Assessment of Urothelial Cytotoxicity at Morphological and Molecular Levels: Urinary Bladder as Target Organ.

The urinary bladder is a target organ of several toxic agents. Exposure to those agents induces mild-to-severe changes, which can be evaluated by different methods. Among them, the scanning-electron microscopy (SEM) is the "gold standard" for characterizing urothelial damage since it provides high-definition images, making it possible to detect early lesions on the surface of the urinary bladder. In addition, molecular technologies allow detecting changes in genetic material and investigating the interaction between genes and environmental stress in disease causation. The urinary bladder epithelium is where the most common type of bladder cancer occurs in humans, that is, the transitional-cell carcinoma (TCC). In animal models, the TCC can be similar to the disease in humans. Techniques to evaluate urothelium in experimental models aid in the comprehension of risk factors for urothelial carcinogenesis.

Contemporary Patterns of Third-line Treatments for Privately Insured Individuals With Overactive Bladder in the United States.

OBJECTIVE: To evaluate utilization of third-line overactive bladder (OAB) treatments including percutaneous tibial nerve stimulation (PTNS), sacral nerve stimulation (SNS), and intradetrusor botulinum toxin A (BTX) among privately insured patients and examine factors associated with their use. MATERIALS AND METHODS: Using MarketScan claims (2015-2017), we identified patients who underwent third-line OAB treatments based on procedure codes. Factors of interest included location, age, health plan, among others. We fit multivariable logistic regression models to estimate associations between pertinent factors with receipt of PTNS and SNS relative to BTX and associations between provider type and practice location with each treatment modality. RESULTS: We identified 7383 patients (mean age 50.9) in our cohort. SNS was used most frequently (n = 3602, 48.8%), while PTNS was used least frequently (n = 955, 12.9%). PTNS patients were more likely to reside in metropolitan areas (vs BTX: OR 1.6, 95%CI 1.3-2.1; vs SNS: OR 2.2, 95%CI 1.7-2.8), be aged 55 years or older (vs BTX: 54% vs 47%, OR 1.6, 95%CI 1.2-2.1; vs SNS: 54% vs 45%, OR 1.6, 95%CI 1.2-2.0), and be covered under a health maintenance organization (vs BTX: 17% vs 10%; vs SNS: 17% vs 10%, P <.01). Urologists were most likely to perform SNS, and gynecologists were most likely to perform BTX. 91% of PTNS procedures were performed in office settings. CONCLUSION: Among patients receiving third-line OAB treatment, PTNS was used infrequently. PTNS utilization was concentrated within urban areas, and among older patients and those covered by cost-conscious health maintenance organizations.

Assessment of Inhibitory Effects of Hypnotics on Acetylcholine-Induced Contractions in Isolated Rat Urinary Bladder Smooth Muscle.

The present study aimed to investigate the potential inhibitory effects of 21 clinically available hypnotics on acetylcholine (ACh)-induced contractions in rat urinary bladder smooth muscle (UBSM) in order to predict whether these hypnotics could induce voiding impairment. ACh-induced contraction in rat UBSM was inhibited only by diphenhydramine (a histamine H1 receptor antagonist) at a concentration that was clinically relevant. ACh-induced contraction was also significantly inhibited by flurazepam (a benzodiazepine hypnotic) and suvorexant (an orexin receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. These three drugs (at 10-5 M) also inhibited high-KCl (80 mM) Locke-Ringer solution-induced contractions. In contrast to the effects of the abovementioned hypnotics, ACh-induced contractions were not significantly affected by triazolam, etizolam, brotizolam, lormetazepam, estazolam, flunitrazepam, nitrazepam (benzodiazepine hypnotics), thiopental, thiamylal, pentobarbital, amobarbital, secobarbital, phenobarbital (barbiturate hypnotics), zolpidem (an imidazopyridine hypnotic), zopiclone (a cyclopyrrolone hypnotic), ramelteon (a melatonin receptor agonist), bromovalerylurea, and chloral hydrate. These findings suggest that most clinically used hypnotics are not likely to result in anticholinergic-induced dysuria within their clinically achievable blood concentration ranges. Diphenhydramine may, however, induce voiding impairment, an action attributable to diminished UBSM contractility within its clinical dose range.

