tolterodine-tartrate and darifenacin

Overactive bladder (OAB) is often treated with medications that block the cholinergic receptors in the bladder (known as anticholinergics). The effect of this medication class on cognition and risk of dementia has been increasingly studied over the past 40 years after initial studies suggested that the anticholinergic medication class could affect memory. Short-term randomized clinical trials demonstrated that the administration of the anticholinergic oxybutynin leads to impaired memory and attention, and large, population-based studies showed associations between several different anticholinergic medications and dementia. However, trials involving anticholinergics other than oxybutynin have not shown such substantial effects on short-term cognitive function. This discordance in results between short-term cognitive safety of OAB anticholinergics and the long-term increased dementia risk could be explained by the high proportion of patients using oxybutynin in the OAB subgroups of the dementia studies, or a study duration that was too short in the prospective clinical trials on cognition with other OAB anticholinergics. Notably, all studies must be interpreted in the context of potential confounding factors, such as when prodromal urinary symptoms associated with the early stages of dementia lead to an increase in OAB medication use, rather than the use of OAB medication causing dementia. In patients with potential risk factors for cognitive impairment, the cautious use of selected OAB anticholinergic agents with favourable physicochemical and pharmacokinetic properties and clinical trial evidence of cognitive safety might be appropriate.

Topics: Benzhydryl Compounds; Benzofurans; Cholinergic Antagonists; Cognition; Cognitive Dysfunction; Dementia; Humans; Mandelic Acids; Prodromal Symptoms; Pyrrolidines; Risk Assessment; Risk Factors; Solifenacin Succinate; Tolterodine Tartrate; Urinary Bladder, Overactive

overactive bladder (OAB) affects 17-41% older adults in community dwelled setting. For several years, antimuscarinics have been validated as the first-line medical treatment for OAB. Despite abundant data obtained from clinical trials provisions the use of antimuscarinics, investigation about the effect of this drug on cognitive function in elderly remains scarce. The objective of this study is to investigate the effect of antimuscarinics therapy on cognitive functions in OAB geriatric patients.. this study design is a systematic review and meta-analysis. Studies were collected using several search engines; those were PubMed, Science Direct, Cochrane, and EBSCOhost using predetermined MeSH keywords with Boolean operators. Selection of studies was done by three reviewers. Studies which fulfilled the inclusion and exclusion criteria underwent full-text review. For every selected full text, we extracted the following data if available: patients demographics, types of antimuscarinics used, placebo, dose, follow-up period, and Mini-Mental State Examination (MMSE) total score.. a total of 8 studies from an initial 146 publications were selected. There were 8 antimuscarinic agents evaluated in the studies, including Oxybutynin, Darifenacin, Tolterodine, Trospium, Imidafenacin, Propiverine hydrochloride, Fesoterodine, and Solifenacin. Oxybutynin was shown to have largest effect towards the decline of MMSE score [Mean difference: -2.90; 95% CI: -4.07, -1.73]. Darifenacin and Tolterodine were also shown to be significant in the decline of total MMSE score, although still inferior to Oxybutynin.. the use of most antimuscarinics medication has little to no effect towards the cognitive function in the management of overactive bladder in elderly patients. However, Oxybutynin, Darifenacin, and Tolterodine was shown to have significant decrease in cognitive functions, as shown in the decline of total MMSE score.

Topics: Aged; Benzofurans; Cognition Disorders; Humans; Mandelic Acids; Mental Status and Dementia Tests; Muscarinic Antagonists; Pyrrolidines; Tolterodine Tartrate; Urinary Bladder, Overactive

To carry out a network meta-analysis of randomised controlled trials (RCTs) of anticholinergic drug treatment for people with overactive bladders.. Comprehensive searches for relevant RCTs were carried out starting with RCTs included in previous systematic reviews with the last search in February 2017. Searches included terms for the anticholinergic drugs tolterodine, oxybutynin, trospium, propiverine, solifenacin, darifenacin, imidafenacin, and fesoterodine. Data was extracted from the systematic reviews or reports of studies for cure or improvement, voids per 24 hr, leakage episodes per 24 hr and dry mouth. Data was analysed using frequentist network meta-analysis.. 128 studies were found. There was no clearly best treatment for cure or improvement. The differences between treatments for voids and leakages were small and unlikely to be of clinical importance. Transdermally delivered oxybutynin was clearly the best treatment for dry mouth but was still worse than placebo.. All the anticholinergic drugs were better than placebo but apart from dry mouth were similar in effect. Transdermal oxybutynin caused less dry mouth than the other treatments, so may be worth considering as the first treatment.

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Cholinergic Antagonists; Humans; Imidazoles; Mandelic Acids; Network Meta-Analysis; Pyrrolidines; Solifenacin Succinate; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder, Overactive

Urinary incontinence (UI) in women adversely affects quality of life.. To conduct a systematic literature review of drugs for urgency UI in women.. MEDLINE, the Cochrane Central Register of Controlled Trials, SCIRUS, and Google Scholar were searched for articles published from 1966 to November 2011.. Randomized, controlled trials (RCTs) reported in English.. Rates of outcomes and risk of bias were extracted by using a standardized form to pool absolute risk differences and calculate the number of attributable events per 1000 patients treated, with 95% CIs.. 94 RCTs were eligible. Pooled analyses showed that among drugs for urgency UI, per 1000 treated women, continence was restored in 130 with fesoterodine (CI, 58 to 202), 85 with tolterodine (CI, 40 to 129), 114 with oxybutynin (CI, 64 to 163), 107 with solifenacin (CI, 58 to 156), and 114 with trospium (CI, 83 to 144). Rates of treatment discontinuation due to adverse effects were 31 per 1000 treated with fesoterodine (CI, 10 to 56), 63 with oxybutynin (CI, 12 to 127), 18 with trospium (CI, 4 to 33), and 13 with solifenacin (CI, 1 to 26). The studies' inconsistent definitions of reduction in UI and quality of life hampered synthesis of evidence.. Evidence for quality-of-life improvements and comparative effectiveness with drugs was limited, and evidence for the effects of race, baseline severity of UI, and comorbid conditions on treatment success was insufficient.. Overall, drugs for urgency UI showed similar small benefit. Therapeutic choices should consider the harms profile. Evidence for long-term adherence and safety of treatments is lacking.

