Anticholinergic deprescribing: A case report demonstrating improved cognition and function with minimal adverse withdrawal effects.

Anticholinergic-induced cognitive impairment may be partially reversible upon cessation. A barrier to deprescribing of anticholinergics is the unknown risk of anticholinergic adverse drug withdrawal events (ADWE), with only limited information available on the incidence, timing and severity of anticholinergic ADWE. We report the case of a 76-year-old woman who experienced significant cognitive improvement following deprescribing long-term use of a strong anticholinergic drug, doxepin, and dose reduction of another possible anticholinergic agent. The patient decided to abruptly stop taking doxepin, despite a planned careful taper with twice weekly monitoring, but did not experience any severe anticholinergic ADWE and subsequently had significantly improved cognitive function. Future research should focus on better understanding the risk of anticholinergic ADWE so that anticholinergic deprescribing decisions, including how often and by how much to taper, can be made confidently and safely.

Treatment of Anticholinergic Delirium with Oral Rivastigmine: A Case Report.

BACKGROUND: Anticholinergic toxicity is commonly encountered in the emergency department. However, the availability of physostigmine, a central acetylcholinesterase inhibitor used to reverse anticholinergic delirium, has been significantly limited due to national drug shortages in the United States. Several articles have explored the viability of rivastigmine as an alternative treatment in these patients. CASE REPORT: A 33-year-old man presented to the emergency department after a suspected suicide attempt. The patient was found with an empty bottle of diphenhydramine at the scene. On arrival, he was tachycardic and delirious, with dilated and nonreactive pupils and dry skin. As the clinical picture was highly suggestive of anticholinergic toxicity, the patient was treated with oral rivastigmine at a starting dose of 4.5 mg to reverse his anticholinergic delirium. Although a repeat dose was required, his delirium resolved without recurrence. Why Should an Emergency Physician Be Aware of This? Oral rivastigmine has been applied successfully here and in other case reports to reverse anticholinergic delirium with the benefit of prolonged agitation control. Emergency physicians may consider this medication in consultation with a specialist, with initial doses starting at 4.5-6 mg, if encountering anticholinergic delirium when physostigmine is not available.

A delayed treatment model for the evaluation of scopolamine for VX nerve agent intoxication.

Most research on medical countermeasures for nerve agent exposure assumes a military scenario, in which (autoinjector) treatment is envisaged to be available immediately. In a civilian setting however, treatment is delayed until arrival of first-aid responders. This may significantly affect treatment efficacy and the requirements for secondary intensive care. The aim of the current study was to develop a guinea pig model to evaluate the efficacy of delayed treatment following nerve agent exposure. We identified a trigger-to-treat based on a progressive stage of the toxidrome following VX exposure, which was associated with the subsiding of clonic movements. This paradigm resulted in treatment consistently being administered between 15 and 25 min post-exposure. Using the model, we investigated the potential for the anticholinergic scopolamine to act as a delayed treatment either as a standalone treatment, or as an adjunct to delayed treatment with Standard of Care (SOC), containing atropine, 2-PAM, and midazolam. The study provides a framework for a small animal model for evaluating the efficacy of treatment administered at a specific stage of the toxidrome, when immediate treatment is absent. As an adjunct, scopolamine treatment did not result in improved survival, but did show a beneficial effect on recovery, in terms of general posture. As a standalone treatment, scopolamine showed a significant, dose-responsive, beneficial effect on survival and recovery. These promising results warrant additional studies to investigate which observed physiological improvements are relevant for the recovery process and residual injury.

Real-world effectiveness of early intervention with fixed-dose tiotropium/olodaterol vs tiotropium in Japanese patients with COPD: a high-dimensional propensity score-matched cohort analysis.