[ypT0N0 after neoadjuvant chemotherapy and cystectomy for muscle-invasive bladder cancer: Incidence and prognosis. A review from the Bladder group of the French Committee of Oncology]. / Pièce opératoire ypT0N0 après séquence chimiothérapie néo-adjuvante ­ cystectomie pour TVIM : épidémiologie et impact pronostique. Une mise au point du CCAFU Vessie.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is recommended for localized muscle-invasive bladder cancer when patients are fit for cisplatin-based chemotherapy. A pathological complete response can be observed, corresponding to ypT0N0 stage on the radical cystectomy specimen. This review discusses the incidence, prognosis and potential therapeutic impact of complete response on pathological specimen in NAC treated patients. METHODS: A comprehensive review of the literature was conducted using Medline database, with no time frame. The articles were selected using the following keywords association: "Bladder cancer" (Mesh) AND "Neoadjuvant chemotherapy" (Mesh) AND "pT0" (Mesh). RESULTS: After NAC, ypT0N0 rates vary from 9 to 46% among the series, reported rates that are higher compared to those of pT0 without NAC administration. The incidence depends on the chemotherapy regimen (maximal local effect with cisplatin-based chemotherapy) and the pathological type of the disease (presence of variant histologies). Molecular analyses of bladder cancer could probably help in the near future to identify and predict NAC responders. Pathological complete response is associated with a favorable prognosis in terms of recurrence-free and overall survival. Nevertheless, disease recurrences are still observed in 10-15% of cases, which underlies the importance of local treatment and close follow-up even in these patients. CONCLUSION: ypT0N0 rate is approximately 25% after NAC, that is 4.3 higher than after bladder resection alone. The prognosis is better than that with residual tumor on specimen and is comparable to that of pT0 without NAC administration.

MORPHOLOGICAL ASSESSMENT OF NO-SYNTHASE DISTRIBUTION IN OVERACTIVE BLADDER AND STRESS URINE INCONTINENCE IN ANIMAL MODELS ADMINISTERED WITH EXPERIMENTAL PHARMACOCORRECTION REGIMENS.

The objective of the study was immunohistochemical evaluation of distribution of various NO synthase fractions in the structural elements of the bladder wall under stress urinary incontinence and its overactivity prior and post Mirabegron, Spasmex, Quercetin therapies and their combinations with Testosterone and Estradiol. Using the immunohistochemical method, we studied the expression of the main fractions of NO synthase in experimental models of hyperactive bladder (OAB) and stress urinary incontinence (SUI). We found that OAB and SUI were characterized by emergence of expression of the inducible fraction (iNOS) predominantly in the interstitial cells of the muscular layer of the bladder and reduced expression of endothelial (eNOS) and neuronal (nNOs) NO synthase fractions. In contrast to Spasmex, Mirabegron and Quercetin in combination with Testosterone and Estradiol contributed to stabilization of eNOS and nNOs expression already at early observation phases, and reduced the level of iNOS expression with its further disappearance in the later observation period.

An investigation of factors predicting the type of bladder antimuscarinics initiated in Medicare nursing homes residents.

