Serum levels of prostate specific antigen, free PSA, [-2]proPSA, fPSA/tPSA ratio, Prostate Health Index, and glycosylation patterns of free PSA in patients with benign prostatic hyperplasia pharmacotherapy.

BACKGROUND: The medication used to treat benign prostate hyperplasia (BPH), a common condition in men over 50 years of age, can alter the levels of biomarkers used in prostate cancer detection. Commonly used medications for BPH include alpha-blockers, 5-alpha reductase inhibitors (5-ARIs), and muscarinic antagonists. We studied the impact of these drugs on total prostate-specific antigen (tPSA), free PSA (fPSA), [-2]proPSA, fPSA/tPSA ratio, and the Prostate Health Index (PHI), as well as novel potential biomarkers in the form of glycan composition of fPSA. PATIENTS AND METHODS: Serum samples were collected from 564 males with BPH, with a mean age of 68.5 years. The samples were used to measure levels of tPSA, fPSA, and [-2]proPSA. The fPSA/tPSA and PHI were then calculated. The glycan composition of fPSA was analyzed using lectin-based glycoprofiling. Pharmacotherapy data was collected from the patients' medical records. RESULTS: Alpha-blocker monotherapy was associated with higher fPSA and fPSA/tPSA ratio, and decreased PHI. Levels of tPSA were not impacted. Alpha-blocker and 5-ARI dual therapy was associated with reduced levels of fPSA, [-2]proPSA, and PHI. Therapy combining alpha-blockers and antimuscarinic agents did not significantly influence biomarker levels apart from an increase in a Maackia amurensis lectin-recognized glycan originating in fPSA. CONCLUSION: BPH pharmacotherapy notably affects prostate cancer biomarkers. Recognizing the impact of pharmacotherapy is crucial for achieving an accurate diagnosis of prostate cancer and for planning treatment.

Assessing the anticholinergic cognitive burden classification of putative anticholinergic drugs using drug properties.

AIMS: This study evaluated the use of machine learning to leverage drug absorption, distribution, metabolism and excretion (ADME) data together with physicochemical and pharmacological data to develop a novel anticholinergic burden scale and compare its performance to previously published scales. METHODS: Experimental and in silico ADME, physicochemical and pharmacological data were collected for antimuscarinic activity, blood-brain barrier penetration, bioavailability, chemical structure and P-glycoprotein (P-gp) substrate profile. These five drug properties were used to train an unsupervised model to assign anticholinergic burden scores to drugs. The model performance was evaluated through 10-fold cross-validation and compared with the clinical Anticholinergic Cognitive Burden (ACB) scale and nonclinical Anticholinergic Toxicity Scores (ATS) scale, which is based primarily on muscarinic binding affinity. RESULTS: In silico software (ADMET Predictor) used for screening drugs for their blood-brain barrier (BBB) penetration correctly identified some drugs that do not cross the BBB. The mean area under the curve for the unsupervised and ACB scale based on the five selected variables was 0.76 and 0.64, respectively. The unsupervised model agreed with the ACB scale on the classification of more than half of the drugs (49 of 88) agreed on the classification of less than half the drugs in the ATS scale (12 of 25). CONCLUSIONS: Our findings suggest that the commonly used ACB scale may misclassify certain drugs due to their inability to cross the BBB. By contrast, the ATS scale would misclassify drugs solely depending on muscarinic binding affinity without considering other drug properties. Machine learning models can be trained on these features to build classification models that are easy to update and have greater generalizability.

Comparative analysis of real-world adherence and persistence patterns with vibegron, mirabegron, and anticholinergics in patients with overactive bladder: A retrospective claims study.