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Comparative Effectiveness Research; Cresols; Female; Humans; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Phenylpropanolamine; Pyrrolidines; Quality of Life; Quinuclidines; Randomized Controlled Trials as Topic; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Incontinence

Antimuscarinics (AMs) are the mainstay of pharmacological treatment of overactive bladder (OAB), a symptom complex defined by the presence of urinary urgency, usually associated with frequency and nocturia, with or without urgency urinary incontinence. The AMs used to treat OAB differ in their pharmacological profiles, which may affect their potential for causing adverse effects (AEs).. The present article aims to review the literature about pharmacokinetics (PK) of the different AMs used in the treatment of OAB. Furthermore, the AEs related to the use of these drugs and their incidence are presented. This systematic review is based on material searched and obtained via Medline, Pubmed and EMBASE up to March 2012 using the search terms "adverse events, pharmacokinetics, tolerability" in combination with "darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium.". Antimuscarinics are the first-line pharmacological treatment for OAB. Despite the development of new molecules that improve their efficacy/safety profile, there are some drugs that are pharmacokinetically more appropriate to be prescribed in specific populations such as patients with neurological disease or the elderly. Moreover, research should be encouraged in evaluating antimuscarinics in conjunction with other drugs such as estrogens or beta-agonists. The identification of prognostic criteria for pharmacological therapy would be helpful.

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Chronic Disease; Cresols; Drug Combinations; Female; Humans; Imidazoles; Mandelic Acids; Muscarinic Antagonists; Nocturia; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder, Overactive; Urinary Incontinence

Around 1.5% of adults in Europe and the USA have urge urinary incontinence (involuntary leakage immediately preceded or accompanied by urgency). This is usually due to overactive bladder syndrome (defined as urgency, with or without urge incontinence, and usually with frequency and nocturia), which occurs in around 12% of adults, and is similarly prevalent in men and women. We last reviewed this condition in 2001. Since then, two new antimuscarinic drugs, darifenacin (Emselex) and solifenacin (Vesicare) have been licensed in the UK for urge incontinence and/or increased urinary frequency and urgency (as may occur in patients with overactive bladder syndrome), as have transdermal oxybutynin (Kentera) and modified-release formulations of tolterodine (Detrusitol XL) and propiverine (Detrunorm XL). Here we review the place of these newer drugs and formulations.

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Cholinergic Antagonists; Cresols; Humans; Mandelic Acids; Muscarinic Antagonists; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Randomized Controlled Trials as Topic; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder, Overactive

Overactive bladder (OAB) is a prevalent and costly condition that can affect any age group. Typical symptoms include urinary urgency, frequency, incontinence and nocturia. OAB occurs as a result of abnormal contractions of the bladder detrusor muscle caused by the stimulation of certain muscarinic receptors. Therefore, antimuscarinic agents have long been considered the mainstay of pharmacologic treatment for OAB. Currently, there are five such agents approved for the management of OAB in the United States: oxybutynin, tolterodine, trospium, solifenacin and darifenacin. This article summarizes the efficacy, contraindications, precautions, dosing and common side effects of these agents. All available clinical trials on trospium, solifenacin and darifenacin were reviewed to determine its place in therapy.

Topics: Benzhydryl Compounds; Benzofurans; Cresols; Humans; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder, Overactive

Overactive bladder (OAB) is a chronic syndrome with debilitating symptoms that negatively affect health-related quality of life. Although anticholinergic agents have been first-line treatment for OAB for many years, the efficacious pharmacologic management of this condition has been compromised by concerns regarding tolerability. Anticholinergic agents prevent involuntary contractions of the bladder detrusor muscle by preventing acetylcholine from binding to the M2 and M3 muscarinic receptor subtypes. Anticholinergics are not tissue specific, and their use for treatment of OAB has been associated with side effects such as dry mouth, constipation, and blurred vision. Recent studies with extended-release formulations and newly developed receptor subtype-specific anticholinergic agents demonstrate that side effects are typically mild to moderate and generally tolerable, seldom leading to patient withdrawal. By incorporating patient-initiated dose adjustment into the protocol, the primary care physician can effectively manage adverse events associated with OAB without compromising efficacy. Recent dose-adjustment data with extended-release oxybutynin suggest that, given some control in the process, patients are willing to tolerate certain side effects in exchange for symptom relief.

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Cholinergic Antagonists; Cresols; Humans; Mandelic Acids; Nortropanes; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Incontinence

Antagonists of muscarinic acetylcholine receptors, such as darifenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium, are the mainstay of the treatment of the overactive bladder syndrome. Fesoterodine is a newer drug awaiting regulatory approval. We briefly review the pharmacological activity of their metabolites and discuss how active metabolites may contribute to their efficacy and tolerability in vivo. Except for trospium, and perhaps solifenacin, all of the above drugs form active metabolites, and their presence and activity need to be taken into consideration when elucidating relationships between pharmacokinetics and pharmacodynamics of these drugs. Moreover, the ratios between parent compounds and metabolites may differ depending on genotype of the metabolizing enzymes, concomitant medication, and/or drug formulation. Differential generation of active metabolites of darifenacin or tolterodine are unlikely to influence the overall clinical profile of these drugs in a major way because the active metabolites exhibit a similar pharmacological profile as the parent compound. In contrast, metabolites of oxybutynin and propiverine may behave quantitatively or even qualitatively differently from their parent compounds and this may have an impact on the overall clinical profile of these drugs. We conclude that more comprehensive studies of drug metabolites are required for an improved understanding of their clinical effects.

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Cresols; Humans; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Parasympatholytics; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder, Overactive

Drug therapy for overactive bladder (OAB) most commonly includes antimuscarinic agents, which work by relaxing bladder smooth muscle through inhibition of acetylcholine receptors in the bladder. The major adverse effects with existing antimuscarinic agents are anticholinergic in nature (e.g., dry mouth, constipation, blurred vision). Oxybutynin and tolterodine have been used for several years for treatment of OAB; both are available in immediate- and extended-release formulations. Fewer or less severe adverse effects are reported with the extended- versus the immediate-release formulations, with little or no difference in efficacy. Oxybutynin is also available as a transdermal patch. Trospium, which was recently approved for use in the United States, has efficacy and an incidence of dry mouth similar to existing agents but does not cross the blood-brain barrier. It requires twice-daily dosing. Two new antimuscarinic agents--darifenacin and solifenacin--are in development. Both show significantly better efficacy compared with placebo for key symptoms of OAB, including urgency. The incidence of dry mouth at the lowest effective dose is 19% for darifenacin and 8% and 14% for solifenacin (2 studies).

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Constipation; Cresols; Delayed-Action Preparations; Humans; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Treatment Outcome; Urinary Incontinence; Vision Disorders; Xerostomia

Limitations exist with regard to the array of available agents for the pharmacologic therapy of overactive bladder, including issues of efficacy and tolerability. It is clear that the ideal agent for this condition has not been identified. However, several new pharmacologic treatments, including some with novel approaches to drug delivery, have emerged in clinical development over the past few years. These agents include a variety of anticholinergics and others. In initial studies, some of the agents appear to compare favorably with existing therapies. Whether these promising results will hold up when subjected to large-scale, well-controlled clinical trials is unclear.