BACKGROUND: Escalation to triple therapy (long-acting muscarinic antagonist/ß2-agonist, inhaled corticosteroid [ICS]) in chronic obstructive pulmonary disorder (COPD) is recommended for patients on LAMA/LABA combinations with frequent exacerbations and severe symptoms. An extended time-to-escalation to triple therapy suggests patients are in a stable condition and is an indicator of treatment effectiveness. No studies in Japanese clinical practice have compared the effectiveness of LAMA/LABA fixed-dose combination therapies with LAMA monotherapy in terms of time-to-escalation to triple therapy. The primary objective of this real-world study in Japan was to compare time-to-escalation to triple therapy among new users of tiotropium/olodaterol or tiotropium monotherapy for COPD without asthma. METHODS: In this active-comparator cohort study, new users of tiotropium/olodaterol (n = 1436) and tiotropium monotherapy (n = 5352) were identified from a large Japanese hospital-based database (Medical Data Vision Co., Ltd., Tokyo; prespecified study period: 1 April 2015 to 31 March 2019); patients in each group were matched 1:1 using high-dimensional propensity scores (hdPS). The primary outcome was time-to-escalation to triple therapy. RESULTS: For the prespecified study period in the hdPS-matched cohort, escalation to triple therapy was infrequent among new users of tiotropium/olodaterol (n = 1302, 7 escalation events) and tiotropium monotherapy (n = 1302, 8 escalation events). The difference in time-to-escalation to triple therapy between groups was not statistically significant (median [interquartile range]: 28 days [15.0-139.2] for tiotropium monotherapy vs 193 days [94.5-302.0] for tiotropium/olodaterol; hazard ratio: 0.89; 95% CI: 0.32-2.46). Similar findings (hazard ratio: 0.71; 95% Cl: 0.36-1.40) were observed in a post hoc analysis, which extended the study period by 1 year to 31 March 2020. Risks of first moderate and/or severe COPD exacerbation were lower for tiotropium/olodaterol than tiotropium monotherapy (between-group differences not significant). There were no significant between-group differences for the risks of all-cause inpatient mortality, major adverse cardiovascular events, and first use of home oxygen therapy. CONCLUSIONS: ICS monotherapy or ICS/LABA added to tiotropium or tiotropium/olodaterol is limited in Japanese clinical settings. The number of escalations to triple therapy was very limited in the dataset and there was insufficient power to detect differences between the treatment groups in the primary hdPS-matched cohort.

Ambulatory Heart Rate Variability in Schizophrenia or Depression: Impact of Anticholinergic Burden and Other Factors.

BACKGROUND: Heart rate variability (HRV) has been found reduced in patients with schizophrenia and depression. However, there is a lack of knowledge on how demographic, lifestyle, and pharmacological factors contribute to the reduction in HRV in these patients. METHODS: We recruited 37 patients with schizophrenia, 43 patients with unipolar depression, and 64 healthy controls. A combined chest-worn HRV and accelerometer device was used in an ambulatory measurement. Age, sex, anticholinergic burden of medication, nicotine use, body mass index, and ongoing physical activity were assessed in multiple regression models regarding their influence on HRV, measured as the standard deviation of all the RR intervals (SDNN). RESULTS: In the fully adjusted model, schizophrenia (ß = -0.23, P = 0.019), depression (ß = -0.18, P = 0.028), age (ß = -0.34, P < 0.000), ongoing physical activity (ß = -0.23, P = 0.001), and anticholinergic burden (ß = -0.19, P = 0.025) influenced SDNN negatively. Sex, nicotine use, and BMI had negligible effects on SDNN. CONCLUSIONS: We show for the first time that a quantified score of anticholinergic burden of medication has a negative relationship to HRV in patients with schizophrenia or depression, but that the diagnoses themselves still exhibit an effect on HRV.

B3 agonists or anticholinergics in the treatment of the lower urinary tract dysfunction in patients with multiple sclerosis?-A randomized study.

