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Summary Introduction To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results. Methods This prespecified pooled analysis of three randomised, double‐blind, placebo‐controlled, 12‐week studies, evaluated efficacy and safety of once‐daily mirabegron 25 mg (safety analysis), 50 or 100 mg (efficacy and safety analyses) and tolterodine ER 4 mg (safety analysis) for the treatment of symptoms of overactive bladder (OAB). Co‐primary efficacy measures were change from baseline to Final Visit in the mean number of incontinence episodes/24 h and mean number of micturitions/24 h. Key secondary efficacy end‐points included mean number of urgency episodes/24 h and mean volume voided/micturitions, while other end‐points included patient‐reported outcomes according to the Treatment Satisfaction‐Visual Analogue Scale (TS‐VAS) and responder analyses [dry rate (posttreatment), ≥ 50% reduction in incontinence episodes/24 h, ≤ 8 micturitions/24 h (post hoc analysis)]. The safety analysis included adverse event (AE) reporting, laboratory assessments, ECG, postvoid residual volume and vital signs (blood pressure, pulse rate). Results Mirabegron (50 and 100 mg once daily) demonstrated statistically significant improvements compared with placebo for the co‐primary end‐points, key secondary efficacy variables, TS‐VAS and responder analyses (all comparisons p < 0.05). Mirabegron is well tolerated and demonstrates a good safety profile. The most common AEs (≥ 3%) included hypertension, nasopharyngitis and urinary tract infection (UTI); the incidence of hypertensive events and UTIs decreased with increasing dose. For mirabegron, the incidence of the bothersome antimuscarinic AE, dry mouth, was at placebo level and of a lesser magnitude than tolterodine. Conclusion The efficacy and safety of mirabegron are demonstrated in this large pooled clinical trial dataset in patients with OAB.

Purpose The aim of this work was to investigate the feasibility of using nanosized microemulsion for transdermal delivery of tolterodine tartrate. Methods The effect of three microemulsions formed by Labrasol: Plurol (3:1), isopropyl myristate and water on the permeation of tolterodine through miniature pig skin was studied in vitro using Franz diffusion cell. For comparison purpose, the effect of different vehicles on the permeation was also studied. Drug pharmacokinetics was studied after transdermal application to human volunteers compared to the commercial oral dosage form using a newly developed LC-MS/MS assay. Results The vehicle PEG 400:Phosphate buffer pH 7.4 in the ratio of 1:1 significantly enhanced tolterodine permeation across pig skin. The microemulsion system (ME3) containing the highest amount of water (50%) significantly enhanced permeation with Q₂₄ of 0.746 mg.cm⁻². In contrast to oral delivery, a sustained activity was observed over a period of 72 h after transdermal application of this microemulsion to human volunteers with significant lower Cmax (1.06 ng/ml), delayed Tmax (3.17 h) and higher MRT value (147.82 h) (p < 0.05). Conclusion This sustained activity was due to the controlled release of drug into the systemic circulation with expected increase in the patient compliance and prevention of nocturnal enuresis.

To compare the efficacy and tolerability of extended-release formulations of oxybutynin chloride and tolterodine tartrate in women with overactive bladder. The OPERA (Overactive bladder: Performance of Extended Release Agents) trial was a randomized, double-blind, active-control study performed at 71 US study centers from November 21, 2000, to October 18, 2001. Extended-release formulations of oxybutynin at 10 mg/d or tolterodine at 4 mg/d were given for 12 weeks to women with 21 to 60 urge urinary incontinence (UUI) episodes per week and an average of 10 or more voids per 24 hours. Episodes of UUI (primary end point), total (urge and nonurge) incontinence, and micturition were recorded in 24-hour urinary diaries at baseline and at weeks 2, 4, 8, and 12 and compared. Adverse events were also evaluated. Improvements in weekly UUI episodes were similar for the 790 women who received extended-release formulations of oxybutynin (n=391) or tolterodine (n=399). Oxybutynin was significantly more effective than tolterodine in reducing micturition frequency ( P=.003), and 23.0% of women taking oxybutynin reported no episodes of urinary incontinence compared with 16.8% of women taking tolterodine ( P=.03). Dry mouth, usually mild, was more common with oxybutynin ( P=.02). Adverse events were generally mild and occurred at low rates, with both groups having similar discontinuation of treatment due to adverse events. Reductions in weekly UUI and total incontinence episodes were similar with extended-release formulations of oxybutynin and tolterodine. In the oxybutynin group, micturition frequency was significantly lower, and the percentage of women reporting no urinary incontinence episodes was significantly higher compared with the tolterodine group. Dry mouth was more common with oxybutynin, but tolerability was otherwise comparable, including adverse events involving the central nervous system.