Topics: Administration, Cutaneous; Administration, Intravesical; Administration, Oral; Adrenergic beta-3 Receptor Antagonists; Benzhydryl Compounds; Benzilates; Benzofurans; Botulinum Toxins; Cresols; Dosage Forms; Dose-Response Relationship, Drug; Drug Compounding; Drug Evaluation; Duloxetine Hydrochloride; Humans; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Phenylpropanolamine; Pyrrolidines; Thiophenes; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder Diseases; Urination Disorders

A wealth of clinical evidence supports the view that muscarinic receptor antagonists are effective in the treatment of overactive bladder. However, treatment-limiting adverse effects such as dry mouth, constipation, and blurred vision have restricted the usefulness of previously available agents, such as oxybutynin. A real need therefore existed for effective and well-tolerated agents for the long-term management of the troublesome symptoms of overactive bladder. This review outlines the various approaches that have been used in attempts to overcome the tolerability problems of oxybutynin. It also describes how advances in our understanding of muscarinic receptors and bladder function has led to the potential development of either tissue- or subtype-selective antimuscarinic agents with improved tolerability. Drugs that have been developed in this way include tolterodine and darifenacin, each of which shows some bladder selectivity in animal models. Unlike darifenacin, however, the bladder selectivity of tolterodine has been confirmed by numerous clinical studies. Tolterodine's improved tolerability compared with oxybutynin, along with its equivalent therapeutic efficacy at recommended dosages, permits patients to experience the beneficial effects of long-term treatment. Tolterodine therefore represents a real alternative for the long-term management of overactive bladder. The results of ongoing clinical studies with darifenacin are awaited before it can be concluded that selective antagonism of M(3) receptors leads to improved tolerability over existing agents in the treatment of overactive bladder. Similarly, the potential improvements in tolerability associated with different dosage formulations of oxybutynin, and the clinical utility of S-oxybutynin, are yet to be conclusively demonstrated.

Topics: Benzhydryl Compounds; Benzofurans; Clinical Trials as Topic; Cresols; Humans; Mandelic Acids; Muscarinic Antagonists; Phenylpropanolamine; Pyrrolidines; Tolterodine Tartrate; Urinary Bladder Diseases; Urinary Incontinence

Continued developments in the understanding of lower urinary tract function have led to improvements in the pharmacologic manipulation of bladder dysfunction. Drug delivery changes have produced drugs that provide better efficacy and tolerability, thus improving patient compliance. Improvements in drug delivery systems have altered drug bioavailability and pharmacokinetics. Active current investigation in new agents and delivery systems for intravesical delivery has yielded intriguing early results that may substantially add to the armamentarium for the management of the overactive bladder (urgency, frequency, urge incontinence). New developments in the understanding of the neuropharmacology of the bladder, peripheral pelvic nerves, and sacral cord may provide agents with entirely new drug effects, either as primary agents or agents to be used in combination with currently available drugs. We herein review newer agents and drug delivery systems.

Topics: Adrenergic alpha-Antagonists; Aged; Animals; Antidepressive Agents, Tricyclic; Benzhydryl Compounds; Benzilates; Benzofurans; Calcium Channel Blockers; Cholinergic Antagonists; Cresols; Delayed-Action Preparations; Drug Administration Routes; Female; Humans; Mandelic Acids; Middle Aged; Muscarinic Antagonists; Muscle Relaxants, Central; Nortropanes; Phenylpropanolamine; Pyrrolidines; Tolterodine Tartrate; Urinary Incontinence

To compare the heart rate increase side effect of different antimuscarinic drugs used in overactive bladder (OAB).. Overall 341 patients were consecutively randomized to take seven different antimuscarinic drugs between January 2014 and June 2016 at three institutions, and 250 patients who completed the follow-up visits were accepted into this study. Ninety-one patients who never came to visits were excluded. Drugs were classified into two groups as selective (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride) and non-selective (fesoterodine fumarate, tolterodine tartrate, trospium chloride and propiverine hydrochloride) antimuscarinic drugs. The cardiac pulse rates and the blood pressures were recorded during the baseline, first visit (1 week) and second visit (1 month). Data were compared for drugs and two groups (selective versus non-selective) by using ANOVA test.. Baseline characteristics were similar among the patients using different antimuscarinic drugs. Statistically significant increase in heart rate occurred in patients treated with non-selective antimuscarinic drugs compared to those treated with selective drugs (p < 0.001), and this increase was especially evident in patients treated with trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride (p < 0.001, 0.003, 0.011 and 0.37, respectively). There was no statistical difference for the other side effects.. Our results showed that heart rate significantly increased in OAB patients treated with non-selective antimuscarinic drugs. Trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride seem to have the most unfavorable properties with regard to increased heart rate side effect when compared to the other antimuscarinic drugs (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride).

Topics: Adult; Aged; Benzhydryl Compounds; Benzilates; Benzofurans; Blood Pressure; Female; Heart Rate; Humans; Male; Mandelic Acids; Middle Aged; Muscarinic Antagonists; Nortropanes; Prospective Studies; Pyrrolidines; Solifenacin Succinate; Tolterodine Tartrate; Urinary Bladder, Overactive

Although in vitro studies show that muscarinic M(3) receptors primarily mediate the effects of acetylcholine on gastrointestinal contractility, the muscarinic receptor subtypes regulating gastrointestinal motor activity and transit in humans in vivo are unclear. We hypothesized that muscarinic M(3)-specific but not nonspecific receptor antagonists would delay gastrointestinal and colonic transit in humans. In this parallel-group study, gastric emptying, small intestinal transit, and colonic transit were assessed by scintigraphy on days 4-6 in 72 healthy subjects (49 women) who received placebo (n = 16), the M(3) antagonist darifenacin ER [7.5 mg (n = 20) or 15 mg daily (n = 17)], or the nonspecific antagonist tolterodine [4 mg daily (n = 19)] for 6 days. Bowel habits were recorded by daily diaries. Both doses of darifenacin substantially delayed [P < 0.01 vs. placebo (for both doses), P < 0.01 vs. tolterodine (for 15 mg)] small intestinal transit, i.e., colonic filling at 6 h (placebo [59.6 +/- 6.4%, mean +/- SE], 7.5 mg ER [34.4 +/- 6.1%], 15 mg ER [20.4 +/- 6.3%)]. Darifenacin (15 mg) also delayed (P < 0.01 vs. placebo and tolterodine) half-time for ascending colonic emptying [placebo (12.0 +/- 1.5 h), 7.5 mg (18.6 +/- 1.9 h), 15 mg (22.9 +/- 2.6 h)] and colonic transit (geometric center) at 24 [placebo (2.8 +/- 0.2), 7.5 mg (2.4 +/- 0.2), 15 mg (1.9 +/- 0.2)] but not 48 h. Darifenacin did not affect gastric emptying and tolterodine did not affect bowel habits or gastrointestinal transit. With muscarinic antagonists used at clinically approved doses, these findings demonstrate that muscarinic M(3) receptors regulate small intestinal and colonic transit in humans; colonic effects are more pronounced in the right than left colon. At doses that affect small and large intestinal transit, M(3) antagonists do not affect gastric emptying in humans. The efficacy of darifenacin in diarrhea-predominant irritable bowel syndrome should be evaluated.

