Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection.

The development of new modalities for high-efficiency intracellular drug delivery is a priority for a number of disease areas. One such area is urinary tract infection (UTI), which is one of the most common infectious diseases globally and which imposes an immense economic and healthcare burden. Common uropathogenic bacteria have been shown to invade the urothelial wall during acute UTI, forming latent intracellular reservoirs that can evade antimicrobials and the immune response. This behaviour likely facilitates the high recurrence rates after oral antibiotic treatments, which are not able to penetrate the bladder wall and accumulate to an effective concentration. Meanwhile, oral antibiotics may also exacerbate antimicrobial resistance and cause systemic side effects. Using a human urothelial organoid model, we tested the ability of novel ultrasound-activated lipid microbubbles to deliver drugs into the cytoplasm of apical cells. The gas-filled lipid microbubbles were decorated with liposomes containing the non-cell-permeant antibiotic gentamicin and a fluorescent marker. The microbubble suspension was added to buffer at the apical surface of the bladder model before being exposed to ultrasound (1.1 MHz, 2.5 Mpa, 5500 cycles at 20 ms pulse duration) for 20 s. Our results show that ultrasound-activated intracellular delivery using microbubbles was over 16 times greater than the control group and twice that achieved by liposomes that were not associated with microbubbles. Moreover, no cell damage was detected. Together, our data show that ultrasound-activated microbubbles can safely deliver high concentrations of drugs into urothelial cells, and have the potential to be a more efficacious alternative to traditional oral antibiotic regimes for UTI. This modality of intracellular drug delivery may prove useful in other clinical indications, such as cancer and gene therapy, where such penetration would aid in treatment.

Urothelial cells may indicate underlying bacteriuria in pregnancy at term: a comparative study.

BACKGROUND: Urinary tract infection is common in pregnancy. Urine is sampled from by mid-stream collection (MSU). If epithelial cells are detected, contamination by vulvo-vagial skin and skin bacteria is assumed. Outside pregnancy, catheter specimen urine (CSU) is considered less susceptible to contamination. We compared MSU and CSU methods in term pregnancy to test these assumptions. METHODS: Healthy pregnant women at term gestation (n = 32, median gestation 38 + 6 weeks, IQR 37 + 6-39 + 2) undergoing elective caesarean section provided a MSU and CSU for paired comparison that were each analysed for bacterial growth and bladder distress by fresh microscopy, sediment culture and immunofluorescent staining. Participants completed a detailed questionnaire on lower urinary tract symptoms. Epithelial cells found in urine were tested for urothelial origin by immunofluorescent staining of Uroplakin III (UP3), a urothelial cell surface glycoprotein. Urothelial cells with closely associated bacteria, or "clue cells", were also counted. Wilcoxons signed rank test was used for paired analysis. RESULTS: Women reported multiple lower urinary tract symptoms (median 3, IQR 0-8). MSU had higher white blood cell counts (median 67 vs 46, z = 2.75, p = 0.005) and epithelial cell counts (median 41 vs 22, z = 2.57, p = 0.009) on fresh microscopy. The proportion of UP3+ cells was not different (0.920 vs 0.935, z = 0.08, p = 0.95), however MSU had a higher proportion of clue cells (0.978 vs 0.772, z = 3.17, p = 0.001). MSU had more bacterial growth on sediment culture compared to CSU specimens (median 8088 total cfu/ml vs 0, z = 4.86, p = 0.001). Despite this, routine laboratory cultures reported a negative screening culture for 40.6% of MSU specimens. CONCLUSION: Our findings have implications for the correct interpretation of MSU findings in term pregnancy. We observed that MSU samples had greater bacterial growth and variety when compared to CSU samples. The majority of epithelial cells in both MSU and CSU samples were urothelial in origin, implying no difference in contamination. MSU samples had a higher proportion of clue cells to UP3+ cells, indicating a greater sensitivity to bacterial invasion. Urinary epithelial cells should not be disregarded as contamination, instead alerting us to underlying bacterial activity.

Aberrant Ca2+ oscillations in smooth muscle cells from overactive human bladders.