INTRODUCTION: Vibegron is a selective ß3-adrenergic receptor agonist that was approved by the US Food and Drug Administration in December 2020 for the treatment of overactive bladder in adults. This retrospective study assessed US pharmacy claims data to evaluate the real-world adherence and persistence of vibegron compared with mirabegron and with anticholinergics. MATERIALS AND METHODS: This analysis used the Optum Research Database to identify adults with ≥1 pharmacy claim for vibegron, mirabegron, or an anticholinergic from April 1, 2021, to August 31, 2022. Patients had ≥ 90 days of continuous commercial or Medicare medical and pharmacy coverage preindex and ≥ 60 days of continuous pharmacy coverage postindex. Two independent propensity-score models matched patients treated with (1) vibegron versus mirabegron and (2) vibegron versus anticholinergics on key variables such as demographics and clinical characteristics, index copay, days' supply, and time of entry into analysis (index quarter). Adherence was measured by proportion of days covered (PDC) from index to the end of follow-up and was defined as PDC ≥ 80%. Persistence was defined as days to discontinuation of index medication (first 30-day gap) or end of follow-up. RESULTS: The matched vibegron and mirabegron cohorts included 4921 and 9842 patients, respectively, and the matched vibegron and anticholinergic cohorts included 4676 and 9352 patients, respectively. Patients receiving vibegron had greater mean PDC versus patients receiving mirabegron (0.67 vs. 0.64, respectively; p < 0.001) or anticholinergics (0.67 vs. 0.58; p < 0.001). A greater percentage of patients receiving vibegron were adherent versus those receiving mirabegron (49.0% vs. 45.1%, respectively; p < 0.001) or anticholinergics (49.1% vs. 38.5%; p < 0.001). Persistence was longer with vibegron compared with both mirabegron (median [95% CI], 171 [159-182] vs. 128 [122-137] days, respectively; p < 0.001) and anticholinergics (172 [159-183] vs. 91 [91] days; p < 0.001). CONCLUSION: In this retrospective analysis of pharmacy claims data, patients receiving vibegron exhibited significantly higher adherence and demonstrated longer persistence in comparison to matched patient cohorts receiving either mirabegron or anticholinergics.

What is the best first choice oral drug therapy for OAB?

AIMS: The management of overactive bladder (OAB) involves lifestyle changes and conservative measures in the first instance with the use of liquid/dietary advice, weight loss, and bladder training. Thereafter oral pharmacotherapy is instigated in symptomatic patients. Antimuscarinics and beta 3 agonists form the main classes of drug therapy in this field. Views on what is the best first line OAB treatment is changing based on recent evidence and adverse event profiles of these medications. METHODS: At the ICI-RS meeting 2023, Bristol, UK this topic was discussed and debated as a proposal. The following article summarizes the concepts presented that day as well as the interactive discussion that took place thereafter. RESULTS: OAB guidelines are moving in many circumstances to an either antimuscarinic or beta 3 agonist approach based on patient factors. Several studies have raised concerns on the long-term impact of antimuscarinics, in relation to cognition, dementia, cardiovascular events, and mortality all related to antimuscarinic load. Neither antimuscarinics nor beta 3 agonists have good persistence and adherence rates in the medium to long term. Several barriers also exist to prescribing including guidelines recommending utilizing drugs with the lowest acquisition cost and "step therapy." A newer approach to managing OAB is personalized therapy in view of the many possible etiological factors and phenotypes. These concepts are highlighted in this article. CONCLUSIONS: Current oral pharmacotherapy in managing OAB is limited by adverse events, adherence and persistence problems. Both antimuscarinics and beta 3 agonists are efficacious but most clinical trials demonstrate significant placebo effects in this field. Personalizing treatment to the individual seems a logical approach to OAB. There is a need for better treatments and further studies are required of existing treatments with high quality longer term outcomes.

Study design of a phase 4, real-world study (COMPOSUR) to evaluate vibegron in patients with overactive bladder.

BACKGROUND: Overactive bladder (OAB) is defined as urinary urgency accompanied by frequency and nocturia, with or without urge urinary incontinence (UUI). Vibegron, a selective ß3-adrenergic receptor agonist approved in the US in December 2020, demonstrated efficacy in reducing symptoms of OAB and was safe and well tolerated in the 12-week EMPOWUR trial and its 40-week, double-blind extension trial. The goal of the COMPOSUR study is to evaluate vibegron in a real-world setting to assess patient treatment satisfaction, tolerability, safety, duration of treatment, and persistence. METHODS: This is a 12-month, prospective, observational, real-world study, with an optional 12-month extension to 24 months, in the US assessing adults ≥ 18 years old starting a new course of vibegron. Patients must be previously diagnosed with OAB with or without UUI, symptomatic for ≥ 3 months before enrollment, and receive prior treatment with an anticholinergic, with mirabegron, or with a combination of an anticholinergic and mirabegron. Enrollment is performed by the investigator following exclusion and inclusion criteria guided by US product labeling, reinforcing a real-world approach. Patients complete the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q) monthly and the OAB Questionnaire short form (OAB-q-SF) and Work Productivity and Activity Impairment Questionnaire (WPAI:US) at baseline and monthly for 12 months. Patients are followed up via phone call, in-person visits, or telehealth (ie, virtual) visits. The primary endpoint is patient treatment satisfaction as determined by the OAB-SAT-q satisfaction domain score. Secondary endpoints include percent positive responses to individual OAB-SAT-q questions, additional OAB-SAT-q domain scores, and safety. Exploratory endpoints include adherence and persistence. DISCUSSION: OAB leads to a significant decrease in quality of life, as well as impairment of work activities and productivity. Persistence with OAB treatments can be challenging, often due to lack of efficacy and adverse effects. COMPOSUR is the first study to provide long-term, prospective, pragmatic treatment data for vibegron in the US and the resultant effect on quality of life among patients with OAB in a real-world clinical setting. Trial registration ClinicalTrials.gov identifier: NCT05067478; registered: October 5, 2021.