INTRODUCTION AND OBJECTIVE: Multiple sclerosis (MS) is the most frequent autoimmune demyelinating disease of the central nervous system. MS patients usually present with lower urinary tract dysfunction (LUTD). Objective of this study is to evaluate and compare the efficacy and safety of treating MS patients with LUTD with either a b3 agonist (mirabegron) or anticholinergics. The study's primary outcome is the LUTD symptom improvement. MATERIAL AND METHODS: This is a multi-center, single-blinded, comparative study including 91 MS patients with LUTD. At baseline, patients underwent thorough clinical examination, urine cultivation and abdominal ultrasound and completed urination diaries and specific, validated questionnaires (NBSS, MusiQoL). At second visit, patients were administered either mirabegron or anticholinergics. Treatment was always carried out alongside with MS treatment. Reevaluation was performed 3 months after first visit. Patients underwent the same clinical and imaging tests that were carried out at first visit. RESULTS: We compared several clinical and imaging parameters between the two groups at first visit and month 3 after treatment. Νo statistical difference was noted between the mirabegron group and the anticholinergic group in terms of LUTD improvement. In both groups, improvement from baseline regarding LUTD was recorded. Statistical analysis was performed using the paired and unpaired t test method. No patient discontinued either medication due to side effects. CONCLUSIONS: MS patients receiving either mirabegron or anticholinergic therapy for LUTD showed improvement. Nevertheless, no statistical difference was noted between the two cohorts at 3 months in terms of drug efficacy in all the statistically significant parameters.

Anticholinergic load and delirium in end-of-life patients.

BACKGROUND: Delirium is a neuropsychiatric syndrome associated with negative outcomes, including worsening of cognitive and functional status and an increased burden on patients and caregivers. Medications with anticholinergic effect have been associated with delirium symptoms, but the relationship is still debated. OBJECTIVE: To assess the relation between delirium and anticholinergic load according to the hypothesis that the cumulative anticholinergic burden increases the risk of delirium. METHODS: This retrospective cross-sectional study was conducted in a sample of end-of-life patients in a hospice or living at home between February and August 2019. Delirium was diagnosed on admission using the 4 'A's Test (4AT) and each patient's anticholinergic burden was measured with the Anticholinergic Cognitive Burden (ACB) scale. RESULTS: Of the 461 eligible for analysis, 124 (26.9%) had delirium. Anticholinergic medications were associated with an increased risk of delirium in univariate (OR (95% CI) 1.26 (1.16-1.38), p < 0.0001) and multivariate models adjusted for age, sex, dementia, tumors, Karnofsky Performance Status (KPS) score, days of palliative assistance, and setting (OR (95% CI) 1.16 (1.05-1.28), p < 0.0001). Patients with delirium had a greater anticholinergic burden than those without, with a dose-effect relationship between total ACB score and delirium. Patients who scored 4 or more had 2 or 3 times the risk of delirium than those not taking anticholinergic drugs. The dose-response relationship was maintained in the multivariate model. CONCLUSIONS: Anticholinergic drugs may influence the development of delirium due to the cumulative effect of multiple medications with modest antimuscarinic activity.

A new medication, a new toxidrome - A case report of anticholinergic wipe toxicity due to improper medication use.

We describe a case of a young female who presented to the emergency department with 4 days of progressive myopia, dry mouth, anhidrosis and urinary hesitancy due to overuse of a new topical anticholinergic wipes, glycopyrronium tosylate (GT). In the United States medication misuse accounts for nearly 10% of pediatric emergency visits with 65% of these visits considered to be preventable [1]. Being familiar with new medications and their side effect profiles can prevent unnecessary or harmful interventions.

Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax): Evaluation of Measurement Performance.

BACKGROUND: Clinical trials of primary axillary hyperhidrosis (AHH) require rigorous measurement of AHH severity from the patient’s perspective. Previously, we reported conceptualization and item content development for the Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax) scale. OBJECTIVE: To evaluate the psychometric performance and estimate clinically meaningful change scores for the HDSM-Ax in a Phase IIb clinical study of sofpironium bromide gel for AHH. METHOD: HDSM-Ax measurement performance was analyzed in trial response data using two psychometric paradigms: Classical Test and Rasch Measurement Theories (CTT; RMT). HDSM-Ax meaningful change scores were estimated from anchor-based methods using two global summary questions of hyperhidrosis severity and the Hyperhidrosis Disease Severity Score (HDSS). RESULTS: HDSM-Ax satisfied CTT and RMT criteria as a fit-for-purpose outcome measure in AHH clinical trials. Within-person anchor-based analyses indicated a 1-point change in HDSM-Ax severity score (range, 0–4) represents a clinically meaningful change in AHH severity. CONCLUSION: HDSM-Ax is a well-defined and reliable measure of AHH severity. A 1-point change in HDSM-Ax score is clinically meaningful. J Drugs Dermatol.20(4):410-418. doi:10.36849/JDD.5569.