Overactive bladder (OAB) syndrome is highly prevalent and costly, but its pathogenesis remains unclear; in particular, the origin of involuntary detrusor muscle activity. To identify the functional substrate for detrusor muscle overactivity, we examined intracellular Ca(2+) oscillations in smooth muscle cells from pathologically overactive human bladders. Basal cytoplasmic Ca(2+) concentration was elevated in smooth muscle cells from overactive bladders. Unprovoked, spontaneous rises of Ca(2+) were also identified. These spontaneous Ca(2+) oscillations were Ca(2+)-dependent, sensitive to L-type Ca(2+) channel antagonist verapamil and also attenuated by blocking SR Ca(2+) reuptake. The fraction of spontaneously active cells was higher in cells from overactive bladders and the magnitude of spontaneous Ca(2+) oscillations also greater. Spontaneous action potentials or depolarising oscillations were also observed, associated with Ca(2+) rise; with a higher percentage of cells from idiopathic OAB, but not in neurogenic OAB. Low concentrations of NiCl(2) attenuated both spontaneous electrical and Ca(2+) activation. This study provides the first evidence that spontaneous, autonomous cellular activity-Ca(2+) and membrane potential oscillations, originates from detrusor smooth muscle in human bladders, mediated by extracellular Ca(2+) influx and intracellular release. Such cellular activity underlies spontaneous muscle contraction and defective Ca(2+) activation contributes to up-regulated contractile activity in overactive bladders.

Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product designs.

OBJECTIVES: To compare the performance and cost-effectiveness of the key absorbent product designs to provide a more solid basis for guiding selection and purchase. Also to carry out the first stage in the development of a quality of life (QoL) instrument for measuring the impact of absorbent product use on users' lives. DESIGN: Three clinical trials focused on the three biggest market sectors. Each trial had a similar crossover design in which each participant tested all products within their group in random order. SETTING, PARTICIPANTS AND INTERVENTIONS: In Trial 1, 85 women with light urinary incontinence living in the community tested three products from each of the four design categories available (total of 12 test products): disposable inserts (pads); menstrual pads; washable pants with integral pad; and washable inserts. In Trial 2a, 85 moderate/heavily incontinent adults (urinary or urinary/faecal) living in the community (49 men and 36 women) tested three (or two) products from each of the five design categories available (total of 14 test products): disposable inserts (with mesh pants); disposable diapers (nappies); disposable pull-ups (similar to toddlers' trainer pants); disposable T-shaped diapers (nappies with waist-band); and washable diapers. All products were provided in a daytime and a (mostly more absorbent) night-time variant. In these first two trials, the test products were selected on the basis of data from pilot studies. In Trial 2b, 100 moderate/heavily incontinent adults (urinary or urinary/faecal) living in 10 nursing homes (27 men and 73 women) evaluated one product from each of the four disposable design categories from Trial 2a. Products were selected on the basis of product performance in Trial 2a and, again, day time and night-time variants were provided. The first phase of developing a QoL tool for measuring the impact of using different pad designs was carried out by interviewing participants from Trials 1 and 2a. MAIN OUTCOME MEASURES: Product performance (e.g. comfort, discreetness) was characterised using a weekly validated questionnaire. A daily pad change and leakage diary was used to record severity of leakage, numbers of laundry items and pads. Skin health changes were recorded weekly. At a final interview preferences were ranked, acceptability of each design recorded, and overall opinion marked on a visual analogue scale (VAS) of 0-100 points. This VAS score was used to estimate cost-effectiveness. In addition, a timed pad changing exercise was conducted with 10 women from Trial 2b to determine any differences between product designs. RESULTS: Disposable inserts are currently the mainstay of management for lightly incontinent women (Trial 1) and they were better for leakage and other variables (but not discreetness) and better overall than the other three designs. However, some women preferred menstrual pads (6/85) or washable pants (13/85), both of which are cheaper to use. Washable inserts were worse both overall and for leakage than the other three designs (72/85 found them unacceptable). For disposable inserts and disposable diapers, findings from the community (Trial 2a) and nursing home trials (Trial 2b) were broadly similar. Leakage performance of disposable inserts was worse than that of the other designs for day and night. Pull-ups were preferred over inserts for the daytime. The new T-shaped diaper was not better overall than the traditional disposable one. However, there were important differences in performance and preference findings for men and women from both trials. Pull-ups (the most expensive) were better overall than the other designs for women during the day and for community-dwelling women during the night. Although disposable diapers were better for leakage than disposable inserts (the cheapest), women did not prefer them (except in nursing homes at night), but for men the diapers were better both overall and for leakage and were the most cost-effective design. No firm conclusions could be drawn about the performance of designs for faecal incontinence. Nursing home carers found pull-ups and inserts easier to apply (in the standing position) and quicker (in the pad change experiment) than the diaper designs; the ability to stand was associated with preference for pull-ups or inserts. The T-shaped diaper was not easier or quicker to change than the diaper. The washable products (Trial 2a) gave diverse results: they were better for leakage at night, but were worse overall for daytime than the other designs. Three-quarters of the women (27/36) found them unacceptable, but nearly two-thirds of men (31/49) found them highly acceptable at night. Findings from the two community trials (Trials 1 and 2a) showed that there were many practical problems in dealing with washable products but, together with the less effective and less expensive products, such as menstrual pads, they were more acceptable at home (and, in the case of washables, at night). This suggests that cost-effective management may involve combining products by using more effective (for a given user) but more expensive designs (e.g. pull-ups) when out and less effective but less expensive designs when at home. The interviews examining the impact of pad use on QoL provided themes and domains that can be further developed into a tool for further evaluation of absorbent products. CONCLUSIONS: This study showed that there were significant and substantial differences between the designs of absorbent products and for moderate/heavy incontinence some designs are better for men/women than others. There was considerable individual variability in preferences and cost-effective management may best be achieved by allowing users to choose combinations of designs for different circumstances within a budget. Further research is needed into the feasibility of providing choice and combinations of designs to users, as well as into the development of more effective washables and of specifically male disposable products. QoL measurement tools are needed for users of absorbent products, as are clinical trials of designs for community-dwelling carer-dependent men and women with moderate/heavy incontinence.

