The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs.

There is evidence that use of drugs with anticholinergic properties increases the risk of cognitive impairment, and increased exposure to these drugs potentiates this risk. Anticholinergic drugs are commonly used even with associated risk of adverse events. Aging, sex, and genetic polymorphisms of cytochrome P450 (CYP) enzymes are associated with alterations in pharmacokinetic processes, which increase drug exposure and may further increase the risk of adverse drug events. Due to the increasing burden of cognitive impairment in our aging population and the future of personalized medicine, the objective of this review was to provide a critical clinical perspective on age, sex, and CYP genetic polymorphisms and their role in the metabolism and exposure to anticholinergic drugs. Age-related changes that may increase anticholinergic drug exposure include pseudocapillarization of liver sinusoidal endothelial cells, an approximate 3.5% decline in CYP content for each decade of life, and a reduction in kidney function. Sex-related differences that may be influenced by anticholinergic drug exposure include women having delayed gastric and colonic emptying, higher gastric pH, reduced catechol-O-methyl transferase activity, reduced glucuronidation, and reduced renal clearance and men having larger stomachs which may affect medication absorption. The overlay of poor metabolism phenotypes for CYP2D6 and CYP2C19 may further modify anticholinergic drug exposure in a significant proportion of the population. These factors help explain findings of clinical trials that show older adults and specifically older women achieve higher plasma concentrations of anticholinergic drugs and that poor metabolizers of CYP2D6 experience increased drug exposure. Despite this knowledge neither age, sex nor CYP phenotype are routinely considered when making decisions about the use or dosing of anticholinergic medications. Future study of anticholinergic medication needs to account for age, sex and CYP polymorphisms so that we may better approach personalized medicine for optimal outcomes and avoidance of medication-related cognitive impairment.

A Population Pharmacokinetic Model of (R)- and (S-) Oxybutynin and Its Active Metabolites After Oral and Intravesical Administration to Healthy Volunteers.

Oxybutynin is a racemic anticholinergic drug used for the symptomatic treatment of detrusor overactivity. The formation of active metabolites related to tolerability problems depends on the route of administration. The objective of this evaluation was to develop a pharmacokinetic model for oral/intravesical administration as the basis for simulations with different dosages. Data from a published changeover clinical study with 18 healthy adults receiving a single oral dose of 5 mg immediate-release oxybutynin and single and multiple intravesical doses of 10 mg oxybutynin solution was evaluated. Enantioselective plasma concentrations of oxybutynin and N-desethyloxybutynin (NDO) were used to establish a population pharmacokinetic model using nonlinear mixed-effects modeling with NONMEM 7.4.1. For both enantiomers, the data were described well by a 2-compartment model for oxybutynin with an additional compartment for NDO. Oxybutynin absorption was modeled by transit compartments for oral and first-order absorption for intravesical application. Bioavailability of the more active (R)-enantiomer was 7% for oral and 10%-22% for intravesical administration. In simulations, intravesical doses of 5 to 15 mg (R)-oxybutynin administered 2 to 3 times daily decreased peak-trough fluctuations of NDO to 8% compared with 24% after oral administration. The NDO/oxybutynin ratio was reduced from 17 after oral administration to unity. Chronic intravesical versus oral administration of (R)-oxybutynin generates distinctly lower and less variable concentrations of (R)-NDO. Pharmacokinetic simulations suggest that exposure for 12.5 mg (R)-oxybutynin administered twice daily might not compromise efficacy and tolerability compared with exposure for standard thrice-daily administrations. This assumption needs to be assessed in clinical studies.

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.

Evaluation of Choline and Acetylcholine Levels in Responders and Nonresponders to Anticholinergic Therapy for Overactive Bladder Syndrome.

OBJECTIVE: This study aimed to determine whether levels of choline (Ch) and acetylcholine (Ach) differ between responders and nonresponders to anticholinergic therapy. METHODS: Patients prescribed an anticholinergic were evaluated using the Overactive Bladder Symptom Score; Medical, Epidemiologic and Social Aspects of Aging and Incontinence Questionnaire; and Incontinence Impact Questionnaire-7. A 1-day voiding diary and a urine sample were collected. After treatment for 12 weeks, the questionnaires were administered and 1-day voiding diary was completed. Levels of Ach and Ch were measured by liquid chromatography with tandem mass spectrometry. Subjects were divided into responders and nonresponders. Wilcoxon rank sum test and Fisher exact test were used to express differences between groups. Spearman ρ correlation coefficient was used to determine the relationship between Ach and Ch and symptom severity, patient demographics, and questionnaire scores. RESULTS: Thirty-one women were included in the analysis. The treatment response rate was 48.8%. The median age was 67 years (interquartile range, 50-76 years), and median body mass index was 32.3 kg/m2 (27.5-40.6 kg/m2), with 41.2% having an additional complaint of stress incontinence. There were no significant differences in symptom severity or questionnaire scores between groups.The median Ch and Ach levels were higher in responders (28.6 vs 9.2 µL, P = 0.04) and (83.1 vs 18.7 nL, P = 0.02), respectively. Levels of both Ch and Ach had moderate positive correlations with the Medical, Epidemiologic and Social Aspects of Aging and Incontinence Questionnaire urgency urinary incontinence score (ρ = 0.533 [P = 0.002] and ρ = 0.453 [P = 0.01], respectively). CONCLUSION: In women with overactive bladder, urinary Ach and Ch levels are higher in responders to anticholinergic therapy compared with nonresponders.