Management of Primary Focal Hyperhidrosis: An Algorithmic Approach.

Hyperhidrosis (HH) is defined as perspiration beyond the level required to maintain temperature regulation. HH affects nearly 4.8% of the population in the United States. It can have a great impact on patient’s quality of life by disturbing daily activity, performance, confidence, social interactions, and mental health. In the majority of patients with HH (93%), the etiology of excess sweating is idiopathic, which classifies it as primary focal HH. Mild HH may be controlled with topical antiperspirants and lifestyle modifications. Based on the location of involvement, iontophoresis and botulinum toxin may be considered if the patient does not respond to topical therapies. Despite minimizing sweating, chronic use of systemic anticholinergics, in particular oxybutynin, may result in detrimental adverse effects such as dementia. Local surgery, radiofrequency, microwave, and lasers are other potential modalities for HH. Sympathectomy can be a last resort for the treatment of focal HH of the palmar, plantar, axillary, and craniofacial areas after failure of less invasive therapeutic options. In this review, we conducted a comprehensive search in the PubMed electronic database to summarize an algorithmic approach for the treatment of HH. This can help broaden options for managing this difficult disease. J Drugs Dermatol. 20(5): doi:10.36849/JDD.5774.

Effect of Prophylactic Subcutaneous Scopolamine Butylbromide on Death Rattle in Patients at the End of Life: The SILENCE Randomized Clinical Trial.

Importance: Death rattle, defined as noisy breathing caused by the presence of mucus in the respiratory tract, is relatively common among dying patients. Although clinical guidelines recommend anticholinergic drugs to reduce the death rattle after nonpharmacological measures fail, evidence regarding their efficacy is lacking. Given that anticholinergics only decrease mucus production, it is unknown whether prophylactic application may be more appropriate. Objective: To determine whether administration of prophylactic scopolamine butylbromide reduces the death rattle. Design, Setting, and Participants: A multicenter, randomized, double-blind, placebo-controlled trial was performed in 6 hospices in the Netherlands. Patients with a life expectancy of 3 or more days who were admitted to the participating hospices were asked to give advance informed consent from April 10, 2017, through December 31, 2019. When the dying phase was recognized, patients fulfilling the eligibility criteria were randomized. Of the 229 patients who provided advance informed consent, 162 were ultimately randomized. The date of final follow-up was January 31, 2020. Interventions: Administration of subcutaneous scopolamine butylbromide, 20 mg four times a day (n = 79), or placebo (n = 78). Main Outcomes and Measures: The primary outcome was the occurrence of a grade 2 or higher death rattle as defined by Back (range, 0-3; 0, no rattle; 3, rattle audible standing in the door opening) measured at 2 consecutive time points with a 4-hour interval. Secondary outcomes included the time between recognizing the dying phase and the onset of a death rattle and anticholinergic adverse events. Results: Among 162 patients who were randomized, 157 patients (97%; median age, 76 years [IQR, 66-84 years]; 56% women) were included in the primary analyses. A death rattle occurred in 10 patients (13%) in the scopolamine group compared with 21 patients (27%) in the placebo group (difference, 14%; 95% CI, 2%-27%, P = .02). Regarding secondary outcomes, an analysis of the time to death rattle yielded a subdistribution hazard ratio (HR) of 0.44 (95% CI, 0.20-0.92; P = .03; cumulative incidence at 48 hours: 8% in the scopolamine group vs 17% in the placebo group). In the scopolamine vs placebo groups, restlessness occurred in 22 of 79 patients (28%) vs 18 of 78 (23%), dry mouth in 8 of 79 (10%) vs 12 of 78 (15%), and urinary retention in 6 of 26 (23%) vs 3 of 18 (17%), respectively. Conclusions and Relevance: Among patients near the end of life, prophylactic subcutaneous scopolamine butylbromide, compared with placebo, significantly reduced the occurrence of the death rattle. Trial Registration: trialregister.nl Identifier: NTR6264.

Factors affecting the effect of naldemedine for opioid-induced constipation: a single-institution, retrospective analysis.