Autonomic side effects of Botulinum toxin Type B intravesical injections: report of 4 cases and review of the literature.

Recently, intravesical injections of Botulinum toxin type B (BT-B) have been trialled in an attempt to treat detrusor overactivity. Use of Botulinum toxin A (BT.-A), for the same in the past, has been quite successful without many reported side effects. Soon after commencing the clinical use of BT-B, a side effect profile was noticed not reported with BT-A. A total of 20 patients with refractory detrusor overactivity were included in this randomized, double blind, placebo controlled, cross over trial. As per protocol, 5000 MU (1 ml) BT-B diluted to a volume of 20 mls with normal saline were injected in 10 different sites into the detrusor, sparing the trigone. We report four cases of autonomic side effects after these injections which strongly suggest clinically relevant systemic spread of the toxin.

Case series data to encourage randomized trials of bladder retraining compared to antimuscarinic agents.

PURPOSE: This study was designed to test the power potential of a number of different clinical trial designs that could be deployed to test the efficacy of an antimuscarinic drug against bladder retraining. MATERIALS AND METHODS: This was an observational cohort study. Data were collected prospectively from patients treated for an overactive bladder by antimuscarinic agents with bladder retraining, or by bladder retraining alone. At initiation and at followup data on frequency, incontinence, urgency and urge incontinence were collected. Data from visits up to 16 weeks of treatment were analyzed using the parametric methods.708 patients were studied, 44 males and 664 females, and their mean age was 54 (sd 22). 52 patients used pure bladder retraining and 656 used bladder retraining and an antimuscarinic agent. The drug was oxybutynin, tolterodine or imipramine combined with oxybutynin or tolterodine as combination therapy. RESULTS: A between groups analysis demonstrated that bladder retraining was associated with a greater improvement in urinary frequency compared to antimuscarinic therapy (Z = -4.6, 95% CI of difference -3.3, -1.4, p <0.001) whereas antimuscarinic therapy was associated with a greater improvement in incontinence compared to bladder retraining (Z = -2.6, 95% CI of difference -0.93, -0.27, p = 0.024). The within group change in incontinence episodes in the bladder retraining group did not appear to show an effect (95% CI of change -0.19, 0.43). A subgroup showing greatest DeltaInc was sought. Boxplots of DeltaInc against age group, sex and the grading of symptoms were examined for maximum effect. Female sex, age group of 50 or greater and patients describing urge incontinence demonstrated the greatest DeltaInc. Their mean daily frequency was 11.45 (sd 6.1) and incontinence 1.6 (sd 2.1). A sample with such characteristics would be most sensitive to treatment effect. The bladder retraining group had a higher daily frequency (Z = -3.2, p = 0.001, 95% CI for bladder retraining 10 to 11, 95% CI for antimuscarinic group 10 to 12) and a lower daily incontinence compared to the antimuscarinic group (Z = -3.4, p <0.001, 95% CI of median for bladder retraining 0.75, 0.85, 95% CI of median for antimuscarinic group 0.75, 1.75). CONCLUSIONS: Change in frequency is a poor outcome measure, DeltaInc is significantly superior. An antimuscarinic tested against bladder retraining, using DeltaInc for outcome, would probably compare favorably.