Anticholinergic Load and Nutritional Status in Older Individuals.

OBJECTIVES: The association between anticholinergic load-based Anticholinergic Risk Scale scores and nutritional status is unclear in Japanese patients. The aim of this study was to establish whether anticholinergic load affects the nutritional status of geriatric patients in convalescent stages. DESIGN: Retrospective longitudinal cohort study. SETTING: Convalescent rehabilitation wards. PARTICIPANTS: Of the 1490 patients aged ≥65 years who were discharged from convalescent rehabilitation wards between July 2010 and October 2018, 908 patients met the eligibility criteria. They were categorized according to the presence or absence of increased anticholinergic load from admission to discharge. MEASUREMENTS: Demographic data, laboratory data, the Functional Independence Measure were analyzed between the groups. The primary outcome was Geriatric Nutritional Risk Index (GNRI) at discharge. Multiple linear regression analysis was performed to analyze the relationship between anticholinergic load and GNRI at discharge. RESULTS: Multiple linear regression analysis after adjusting for confounding factors revealed that anticholinergic load was independently and negatively correlated with GNRI at discharge. Particularly, the use of chlorpromazine, hydroxyzine, haloperidol, metoclopramide, risperidone, etc. increased significantly from admission to discharge. CONCLUSION: Increased anticholinergic load during hospitalization may be a predictor of nutritional status in geriatric patients.

Anticholinergic Drug Exposure and the Risk of Dementia: There Is Modest Evidence for an Association but Not for Causality.

Many observational studies published during the past 15 years have found an association between anticholinergic drug exposure and the risk of incident dementia. Animal data suggest plausible causal mechanisms for this finding. The results of a recent, large, and well-conducted study on the subject were widely disseminated by the lay and scientific media. This study addressed protopathic bias by examining anticholinergic drug exposure in time windows 1-11, 3-13, and 5-20 years before the identification of dementia. In brief, the study found that, pooling anticholinergic drug exposure across 11 drug categories, exposure in smallest to largest cumulative dosing groups was significantly associated with incident dementia risk, with an apparently dose-dependent relationship in unadjusted as well as adjusted analyses in all time windows prior to dementia identification. Whereas these findings appear compelling, there are at least 4 elephants in the room. First, only 3 of 11 anticholinergic drug categories were consistently associated with an increased risk of dementia; this suggests that anticholinergic activity may be an irrelevant common denominator. Second, for 2 of these 3 categories (antidepressant and antipsychotic drugs), confounding by indication seemed a distinct possibility. Third, in many analyses it seemed that exposure for as little as the equivalent of 1-90 days sufficed to increase the risk of dementia at a time interval of up to 20 years later; a causal mechanism here would need to have strong neurotoxic effects to result in the widespread brain changes that characterize dementia. Finally, the associations were almost uniformly stronger for vascular dementia than for Alzheimer's disease, making the identification of a causal mechanism even more challenging. Deprescribing anticholinergics to reduce state-dependent cognitive impairment, or to reduce the risk of delirium in vulnerable demographic and medical populations, is reasonable. Deprescribing anticholinergics to reduce the risk of future dementia is presently unwarranted.

The first synthesis, carbonic anhydrase inhibition and anticholinergic activities of some bromophenol derivatives with S including natural products.