Naldemedine is the newest orally available, peripherally selective µ-opioid receptor antagonist blocker approved for opioid-induced constipation (OIC) treatment in adult patients. On the other hand, some patients have insufficient OIC control even with naldemedine. Thus, this retrospective study was conducted to identify factors affecting the effect of naldemedine. The participants were 210 patients who had received naldemedine at our institute between June 2017 and August 2019. Variables associated with alleviation of OIC were extracted from clinical records and used for regression analysis. The effect of naldemedine was determined according to the degree of constipation. The degree of constipation was categorized as grade 0 - 2 with reference to the CTCAE version 5.0. Multivariate ordered logistic regression analysis was conducted to identify factors affecting the effect of naldemedine. Use of naldemedine within 2 days of opioid initiation [odds ratio (OR) =0.346, 95% confidence interval (CI) =0.173-0.693; P = 0.003], concomitant use of anticholinergics (OR = 2.033, 95% CI = 1.150-3.594; P = 0.015), tramadol (OR = 0.488, 95% CI = 0.250-0.953; P =0.036), and chronic non-cancer pain (OR = 0.429, 95% CI = 0.197-0.937; P = 0.034) were identified as significant factors related to the effect of naldemedine.

Medication burden and frailty in older adults with intellectual disability: An observational cross-sectional study.

PURPOSE: Recently, efforts have been made to quantify frailty among older adults with intellectual disability (ID). Medication exposure is associated with frailty among older adults without ID. However, there is little research on this association among older adults with ID. The aim of this study was to examine specifically in people with ID the association between frailty and medication exposure, including anticholinergic and sedative medication exposure. METHODS: Data were drawn from Wave 2 (2013/2014) of the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA), a nationally representative study of older adults with ID in Ireland. A modified version of Fried's frailty phenotype was constructed. Drug burden measures were polypharmacy, Drug Burden Index (DBI), Anticholinergic Cognitive Burden (ACB) and Sedative Load Model. Multinomial logistic regression was used to calculate odds ratios (ORs) and identify associations between frailty and drug burden. RESULTS: This study included 570 participants with ID. Excessive polypharmacy (use of ≥10 medications) was significantly associated with being pre-frail (P = .017; OR = 2.56; 95% confidence interval [CI] 1.19-5.50) and frail (P < .001; OR 7.13; 95% CI 2.81-18.12), but DBI, ACB or Sedative Load score were not significantly associated with frailty status (P > .05). CONCLUSIONS: This is the first study to examine frailty and its association with medication use including anticholinergic and sedative medication burden among older adults with ID. Further research is required to investigate frailty as measured by other frailty models in relation to medication burden in older adults with ID.

The effect of hyoscine n- butylbromide on labor progress: A systematic review.

BACKGROUND: The objective of this systematic review and meta-analysis was to assess the effectiveness of hyoscine n-butylbromide in labor progress. METHODS: The databases including PubMed, the Cochrane Library, Science-Direct, Scopus and Web of Science were searched for studies published up to December 2019. Articles that published as randomized controlled trials (RCTs), and full-text articles published in English or other languages were included and participants were primi or multigravida women who were in active phase of labor. The intervention included HBB compared to placebo (normal saline) that was used during active phase of labor. Pooled estimates were measured using the fixed or random effect model, while the overall effect was reported in a mean difference (MD). All data were analyzed using Review Manager 5.3. RESULTS: Twenty studies involving 3108 women were included in meta-analysis. Based on subgroup analysis by parity, use of HBB significantly reduced the duration of the first stage of labor in primigravida women (MD = - 57.73; 95% CI: [- 61.48, - 53.60]) and in multigravida women (MD = - 90.74; 95% CI: [- 97.24, - 84.24]). Administering HBB could reduce the second stages of labor in primigravidas and multigravidas about 6 min and 4 min respectively. Also, HBB reduced the duration of the third stage of labor in multigravidas about 3 min. APGAR score at one and 5 min after birth was not affected. The main maternal adverse effect was tachycardia and dry mouth. Labor duration in studies in which the participants were primi-and multigravida was not presented based on separate parities except for four papers, and the route of HBB administration was not the same across all studies. CONCLUSIONS: Although, the effect of HBB was minimal when multigravidas and primigravidas women were considered together, the HBB was clinically effective in primigravida and multigravida women for shortening the first and the second stages of labor. Also, HBB could reduce the length of the third stage of labor in multigravidas.