BACKGROUND: To examine factors predicting type of bladder antimuscarinics (BAM) initiated in nursing home (NH) residents. METHODS: Incident BAM initiators following NH admission were identified by constructing a retrospective cohort from Medicare files and Minimum Data Set (MDS). Participants included all residents 65 years and older admitted in Medicare-certified NH between January 1, 2007 and December 31, 2008 who were prescribed BAM and had continuous Medicare (Part A, B, and D) enrollment. Patient characteristics, medications, and comorbidities were derived from Medicare enrollment and claims. NH characteristics and health status were derived from MDS assessments. The outcome was defined as type of BAM initiated after admission (selective, non-selective extended release, non-selective immediate release). Multinomial logistic regression using generalized estimating equation methodology determined which factors predicted the type of BAM initiated. RESULTS: Twelve thousand eight hundred ninety-nine NH residents initiating BAM therapy were identified; 13.38% of new users were prescribed selective BAM, 45.56% non-selective extended release, and 41.07% non-selective immediate release medications. In both sexes, significant predictors of BAM included region of nursing home, body mass index, cognitive performance score, frailty measures, activities of daily living, and measures of bladder continence. In women, history of fracture and fall-related injuries were significant predictors of type of BAM use, while race and indicators of balance were significant predictors of type of BAM use in men. Non-pharmacological continence management strategies were not predictive of type of BAM initiation. CONCLUSIONS: Several factors are important in predicting type of BAM initiation in both women and men, but other factors are sex-specific. Some observed factors predicting the type of BAM initiated, such as other medications use, body mass index, or provider-related factors are potentially modifiable and could be used in targeted interventions to help optimize BAM use in this population. TRIAL REGISTRATION: Not applicable.

Large-scale Retrospective Monte Carlo Dosimetric Study for Permanent Implant Prostate Brachytherapy.

PURPOSE: To retrospectively compare water-based and full tissue model Monte Carlo dose calculations in a large cohort of patients undergoing 125I permanent implant prostate brachytherapy. METHODS AND MATERIALS: For 613 patients, EGSnrc BrachyDose dose calculations were performed in 2 virtual patient models: TG43sim (simulated American Association of Physicists in Medicine Task Group Report 43 conditions) and MCref (computed tomography-derived heterogeneous tissue model with interseed effects). A sensitivity analysis was performed in a patient subset (25 with and 25 without prostatic calcifications) to explore dose calculation dependence on organ-at-risk (OAR) and calcification tissue elemental compositions and modelling approach. RESULTS: In the target volume, the minimum radiation dose delivered to 90% of prostate (D90) (volume of prostate receiving at least 100% of prescription dose [V100]) was lower with MCref than with TG43sim by 5.9% ± 1.6% (2.6% ± 1.7%), on average. Patients with prostatic calcifications can have substantial underdosed volumes due to calcification shielding, lowering the D90 by ≤25%. In the urethra, the average D5 (D30) was lower with MCref than with TG43sim by 4.4% ± 1.8% (4.7% ± 1.9%). In the rectum (bladder), the minimum dose to the hottest 0.1 cm3 (D_0.1cm3) of the contoured organ was lower (higher) with MCref than with TG43sim by 5.2% ± 1.8% (1.3% ± 1.8%). Doses to the target and OARs can increase or decrease by several percentages, depending on the assumed tissue elemental composition. In patients with calcifications, differences between approaches to model calcifications can change the target and OAR dose metrics by upward of 10%. CONCLUSIONS: TG43sim typically overestimates the target and OAR doses by several percentages, on average, compared with MCref. The considerable variation in the relative TG43sim and MCref doses between patients, and the larger dose differences for patients with calcification, suggests that clinical adoption of Monte Carlo dose calculations for permanent implant prostate brachytherapy should be pursued. The substantial sensitivity of the Monte Carlo dose calculations to the patient modelling approach supports the adoption of a consensus modelling scheme, such as MCref described in the present study, to ensure consistency of practice.

A randomized, open-label, multicenter study of the efficacy and safety of intravesical hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in women with bladder pain syndrome/interstitial cystitis.