Background Overactive bladder (OAB) is highly prevalent and is associated with considerable morbidity and reduced health-related quality of life. β 3 -adrenergic receptor (β 3 -AR) stimulation is a novel alternative to antimuscarinic therapy for OAB. Objective The objective of this analysis was to assess the cost effectiveness of the β 3 -AR agonist mirabegron relative to tolterodine extended release (ER) in patients with OAB from a UK National Health Service (NHS) perspective. Methods A Markov model was developed to simulate the management, course of disease, and effect of complications in OAB patients over a period of 5 years. Transition probabilities for symptom severity levels and probabilities of adverse events were estimated from the results of the randomised, double-blind SCORPIO trial in 1,987 patients with OAB. Other model inputs were derived from the literature and on assumptions based on clinical experience. Results Total 5-year costs per patient were £1,645.62 for mirabegron 50 mg/day and £1,607.75 for tolterodine ER 4 mg/day. Mirabegron was associated with a gain of 0.009 quality-adjusted life-years (QALYs) with an additional cost of £37.88. The resulting incremental cost-effectiveness ratio (ICER) was £4,386/QALY gained. In deterministic sensitivity analyses in the general OAB population and several subgroups, ICERs remained below the generally accepted willingness-to-pay (WTP) threshold of £20,000/QALY gained. The probability of mirabegron 50 mg being cost effective relative to tolterodine ER 4 mg was 89.4 % at the same WTP threshold. Conclusions Mirabegron 50 mg/day is likely to be cost effective compared with tolterodine ER 4 mg/day for adult patients with OAB from a UK NHS perspective.

To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder. The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallel-group study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline. A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups. Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events.

UV-P (2-(2 H -Benzotriazol-2-yl)-p-cresol) is used as an ultraviolet (UV) light absorber in coating products, paints, adhesives, and sealants. Due to its widespread industrial and consumer uses, human exposure to UV-P is conceivable. In the study presented herein, initial data on its human in vivo metabolism were obtained for three study participants after single oral administration of 0.3 mg of UV-P/kg body weight. Urine and blood samples of two volunteers were collected up to 48 h after exposure. The third study participant donated urine and blood samples up to 72 h. Maximum levels of UV-P in blood of 184 ± 36 µg/l (85 ± 3% as conjugates) were reached 2.4 ± 1.2 h post-exposure. Maximum excretion rates of UV-P in urine of 2896 ± 884 µg/h (completely conjugated) were reached 3.5 ± 1.1 h post-exposure. 37.2 ± 5.4% of the orally administered dose of UV-P was recovered in urine within 48 h post-exposure. The present study provides insight into the complex absorption, distribution, metabolism, and elimination (ADME) processes of benzotriazole UV stabilizers (BUVS). The study also demonstrates differences in the ADME between sterically hindered BUVS, such as UV-327 and UV-328, and sterically unhindered BUVS, such as UV-P, in which the phenolic hydroxyl group is readily accessible for conjugation with glucuronic acid or sulfate.

The constituents of the gut microbiome are determined by the local habitat, which itself is shaped by immunological pressures, such as mucosal IgA. Using a mouse model of restricted antibody repertoire, we identified a role for antibody–microbe interactions in shaping a community of bacteria with an enhanced capacity to metabolize l -tyrosine. This model led to increased concentrations of p -cresol sulfate (PCS), which protected the host against allergic airway inflammation. PCS selectively reduced CCL20 production by airway epithelial cells due to an uncoupling of epidermal growth factor receptor (EGFR) and Toll-like receptor 4 (TLR4) signaling. Together, these data reveal a gut microbe–derived metabolite pathway that acts distally on the airway epithelium to reduce allergic airway responses, such as those underpinning asthma. The microbiome can affect susceptibility to developing asthma. Marsland and colleagues show that changes in the microbial population lead to enrichment of an l -tyrosine metabolite, p -cresol sulfate, which can protect mice against allergic inflammation.

Purpose To investigate the potential effect of tolterodine on the human heart rate variability (HRV). Oral antimuscarinic treatment for overactive bladder might significantly alter HRV, which is an important predictor for cardiac and all-cause mortality. Yet, little information exists regarding the influence of oral antimuscarinics on the HRV. Methods Healthy female volunteers were randomly assigned to either placebo, tolterodine extended release (ER) 4 or 8 mg. Before and 4 h post treatment, a 10 min electrocardiogram (ECG) was recorded in supine position. Frequency domain and time domain analysis of both ECG measurements resulted in very low frequency (VLF), low frequency (LF), and high frequency (HF) data, the root mean square of differences of successive NN (= normal to normal, i.e. interval between two R-peaks) intervals (RMSSD), and the standard deviation of the NN intervals (SDNN). Results Thirty subjects (mean age: 23.7 ± 2.3 years) were investigated. Placebo caused no significant HRV changes. Tolterodine 4 mg significantly increased heart rate (HR) and significantly decreased VLF. Tolterodine 8 mg significantly decreased HF, VLF, RMSSD and SDNN and significantly increased HR and LF/HF ratio. The changes observed with 4 mg were not significantly different versus placebo, but 8 mg significantly increased LF/HF as compared to placebo. Conclusions A single dose of 8 mg tolterodine ER, but not 4 mg seems to reduce resting HRV versus placebo in young healthy subjects. This might be particular relevant for patients with pre-existing cardiac conditions on daily overactive bladder drug treatment and should be further investigated in larger trials.