Effects of botulinum toxin B on refractory detrusor overactivity: a randomized, double-blind, placebo controlled, crossover trial.

PURPOSE: Open, observational studies of intradetrusor injections of botulinum toxin for detrusor overactivity have reported beneficial effects. We tested the efficacy and safety of botulinum toxin B for the treatment of the overactive bladder in a randomized, double-blind, placebo controlled crossover trial. MATERIALS AND METHODS: A total of 20 patients 18 to 80 years old with detrusor overactivity unresponsive to oral antimuscarinic agents participated in the study. They were injected with either placebo (20 ml normal saline) or botulinum toxin B (5,000 IU diluted up to 20 ml) intravesically in a day case setting. After 6 weeks the treatments were crossed over without washout in line with previous findings. The primary outcome was the paired difference in change in average voided volumes. Frequency, incontinence episodes and paired differences in quality of life measured by the King's Health Questionnaire were the secondary outcome measures. RESULTS: The Wilcoxon signed ranks test was used to test the paired difference in change between treatment phases. Little carryover was noted in the second arm placebo and the placebo data from both arms were included in analysis. There were clinically statistically significant paired differences in the change in average voided volume, urinary frequency and episodes of incontinence between active treatment and placebo (average voided volume: 95% CI difference 16, 122; Z2.5; p = 0.012/weekly frequency: 95% CI -21, -1; Z2.1, p=0.033/weekly incontinence: 95% CI -26, -7; Z3.3; p = 0.001). There were similarly significant paired differences in the change in quality of life affecting 5 domains of the King's Health Questionnaire. CONCLUSIONS: This double-blind, placebo controlled, crossover study provides evidence of the efficacy of botulinum toxin B in the treatment of overactive bladder. Autonomic side effects were observed in 4 patients. The short duration of action will presumably limit the use to patients who have experienced tachyphylaxis with botulinum toxin A.

Using the circumstances of symptom experience to assess the severity of urgency in the overactive bladder.

PURPOSE: We identified a method for quantifying the symptoms of the overactive bladder that addresses the assessment of urgency. MATERIALS AND METHODS: An observational study of a cohort was used. Data were collected prospectively from 5,423 consultations on 1,797 patients (158 males and 1,639 females) being assessed and treated for the overactive bladder. The study was conducted during 5 years. The reported frequencies and incontinence episodes were recorded. Using ranked ordinal scales (none, mild, moderate, severe) the symptoms of urgency and urge incontinence associated with waking and rising, hearing running water, arriving home ("latchkey"), cold weather and when feeling tired or worried were noted. The experiences of urgency and urge incontinence, without reference to the circumstances in which they were experienced were similarly assessed and if on treatment, they were asked to grade their overall response. RESULTS: Reported urinary frequency and incontinence episodes were strongly associated with patient grading of response to treatment. Therefore, the symptoms assessed on the scale of none, mild, moderate and severe were compared with disease severity by using reported frequency and incontinence episodes. The description of the symptoms with reference to the situations in which they were experienced showed clear associations with frequency and incontinence, falling along a progressive scale. An overall pattern could be detected in that at points on the scale of none, mild, moderate and severe, the least frequency and incontinence tended to be associated with waking, rising and latchkey symptoms. Next followed symptoms precipitated by running water and cold weather. Aggravation by fatigue or worry was associated with the greatest disease severity (ANOVA F = 8.9, p <0.001). This scale covered a wide range from frequencies of 7 to 15 times daily and incontinence episodes through 0 to 4 times daily. CONCLUSIONS: Qualifying the experience of urgency and urge incontinence, according to the circumstances in which these symptoms are experienced, seems to offer a promising new method for assessing the severity of urgency and urge incontinence.

EAU guidelines on chronic pelvic pain.