Shortages of agents used to treat antimuscarinic delirium.

INTRODUCTION: Antimuscarinic delirium (AD), a potentially life-threatening condition frequently encountered by emergency physicians, results from poisoning with antimuscarinic agents. Treatment with physostigmine and benzodiazepines is the mainstay of pharmacotherapy, and use of dexmedetomidine and non-physostigmine centrally-acting acetylcholinesterase inhibitors (cAChEi) such as rivastigmine has also been described. Unfortunately, these medications are subject to drug shortages which negatively impact the ability to provide appropriate pharmacologic treatment of patients with AD. METHODS: Drug shortage data were retrieved from the University of Utah Drug Information Service (UUDIS) database from January 2001 through December 2021. Shortages of first-line agents used to treat AD (physostigmine and parenteral benzodiazepines) and second-line agents (dexmedetomidine and non-physostigmine cAChEi) were examined. Drug class, formulation, route of administration, reason for shortage, shortage duration, generic status, and whether the drug was a single-source product (made by only one manufacturer) were extracted. Shortage overlap and median shortage durations were calculated. RESULTS: Twenty-six shortages impacting drugs used to treat AD were reported to UUDIS from January 1, 2001 to December 31, 2021. Median shortage duration for all medication classes was 6.0 months. Four shortages were unresolved at the end of the study period. The single medication most often on shortage was dexmedetomidine, however benzodiazepines were the most common medication class on shortage. Twenty-five shortages involved parenteral formulations, and one shortage involved the transdermal patch formulation of rivastigmine. The majority (88.5%) of shortages involved generic medications, and 50% of products on shortage were single-source. The most common reported reason for shortage was a manufacturing issue (27%). Shortages were often prolonged and, in 92% of cases, overlapped temporally with other shortages. Shortage frequency and duration increased during the second half of the study period. CONCLUSION: Shortages of agents used in the treatment of AD were common during the study period and affected all agent classes. Shortages were often prolonged and multiple shortages were ongoing at study period end. Multiple concurrent shortages involving different agents occurred, which could hamper substitution as a means of mitigating shortage. Healthcare stakeholders must develop innovative patient- and institution-specific solutions in times of shortage and work to build resilience into the medical product supply chain to minimize future shortages of drugs used for treatment of AD.

The association between anticholinergic burden and mobility: a systematic review and meta-analyses.

