group of patients is unclear and a beneficial effect of prophylactic untethering remains to be proven by controlled prospective studies.

Adolescent↗
PubMed2005

Transdermal oxybutynin in the treatment of adults with overactive bladder: combined results of two randomized clinical trials.

The safety and efficacy of oxybutynin transdermal delivery system (oxybutynin-TDS) versus placebo in adults with urge and mixed urinary incontinence was investigated using combined results from double-blind stages of 2 phase 3 clinical trials. Study 1: placebo-controlled, parallel-group comparison of 3 oxybutynin-TDS doses in 12-week double-blind and open-label periods, followed by a 28-week open-label extension. Study 2 was a 12-week randomized, double-blind, placebo-controlled comparison of oxybutynin-TDS versus long-acting tolterodine and placebo, followed by a 52-week open-label extension. Efficacy analysis included 241 patients receiving oxybutynin-TDS, 244 receiving placebo. Most participants were Caucasian women (92%). Approximately 60% received prior anticholinergic therapy. Primary outcome was determined by changes from baseline to end of treatment in frequency of incontinence episodes, frequency of urination, and void volume. Oxybutynin-TDS was significantly more effective than placebo in reducing median daily incontinence episodes (-3.0 vs placebo -2.0; P=.00004) and daily urinary frequency (-2.0 vs -1.0; P=.0023), and in increasing void volume (25 mL vs 5.5 mL; P<.00001). Overall rates of anticholinergic adverse events (AEs) were 12.8% for oxybutynin-TDS and 11.0% for placebo (P=0.5421). The most common systemic anticholinergic AEs were dry mouth (7.0% for oxybutynin-TDS vs 5.3% for placebo) and constipation (2.1% vs 2.0%). Application site erythema occurred in 7.0% of participants who received oxybutynin-TDS (3.7% discontinuation rate); pruritus occurred in 16.1% (3.3% discontinuation rate). Transdermal oxybutynin was shown to be efficacious, with a proven safety profile. It may be utilized for patients with overactive bladder as a treatment option that could enhance compliance.

Administration, Cutaneous↗
PubMed2004

In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats.

Solifenacin succinate [YM905; (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. The aim of the present study was to evaluate the in vitro and in vivo bladder selectivity profile of solifenacin over salivary gland in the same animal species, and to compare the results with those obtained for tolterodine, oxybutynin, darifenacin and atropine. Solifenacin and the other antimuscarinic drugs inhibited carbachol-induced increases in intracellular Ca(2+) levels in bladder smooth muscle cells and salivary gland cells isolated from rats in a concentration-dependent manner. The inhibitory effect of solifenacin for bladder smooth muscle cells (pK(i)=8.12) was 3.6-fold more potent than that for salivary gland cells (pK(i)=7.57). In contrast, the inhibitory effects of the other antimuscarinic drugs for bladder smooth muscle cells were 1.7- to 2.2-fold more potent than those for salivary gland cells. In anesthetized rats, solifenacin dose-dependently inhibited carbachol-induced intravesical pressure elevation and salivary secretion, and exhibited functional selectivity (3.7- to 6.5-fold) for urinary bladder over salivary gland. Tolterodine was also 2.2- to 2.4-fold more selective in inhibition of bladder response. In contrast, oxybutynin, darifenacin and atropine did not show functional selectivity for urinary bladder. These results indicate that solifenacin exerts greater selectivity for urinary bladder over salivary gland than tolterodine, oxybutynin, darifenacin and atropine, and may consequently provide symptomatic benefit in the treatment of overactive bladder with less dry mouth than currently used antimuscarinic drugs.

Animals↗
PubMed2007

Tools to study beta3-adrenoceptors.

Beta(3)-adrenoceptors mediate some of the effects of catecholamines on tissues such as blood vessels or the urinary bladder and are putative targets for the treatment of diseases such as the overactive bladder syndrome. Progress in the understanding of the presence, function, and regulation of beta(3)-adrenoceptors has been hampered by a lack of highly specific tools. "Classical" beta(3)-adrenoceptor agonists such as BRL 37,344 [(R*, R*)-(+/-)-4[2-[(3-chlorophenyl)-2-hydroxyethyl) amino] propyl] phenoxyacetic acid] and CGP 12,177 [(+/-)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazol-2-one] are only partial agonists in many settings, have limited selectivity over other beta-adrenoceptor subtypes, and may additionally act on receptors other than beta-adrenoceptors. More efficacious and more selective agonists have been reported and, in some cases, are in clinical development but are not widely available for experimental studies. The widely used antagonist SR 59,230 [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanoloxalate] is not selective for beta(3)-adrenoceptors, at least in humans, and may actually be a partial agonist. Radioligands, which are suitable either for the selective labeling of beta(3)-adrenoceptors or for the nonselective labeling of all beta-adrenoceptor subtypes, are also missing. beta(3)- and beta(1)/beta(2) double knockout mice have been reported, but their usefulness for extrapolations in humans is questionable based upon major differences between humans and rodents with regard to the ligand recognition and expression profiles of beta(3)-adrenoceptors. While the common availability of more selective agonists and antagonists at the beta(3)-adrenoceptor is urgently awaited, the limitations of the currently available tools need to be considered in studies of beta(3)-adrenoceptor for the time being.

Adrenergic beta-3 Receptor Agonists↗