Starting from vanillin, known four benzyl bromides with Br were synthesized. The first synthesis of natural product 3,4-dibromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (2) and 3,4,6-tribromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (3) and derivatives were carried out by demethylation, acetylatilation, oxidation and hydrolysis reactions of the benzyl bromides. Also, these compounds were tested against some important enzymes like acetylcholinesterase and butyrylcholinesterase enzymes, carbonic anhydrase I, and II isoenzymes. The novel bromophenols showed Ki values of in range of 53.75 ±â€¯12.54-234.68 ±â€¯46.76 nM against hCA I, 42.84 ±â€¯9.36 and 200.54 ±â€¯57.25 nM against hCA II, 0.84 ±â€¯0.12-14.63 ±â€¯3.06 nM against AChE and 0.93 ±â€¯0.20-18.53 ±â€¯5.06 nM against BChE. Induced fit docking process performed on the compounds inhibiting hCA I, hCA II, AChE, and BChE receptors. Hydroxyl group should exist at the aromatic ring of the compounds for inhibition of the enzymes. The moieties reported in this study will be useful for design of more potent and selective inhibitors against the enzymes.

In vitro and clinical characterization of the valved holding chamber AeroChamber Plus® Flow-Vu® for administrating tiotropium Respimat® in 1-5-year-old children with persistent asthmatic symptoms.

BACKGROUND: When characterizing inhalation products, a comprehensive assessment including in vitro, pharmacokinetic (PK), and clinical data is required. We conducted a characterization of tiotropium Respimat® when administered with AeroChamber Plus® Flow-Vu® anti-static valved holding chamber (test VHC) with face mask in 1-5-year-olds with persistent asthmatic symptoms. METHODS: In vitro tiotropium dose and particle size distribution delivered into a cascade impactor were evaluated under fixed paediatric and adult flow rates between actuation and samplings. The tiotropium mass likely to reach children's lungs was assessed by tidal breathing simulations and an ADAM-III Child Model. PK exposure to tiotropium in preschool children with persistent asthmatic symptoms (using test VHC) was compared with pooled data from nine Phase 2/3 trials in older children, adolescents, and adults with symptomatic persistent asthma not using test VHC. RESULTS: At fixed inspiratory flow rates, emitted mass and fine particle dose decreased under lower flow conditions; dose reduction was observed when Respimat® was administered by test VHC at paediatric flow rates. In <5-year-old children, such a dose reduction is appropriate. In terms of dose per kg/body weight, in vitro-delivered dosing in children was comparable with adults. Transmission and aerosol holding properties of Respimat® when administered with test VHC were fully sufficient for aerosol delivery to patients. At zero delay, particles <5 µm (most relevant fraction) exhibited a transfer efficacy of ≥60%. The half-time was>10 s, allowing multiple breaths. Standardized tidal inhalation resulted in an emitted mass from the test VHC of approximately one-third of labelled dose, independent of coordination and face mask use, indicating predictable tiotropium administration by test VHC with Respimat®. Tiotropium exposure in 1-5-year-old patients using the test VHC, when adjusted by height or body surface, was comparable with that in older age groups without VHCs; no overexposure was observed. Adverse events were less frequent with tiotropium (2.5 µg, n = 20 [55.6%]; 5 µg, n = 18 [58.1%]) than placebo (n = 25 [73.5%]). CONCLUSIONS: Our findings provide good initial evidence to suggest that tiotropium Respimat® may be administered with AeroChamber Plus® Flow-Vu® VHC in 1-5-year-old patients with persistent asthmatic symptoms. To confirm the clinical efficacy and safety in these patients, additional trials are required. CLINICAL TRIALS REGISTRY NUMBER: The trial was registered under NCT01634113 at http://www.clinicaltrials.gov.

Estudio multicéntrico sobre el uso de oxibutinina oral en hiperhidrosis local y multifocal / Oral Oxybutynin for Local and Multifocal Hyperhidrosis: A Multicenter Study

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Anticholinergic prescription: are healthcare professionals the real burden?

INTRODUCTION AND HYPOTHESIS: Anticholinergic medication is the medical treatment for overactive bladder (OAB). These drugs can act on the central nervous system and can lead to cognitive decline, dementia, and potentially death. Patients taking drugs with anticholinergic effects increase their anticholinergic burden-defined as the cumulative effect of taking one or more drugs that can have adverse effects. When prescribing anticholinergic medication for the elderly, we must choose the right drug. We aimed to discover the level of understanding on this subject and its application to real clinical practice amongst our healthcare professionals (HCPs). METHODS: An 18-point questionnaire was distributed to urogynaecologists, general gynaecologists, urologists, geriatricians, general practitioners (GPs), and nurse specialists to assess knowledge on the subject. RESULTS: A total of 96 HCPs completed the questionnaire. The nurse specialists had the highest score in identifying that oxybutynin was the drug most likely to cross the blood-brain barrier (BBB). The urogynaecologists had the highest score in identifying that trospium chloride was least likely to cross the BBB, whereas the GPs had the lowest score. Solifenacin was the most popular anticholinergic drug prescribed in the elderly without dementia. Trospium chloride was the most popular drug prescribed in the elderly with dementia. CONCLUSIONS: We have found that knowledge is lacking amongst all our HCPs, but especially amongst our first-line doctors, our GPs. Education is key in developing knowledge and safe prescribing, to improve the care we give to our patients.