BACKGROUND: As people age, they accumulate several health conditions, requiring the use of multiple medications (polypharmacy) to treat them. One of the challenges with polypharmacy is the associated increase in anticholinergic exposure to older adults. In addition, several studies suggest an association between anticholinergic burden and declining physical function in older adults. OBJECTIVE/PURPOSE: This systematic review aimed to synthesise data from published studies regarding the association between anticholinergic burden and mobility. The studies were critically appraised for the strength of their evidence. METHODS: A systematic literature search was conducted across five electronic databases, EMBASE, CINAHL, PSYCHINFO, Cochrane CENTRAL and MEDLINE, from inception to December 2021, to identify studies on the association of anticholinergic burden with mobility. The search was performed following a strategy that converted concepts in the PECO elements into search terms, focusing on terms most likely to be found in the title and abstracts of the studies. For observational studies, the risk of bias was assessed using the Newcastle Ottawa Scale, and the Cochrane risk of bias tool was used for randomised trials. The GRADE criteria was used to rate confidence in evidence and conclusions. For the meta-analyses, we explored the heterogeneity using the Q test and I2 test and the publication bias using the funnel plot and Egger's regression test. The meta-analyses were performed using Jeffreys's Amazing Statistics Program (JASP). RESULTS: Sixteen studies satisfied the inclusion criteria from an initial 496 studies. Fifteen studies identified a significant negative association of anticholinergic burden with mobility measures. One study did not find an association between anticholinergic intervention and mobility measures. Five studies included in the meta-analyses showed that anticholinergic burden significantly decreased walking speed (0.079 m/s ± 0.035 MD ± SE,95% CI: 0.010 to 0.149, p = 0.026), whilst a meta-analysis of four studies showed that anticholinergic burden significantly decreased physical function as measured by three variations of the Instrumental Activities of Daily Living (IADL) instrument 0.27 ± 0.12 (SMD ± SE,95% CI: 0.03 to 0.52), p = 0.027. The results of both meta-analyses had an I2 statistic of 99% for study heterogeneity. Egger's test did not reveal publication bias. CONCLUSION: There is consensus in published literature suggesting a clear association between anticholinergic burden and mobility. Consideration of cognitive anticholinergic effects may be important in interpreting results regarding the association of anticholinergic burden and mobility as anticholinergic drugs may affect mobility through cognitive effects.

Treatment of Ureteral Stent-Related Symptoms.

BACKGROUND: The aim of the study was to assess the effectiveness of the main classes of drugs used at reducing morbidity related to ureteric stents. SUMMARY: After establishing a priori protocol, a systematic electronic literature search was conducted in July 2019. The randomized clinical trials (RCTs) selection proceeded in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and was registered (PROSPERO ID 178130). The risk of bias and the quality assessment of the included RCTs were performed. Ureteral Stent Symptom Questionnaire (USSQ), International Prostate Symptom Score (IPSS), and quality of life (QoL) were pooled for meta-analysis. Mean difference and risk difference were calculated as appropriate for each outcome to determine the cumulative effect size. Fourteen RCTs were included in the analysis accounting for 2,842 patients. Alpha antagonist, antimuscarinic, and phosphodiesterase (PDE) inhibitors significatively reduced all indexes of the USSQ, the IPSS and QoL scores relative to placebo. Conversely, combination therapy (alpha antagonist plus antimuscarinic) showed in all indexes of the USSQ, IPSS, and QoL over alpha antagonist or antimuscarinic alone. On comparison with alpha blockers, PDE inhibitors were found to be equally effective for urinary symptoms, general health, and body pain parameters, but sexual health parameters improved significantly with PDE inhibitors. Finally, antimuscarinic resulted in higher decrease in all indexes of the USSQ, the IPSS, and QoL relative to alpha antagonist. KEY MESSAGE: Relative to placebo, alpha antagonist alone, antimuscarinics alone, and PDE inhibitors alone have beneficial effect in reducing stent-related symptoms. Furthermore, there are significant advantages of combination therapy compared with monotherapy. Finally, PDE inhibitors are comparable to alpha antagonist, and antimuscarinic seems to be more effective than alpha antagonist alone.

SUFU white paper on overactive bladder anticholinergic medications and dementia risk.

AIMS: Anticholinergic medications are widely used in the treatment of overactive bladder (OAB), as well as for short-term treatment of bladder symptoms following a variety of urologic surgeries. Mounting evidence points to an association between anticholinergic medications and the increased risk of incident dementia. The Society for Urodynamics, Female Pelvic Medicine, and Urogenital Reconstruction (SUFU) thus convened a committee of subject experts to contextualize the current understanding of the cognitive risks of anticholinergic medications in the urologic patient population and to provide practical clinical guidance on this subject. METHODS: Statements are based on an expert literature review and the committee's opinion. The document has been reviewed and approved by the SUFU board. RESULTS: Chronic use (>3 months) of OAB anticholinergic medications is likely associated with an increased risk of new-onset dementia. Short-term (<4 weeks) use of most OAB anticholinergic medications is likely safe in most individuals. Clinicians should consider potential cognitive risks in all patient populations when prescribing OAB anticholinergics for chronic use. Consideration should be given to progressing to advanced therapy (botulinum toxin or neuromodulation) earlier in the OAB treatment paradigm CONCLUSIONS: The current body of literature supports a likely small but significant increased risk of dementia with chronic exposure to OAB anticholinergic medications. Potential harms should be balanced against potential quality of life improvement with treatment.