Variables Affecting Delivery of Glycopyrronium Tosylate Through Human Skin In Vitro.

BACKGROUND: Hyperhidrosis is a condition characterized by excessive sweating beyond what is required for normal thermal regulation. It can involve multiple body areas including the axillae, palms, soles, or craniofacial regions. Glycopyrronium tosylate (GT) is a topical anticholinergic approved by the FDA (2018) for treatment of primary axillary hyperhidrosis in patients 9 years and older. OBJECTIVE: Gain insight into variables (anatomical sites, occlusion, exposure time) affecting GT delivery into human skin. METHODS: Human skin from different anatomical regions (palmar, plantar, axillary, and abdominal skin) was mounted into flow-through diffusion cells (MedFlux-HT®). GT solution (2.4%) was applied at 10 mg/cm2 and the receiving fluid was collected every 2 hours, for 24 hours. GT penetration was determined using LC/MS/MS. The effect of occlusion was assessed by covering the skin with either parafilm or saran wrap, and the effect of exposure time was assessed by incubating the skin for 5, 15, or 60 minutes before washing off the GT from the surface. RESULTS: GT delivery through palmar and plantar skin was up to 40-fold lower compared to delivery through axillary or abdominal skin. Occlusion increased GT delivery up to 10-fold. Reducing exposure time from 24 hours to either 5, 15, or 60 minutes, decreased GT flux by 90%. However, occlusion during these varied exposure times was able to restore GT delivery to levels found in the 24-hour exposed, non-occluded control group. CONCLUSION: These in vitro skin penetration studies showed that skin thickness, exposure time, and occlusion substantially influenced GT delivery, potentially impacting clinical trial design. J Drugs Dermatol. 2020;19(11): doi:10.36849/JDD.2020.5062.

[Urinary disorders of Wolfram syndrome. Clinical and urodynamic analysis from 6 observations]. / Les troubles vésico-sphinctériens du syndrome de Wolfram. Analyse clinique et urodynamique à partir de 6 observations.

Wolfram syndrome is a neurodegenerative disorder characterized by childhood onset diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing impairment, brainstem alteration and commonly bladder and bowel dysfunction. OBJECTIVE: We present here, 6 new cases of urinary dysfunction in this rare disease. RESULTS: All patients had urinary retention with overactive bladder. The urodynamic assessment found overactive detrusor in 3 cases. Five out of six patients performed self-catheterization and were treated with anticholinergics or intradetrusor injection of botulinum toxin. The follow-up at 5 years found an alteration of the upper urinary tracts and a renal failure 3/6. CONCLUSION: Urinary dysfunction is common in Wolfram syndrome, mainly characterized by overactive bladder and urinary retention. The urological risk is major requiring a systelmatic follow-up of these patients. LEVEL OF EVIDENCE: 4.

[Study of cholinesterase activity in mixed saliva of patients with somatic pathology.]

Cholinesterase activity in mixed saliva of patients with somatic pathology was investigated. The results showed differences in enzyme activity depending on the disease. The highest salivary cholinesterase activity was detected in patients with bronchopulmonary pathology, and the lowest - in cardiovascular diseases. A reliable relationship between the changes in the activity of cholinesterase in saliva and the rate of salivation, and with patients taking atypical antipsychotics and M, H-anticholinergic drugs, was revealed.

Tiotropium add-on therapy is safe and reduces seasonal worsening in paediatric asthma patients.

There remains an unmet need for effective, well-tolerated therapeutic options in paediatric patients with not fully controlled asthma, for whom safety is of paramount importance.Data were pooled from five randomised, double-blind, placebo-controlled studies evaluating tiotropium 5 or 2.5 µg versus placebo add-on therapy in patients with symptomatic asthma aged 1-17 years. Analysis included adverse events (AEs) and serious AEs (SAEs) reported throughout and for 30 days following treatment.Of 1691 patients treated, 1119 received tiotropium. Reporting of AEs was low and comparable across all groups: tiotropium 5 µg (51%), tiotropium 2.5 µg (51%) and placebo (54%). Reporting of drug-related AEs, those leading to discontinuation and SAEs was also low and balanced between treatment groups, irrespective of age, disease severity or sex. The number of AEs related to asthma symptoms and exacerbations was lower with tiotropium (5 µg) than with placebo, particularly during the seasonal peaks of these AEs.This comprehensive analysis of a large safety database allowed subgroup analyses that are often impractical with individual trials and provides further support for the safety of once-daily tiotropium Respimat add-on therapy in paediatric patients with symptomatic asthma.