Background Acute sore throat (pharyngitis) is one of the most common illnesses for which children are seen by primary care physicians. Most cases are caused by viruses and are benign and self-limiting. Clinically proven, over-the-counter throat lozenges provide rapid and effective relief of acute sore throat symptoms, and are increasingly important in self-management of this condition. Objective The purpose of this study (International Standard Randomized Controlled Trial Number: ISRCTN34958871) was to evaluate the acceptability of two licensed, commercially available sore throat lozenges containing amylmetacresol and 2,4-dichlorobenzyl (AMC/DCBA)—one strawberry flavored and the other orange flavored—in healthy children. Study design This was an open-label, single-dose, crossover, taste-testing study in children recruited via a clinical database and advertisements over a 3.5-week period. Setting Potentially eligible participants were invited to attend the taste-testing session at a clinic. Participants At the screening session, which took place either before or on the day of taste testing, details of relevant medical history, medication, and demographics were recorded. Of the 108 screened subjects, 102 were recruited. These were healthy male and female children aged 6–12 years. Intervention Each child cleansed their palate with water and water biscuits before tasting a strawberry-flavored lozenge (Strepsils ® strawberry sugar free, Reckitt Benckiser Healthcare Limited, Nottingham, UK; PL 00063/0395), which was sucked for 1 minute and then expelled. The orange-flavored lozenge (Strepsils ® orange with vitamin C, Reckitt Benckiser Healthcare Limited, Nottingham, UK; PL 016242152) was tasted at least 15 minutes later following further cleansing of the palate. The spontaneous reaction of the child on tasting each lozenge was observed and recorded. Subjects were asked to indicate their liking for each lozenge, using a 7-point hedonic facial scale, and were required to answer a series of questions relating to what they liked and disliked about the taste and the feel of the lozenge in the mouth and throat. The primary endpoint was the proportion of subjects with a hedonic facial score of >4. Secondary endpoints included the spontaneous reaction of the child on tasting the lozenge and responses to questions related to taste. Results The taste of the lozenge was scored >4 (i.e. ‘good’, ‘really good’, or ‘super good’) by 85.3 % of subjects for the strawberry flavor and 49.0 % for the orange flavor ( p  < 0.0001). The mean (standard deviation) score was 5.72 (1) for the strawberry-flavored lozenge and 4.35 (2) for the orange-flavored lozenge. The proportion of subjects willing to take the lozenge again was 94 % for the strawberry flavor and 56 % for the orange flavor. Conclusions Strawberry-flavored AMC/DCBA lozenges were liked by, and acceptable to, the majority of the children. AMC/DCBA orange-flavored lozenges were also liked by, and acceptable to, approximately half the children. Overall, both strawberry and orange would be suitable flavors for lozenges intended for children when they suffer from sore throat.

We performed a randomized, prospective study to assess the possible role of combined tamsulosin and tolterodine therapy for the relief of vesical irritability and in facilitating the spontaneous expulsion of intramural ureteral stones. Patients were randomized to one of three treatment groups. Treatment group 1 patients received tamsulosin 0.4 mg/day, group 2 patients received tamsulosin 0.4 mg/day plus tolterodine 2 mg (twice a day), and group 3 patients received tolterodine 2 mg (twice a day). Subjects rated the urgency associated with each micturition using the Urinary Sensation Scale. Pain descriptions were recorded by the patients using the Visual Analog Scale. Stone expulsion was observed in 30 patients in group 1, 29 patients in group 2 and 18 patients in group 3. Kaplan-Meier curves were plotted to access the expulsion rate of each group over time. A significant difference was shown for the expulsion rate between the tolterodine group and the other two groups. (P = 0.003 by log rank test). Average time to expulsion for groups 1, 2 and 3 was 7.62 ± 2.42, 7.79 ± 2.11 and 10.57 ± 2.71 days, respectively (P = 0.000). In groups 1, 2 and 3, the mean number of pain episodes was 2.27 ± 0.91, 1.39 ± 1.34 and 1.38 ± 1.20, respectively (P = 0.023). Treatment with tamsulosin and tolterodine appears to be beneficial in intramural ureteral stone clearance, particularly in intramural ureter stone with symptoms of vesical irritability.[PUBLICATION ABSTRACT]