Topics: Adult; Benzhydryl Compounds; Benzofurans; Colon; Cresols; Defecation; Female; Gastric Emptying; Gastrointestinal Transit; Humans; Intestine, Small; Male; Middle Aged; Muscarinic Antagonists; Phenylpropanolamine; Pyrrolidines; Receptor, Muscarinic M3; Time Factors; Tolterodine Tartrate; Young Adult

Antimuscarinics, used commonly to treat overactive bladder, may differ in their potential to increase heart rate via effects on cardiac muscarinic M2 receptors. This prospective, 3-way crossover, randomized, double-blind study assessed the heart rate effects of 7 days' exposure to a nonselective M2/M3 receptor blocker (tolterodine; 4 mg/d), a highly selective M3 receptor blocker (darifenacin; 15 mg/d), and placebo in 162 healthy participants > or = 50 years. Heart rate was measured by 24-hour Holter monitoring. Tolterodine significantly increased heart rate versus darifenacin and heart rate versus placebo, while darifenacin did not affect heart rate versus placebo. The proportion of participants with an increase in mean heart rate per 24 hours of > or =5 beats per minute was higher with tolterodine than with darifenacin (P = .0004) or with placebo (P = .0114) but did not differ between darifenacin and placebo. The results show that antimuscarinics exert differential effects on heart rate depending on their muscarinic receptor profile. This should be considered when selecting a treatment.

Topics: Age Factors; Aged; Aged, 80 and over; Benzhydryl Compounds; Benzofurans; Constipation; Cresols; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Heart Rate; Humans; Male; Middle Aged; Muscarinic Antagonists; Phenylpropanolamine; Prospective Studies; Pyrrolidines; Time Factors; Tolterodine Tartrate; Xerostomia

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Antidepressive Agents; Benzilates; Benzofurans; Brazil; Clinical Decision-Making; Drug Therapy, Combination; Humans; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Pyrrolidines; Solifenacin Succinate; Thiazoles; Tolterodine Tartrate; Urinary Bladder, Overactive

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aged; Aged, 80 and over; Benzhydryl Compounds; Benzofurans; Denmark; Female; Humans; Male; Mandelic Acids; Middle Aged; Muscarinic Antagonists; Norway; Practice Patterns, Physicians'; Prospective Studies; Pyrrolidines; Registries; Solifenacin Succinate; Sweden; Thiazoles; Tolterodine Tartrate; Urinary Bladder, Overactive

Overactive bladder associated with bladder outlet obstruction (BOO) is a highly prevalent condition, which is usually treated with antimuscarinics. However, the potential effects of antimuscarinics on the structure and function of bladder have not been investigated thus far.. Sprague-Dawley(R) rats accepted bladder neck obstruction surgery or sham surgery, and then received treatment of three different antimuscarinics (Solifenacin, Darifenacin, and Tolterodine) or vehicle. After 3, 6 and 12 weeks, the bladder function and structure were measured. The effect of antimuscarinics on cellular alteration in vitro was observed under mechanical stimulation. Bladder morphology were examined by immunohistochemistry, and the bladder function were investigated by cystometry and strip contractility test. The expression of muscarinic receptors and inflammatory cytokines were measured by PCR and Western blotting.. Here we demonstrate, both in vitro and in vivo, that antimuscarinics are protective regulators for the bladder structure and function. Antimuscarinics decrease the weight of bladders with BOO. Antimuscarinics improve the voiding parameter and enhance the contraction of bladder smooth muscle. The results also show that antimuscarinics inhibit the proliferation of bladder smooth muscle cells both in vivo and in vitro, it can reduce the collagen deposition and inflammatory cytokines in bladders with BOO. During this process, the expression of M2 and M3 receptors was altered by antimuscarinics.. Antimuscarinics could reverse the structural and functional changes of BOO bladder wall at cellular and tissue level, and the alteration of M2 and M3 receptors may be involved in this biological process.

Topics: Animals; Benzofurans; Cell Line; Cell Proliferation; Collagen; Cytokines; Disease Models, Animal; Female; Humans; Immunohistochemistry; Muscarinic Antagonists; Muscle Contraction; Myocytes, Smooth Muscle; Potassium Chloride; Proliferating Cell Nuclear Antigen; Protective Agents; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Tolterodine Tartrate; Urinary Bladder; Urinary Bladder Neck Obstruction

Incidences of overactive bladder (OAB) and cognitive dysfunction increase with aging. Treatment of OAB with antimuscarinic agents may result in cognitive decline, especially in patients with Alzheimer's disease (AD). The aim of this study is to evaluate the effect of antimuscarinic treatment on cognitive functions, depression, and quality of life (QOL) of patients with OAB.. This non-interventional prospective observational study was conducted in a geriatric medicine outpatient clinic. Overall, 168 OAB patients were enrolled. Patients were followed up in five groups: oxybutynin, darifenacin, tolterodine, trospium, and control groups. Follow-up visits were done at second, third, and sixth months. Comprehensive geriatric assessment, cognitive and mood assessment, QOL scales (IIQ-7, UDI-6) were performed.. Mean age of the patients was 73.5 ± 6.1. Of the 168 patients, 92.3% were female, 83.3% benefited from the treatment, and 37.1% discontinued the medication. Discontinuation rate and frequency of side effects were more frequent in the oxybutynin group. Mini Mental State Examination scores did not decline after treatment, even in AD patients. Geriatric Depression Scale scores, Activities of Daily Living scores, and QOL scores significantly improved after treatment.. Antimuscarinic agents are effective in OAB treatment. They have a positive impact on daily life activities, depression, and QOL indices. Furthermore, they do not have a negative effect on cognitive function in older adults with or without AD.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Benzhydryl Compounds; Benzilates; Benzofurans; Cognition Disorders; Cresols; Depression; Female; Follow-Up Studies; Geriatric Assessment; Humans; Male; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Phenylpropanolamine; Pyrrolidines; Quality of Life; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder, Overactive

Patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) often present with voiding and storage symptoms, which may require combination therapy with an alpha blocker and an antimuscarinic (AM). This study compared treatment persistence in LUTS/BPH patients on alpha blocker monotherapy with those using combination alpha blocker and AM therapy (AB/AM).. Retrospective analysis of anonymized patient longitudinal prescription reimbursement claims data. All patients who had claims for any of four alpha blocker medications and six AM agents during an index period from April 1, 2011 to March 31, 2012 were included. For the combination therapy group, the effect of adherence with the AM medication on persistence to the alpha blocker was examined.. Patients on AB/AM combination therapy remained on alpha blockers for longer than those on alpha blocker monotherapy (p = 0.04); 92.4% were persistent at 3 months versus 89.0%, and at 1 year 50.8% were persistent versus 49.6%, respectively. The highest number of days on therapy was reported for tamsulosin plus solifenacin. As confirmed by multivariate analysis, patients with the highest adherence to AM medication (= 80%) persisted on alpha blockers for longer than those with the lowest (< 50%) adherence (p < 0.05).. Patients taking an AM in combination with an alpha blocker showed greater persistence with alpha blocker treatment over a 1 year period. When an AM is combined with an alpha blocker in patients with LUTS/BPH, the additional medication burden does not have a negative impact on persistence and may even improve it.

Topics: Administrative Claims, Healthcare; Adrenergic alpha-Antagonists; Aged; Benzofurans; Doxazosin; Drug Therapy, Combination; Humans; Longitudinal Studies; Male; Mandelic Acids; Medication Adherence; Middle Aged; Muscarinic Antagonists; Ontario; Prazosin; Prostatic Hyperplasia; Prostatism; Pyrrolidines; Quinazolines; Retrospective Studies; Solifenacin Succinate; Sulfonamides; Tamsulosin; Tolterodine Tartrate

To investigate the pattern of use of anticholinergic drugs for overactive bladder among women in Norway with regard to persistence, adherence and switch rates.. Observational study.. Data from the Norwegian Prescription Database on prescriptions for tolterodine, solifenacin, darifenacin and fesoterodine filled in Norwegian pharmacies from 1 January 2004 to 31 December 2010.. Data from the database were analysed at an individual level, and drug persistence, discontinuation rates and switch rates during a follow-up period of 365 days after the first prescription were calculated.. Overall 1-year persistence for new users was 38.0%. Within the same period, a total of 10.3% switched from the index drug to another drug in the same group, whereas 51.7% discontinued without switching. Users of solifenacin and tolterodine were somewhat more persistent than users of darifenacin and fesoterodine. Persistence was lowest (20.9%) in the age group 18-39 years, increased with age and was highest in the age groups 70-79 years and 80 years and above (43.5 and 43.3%, respectively). In total, 31.9% filled only one prescription of the drug and, of these, only one of four women switched to another drug. The proportion who were adherent during treatment was 60.4%.. The discontinuation rate for anticholinergic drugs for overactive bladder in women is high. The reasons why patients stop using them remain obscure but could be related both to a limited clinical effect and an unacceptable adverse effect burden.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzhydryl Compounds; Benzofurans; Cholinergic Antagonists; Cresols; Databases, Pharmaceutical; Drug Substitution; Female; Follow-Up Studies; Humans; Medication Adherence; Middle Aged; Norway; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder, Overactive; Young Adult

To compare the brain anticholinergic activities of five urinary spasmolytic drugs (USDs).. In vitro study.. Laboratory.. None.. A validated 96-well anticholinergic radio receptor bioassay using small incubation volumes (240 μL per well) was applied in the current study. The different USDs (tolterodine, oxybutynin, solifenacin, darifenacin, and 5-hydroxy-methyl-tolterodine (5-HMT; the active metabolite of fesoterodine) were dissolved in plasma in their respective therapeutic concentration ranges. The plasma samples were added directly to the wells of 96 filter plates, wherein the incubation, filtration, and counting of undisplaced radioactivity was performed. Standard curves with atropine were used as reference for estimations of anticholinergic activity (AA).. 5-HMT and tolterodine displayed the highest AA of the tested USDs. In the middle of the therapeutic concentration range, the central anticholinergic potency of 5-HMT and tolterodine was more than 10 times as high as that of oxybutynin, solifenacin, and darifenacin. Darifenacin exhibited the lowest AA at therapeutic serum concentrations (< one-third the AA of oxybutynin and solifenacin).. Tolterodine and fesoterodine appear to have the highest pharmacodynamic potential to induce central anticholinergic side effects of the tested USDs. Darifenacin displayed the lowest AA, and combined with a low degree of brain distribution, it has probably the most favorable pharmacological profile of the USDs with respect to risk of cognitive impairment in older adults.

Topics: Benzhydryl Compounds; Benzofurans; Biological Assay; Brain; Cognition Disorders; Cresols; Humans; In Vitro Techniques; Mandelic Acids; Muscarinic Antagonists; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate

This study provides antimuscarinic agents for overactive bladder (OAB) display variable association with side effects mediated by the central nervous system (CNS), which may be of particular concern in the elderly. Adverse effects on CNS functioning are related to muscarinic receptor subtype selectivity and the ability of the agent to cross the blood-brain barrier, where P-gp plays a role in limiting permeability.. This study provides a parallel investigation of CNS penetration of antimuscarinic OAB agents in vivo and assessment of physical properties and permeability in cell monolayers in vitro. It adds further understanding of the roles of passive transcellular permeability and P-gp in determining CNS penetration of antimuscarinic OAB agents. It also enables a comparison of CNS side-effect profiles of OAB agents with preclinical CNS penetration data.. To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents.. Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays.. Oxybutynin displayed extensive CNS penetration, with brain:plasma ratios (B:P), unbound brain:unbound plasma ratios (Kp,free) and CSF:free plasma ratios each >1. Tolterodine (B:P = 2.95, Kp,free = 0.23 and CSF:free plasma = 0.16) and solifenacin (B:P = 3.04, Kp,free = 0.28 and CSF:free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B:P (0.03-0.16), Kp,free (0.01-0.04) and CSF:free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10(-6) cm s(-1) ), moderate for 5-HMT (11.7 × 10(-6) cm s(-1) ) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 × 10(-6) cm s(-1) ). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates.. Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; Benzhydryl Compounds; Benzofurans; Blood-Brain Barrier; Brain; Cell Line; Chromatography, High Pressure Liquid; Cresols; Humans; Male; Mandelic Acids; Muscarinic Antagonists; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Solifenacin Succinate; Tandem Mass Spectrometry; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder, Overactive