AIMS: Intravesical instillation of hyaluronic acid (HA) plus chondroitin sulfate (CS) in women with bladder pain syndrome/interstitial cystitis (BPS/IC) has shown promising results. This study compared the efficacy, safety, and costs of intravesical HA/CS (Ialuril® , IBSA) to dimethyl sulfoxide (DMSO). METHODS: Randomized, open-label, multicenter study involving 110 women with BPS/IC. The allocation ratio (HA/CS:DMSO) was 2:1. Thirteen weekly instillations of HA (1.6%)/CS (2.0%) or 50% DMSO were given. Patients were evaluated at 3 (end-of-treatment) and 6 months. Primary endpoint was reduction in pain intensity at 6 months by visual analogue scale (VAS) versus baseline. Secondary efficacy measurements were quality of life and economic analyses. RESULTS: A significant reduction in pain intensity was observed at 6 months in both treatment groups versus baseline (P < 0.0001) in the intention-to-treat population. Treatment with HA/CS resulted in a greater reduction in pain intensity at 6 months compared with DMSO for the per-protocol population (mean VAS reduction 44.77 ± 25.07 vs. 28.89 ± 31.14, respectively; P = 0.0186). There were no significant differences between treatment groups in secondary outcomes. At least one adverse event was reported in 14.86% and 30.56% of patients in the HA/CS and DMSO groups, respectively. There were significantly fewer treatment-related adverse events for HA/CS versus DMSO (1.35% vs. 22.22%; P = 0.001). Considering direct healthcare costs, the incremental cost-effectiveness ratio of HA/CS versus DMSO fell between 3735€/quality-adjusted life years (QALY) and 8003€/QALY. CONCLUSIONS: Treatment with HA/CS appears to be as effective as DMSO with a potentially more favorable safety profile. Both treatments increased health-related quality of life, while HA/CS showed a more acceptable cost-effectiveness profile.

Comprehensive Assessment of Compliance with Antimuscarinic Drug Treatment in the Case of Urge Urinary Incontinence of Older Patients.

AIM: To investigate the heterogeneous factors affecting the stability of patients older than 60 years in the UI treatment with Antimuscarinics. BACKGROUND: The prevalence of Urge Incontinence (UI) in older persons reaches 29.3%. The symptoms of urinary incontinence in older people reduce the health related life quality. MATERIALS AND METHODS: In 1257 patients over 60 years (857 (68.2%) women - average age 67.8, 400 (31.8%) men - 71.4), who received AM for one year, demographic, socio-economic and health parameters were studied. OABq-SF questionnaires, MOS SF-36, urination diaries, uroflowmetry, income information from the tax offices and outpatient records were used. RESULT: The compliance to AM treatment within 6 months was retained in 44.2%, and within the year - 26.8% of older patients. At least 40% of the total number of patients refused to continue the treatment for medical reasons. The persons taking Solifenacin (p≤ 0.01), Trospium (p≤ 0.05), or Darifenacin (p≤ 0.05), suffering from severe UI symptoms (p≤ 0.01), and experiencing minor side effects (p≤ 0.01), well-informed about UI treatment methods (p≤ 0.01) prevailed among the treatment compliant patients. At least 20.4% of the patients discontinued their treatment due to economic reasons. The persons with significantly larger annual income (p≤ 0.05) and annual medical cost (p≤ 0.01) prevailed among the treatment compliant patients. About 12.2% of the patients stopped their treatment for reasons related to the social background and psychological status. CONCLUSION: In this experiment, we found that AM treatment compliance in older patients, in addition to medical parameters and health conditions, is largely affected by the economic as well as social, demographic and psychological factors. The study results can be claimed by practitioners involved in correcting UI symptoms in older people.

Noninvasive Evaluation of Bladder Wall Mechanical Properties as a Function of Filling Volume: Potential Application in Bladder Compliance Assessment.

PURPOSE: We propose a novel method to monitor bladder wall mechanical properties as a function of filling volume, with the potential application to bladder compliance assessment. The proposed ultrasound bladder vibrometry (UBV) method uses ultrasound to excite and track Lamb waves on the bladder wall from which its mechanical properties are derived by fitting measurements to an analytical model. Of particular interest is the shear modulus of bladder wall at different volumes, which we hypothesize, is similar to measuring the compliance characteristics of the bladder. MATERIALS AND METHODS: Three experimental models were used: 1) an ex vivo porcine model where normal and aberrant (stiffened by formalin) bladders underwent evaluation by UBV; 2) an in vivo study to evaluate the performance of UBV on patients with clinically documented compliant and noncompliant bladders undergoing UDS; and 3) a noninvasive UBV protocol to assess bladder compliance using oral hydration and fractionated voiding on three healthy volunteers. RESULTS: The ex vivo studies showed a high correlation between the UBV parameters and direct pressure measurement (R2 = 0.84-0.99). A similar correlation was observed for 2 patients with compliant and noncompliant bladders (R2 = 0.89-0.99) undergoing UDS detrusor pressure-volume measurements. The results of UBV on healthy volunteers, performed without catheterization, were comparable to a compliant bladder patient. CONCLUSION: The utility of UBV as a method to monitor changes in bladder wall mechanical properties is validated by the high correlation with pressure measurements in ex vivo and in vivo patient studies. High correlation UBV and UDS in vivo studies demonstrated the potential of UBV as a bladder compliance assessment tool. Results of studies on healthy volunteers with normal bladders demonstrated that UBV could be performed noninvasively. Further studies on a larger cohort are needed to fully validate the use of UBV as a clinical tool for bladder compliance assessment.