Clinical preferences and treatment attitudes among urologists, gynecologists, and geriatricians: An independent online questionnaire survey for comparison of treatment choices in the management of overactive bladder.

OBJECTIVE: Overactive bladder (OAB) is a common clinical problem with associated morbidities both in men and women. Although real-life management strategies have been examined among urologists (URO), treatment choices may differ between different specialties. In the present study, an online survey was conducted to determine and compare the management strategies and clinical preferences of UROs, obstetricians/gynecologists (OB/GYN), and geriatricians (GER) in the treatment of OAB in their daily practices. METHODS: Between December 2020 and February 2021, an online questionnaire was sent to URO, OB/GYN, and GER specialists/residents. Current strategies and attitudes toward treatment of OAB in patients <65 years were compared between URO and OB/GYN, whereas the responses were compared between all three specialties in patients ≥65 years. RESULTS: A total of 733 specialists/physicians (433 URO, 236 OB/GYN, and 64 GER) completed the online survey. Patients with OAB were more likely to present to URO compared to OB/GYN and GER (p = 0.001). A combination of behavioral modification and pharmacotherapy (antimuscarinics and/or beta-3 agonists) were chosen for the initial treatment of patients with OAB in both specialties with a significantly higher proportion by URO than by OB/GYN (51.9% vs. 38.1%; p = 0.001). Antimuscarinics were the most frequently prescribed medications by both the URO and OB/GYN specialties (81.8% vs. 78.4%; p = 0.27). Combination therapy with antimuscarinics was preferred more often by URO (91.5% vs. 77.1%; p = 0.001) when no or an inadequate response after initial treatment occurred. Multiple medication use, comorbidities, and risk of cognitive side effects affected medication preference by all specialists, especially by GER (p = 0.018). CONCLUSIONS: Patients with OAB present to UROs, OB/GYN and GER more frequently compared to other specialities. Although antimuscarinics and beta-3 adrenoceptor agonists are equally recommended as first-line pharmacotherapy for OAB, antimuscarinics were preferred for most patients as the initial molecule by all specialties. Beta-3 agonists are increasingly preferred for elderly patients.

Unintentional cetirizine overdose causing anticholinergic syndrome.

The incidence of anticholinergic syndrome due to second generation antihistamines is infrequently reported. Largely due to their decreased affinity for central nervous system (CNS) receptors, second generation antihistamines are rarely associated with anticholinergic symptoms, though toxicity is still possible particularly when taken in excess. We report a case of a six year old boy who presented with agitation, hallucinations, fixed and dilated pupils, tachycardia, and hyperthermia consistent with anticholinergic toxicity several hours after accidental overdose of a second generation antihistamine, cetirizine. Early identification of this rare phenomenon is important not only for appropriate emergency management but also for avoidance of potentially invasive and unnecessary tests which may further increase patient morbidity.

Impact of Bladder Wall Thickness on the Outcomes of Antimuscarinic Treatment in Women with Overactive Bladder.

AIM: This study aimed to evaluate the effect of bladder wall thickness (BWT) (using transabdominal ultrasound) on the outcomes of antimuscarinic treatment in women with overactive bladder. METHODS: A total of 102 female patients with symptoms of OAB were recruited. All patients completed the Overactive Bladder version 8 (OAB-V8) (Arabic validation) and the International Consultation of Incontinence Questionnaire (ICIQ-SF). Patients completed the urodynamic study (UDS) including uroflowmetry and PVR and measures of BWT by transabdominal ultrasound. The patients were classified into 2 major groups: G1 (patients with BWT <5 mm) and G2 (patients with BWT ≥5 mm). The patients were re-evaluated after 3-month medication with solifenacin 10-mg oral tablet. RESULTS: At baseline, the results of OAB-V8 and ICIQ-SF were significantly higher in G2 than G1 (p < 0.001). Regarding UDS, volume at 1st desire to void, volume at strong desire to void, and MBC were significantly higher in group 1 compared to group 2 (p = 0.001). Intravesical pressure at strong desire and patients' number of DO were significantly increased in G2 (p < 0.05 and p = 0.001, respectively). After treatment, there was an improvement in both groups regarding OAB-V8, ICIQ-SF, bladder volume at 1st desire to void, bladder volume at strong desire to void, bladder volume at DO, MBC, intravesical pressure at strong desire, and the patients' number with DO (decreased), and these improvements were statistically significant in group 1 compared to group 2 (p < 0.05). CONCLUSION: BWT showed a significant association with both OAB symptom scores and UDS parameters. The decrease in BWT is associated with a significantly higher response to solifenacin therapy regarding the UDS results.