Quantification of anticholinergic and sedative drug load with the Drug Burden Index: a review of outcomes and methodological quality of studies.

PURPOSE: The Drug Burden Index (DBI) is a non-invasive method to quantify patients' anticholinergic and sedative drug burden from their prescriptions. This systematic review aimed to summarise the evidence on the associations between the DBI and clinical outcomes and methodological quality of studies. METHODS: A search in PubMed and Embase (search terms: 'drug', 'burden', and 'index') was performed and experts were contacted. We excluded publications that did not report empirical results or clinical outcomes. Methodological quality was assessed using the Newcastle-Ottawa Scale. Potential omissions of relevant clinical outcomes and populations were studied. RESULTS: Of the 2998 identified publications, 21 were eligible. Overall, methodological quality of studies was good. In all but one study, adjustment was made for prevalent co-morbidity. The DBI was examined in diverse older individuals, i.e. both males and females from different settings and countries. However, no studies were conducted in other relevant patient groups, e.g. psychiatric patients. Exposure to anticholinergic and sedative drugs was thoroughly ascertained, though the specific calculation of the DBI differed across studies. Outcomes were assessed from medical records, record linkage or validated objective tests or questionnaires. Many studies found associations between the DBI and outcomes including hospitalisation, physical and cognitive function. Cognitive function and quality of life were understudied and the number and scope of longitudinal studies was limited. CONCLUSIONS: An accumulating body of evidence supports the validity of the DBI. Longitudinal studies of cognitive function and quality of life and in other patient groups, e.g. psychiatric patients, are warranted.

A rapid and efficient analytical method for the quantification of a novel anticholinergic compound, R-phencynonate, by stable isotope-dilution LC-MS/MS and its application to bioavailability and dose proportionality studies.

A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C8 column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r2 > 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.

Relevance of dosage in adherence to treatment with long-acting anticholinergics in patients with COPD.

INTRODUCTION: The aim of this study was to assess the degree of adherence for two standard regimens for administrating anticholinergic drugs (12 and 24 hours) in patients with chronic obstruction of the airflow and to establish whether the use of a once-daily dose improves the level of treatment adherence. METHODS: We used long-acting anticholinergics (LAMAs) as a study variable, and included the entire health area of Castile-La Mancha, numbering 2,100,998 inhabitants, as the study population. We analyzed a total of 16,446 patients who had been prescribed a LAMA between January 1, 2013 and December 31, 2013. The follow-up period, based on a centralized system of electronic prescription management, was extended until December 2014. RESULTS: During 2013, the medication collected was 7.4%-10.7% higher than indicated by labeling. This was very similar for all LAMAs, irrespective of the patient's sex, the molecule, the device, and the drug dosage. We did not observe seasonal variations in the consumption of LAMAs, nor did we detect differences between prescription drugs for once-daily (every 24 hours) versus twice-daily (every 12 hours) administration, between the different molecules, or between different types of inhalers for the same molecule. The results were similar in 2014. CONCLUSION: The principal conclusion of this study is that, in an area with a centralized management system of pharmacological prescriptions, adherence to treatment with LAMAs is very high, irrespective of the molecules or inhalation device. We did not find that patients who used twice-daily medication had a lower adherence.

Combined bronchodilators (tiotropium plus olodaterol) for patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), a respiratory disease characterized by a progressive decline in lung function, is considered to be a leading cause of morbidity and mortality. Long-acting inhaled bronchodilators, such as long-acting ß2 agonists (LABAs) or long-acting muscarinic antagonists (LAMAs), are the cornerstone of maintenance therapy for patients with moderate-to-very-severe COPD. For patients not sufficiently controlled on a single long-acting bronchodilator, a combination of different bronchodilators has shown a significant increase in lung function. Tiotropium, a once-daily dosing LAMA, demonstrated sustained improvements in lung function as well as improved health-related quality of life, reduced exacerbations, and increased survival without altering the rate of decline in the mean forced expiratory volume in 1 second (FEV1) with fairly tolerable side effects. Olodaterol is a once-daily dosing LABA that has proven to be effective in improving lung function, reducing rescue medication use, and improving dyspnea and health-related quality of life, as well as improving exercise endurance with an acceptable safety profile. The combination of olodaterol and tiotropium provided additional improvements in lung function greater than monotherapy with each drug alone. Several well-designed randomized trials confirmed that the synergistic effect of both drugs in combination was able to improve lung function and health-related quality of life without a significant increase in adverse effects. The objective of this paper is to review available evidence on the clinical efficacy and safety of tiotropium, olodaterol, and their combination in patients with COPD.