What is the role of combination drug therapy in the treatment of overactive bladder? ICI-RS 2014.

AIMS AND METHODS: The role of combination therapy using oral antimuscarinic medications for the treatment of overactive bladder was proposed at the 2014 International Consultation on Incontinence-Research Society in Bristol, UK to identify key factors to consider when making clinical decisions and to guide future research design. RESULTS: Combination therapy is justified if monotherapy is associated with suboptimal efficacy or bothersome side effects. Combination therapy has the potential to improve efficacy with fewer side effects than monotherapy. Two Phase 2 studies comparing combination therapy that included an antimuscarinic demonstrated improvement in mean voided volume, the primary outcome chosen, with some combinations showing improved micturition frequency and quality of life. The two studies found no evidence of an increased safety risk with combination therapy compared to monotherapy. Future studies should use clinically meaningful or patient reported outcomes such as incontinence episodes when comparing efficacy. If surrogate measures are used, a clear justification should be provided. Cost analyses should be planned for clinical research trials evaluating combination drug therapy. CONCLUSIONS: Combination therapy is reasonable when monotherapy has suboptimal efficacy or bothersome side effects. Future research studies evaluating combination therapy for urgency urinary incontinence should ideally(1) be performed as part of a randomized clinical trial,(2) evaluate non-responders to monotherapy,(3) evaluate combination therapy using medications with different mechanisms of action,(4) include clinically meaningful and patient reported outcomes when evaluating efficacy, and(5) include cost-effectiveness analyses to justify any increased cost by showing improvement in efficacy or reduction in side effects.

Pharmacological methods for the preclinical assessment of therapeutics for OAB: an up-to-date review.

INTRODUCTION: Licenced oral pharmacotherapies for overactive bladder (OAB) act on muscarinic receptors or ß3-adrenoceptors. The search for new drugs to treat OAB that have novel mechanisms of action is very active, with the aim of discovering more effective and/or better tolerated agents. METHODS: A literature review of the most frequently used pharmacological methods for the preclinical assessment of new agents aimed at treating OAB, such as isolated organ technique, electrophysiological techniques, radioligand binding assay, and animal models, was carried out. Novel potential developments based on recent knowledge of urothelial and neural mechanisms are also discussed. RESULTS: The isolated organ technique, electrophysiological techniques, and the radioligand binding assay are very effective methods for the demonstration that a novel pharmacological target with a specific and high affinity binding site for a new drug is present in the bladder and its modulation regulates functions critical for the pathophysiology of OAB. Afterward, the new drug should be shown to be effective in animal models of OAB, although the translational value of these models is limited by a poor pathophysiological relationship with human OAB. Exciting novel perspectives focusing in particular on the theory of the mucosal-bladder network have recently opened new paths in the discovery and assessment of new therapeutics in this field. CONCLUSIONS: Available experimental models still play a central role in the appraisal of OAB therapeutics; however, their shortcomings and the paucity of very effective drugs indicate the need for new models that better reproduce the pathophysiological features of OAB. Some emerging lines of research show promise. A change of perspective in the future evaluation of putative drugs is required, especially in the light of the latest knowledge on the key role of the mucosal-bladder network and the brain-bladder neural pathways.

Cost-Effectiveness of Mirabegron Compared with Antimuscarinic Agents for the Treatment of Adults with Overactive Bladder in the United Kingdom.