Efficacy and Safety of Tolterodine and Pilocarpine in Patients with Overactive Bladder.

PURPOSE: We evaluated the efficacy and safety of a combination of 2 mg tolterodine and 9 mg pilocarpine, vs tolterodine monotherapy in patients with overactive bladder. MATERIALS AND METHODS: We enrolled patients with overactive bladder symptoms in a multicenter, randomized, double-blind, parallel, active control study. Patients were randomized to the combination or 2 mg tolterodine twice daily for 12 weeks. After the double-blind period finished all patients were started on the combination for 12 weeks. Study co-primary end points were the change from baseline in the mean number of daily micturitions and cumulative incidence of dry mouth at the end of 12 weeks. Secondary end points were other overactive bladder symptoms, the total xerostomia inventory score and results of a visual analogue scale for dry mouth at the end of 12 and 24 weeks. RESULTS: The mean change in the number of daily micturitions from baseline to 12 weeks was -1.49 and -1.74 in the combination and tolterodine monotherapy groups, respectively. The mean difference was -0.26 (95% CI -0.79-0.27), confirming noninferiority. At 12 weeks the incidence of dry mouth was lower in the combination group than in the tolterodine monotherapy group (30.0% vs 42.9%, p = 0.009). All secondary and other efficacy outcomes related to overactive bladder symptoms improved in each group with no significant differences between the groups at 12 weeks. Changes from baseline in the total xerostomia inventory score and the visual analogue scale for dry mouth were significantly lower in the combination group than in the tolterodine monotherapy group. CONCLUSIONS: Tolterodine and pilocarpine alleviated dry mouth in patients with overactive bladder while maintaining anticholinergic efficacy similar to that of tolterodine.

Anticholinergic exposure and cognitive decline in older adults: effect of anticholinergic exposure definitions in a 3-year analysis of the multidomain Alzheimer preventive trial (MAPT) study.

AIM: The aim of the present study was to assess the association between anticholinergic (atropinic) burden and cognitive decline in older adults over the course of 3 years. METHODS: We used data from Multidomain Alzheimer Preventive Trial (MAPT) study participants aged ≥70 years and at risk of cognitive decline. Cognitive function was assessed with a composite score [Mini-Mental State Examination (MMSE) orientation, Free and Cued Selective Reminding Test, Category Naming Test, Digit Symbol Substitution Test] at 12, 24 and 36 months. Participants declining by more than 0.236 points on the composite score (representing the lowest quintile of 1-year cognitive change) during any 1-year period were considered to have undergone cognitive decline. Anticholinergic exposure was defined by four methods for each of four anticholinergic scales (Anticholinergic Drug Scale, Anticholinergic Cognitive Burden, Anticholinergic Risk Scale, the Durán list). The association between cognitive decline and time-varying anticholinergic exposure [primary analysis using the Durán list and maximal anticholinergic score (0, 1 or 3)] was assessed using Cox proportional hazards models. Other cognitive decline definitions were used in sensitivity analyses. RESULTS: At baseline, among 1396 patients included, 7.4-23.5% were exposed to anticholinergic agents, depending on the anticholinergic scale used. Sixty-four per cent of participants experienced cognitive decline during follow-up. Regardless of the anticholinergic scale/exposure measurement used, no significant association was observed with cognitive decline {primary analysis: compared with non-anticholinergic agent users, hazard ratio [HR] = 1.14 [95% confidence interval (CI) = 0.95, 1.38] for anticholinergic score = 1; HR = 0.92 [95% CI = 0.65, 1.30] for score = 3}. Results were stable in sensitivity analyses. CONCLUSION: We found no significant association between anticholinergic exposure and cognitive decline in older adults using anticholinergic scales and definitions of exposure.