OBJECTIVES: On behalf of the European Association of Urology (EAU) guidelines for diagnosis, therapy and follow-up of chronic pelvic pain patients were established. METHOD: Guidelines were compiled by a working group and based on current literature following a systematic review using MEDLINE. References were weighted by the panel of experts. RESULTS: The full text of the guidelines is available through the EAU Central Office and the EAU website (www.uroweb.org). This article is a short version of this text and summarises the main conclusions from the guidelines on management of chronic pelvic pain. CONCLUSION: A guidelines text is presented including chapters on prostate pain and bladder pain syndromes, urethral pain, scrotal pain, pelvic pain in gynaecological practice, role of the pelvic floor and pudendal nerve, general treatment of chronic pelvic pain and neuromodulation. These guidelines have been drawn up to provide support in the management of the large and difficult group of patients suffering from chronic pelvic pain.

Pressure-flow variables in patients treated with tolterodine for detrusor overactivity.

OBJECTIVE: To test the hypothesis that drug treatment which modifies detrusor function (tolterodine) may influence the higher detrusor pressure at urethral opening and closure recorded in patients with detrusor overactivity than in those with stable bladders. PATIENTS AND METHODS: All patients treated with tolterodine in the treatment arm of a phase III, randomized, placebo-controlled trial of tolterodine were eligible for the study. Patients underwent urodynamics before and immediately after 4 weeks of therapy. The detrusor pressure at urethral opening, at maximum flow and at urethral closure, and the maximum bladder capacity and postvoid residual urine volume were recorded from matched urodynamic studies in the trial. Patients with a reduction in urinary frequency of more than two voids per 24 h were defined as responders to treatment and urodynamic data were dichotomised accordingly to allow comparison. RESULTS: There were no between-group differences in either the detrusor pressure at opening or closure when responders were compared with non-responders. Successful treatment was associated with a statistically significant change in bladder capacity and postvoid residual volume, although the change in residual volume was not clinically significant. Values of detrusor pressure at opening before treatment were greater in non-responders. CONCLUSION: The absence of changes in the pressure-flow plot variables is in keeping with previous studies reporting the search for a urodynamic variable which might be used to predict a favourable outcome after drug treatment.

Urodynamic verification of an overactive bladder is not a prerequisite for antimuscarinic treatment response.

OBJECTIVE: To investigate the place of urodynamics in the evaluation of patients with symptoms of the overactive bladder by comparing the response to antimuscarinic therapy in those with and with no urodynamically verified symptoms. PATIENTS AND METHODS: In a prospective observational study, 356 female patients with urinary frequency (> or = 8 voids/24 h) and urgency, with or without urge incontinence, underwent cystometry. Patients were diagnosed with detrusor instability if there were spontaneous, uninhibited increases in detrusor pressure during bladder filling. All patients, regardless of urodynamic findings, were subsequently treated with oxybutynin 2.5 mg twice daily and bladder retraining. The outcome was evaluated as the change in urinary frequency and incontinence episodes after 6-8 weeks of treatment. RESULTS: Among 352 evaluable patients, 266 (76%) had detrusor instability on cystometry and the remainder did not. There was no significant between-group difference in mean age, urinary frequency or the number of incontinence episodes at presentation. Both groups improved equally well during oxybutynin and bladder retraining therapy; after 6-8 weeks there was no significant between-group difference for the mean change from baseline in urinary frequency or incontinence episodes. Tolerability profiles were comparable for the two groups. CONCLUSION: Patients with symptoms of an overactive bladder, but apparently normal urodynamic findings, respond equally well to antimuscarinic therapy as those with urodynamically verified symptoms. Such findings cast further doubt on the clinical validity of using invasive urodynamic procedures to characterize patients with irritative lower urinary tract symptoms before starting antimuscarinic therapy.

Sheaths for urinary incontinence: a randomized crossover trial.