BACKGROUND: Mirabegron, a first-in-class selective oral ß3-adrenoceptor agonist, has similar efficacy to most antimuscarinic agents and a lower incidence of dry mouth in patients with overactive bladder (OAB). OBJECTIVES: To evaluate the cost-effectiveness of mirabegron 50 mg compared with oral antimuscarinic agents in adults with OAB from a UK National Health Service perspective. METHODS: A Markov model including health states for symptom severity, treatment status, and adverse events was developed. Cycle length was 1 month, and the time horizon was 5 years. Antimuscarinic comparators were tolterodine extended release, solifenacin, fesoterodine, oxybutynin extended release and immediate release (IR), darifenacin, and trospium chloride modified release. Transition probabilities for symptom severity levels and adverse events were estimated from a mirabegron trial and a mixed treatment comparison. Estimates for other inputs were obtained from published literature or expert opinion. Quality-adjusted life-years (QALYs) and total health care costs, including costs of drug acquisition, physician visits, incontinence pad use, and botox injections, were modeled. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Base-case incremental cost-effectiveness ratios ranged from £367 (vs. solifenacin 10 mg) to £15,593 (vs. oxybutynin IR 10 mg) per QALY gained. Probabilistic sensitivity analyses showed that at a willingness-to-pay threshold of £20,000/QALY gained, the probability of mirabegron 50 mg being cost-effective ranged from 70.2% versus oxybutynin IR 10 mg to 97.8% versus darifenacin 15 mg. A limitation of our analysis is the uncertainty due to the lack of direct comparisons of mirabegron with other agents; a mixed treatment comparison using rigorous methodology provided the data for the analysis, but the studies involved showed heterogeneity. CONCLUSIONS: Mirabegron 50 mg appears to be cost-effective compared with standard oral antimuscarinic agents for the treatment of adults with OAB from a UK National Health Service perspective.

A re-assessment of treatment with a tyrosine kinase inhibitor (imatinib) on tissue sparing and functional recovery after spinal cord injury.

This study was undertaken as part of the NIH "Facilities of Research Excellence-Spinal Cord Injury" project to support independent replication of published studies. Here, we repeat key parts of a study reporting that rats treated with imatinib (Gleevec®, Novartis) after spinal cord contusion injury exhibited enhanced bladder function, greater recovery of motor function, and increased tissue sparing. Young adult female SCA Sprague-Dawley rats received moderate contusion injuries at T9-T10 using the MASCIS weight drop device. One group (n=16) received oral doses of imatinib 30min after injury and then daily doses for 5days. A control group (n=18) received vehicle. Motor function was assessed with the BBB locomotor rating scale and a contact plantar placement task. Bladder function was assessed by measuring the amount of urine retained in the bladder. Tissue preservation was assessed by immunostaining and stereological analysis. Rats that received imatinib had lower volumes of retained urine, suggesting improved bladder function, but there were no significant differences in motor function on any of the other tasks. Tissue preservation was assessed by immunostaining and stereological analysis. Quantitative analysis of spared tissue, cyst size, spared white matter, and inflammatory cell invasion revealed no significant differences between imatinib treated and control rats. Taken together our results confirm the findings that treatment with imatinib improves bladder function after SCI but fail to replicate findings of improved motor function, enhanced tissue sparing, and decreased inflammatory cell invasion.

Anticholinergic drugs for adult neurogenic detrusor overactivity: a systematic review and meta-analysis.