To investigate the effects of tissue stretch and muscarinic receptor stimulation on the spontaneous activity of the urothelium/lamina propria and identify the specific receptor subtype mediating these responses.. Isolated strips of porcine urothelium with lamina propria were set up for in vitro recording of contractile activity. Muscarinic receptor subtype-selective antagonists were used to identify the receptors influencing the contractile rate responses to stretch and stimulation with carbachol.. Isolated strips of urothelium with lamina propria developed spontaneous contractions (3.7 cycles/min) that were unaffected by tetrodotoxin, Nω-nitro-L-arginine, or indomethacin. Carbachol (1 μM) increased the spontaneous contractile rate of these tissue strips by 122% ± 27% (P < .001). These responses were significantly depressed in the presence of the M3-selective muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (10-30 nM) but were not affected by the M1-selective antagonist pirenzepine (30-100 nM) or the M2-selective antagonist methoctramine (0.1-1 μM). Stretching of the tissue also caused an increase in the spontaneous contractile rate, and these responses were abolished by atropine (1 μM) and low concentrations of 4-diphenylacetoxy-N-methylpiperidine methiodide (10 nM). Darifenacin, oxybutynin, tolterodine, and solifenacin (1 μM) all significantly depressed the frequency responses to carbachol (1 μM).. The urothelium with the lamina propria exhibits a spontaneous contractile activity that is increased during stretch. The mechanism appears to involve endogenous acetylcholine release acting on M3 muscarinic receptors. Anticholinergic drugs used clinically depress the responses of these tissues, and this mechanism might represent an additional site of action for these drugs in the treatment of bladder overactivity.

Topics: Animals; Atropine; Benzhydryl Compounds; Benzofurans; Carbachol; Cresols; Diamines; Mandelic Acids; Mucous Membrane; Muscarinic Antagonists; Muscle Contraction; Phenylpropanolamine; Piperidines; Pirenzepine; Pyrrolidines; Quinuclidines; Receptor, Muscarinic M3; Solifenacin Succinate; Stress, Mechanical; Swine; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder; Urothelium

To clarify the basic mechanism involved in the pathophysiology of cystitis by characterizing the urodynamic parameters, pharmacologically relevant (muscarinic and purinergic) receptors, and the in vivo release of adenosine triphosphate (ATP) in the bladder of hydrochloric acid (HCl)-treated rats.. The muscarinic and purinergic receptors in rat tissue were measured by radioreceptor assays using (N-methyl-³H) scopolamine methyl chloride ([³H]NMS) and αβ-methylene-ATP (2,8-³H) tetrasodium salt ([³H]αβ-MeATP), respectively. The urodynamic parameters and ATP levels were measured using a cystometric method and the luciferin-luciferase assay, respectively.. In the HCl-treated rats, the micturition interval and micturition volume were significantly (48% and 55%, respectively, P <.05) decreased and the number of micturitions was significantly (3.2-fold, P <.05) increased compared with those of the control rats. The maximal number of binding sites for [³H]NMS and [³H]αβ-MeATP was significantly (55% and 72%, respectively, P <.001) decreased in the bladder of HCl-treated rats, suggesting downregulation of both muscarinic and purinergic receptors. In the HCl-treated rats, the inhibition constant, K(i), values for oxybutynin, solifenacin, and darifenacin were significantly (1.3-1.4-fold, P <.05) increased, but those for tolterodine and AF-DX116 were unchanged. Similarly, the inhibition constant for A-317491, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium, and MRS2273 was significantly (5.5, 11, and 7.6-fold, respectively, P <.001) increased. Furthermore, the in vivo release of ATP was significantly (P <.05) enhanced in the HCl-treated rat bladder.. Both muscarinic and purinergic mechanisms might be, at least in part, associated with the urinary dysfunction due to cystitis.

Topics: Adenosine Triphosphate; Animals; Benzhydryl Compounds; Benzofurans; Cresols; Cystitis; Disease Models, Animal; Down-Regulation; Female; Hydrochloric Acid; Mandelic Acids; N-Methylscopolamine; Organophosphonates; Phenols; Phenylpropanolamine; Pirenzepine; Polycyclic Compounds; Pyridoxal Phosphate; Pyrrolidines; Quinuclidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Receptors, Purinergic; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder; Urination; Urodynamics

Recent studies have described muscarinic receptors on the mucosa and the detrusor of the human urinary bladder. Muscarinic receptor antagonists are effective in the treatment of overactive bladder (OAB), but their site(s) of action and actual therapeutic target are unclear. Our aim was to compare, in human bladder mucosa and detrusor, the radioligand binding characteristics of newer, clinically effective agents: darifenacin, its hydroxylated metabolite UK-148,993, fesoterodine, solifenacin, tolterodine, and trospium. Specimens were collected from asymptomatic patients (50-72 years old) undergoing open bladder surgery. Radioligand binding studies with the muscarinic antagonist [3H]quinuclidinyl benzilate (QNB) were performed separately on detrusor and mucosal membranes. All antagonists displayed high affinity when competing for [3H]QNB binding in both detrusor and mucosa. Inhibition constants were also obtained for all antagonists against individual muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Here, fesoterodine showed anomalous binding results, suggesting that some conversion to its metabolite had occurred. Global nonlinear regression analysis of bladder binding data with five antagonists demonstrated 82% low-affinity sites in mucosa and 78% low-affinity sites in detrusor, probably representing M(2)/M(4) receptors. There was an excellent correlation (r(2) = 0.99) of low-affinity global estimates between detrusor and mucosa, whereas the corresponding high-affinity estimates ( approximately 20% of sites) were dissimilar. In conclusion, commonly used and clinically effective muscarinic receptor antagonists bind to receptors located on the bladder mucosa and the detrusor, providing support for the hypothesis that muscarinic receptors in the mucosa may represent an important site of action for these agents in OAB.

Topics: Aged; Benzhydryl Compounds; Benzofurans; Cresols; Cystectomy; Female; Humans; Male; Middle Aged; Mucous Membrane; Muscarinic Antagonists; Phenylpropanolamine; Prostatectomy; Pyrrolidines; Quinuclidines; Quinuclidinyl Benzilate; Radioligand Assay; Receptors, Muscarinic; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder; Urinary Bladder, Overactive

Highly selective M(3) muscarinic receptor antagonists may represent a better treatment for overactive bladder syndrome, diminishing side effects. Cardiac side effects of non-selective antimuscarinics have been associated with activity at M(2) receptors as these receptors are mainly responsible for muscarinic receptor-dependent bradycardia. We have investigated a novel antimuscarinic, SVT-40776, highly selective for M(3) over M(2) receptors (Ki = 0.19 nmol.L(-1) for M(3) receptor affinity). This study reports the functional activity of SVT-40776 in the bladder, relative to its activity in atria.. In vitro and ex vivo (oral dosing) inhibition of mouse detrusor and atrial contractile responses to carbachol were used to study the functional activity of SVT-40776. The in vivo efficacy of SVT-40776 was characterized by suppression of isovolumetric spontaneous bladder contractions in anaesthetized guinea pigs after intravenous administration.. SVT-40776 was the most potent in inhibiting carbachol-induced bladder contractions of the anti-cholinergic agents tested, without affecting atrial contractions over the same range of concentrations. SVT-40776 exhibited the highest urinary versus cardiac selectivity (199-fold). In the guinea pig in vivo model, SVT-40776 inhibited 25% of spontaneous bladder contractions at a very low dose (6.97 microg.kg(-1) i.v), without affecting arterial blood pressure.. SVT-40776 is a potent inhibitor of M(3) receptor-related detrusor contractile activity. The absence of effects on isolated atria preparations represents an interesting characteristic and suggests that SVT-40776 may lack unwanted cardiac effects; a feature especially relevant in a compound intended to treat mainly elderly patients.