OBJECTIVE: To evaluate the full range of self-adhesive continence sheaths for men available in the UK and thus provide clinicians and consumers with a basis for product selection. PATIENTS AND METHODS: Fifty-eight volunteers (aged 30-89 years) tested each of six different self-adhesive sheaths available in the UK in September 1998 for 1 week each. Thirty subjects applied the sheaths themselves and 28 subjects relied on a carer to do so. During each week subjects completed a diary recording sheath changes and the result of skin inspection, to note any unscheduled sheath changes (because of sheath detachment) and any skin problems. At the end of each week an 11-item questionnaire was completed using a three-point rating scale ('good', 'acceptable', 'unacceptable') to assess the key aspects of product performance. RESULTS: A significantly higher proportion of subjects scored the 'Aquadry Clear Advantage' sheath as 'good' than four of the other sheaths (P < 0.01) and a significantly higher proportion found the 'Incare' sheath to be 'unacceptable' than all of the other sheaths (P < 0.001) for the 'overall opinion' question. Sheath detachments (sheath falling off or blowing off) for the 'Incare' were significantly more common than for four of the other products (P < 0.01). Sheath detachments for the 'Aquadry Clear Advantage' were significantly less common than for two of the other products (P < 0.01). A significantly higher proportion of subjects found sheaths with an applicator to be 'unacceptable' than sheaths with no applicator (P < 0.001) for the 'ease of putting on' and 'overall opinion' questions (when adjusted for previous product use and person applying the sheath). CONCLUSIONS: There were substantial differences between products in their general performance and ergonomics, and for the frequency of detachment as recorded in the diary. The 'Aquadry Clear Advantage' was particularly successful and the 'Incare' particularly unsuccessful when compared with the other sheaths. Sheaths with no applicators were preferred to those with applicators. Applicators are mainly designed to make sheaths easier to put on, especially for carers, but there was no evidence that carers preferred applicators. This may have implications for manufacturers.

Coated catheters for intermittent catheterization: smooth or sticky?

OBJECTIVE: To evaluate the current range of hydrophilic-coated catheters for intermittent self-catheterization, focusing on the adherence of the catheter to the urethral mucosa at the end of catheterization. PATIENTS AND METHODS: In a prospective randomized study, 61 community-based men tested each of four different hydrophilic-coated catheters available in the UK at the time. Subjects used each of the four test catheters for 1 week in a random order, and were provided with the number and size of catheter they normally used. To assess the products, the subjects: (i) timed seven catheterizations using a stop-watch to determine the time taken from extracting the catheter from the water-filled package, to removing the catheter from the penis, having emptied the bladder; (ii) recorded the severity of 'sticking' on catheter removal on a three-point scale (not at all, a little, a lot); and (iii) completed a product-performance questionnaire. RESULTS: There were no significant differences in ratings of 'sticking' between the 'Easicath' and 'Lofric' (P > 0.05), but there were significant differences between these two products and the 'Aquacath' and the 'Silky', which were found to 'stick' more (P < 0.001). The 'Silky' was reported to stick significantly more than the 'Aquacath' (P < 0.001). CONCLUSIONS: Adherence to the urethral mucosa on catheter removal was a common problem, occurring with all catheters, but two products were significantly more likely to stick than the other two. The clinical importance of 'sticking' and the long-term implications are currently unknown. The relative 'sticking' of uncoated catheters has also not been established.

Twelve-month treatment of overactive bladder: efficacy and tolerability of tolterodine.

CONTEXT: Tolterodine is a bladder-selective antimuscarinic agent designed for the treatment of overactive bladder. Traditional antimuscarinic therapies are poorly tolerated due to a high incidence of anticholinergic adverse events and consequently few patients remain on long term therapy. OBJECTIVE: To evaluate the long term efficacy and tolerability of tolterodine in patients with symptoms of overactive bladder. DESIGN: Twelve-month open-label extension of 4 randomised, placebo-controlled, double-blind, multinational, multicentre trials of 4 weeks' duration. PATIENTS: 714 patients (aged 18 to 92 years) with symptoms of overactive bladder who completed the double-blind portion of the studies. INTERVENTION: Tolterodine 2 mg twice daily for up to 12 months. MAIN OUTCOME MEASURES: Micturition diary variables: number of micturitions per 24 hours, number of urge incontinence episodes per 24 hours, mean urine volume voided per micturition. Safety variables: adverse events, study discontinuation rate. RESULTS: A total of 441 patients (62%) completed 12 months' open-label treatment with tolterodine, which significantly reduced the number of micturitions per 24 hours [mean change -2.4, 95% confidence interval (CI) -2.7 to -2.2, median change -20%, p < 0.0001] and number of urge incontinence episodes per 24 hours (mean change -1.3, 95% CI -1.6 to -1.0, median change -74%, p < 0.0001), while the mean volume voided per micturition was significantly increased (+33 ml, 95% CI +28 to +38, median change +18%; p < 0.0001). 41% of patients reported dry mouth (27% mild, 10% moderate, 3% severe). Dosage reduction to 1 mg twice daily was required in 23% of patients. 15% of patients withdrew from the study due to adverse events, with 5% having associated dry mouth. CONCLUSIONS: The high percentage of patients completing 12 months' treatment indicates that tolterodine is an effective and well tolerated agent for long term treatment of overactive bladder.