CONTEXT: There is a lack of evidence about the efficacy and safety of anticholinergic drugs and about the optimal anticholinergic drug, if any, for the treatment of adult neurogenic detrusor overactivity (NDO). OBJECTIVE: Review the current evidence on the efficacy, safety, and tolerability of anticholinergic drugs in the treatment of adult NDO. EVIDENCE ACQUISITION: A literature search was conducted from 1966 to May 2011. Meta-analysis of all published randomised controlled trials (RCTs) comparing anticholinergic drugs with placebo and comparing different types, doses, and routes of administration of anticholinergic drugs, in adults with NDO, was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. The primary outcome was patient-reported cure/improvement of overactive bladder symptoms. Secondary outcomes were quality of life (QoL) changes, bladder diary events, urodynamic outcomes, adverse events, and costs to health services. EVIDENCE SYNTHESIS: A total of 960 patients from 16 RCTs with mean follow-up of 3.8 wk were included. Anticholinergic drugs were associated with statistically significantly better patient-reported cure/improvement (risk ratio: 2.80; 95% confidence interval [CI], 1.64 to 4.77), higher maximum cystometric capacity (weighted mean difference [WMD]: 49.49; 95% CI, 15.38 to 84.20), higher volume at first contraction (WMD: 49.92; 95% CI, 20.06 to 79.78), and lower maximum detrusor pressure (WMD: -38.30; 95% CI, -53.17 to -23.43) when compared with placebo. The dry-mouth rates were statistically significantly higher with anticholinergics, with no difference in withdrawals because of adverse events. There was no statistically significant difference in any of the outcomes between oxybutynin and other anticholinergics or among different doses and preparations of anticholinergic drugs. No study reported QoL changes or costs to health services. CONCLUSIONS: Compared with placebo, anticholinergic treatment in patients with NDO is associated with better patient-reported cure/improvement and significant reduction of maximum detrusor pressure; however, there is a higher incidence of adverse events. None of the anticholinergic drugs or different dosages assessed in this review was superior to another.

A re-assessment of the effects of treatment with an epidermal growth factor receptor (EGFR) inhibitor on recovery of bladder and locomotor function following thoracic spinal cord injury in rats.

This study was undertaken as part of the NIH "Facilities of Research Excellence-Spinal Cord Injury" project to support independent replication of published studies. Here, we repeat an experiment in which rats that received an inhibitor of the epidermal growth factor receptor (EGFR) exhibited greater sparing/recovery of bladder and motor function and enhanced sparing at the lesion site after contusion injuries at the thoracic level. Young adult female Sprague-Dawley rats received moderate contusions with the NYU impactor (10 g from 12.5 mm, 2 mm rod diameter), and then were implanted with catheters attached to osmotic minipumps for intra-spinal delivery of either PD168393 dissolved in 5% DMSO and HBSS or vehicle alone. Motor function was assessed with the Basso, Beattie, and Bresnahan Locomotor Rating Scale (BBB) and with a grid walk task. Bladder function was assessed by measuring the amount of urine retained in the bladder. Tactile sensitivity was assessed using von Frey hairs and heat and cold sensitivity were assessed by testing hindlimb sensitivity to ethylchloride spray and a hotplate respectively. Rats that received PD168393 were more impaired on motor assessments and also showed greater bladder impairment (larger amounts of retained urine) than rats that received vehicle. These results thus fail to confirm previous studies reporting enhanced recovery following treatment with PD168393.

Pharmacotherapy for overactive bladder: minimally invasive treatment -- botulinum toxins.

INTRODUCTION: Considered by many a 'revolution' in the treatment of intractable overactive bladder (OAB) and with an increasing number of centers including it in their practice worldwide, botulinum neurotoxin A (BoNT/A) injected into the bladder wall is a treatment of significant potential. In anticipation of the results of multicenter, placebo-controlled, dose-ranging studies, this is a critical review of the available literature on the use of botulinum toxins in the treatment of either neurogenic or idiopathic OAB. AREAS COVERED: The review is based on the English-language literature published by Medline on the use of botulinum toxins in neurogenic or idiopathic detrusor overactivity/OAB since the seminal publication in 2000. The reader is exposed to the cumulative data as well as to a more critical insight on the clinical efficacy of single and repeat injections of the most widely used formulations, the injection techniques, including different doses, dilutions and injection sites, the mechanism of action, the side effects and the cost-effectiveness of the treatment. EXPERT OPINION: Despite the markedly heterogeneous methodologies, published studies suggest that BoNT/A is effective when a number of outcomes are considered, and is considered safe. As results of large registration studies are awaited, additional research on the optimization of clinical practice parameters such as benefit-risk ratio, injection technique, predictors of response and long-term safety, as well as on the mechanism of action and the cost-effectiveness of the treatment, would be welcome.