Baseline anticholinergic burden from medications predicts poorer baseline and long-term health-related quality of life in 16 675 men and women of EPIC-Norfolk prospective population-based cohort study.

PURPOSE: Previous studies investigating the association between anticholinergic burden (ACB) and health-related quality of life (HRQoL) showed conflicting results and focused on older adults or specific patient groups only. METHODS: Participants from the European Prospective Investigation of Cancer-Norfolk study were divided into three groups according to their ACB from medications at baseline, representing ACB scores of 0, 1 and ≥2. Outcomes of interest were the physical and mental component summary scores (PCS and MCS) of the Short Form-36, collected at 18 months from the baseline and again after a mean 13 years of follow-up. Linear regression and logistic regression for cross-sectional and longitudinal associations between ACB and HRQoL were constructed adjusting for potential confounders. RESULTS: A total of 16 675 participants, mean age 58.9 ± 9.1 years (55.6% female) and 7133 participants, mean age at follow-up 69.1 ± 8.7 years (56.8% female), were included in the cross-sectional and longitudinal analyses, respectively. In cross-sectional analysis, higher anticholinergic burden was associated with higher odds of being in the lowest quartile of PCS (ACB = 1; OR, 1.85[1.64, 2.09] and ACB ≥ 2:2.19[1.85, 2.58] and MCS (ACB = 1:1.47[1.30, 1.66] and ACB ≥ 2:1.68[1.42, 1.98]). In longitudinal analysis, higher anticholinergic burden was similarly associated with higher odds of being in the lowest quartile of PCS (ACB = 1:1.56[1.24, 1.95] and ACB ≥ 2:1.48[1.07, 2.03]) compared with ACB 0 group. The association with MCS scores did not reach statistical significance. CONCLUSION: The use of anticholinergic medications is associated with both short and long-term poorer physical functions but association with mental functioning appears more short-term.

Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial.

BACKGROUND AND OBJECTIVE: Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). METHODS: Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. RESULTS: The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H2 O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. CONCLUSION: Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.

A systematic review of neurocognitive dysfunction with overactive bladder medications.

INTRODUCTION AND HYPOTHESIS: The aim of this study is to report cognitive dysfunction with commonly used antimuscarinic overactive bladder medications in patients suffering from overactive bladder disorder with and without baseline neurologic conditions. METHODS: We conducted an Ovid MEDLINE, Embase, and PsycINFO search from January 1998 to December 2018 using PRISMA guidelines. Eighteen studies met the inclusion criteria, including 5 randomized controlled trials and 13 observational studies. RESULTS: Cognitive decline was reported with oxybutynin use (5 of 8 studies) and tolterodine use (4 of 7 studies) among patients with and without baseline cognitive impairment. Oxybutynin use was linked to functional, mental, and behavioral decline among patients with Alzheimer's disease (2 studies). No cognitive decline was detected among patients with and without baseline cognitive impairment taking trospium (6 studies), darifenacin (3 studies), imidafenacin (2 studies), and fesoterodine (1 study). Solifenacin was not associated with cognitive decline (2 studies) but was linked to an increased risk of dementia among patients with diabetes (1 study). CONCLUSION: In this review, cognitive decline was reported with oxybutynin and tolterodine use and should be used with caution in adults over 65 years of age. Solifenacin, fesoterodine, and imidafenacin showed mixed results related to central nervous system effect. Trospium and darifenacin were not associated with cognitive decline among patients with and without baseline cognitive impairment.

Is imidafenacin an alternative to current antimuscarinic drugs for patients with overactive bladder syndrome?