Tolterodine: a safe and effective treatment for older patients with overactive bladder.

OBJECTIVE: To investigate the clinical safety and efficacy of two dosages of tolterodine in older patients with symptoms attributable to overactive bladder. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group, multinational, phase III study. SETTING: Incontinence, older care, urological, and urogynecological clinics in the United Kingdom, France, and the Republic of Ireland. PARTICIPANTS: One hundred and seventy-seven older patients (age > or =65 years) with symptoms of urinary urgency, increased frequency of micturition (> or =8 micturitions/24 hours), and/or urge incontinence (> or =1 episode/24 hours). INTERVENTION: Tolterodine 1 mg or 2 mg twice daily (bid), or placebo, for 4 weeks. MEASUREMENTS: Safety and tolerability were evaluated through spontaneously reported adverse events, electrocardiogram, and blood pressure measurements. Efficacy was assessed using micturition diary variables: mean change from baseline in frequency of micturition and number of incontinence episodes/24 hours. RESULTS: The mean age of the patient population was 75 years. Overall, > or =87% of patients completed the study. Neither dosage of tolterodine was associated with serious drug-related adverse events during the study. No cardiac arrythmogenic events were noted. Dry mouth (mild to moderate intensity) was the most common adverse event in both the placebo and tolterodine treatment groups. Three percent of patients in the tolterodine 2 mg bid group discontinued treatment because of dry mouth, compared with 2% of placebo-treated patients. Compared with placebo, statistically significant decreases in micturition frequency were apparent in both tolterodine treatment groups. Furthermore, patients treated with tolterodine 2 mg bid had statistically significant decreases in urge incontinence episodes/24 hours and increases in volume voided per micturition compared with placebo. CONCLUSION: Tolterodine (taken for 4 weeks) is safe and shows efficacy, particularly at a dosage of 2 mg bid, in the treatment of older patients with urinary symptoms attributable to overactive bladder.

Tolterodine: superior tolerability than and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial.

PURPOSE: We compared the tolerability and clinical efficacy of tolterodine with those of oxybutynin in patients with an overactive bladder using an upward oxybutynin dose titration strategy analogous to that used in routine clinical practice in the United Kingdom and Republic of Ireland. MATERIALS AND METHODS: In a randomized double-blind trial 378 male and female patients 50 years old or older with symptoms of overactive bladder (a urinary frequency of 8 or more voids per 24 hours with urgency and/or urge incontinence, that is 1 or more urge incontinence episodes per 24 hours) received 10 weeks of treatment with 2 mg. tolterodine twice daily/or an initial dose of 2.5 mg. oxybutynin twice daily, increasing to 5 mg. twice daily after 2 weeks of treatment. The main outcome measures were changes in voiding diary variables combined with detailed tolerability-safety assessments. RESULTS: Patients treated with tolterodine had significantly fewer adverse events (69% versus 81%, p = 0.01), notably dry mouth (37% versus 61%, p <0.0001), as well as a lower incidence of dose reduction (6% versus 25%, p <0.0001) than those in the oxybutynin group. Each agent had comparable efficacy for improving urinary symptoms. Tolterodine and oxybutynin caused a significant decrease (p = 0.0001) in the mean number of voids per 24 hours (-1.7 or -15% and -1.7 or -15%, respectively), urge incontinence episodes per 24 hours (-1.3 or -54% and -1.8 or -62%, respectively) and mean voided volume per void (33 ml. or 22% and 34 ml. or 23%) after 10 weeks of treatment. CONCLUSIONS: Tolterodine is as effective as oxybutynin for improving the symptoms of overactive bladder but it has superior tolerability. The combination of these qualities makes tolterodine the preferred pharmacological therapy for the long-term treatment of this condition.

Rapid urinalysis assays for the diagnosis of urinary tract infection.