Comparative study on pharmacokinetics of a series of anticholinergics, atropine, anisodamine, anisodine, scopolamine and tiotropium in rats.

The compound series of traditional anticholinergics [atropine (Atr), anisodamine (Ani), anisodine (AT3), and scopolamine (Sco)], naturally occurring belladonna alkaloid, have been approved for numerous therapeutic uses since 1970s. Tiotropium, a novel M receptor antagonist for the treatment of chronic obstructive pulmonary disease, was structurally modified based on atropine-like drugs. Clinical phenomena suggested that the changes of substituent group were related to the pharmacokinetic and pharmacodynamic characteristics of the agents. In an attempt to compare the pharmacokinetics of the series of anticholinergics and investigate the subsets motivating selective anticholinergic potencies, a sensitive LC-MS/MS method was established to analyze the differences of pharmacokinetic parameters. In this paper, we determined the pharmacokinetics of atropine, anisodamine, anisodine, scopolamine, and tiotropium after i.v. and i.g. single dose administration. After i.v. administration, the maximum drug plasma concentrations (C max) of Atr, Ani, AT3, and Sco were 274.25 ± 53.66, 267.50 ± 33.16, 340.50 ± 44.52, and 483.75 ± 78.13 ng/mL. Tiotropium had a slightly higher area under the curve with a significant increase of C max value. Because of their partial solubility, Atr, Ani, AT3, and Sco had different bioavailability in rats of 21.62, 10.78, 80.45 and 2.52 %, respectively. Following i.g. administration of tiotropium, the C max value below 20 ng/mL revealed the very low oral absorption. The urinary excretion rates of Atr, Ani, AT3, Sco and tiotropium were 11.33, 54.86, 32.67, 8.69 and 73.91 %. This work provided relatively comprehensive preclinical data on the series of anticholinergics, which may be used to explain the clinical adverse effects and applications.

Safety, tolerability, and plasma exposure of tiotropium Respimat® in children and adults with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (CF) suffer from chronic lung disease that is often treated with a bronchodilator. This trial evaluated the pharmacokinetics, safety, and tolerability of single and multiple doses of tiotropium inhaled via the Respimat® Soft Mist™ Inhaler in patients with CF. METHODS: Patients received a single dose (placebo, 2.5 µg, 5 µg, or 10 µg) and/or multiple doses (placebo, 2.5 µg, or 5 µg) of tiotropium daily for 28 days. RESULTS: Ninety-two patients, aged 5-57 years, were treated. All doses showed a satisfactory safety profile for adverse events, vital signs, laboratory evaluations, and physical examination. At steady-state, peak exposure to tiotropium was comparable between adult patients with CF and patients with chronic obstructive pulmonary disease. CONCLUSIONS: Tiotropium 2.5 µg or 5 µg inhaled via the Respimat® Soft Mist™ Inhaler once daily was well tolerated in patients with CF.

Aclidinium bromide for the treatment of chronic obstructive pulmonary disease.

PURPOSE: The safety and efficacy of the second U.S.-approved long-acting inhaled anticholinergic for controlling bronchospasm in patients with chronic obstructive pulmonary disease (COPD) are reviewed. SUMMARY: Aclidinium bromide (Tudorza, Forest Pharmaceuticals) is indicated for long-term maintenance therapy for COPD-associated bronchospasm. It is marketed as a 60-dose metered-dose inhaler to be used twice daily. In Phase II and III clinical trials involving a total of more than 3000 patients, daily use of aclidinium bromide was found to significantly improve selected key indicators of lung function (trough values for forced expiratory volume at one second [FEV1] and other FEV1 outcome measures) compared with placebo use. Other benefits of aclidinium bromide therapy, including a significant reduction in nighttime COPD symptoms, were demonstrated for up to one year. However, aclidinium bromide has not been consistently demonstrated to be more effective than the other currently available long-acting inhaled anticholinergic, tiotropium bromide. Furthermore, the clinical trials indicated no significant difference between aclidinium bromide and tiotropium bromide with regard to rates of systemic adverse effects. For some patients, aclidinium bromide may offer advantages over tiotropium bromide (e.g., a faster time to peak FEV1, lower cost of therapy). CONCLUSION: Aclidinium bromide is an inhaled anticholinergic that improves lung function measures in patients with COPD. The most common adverse effects during clinical trials of the drug were headache, nasopharyngitis, and cough, none of which occurred at significantly higher rates than were seen with placebo use.