PURPOSE: Previous studies have included a limited number of randomized controlled trials (RCTs) and compared limited parameters after treatment with imidafenacin and other anticholinergic drugs (ADs) for overactive bladder syndrome (OAB), and controversy about the superiority of these ADs still remains. We aim to update the evidence and provide better clinical guidance. METHODS: A systematic search of PubMed, Embase, ClinicalTrial.gov and Cochrane Library Central Register of Controlled Trials was conducted from January 2007 to April 2019. Meta-analysis of all published RCTs comparing imidafenacin with other ADs in patients with OAB was performed. The primary outcomes were the changes in OAB symptoms and OAB symptom score (OABSS). Secondary outcomes included adverse events (AEs) and the dropout rate related to AEs. RESULTS: A total of 6 studies including 7 RCTs involving 1430 patients with mean follow-up of 23.43 weeks were included. All ADs improved OAB symptoms. Regarding efficacy, these drugs had similar efficacy in voids, urgency episodes, urgency incontinence episodes, incontinence episodes and OABSS. However, imidafenacin performed better in the reduction of nocturia episodes (MD = -0.24, 95% CI -0.44 to -0.04, P = 0.02). Moreover, imidafenacin was associated with a statistically lower dry mouth rate (RR = 0.87, 95% CI 0.75-1.00, P = 0.04), lower constipation rate (RR = 0.68, 95% CI 0.50-0.93, P = 0.01) and lower AE-related withdrawal rate (RR = 0.51, 95% CI 0.29-0.89, P = 0.02). There was no significant difference in terms of other complications. CONCLUSIONS: In conclusion, imidafenacin was comparable to other ADs in the treatment of OAB. Moreover, imidafenacin presented a lower dry mouth rate, lower constipation rate and higher adherence and persistence.

[Overactive bladder in a complicated patient: which drug to choose?]

A literature review, including 60 national and foreign publications, was carried out. The review focuses on aspects of the pathogenesis and pathophysiology of overactive bladder (OAB). The effect of OAB on a woman's sexual function is described, as well as the features of OAB treatment in comorbid patients and complications of using anticholinergics drugs. The analysis showed that currently available drugs are highly effective, but have some adverse effects. A combination of various M-anticholinergics or M-anticholinergic drugs with -blockers or 3-adrenoceptor agonists can be used. Trospium chloride is preferrable drug for older patients, especially with cognitive impairment and dementia, as well as for patients receiving drugs metabolized by the cytochrome P450 for concomitant diseases or those with bladder tuberculosis.

[Charasteristics of the treatment of urinary disorders in postmenopausal women].

INTRODUCTION: Overactive bladder syndrome (OAB) is very common. It has been shown that urge incontinence is more difficult for women than for men, sinse they have higher levels of stress, depression, and more pronounced sexual dysfunction. MATERIAL AND METHODS: The study included 47 patients aged 54.6+/-3.5 years with symptoms of OAB. The Overactive Bladder Symptom Score (OABSS) was used to assess the symptoms, while the sexual function of the patients was evaluated using the Female Sexual Dysfunction Index (FSFI). In addition, Mini Mental State Examination (MMSE) scale was used for assessing the cognitive function. In comparison group there were 22 women who were comparable in socio-demographic characteristics, but didnt have symptoms of OAB. The comparison between two groups was carried out using FSFI scale. Patients in the OAB group were prescribed trospium chloride (Spazmex) 15 mg b.i.d. for three months, after which the patients completed the OABSS, FSFI, and MMSE questionnaires again. RESULTS: All patients with OAB reported sexual dysfunction, which was significantly more profound than in the control group. The FSFI scores were, respectively, 15.23+/-6.12 versus 22.46+/-5.47. The average assessment of the cognitive abilities of patients with OAB was 27.9+/-1.4, which indicates that their cognitive functions were completely intact. The mean score on the OABSS scale was 11.8+/-2.7, and 11 women (23.4%) had a mild OAB, and 36 (76.6%) had moderate severity of symptoms. After three months of therapy, the mean score on the OABSS scale decreased by half, to an average of 5.4+/-1.2 points; the overall score of the FSFI approached the level of healthy women (20.64 and 22.46, respectively). The repeated assessment of the mental status did not reveal any changes, since the mean score of MMSE was 27.8+/-1.3. No significant adverse events were noted in any case. None of the patients required dose adjustment of the drugs that they received for concomitant diseases. CONCLUSION: All women with OAB syndrome had decreased sexual function compared to healthy women of the same age and social status. A three-month course of trospium chloride (Spazmex), 30 mg daily, significantly improved both the parameters of urination and the sexual function, without having any adverse effect on their cognitive abilities. Moreover, there was no need to adjust the doses of drugs taken for concomitant diseases.