Topics: Animals; Atrial Function; Benzhydryl Compounds; Benzofurans; Carbamates; Cresols; Guinea Pigs; In Vitro Techniques; Male; Mice; Muscle Contraction; Muscle, Smooth; Myocardial Contraction; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Receptor, Muscarinic M3; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder

Nationwide use and costs of anticholinergic drug for overactive bladder are unknown.. We performed a nationwide study based on the Swedish Register on Prescribed Pharmaceuticals.. From 2000 to 2007, there was a 68.8% increase in dispensed anticholinergic drugs in a population of 9 million. More than 93 million DDDs (calculated average maintenance dose per day) of anticholinergic drugs were dispensed corresponding to an overall DDD/TID (DDD per 1,000 inhabitants per day) of 3.5 per 1,000 persons per year. Approximately two thirds of anticholinergic drugs were prescribed to women, regardless of drug type. In 2007, the cost for anticholinergic drugs was 22 million of which tolterodine comprised 70.8%. Solifenacin and darifenacin steadily increased their DDD/TIDs after market introduction.. In this nationwide study, there was a 70% increased rate of expedited prescriptions of anticholinergic drugs for the treatment of overactive bladder in a relatively stable population.

Topics: Benzhydryl Compounds; Benzofurans; Cholinergic Antagonists; Cresols; Female; Health Care Costs; Humans; Muscarinic Antagonists; Pharmacoepidemiology; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Registries; Retrospective Studies; Solifenacin Succinate; Sweden; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder, Overactive

The objective of the study was to evaluate the local effects of three antimuscarinics excreted into human urine after oral ingestion. Two normal adult collected their voided urine after taking oral doses of tolterodine, darifenacin, and solifenacin for 7 days with a 14-day washout period. The urodynamic effect of intravesically administered human urine on carbachol-induced bladder overactivity was studied in female rats. Cystometric parameters were measured during continuous infusion of saline and human urine and then a mixture of carbachol (30 microM) and human urine. Carbachol significantly reduced the intercontraction interval and bladder capacity in the control (urine taken in the absence of oral antimuscarinics) and tolterodine- or darifenacin-administered groups. However, human urine obtained after taking solifenacin prevented the carbachol-induced detrusor overactivity. Urine excreted after oral ingestion of solifenacin provides a localized pharmacological advantage for the treatment of the overactive bladder syndrome.

Topics: Administration, Oral; Animals; Benzhydryl Compounds; Benzofurans; Cresols; Disease Models, Animal; Female; Humans; Muscarinic Antagonists; Muscle, Smooth; Phenylpropanolamine; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder, Overactive; Urine

Solifenacin succinate [YM905; (3R)-1-azabicyclo[2.2.2]oct-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-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 antimuscarinic properties of solifenacin and to compare the results with those obtained for tolterodine, oxybutynin, darifenacin, propiverine and atropine. In radioligand receptor binding assay, Ki values of solifenacin for human muscarinic M1, M2, M3, M4 and M5 receptors were 26, 170, 12, 110 and 31 nM, respectively. In isolated rat urinary bladder, solifenacin competitively antagonized carbachol-induced contractions, with a pA2 value of 7.44+/-0.09. In these in vitro studies, the antimuscarinic action of solifenacin was more potent than that of propiverine and less potent than those of tolterodine, oxybutynin, darifenacin and atropine. In anesthetized rats, solifenacin and oxybutynin increased the maximum bladder capacity in a dose-dependent manner and also decreased the maximum intravesical pressure. The dosages required to produce a 30% increase in maximum bladder capacity (ED30 values) of solifenacin and oxybutynin were 0.35 and 0.30 mg/kg i.v., respectively, indicating approximately equal efficacies. These results support the fact that solifenacin, similarly to currently used antimuscarinic agents, is an effective agent in the treatment of overactive bladder symptoms such as urinary frequency and urge incontinence.

Topics: Animals; Atropine; Benzhydryl Compounds; Benzilates; Benzofurans; Binding, Competitive; Carbachol; CHO Cells; Cholinergic Agonists; Cresols; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Mandelic Acids; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; N-Methylscopolamine; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Muscarinic; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Transfection; Urinary Bladder; Urinary Bladder, Overactive; Urination

We characterized muscarinic receptor binding in the mouse cerebral cortex after oral administration of anticholinergic agents used to treat overactive bladder.. Muscarinic receptors in the mouse cerebral cortex and bladder after oral administration of anticholinergic agents were measured using [(3)H]N-methylscopolamine.. In vitro binding affinities of tolterodine and its metabolite 5-hydroxymethyl metabolite in the mouse cerebral cortex and bladder were considerably greater than those of oxybutynin and darifenacin. Also, muscarinic receptor binding affinity of oxybutynin and its metabolite N-desethyl-oxybutynin in the cerebral cortex compared with that in the bladder was 2 to 3 times higher, whereas that of tolterodine and 5-hydroxymethyl metabolite was approximately 2 times lower. Oral administration of oxybutynin (76.1 micromol/kg), tolterodine (6.31 micromol/kg) and darifenacin (59.1 micromol/kg) showed binding activity that was approximately equal to that of bladder muscarinic receptors. Oral administration of oxybutynin (76.1 micromol/kg) showed significant binding of cerebral cortical muscarinic receptors in mice, as indicated by about a 2-fold increase in K(d) values for specific [(3)H]N-methylscopolamine binding 0.5 and 2 hours later. On the other hand, tolterodine and darifenacin given at oral doses that would exert a similar extent of bladder receptor binding activity as oxybutynin showed only a low level of binding activity of central muscarinic receptors in mice.. Significant binding of brain muscarinic receptors in mice was observed by the oral administration of oxybutynin but not tolterodine and darifenacin.