Urinary tract infection (UTI) in premenopausal women is a frequent complaint in general practice. UTI is usually diagnosed on the basis of clinical symptoms and the use of one or more laboratory tests, the most common being rapid urinalysis reagent assays (urine dip) or midstream urine culture. In order to correlate the leucocyte esterase results of a rapid urinalysis assay with direct urine microscopy for pyuria, undiluted non-centrifuged urine samples from 206 volunteer female healthcare professionals were subjected to analysis using direct urine microscopy using a counting chamber and a rapid urinalysis assay. Of the 206 specimens, 74 were positive for leucocyte esterase using the rapid urinalysis assay, and 39 specimens demonstrated significant pyuria (greater than or equal to 10 leucocytes/microl) on direct microscopy. When the leucocyte esterase results were correlated with the direct urine microscopy results, an assay reading of 15 leucocytes/microl ('trace' on the visual scale) had a sensitivity of 91%, specificity of 79%, positive predictive value of 53% and a negative predictive value of 97%. An assay reading of 25 leucocytes/microl ('+' on the visual scale) or greater had a sensitivity of 63%, specificity of 95%, positive predictive value of 75% and a negative predictive value of 91%. In premenopausal, non-pregnant females, a rapid urinalysis assay result of 25 leucocytes/microl or greater will predict significant pyuria on urine microscopy with reasonable confidence, thereby reducing the need for more costly urine cultures.

A randomized controlled trial comparing the efficacy of controlled-release oxybutynin tablets (10 mg once daily) with conventional oxybutynin tablets (5 mg twice daily) in patients whose symptoms were stabilized on 5 mg twice daily of oxybutynin.

OBJECTIVE: To compare the efficacy of a controlled-release (CR) formulation of oxybutynin with that of conventional oxybutynin in patients with detrusor instability or detrusor hyper-reflexia whose symptoms were stabilized on conventional oral oxybutynin tablets. PATIENTS AND METHODS: The study comprised a randomized, double-blind, parallel-group trial involving 130 patients drawn from 15 centres in the UK. The study was of 6 weeks' duration, i.e. 2 weeks of screening whilst taking conventional oxybutynin tablets (5 mg twice daily) followed by 4 weeks of double-blind treatment with either CR oxybutynin tablets (10 mg once daily) or conventional oxybutynin tablets (5 mg twice daily). Outcome measures were changes in 24-h frequency and 24-h incontinence episodes recorded throughout the study on diary charts. Adverse events were recorded by patients in their diary charts and serum concentrations of oxybutynin and its active metabolite, N-desethyloxybutynin, were measured at baseline and at completion of the study to detect possible drug accumulation. RESULTS: The treatments did not differ significantly in any of the outcome measures. The primary efficacy criterion was the daytime continence at completion of the study; 53% and 58% of patients were continent on CR and conventional oxybutynin treatments, respectively (the 95% confidence interval of the difference in the proportion being - 22% to 13%; P = 0.62). The total number of side-effects experienced by those patients receiving treatment with the CR formulation was 57% of that for patients receiving treatment with conventional oxybutynin. Individual side-effects showed a similar distribution within treatment groups. There was no evidence of the accumulation of oxybutynin or N-desethyloxybutynin during the multiple dosing of CR or conventional oxybutynin tablets. CONCLUSION: The CR and conventional formulations of oxybutynin did not differ in their efficacy, and the CR formulation was associated with fewer side-effects. In addition, CR oxybutynin appeared to maintain therapeutic blood levels over the 24 h dosing interval with no accumulation of oxybutynin or its active metabolite. Once-daily dosing with a CR tablet is seen as convenient for the patient and is expected to result in improved compliance in patients already stabilized on conventional oxybutynin treatment.

Overactive bladder: special considerations in the geriatric population.

Overactive bladder (OAB) is a highly prevalent condition among older patients, and its presence is associated with the use of substantial healthcare resources and economic costs. Within the next 30 years, it is expected that the demand for services related to OAB will increase dramatically. Treatment of OAB is challenging and depends on several factors, including the age of the patient, cognitive functioning, and the degree of mobility. Pharmacotherapy, such as the use of tolterodine and oxybutynin, is a viable option for the treatment of OAB, and muscarinic antagonists are commonly used. The efficacy of an agent may differ in older patients compared with younger ones. In addition, certain side effects can be particularly troublesome in the geriatric population. A retrospective analysis of a large managed care database showed an age-related increase in the number of women seeking care for OAB. Caring for incontinent patients in the long-term care setting was shown to result in substantial additional costs, which were higher in those with more frequent incontinent episodes. Prompted voiding may be effective in reducing the number of incontinent episodes for those in institutionalized care; however, this practice is labor intensive and generally is only effective in 40% of cases. Moreover, assistance with prompted voiding must be maintained continuously. Future research should focus on defining the most cost-effective methods of treating OAB in the long-term care setting.