Risk of Mortality Associated with Non-selective Antimuscarinic medications in Older Adults with Dementia: a Retrospective Study.

BACKGROUND: Selective antimuscarinics may offer a favorable safety profile over non-selective antimuscarinics for the management of overactive bladder (OAB) in patients with dementia. OBJECTIVE: To test the hypothesis that non-selective antimuscarinics are associated with increased risk of mortality compared to selective antimuscarinics in older adults with dementia and OAB. DESIGN: Propensity score-matched retrospective new-user cohort design among Medicare beneficiaries in community settings. PATIENTS: Older adults with dementia and OAB with incident antimuscarinic use. MAIN MEASURES: The primary exposure was antimuscarinic medications classified as non-selective (oxybutynin, tolterodine, trospium, fesoterodine) and selective (solifenacin, darifenacin) agents. All-cause mortality within 180 days of incident antimuscarinic use formed the outcome measure. New users of non-selective and selective antimuscarinics were matched on propensity scores using the Greedy 5 → 1 matching technique. Cox proportional-hazards model stratified on matched pairs was used to evaluate the risk of mortality associated with the use of non-selective versus selective antimuscarinics in the sample. KEY RESULTS: The study identified 16,955 (77.6%) non-selective antimuscarinic users and 4893 (22.4%) selective antimuscarinic users. Propensity score matching yielded 4862 patients in each group. The unadjusted mortality rate at 180 days was 2.6% (126) for non-selective and 1.6% (78) for selective antimuscarinic users in the matched cohort (p value < 0.01). The Cox model stratified on matched pairs found 50% higher risk of 180-day mortality with non-selective antimuscarinics as compared to selective ones (hazard ratio (HR) 1.50; 95% confidence interval (CI) 1.04-2.16). The study findings remained consistent across multiple sensitivity analyses. CONCLUSIONS: Use of non-selective antimuscarinics was associated with a 50% increase in mortality risk among older adults with dementia and OAB. Given the safety concerns regarding non-selective antimuscarinic agents, there is a significant need to optimize their use in the management of OAB for older patients with dementia.

Treatment patterns and costs among patients with OAB treated with combination oral therapy, sacral nerve stimulation, percutaneous tibial nerve stimulation, or onabotulinumtoxinA in the United States.

INTRODUCTION: Treatment patterns and costs were characterized among patients with overactive bladder (OAB) receiving later-line target therapies (combination mirabegron/antimuscarinic, sacral nerve stimulation [SNS], percutaneous tibial nerve stimulation [PTNS], or onabotulinumtoxinA). METHODS: In a retrospective cohort study using 2013 to 2017 MarketScan databases, two partially overlapping cohorts of adults with OAB ("IPT cohort": patients with incident OAB pharmacotherapy use; "ITT cohort," incident target therapy) with continuous enrollment were identified; first use was index. Demographic characteristics, treatment patterns and costs over the 24-month follow-up period were summarized. Crude mean (standard deviation [SD]) OAB-specific (assessed by OAB diagnostic code or pharmaceutical dispensation record) costs were estimated according to target therapy. RESULTS: The IPT cohort comprised 54 066 individuals (mean [SD] age 58.5 [15.0] years; 76% female), the ITT cohort, 1662 individuals (mean [SD] age 62.8 [14.9] years; 83% female). Seventeen percent of the IPT cohort were treated with subsequent line(s) of therapy after index therapy; among those, 73% received antimuscarinics, 23% mirabegron, and 1.4% a target therapy. For the ITT cohort, 32% were initially treated with SNS, 27% with onabotulinumtoxinA, 26% with combination mirabegron/antimuscarinic, and 15% with PTNS. Subsequently, one-third of this cohort received additional therapies. Mean (SD) costs were lowest among patients receiving index therapy PTNS ($6959 [$7533]) and highest for SNS ($29 702 [$26 802]). CONCLUSIONS: Costs for SNS over 24 months are substantially higher than other treatments. A treatment patterns analysis indicates that oral therapies predominate; first-line combination therapy is common in the ITT cohort and uptake of oral therapy after procedural options is substantial.