Topics: Animals; Benzhydryl Compounds; Benzofurans; Cerebral Cortex; Cresols; In Vitro Techniques; Male; Mandelic Acids; Mice; Muscarinic Antagonists; Phenylpropanolamine; Pyrrolidines; Receptors, Muscarinic; Tolterodine Tartrate; Urinary Bladder; Urinary Bladder, Overactive

The aim of this study was to describe a new experimental animal model for simultaneous measurement of carbachol-induced increase in intravesical pressure and salivary secretion in rabbits. Further, we also compared the in vivo potency and urinary bladder versus salivary gland selectivity profiles of Oxybutynin, Tolterodine, Solifenacin and Darifenacin. The intravesical pressure and salivary secretion were evoked by intra-arterial injection of carbachol (1.5 microg/kg). The carbachol-induced increase in intravesical pressure and salivation was simultaneously recorded before and after increasing doses of test drugs administered intravenously. The basal mean changes in intravesical pressure and salivation subsequent to carbachol administration were in the range of 6.7-7.5 mm Hg and 0.5-0.7 g respectively. Repeated administration of vehicle did not elicit any appreciable changes in intravesical pressure and salivary secretion to carbachol administration from the basal values till 3 h. All the test drugs exhibited a dose-dependent inhibition of carbachol-induced increase in intravesical pressure and salivary secretion. Darifenacin demonstrated a greater potency compared to other muscarinic receptor antagonists for inhibiting carbachol-induced increase in intravesical pressure. It also exhibited functional selectivity for the urinary bladder versus salivary gland. In contrast, Oxybutynin was functionally more selective in inhibiting carbachol-induced increase in salivary secretion. The observed urinary bladder versus salivary selectivity values were 0.6+/-0.2, 1.1+/-0.2, 1.7+/-0.5, and 2.3+/-0.5 for Oxybutynin, Tolterodine, Solifenacin and Darifenacin respectively. These results suggest that the functional selectivity of muscarinic receptor antagonists between urinary bladder and salivary glands can be readily detected in this model. Thus rabbits may represent a useful animal model for evaluating putative bladder selective muscarinic receptor antagonists for the treatment of overactive bladder.

Topics: Anesthesia; Animals; Benzhydryl Compounds; Benzofurans; Carbachol; Cholinergic Antagonists; Cresols; Injections, Intra-Arterial; Male; Mandelic Acids; Phenylpropanolamine; Pressure; Pyrrolidines; Quinuclidines; Rabbits; Salivary Glands; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder

We investigated the effects of the new muscarinic receptor antagonist solifenacin succinate [YM905; (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate] and the current antimuscarinic drugs for the treatment of overactive bladder (oxybutynin, tolterodine and darifenacin) on intracellular Ca(2+) mobilization in response to M(3) muscarinic receptor activation in bladder smooth muscle and submandibular gland cells isolated from Cynomolgus monkeys. Solifenacin concentration-dependently inhibited carbachol-induced Ca(2+) mobilization, with affinity constant values (pKi) of 8.5 +/- 0.053 in bladder smooth muscle cells and 8.2 +/- 0.051 in submandibular gland cells (n = 5). The pKi value of solifenacin was almost equivalent to the values of oxybutynin, tolterodine and darifenacin in bladder smooth muscle cells (8.7, 8.5 and 8.4, respectively), while being lower than those in submandibular gland cells (9.0, 8.7 and 8.8, respectively). The bladder-selectivity index (Ki ratio: submandibular gland/bladder) for solifenacin (2.1) was statistically higher, moreover, than those for oxybutynin, tolterodine and darifenacin (0.51, 0.65 and 0.46, respectively). These findings consequently indicate solifenacin's unique profile in terms of its selectivity for bladder smooth muscle cells over salivary gland cells in non-human primates, relative to oxybutynin, tolterodine and darifenacin. Solifenacin may, therefore, confer a promising therapeutic advantage for reducing adverse effects, such as dry mouth, exhibited by current antimuscarinic therapy for overactive bladder.

Topics: Animals; Benzhydryl Compounds; Benzofurans; Calcium; Calcium Signaling; Carbachol; Cresols; Dose-Response Relationship, Drug; In Vitro Techniques; Inhibitory Concentration 50; Macaca fascicularis; Male; Mandelic Acids; Muscarinic Antagonists; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Submandibular Gland; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder

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.

Topics: Animals; Atropine; Benzhydryl Compounds; Benzofurans; Calcium; Cresols; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Mandelic Acids; Muscarinic Antagonists; Myocytes, Smooth Muscle; Organ Specificity; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Rats; Rats, Wistar; Solifenacin Succinate; Submandibular Gland; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder

Tolterodine [(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine ] is a new potent and competitive muscarinic receptor antagonist developed for the treatment of urinary urge incontinence and other symptoms of overactive bladder. In vivo, tolterodine exhibits functional selectivity for the urinary bladder over salivary glands, a profile that cannot be explained in terms of selectivity for a single muscarinic receptor subtype. The aim of this study was to compare the in vitro and in vivo antimuscarinic profiles of tolterodine with those of muscarinic receptor antagonists with distinct receptor subtype-selectivity profiles: darifenacin [(S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl]-2,2-d iphenylacetamide; selective for muscarinic M3 receptors]; UH-AH 37 (6-chloro-5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-dibenzo-[b ,e][1,4]diazepine-11-one; low affinity for muscarinic M2 receptors); and AQ-RA 741 (11-([4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl)-5,11-dihydro-6H-py rido[2,3-b][1,4]benzodiazepine-6-one; high affinity for muscarinic M2 receptors). The in vitro profiles of these compounds were in agreement with previous reports; darifenacin and UH-AH 37 demonstrated selectivity for muscarinic M3/m3 over M2/m2 receptors, while the converse was observed for AQ-RA 741. In vivo, AQ-RA 741 was more potent (1.4-2.7-fold) in inhibiting urinary bladder contraction than salivation in the anaesthetised cat (i.e., a profile similar to that of tolterodine [2.5-3.3-fold]), while darifenacin and UH-AH 37 showed the reverse selectivity profile (0.6-0.8 and 0.4-0.5-fold, respectively). The results confirm that it is possible to separate the antimuscarinic effects on urinary bladder and salivary glands in vivo. The data on UH-AH 37 and darifenacin support the view that a selectivity for muscarinic M3/m3 over M2/m2 receptors may result in a more pronounced effect on salivation than on bladder contraction. The data on AQ-RA 741 may indicate that muscarinic M2/m2 receptors may have a role in bladder contraction.

Topics: Animals; Benzhydryl Compounds; Benzodiazepinones; Benzofurans; Cats; Cerebral Cortex; CHO Cells; Cresols; Cricetinae; Dibenzazepines; Electric Stimulation; Female; Guinea Pigs; Male; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Myocardium; Phenylpropanolamine; Piperidines; Pyrrolidines; Receptors, Muscarinic; Saliva; Salivary Glands; Tolterodine Tartrate; Urinary Bladder