Simulated driving performance in healthy adults after night-time administration of 20 mg tasimelteon.

An impairment in next day driving performance has been reported for almost every drug currently United States Food and Drug Administration (FDA) approved for improvement of sleep in chronic and transient insomnia. Tasimelteon, a melatonin receptor agonist, demonstrated significant improvements in night-time sleep, daytime naps, and sleep timing in non-24-hr sleep-wake disorder (Non-24) by entraining these patients to a 24-hr day as measured by melatonin and cortisol rhythms. Given this new mechanism of action of entraining the biological clock, we conducted a study to evaluate the potential effect tasimelteon may have on the ability to operate a motor vehicle. The study was conducted in 48 healthy adult subjects using a randomised, double-blind, placebo and active (zopiclone 7.5 mg) controlled study with a 3-period cross-over design. Driving performance was assessed by measuring standard deviation of lateral position (SDLP) using the validated Cognitive Research Corporation Driving Simulator-MiniSim. The difference in least square mean SDLP for tasimelteon was 1.22 cm reflecting a non-significant increase in SDLP change from placebo (p = .1119). In contrast, treatment with the active control, zopiclone 7.5 mg, was associated with a meaningful and significant increase in SDLP, change from placebo for zopiclone was 4.14 cm (p < .0001). The lack of clinically meaningful and statistically significant finding with tasimelteon was further supported by the symmetry analysis, which showed the distribution of within-subject differences between tasimelteon and placebo was symmetric about zero. At the FDA-approved 20 mg dose to treat Non-24, tasimelteon did not impair next-day driving performance compared to placebo in adult healthy volunteers.

Effects of lasmiditan on simulated driving performance: Results of two randomized, blinded, crossover studies with placebo and active controls.

OBJECTIVE: To evaluate the impact of lasmiditan, an oral, centrally-penetrant, selective serotonin 1F (5-HT1F ) receptor agonist developed for the acute treatment of migraine, on simulated driving. METHODS: Healthy adult volunteers enrolled in two randomized, placebo and active comparator-controlled, crossover studies. Study 1 (N = 90) tested lasmiditan (50-, 100-, 200-mg), alprazolam (1-mg), and placebo at 1.5 hr post-dose. Study 2 (N = 68) tested lasmiditan (100-, 200-mg), diphenhydramine (50-mg, administered 2 hr pre-assessments), and placebo at 8, 12 and 24 hr post-dose. Driving performance was assessed using a validated driving simulator employing a 100 km driving scenario. Standard deviation of lateral position (SDLP), a measure of lane position control, was the primary endpoint. RESULTS: Assay sensitivity was confirmed by increased SDLP for active comparators at 1.5- and 8-hr time points. Lasmiditan doses showed significant driving impairment versus placebo at 1.5 hr post-dose. Lasmiditan doses were non-inferior to placebo at 8 hr. Driving impairment was concentration-dependent at 1.5 hr but not at 8 hr. Common adverse events were central nervous system-related and mild-to-moderate in severity. CONCLUSIONS: Lasmiditan was associated with impaired simulated driving performance at 1.5 hr post-dose, but showed no clinically meaningful impairment at 8 hr post-dose.

Next-day residual effects of flibanserin on simulated driving performance in premenopausal women.

OBJECTIVE: The objective of this study was to determine the next-day residual effects of acute and steady-state nighttime dosing of flibanserin on simulated driving performance and cognitive function in healthy premenopausal women. METHODS: In this randomized, double-blind, placebo-controlled, four-way crossover study, 72 subjects were treated with either acute oral doses of placebo, zopiclone 7.5 mg (positive control) or flibanserin 100 mg at bedtime (indicated therapeutic dose), or after chronic nightly oral doses of flibanserin 100 mg for 1 week followed by a single bedtime dose of flibanserin 200 mg (supratherapeutic dose). Simulated driving assessments were conducted 9 hr after dosing and cognitive function tests were administered immediately before or during the driving assessment. RESULTS: Zopiclone increased standard deviation of lateral position (≥3.1 cm; p < .0001) relative to placebo and impaired other parameters previously shown to be sensitive to sedation. No impairment was detected for flibanserin at either dose relative to placebo. Flibanserin 200 mg was similar to the 100-mg dose on cognitive testing and driving performance even though commonly reported adverse events for flibanserin were predictably increased at the higher dose. CONCLUSIONS: At both therapeutic and supratherapeutic doses, flibanserin did not impair next-day driving performance and cognitive function compared to placebo.

Next-day residual effects of gabapentin, diphenhydramine, and triazolam on simulated driving performance in healthy volunteers: a phase 3, randomized, double-blind, placebo-controlled, crossover trial.

OBJECTIVE: Next-day residual effects of a nighttime dose of gabapentin 250 mg were evaluated on simulated driving performance in healthy participants in a randomized, placebo-controlled, double-blind, multicenter, four-period crossover study that included diphenhydramine citrate 76 mg and triazolam 0.5 mg. METHODS: At treatment visits, participants (n = 59) were dosed at ~23:30, went to bed immediately, and awakened 6.5 h postdose for evaluation. The primary endpoint was the standard deviation of lateral position for the 100-km driving scenario. Additional measures of driving, sleepiness, and cognition were included. RESULTS: Study sensitivity was established with triazolam, which demonstrated significant next-day impairment on all driving endpoints, relative to placebo (p < 0.001). Gabapentin demonstrated noninferiority to placebo on standard deviation of lateral position and speed deviation but not for lane excursions. Diphenhydramine citrate demonstrated significant impairment relative to gabapentin and placebo on speed deviation (p < 0.05). Other comparisons were either nonsignificant or statistically ineligible per planned, sequential comparisons. Secondary endpoints for sleepiness and cognitive performance were supportive of these conclusions. CONCLUSIONS: Together, these data suggest that low-dose gabapentin had no appreciable next-day effects on simulated driving performance or cognitive functioning. Copyright © 2016 John Wiley & Sons, Ltd.

A randomized, crossover, placebo-controlled clinical trial to assess the sensitivity of the CRCDS Mini-Sim to the next-day residual effects of zopiclone.

OBJECTIVES: We sought to validate Cognitive Research Corporation's Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability. METHODS: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design. RESULTS: Evening administration of 7.5 mg zopiclone increased next-day standard deviation of lateral lane position (SDLP) by 2.62 cm on average compared with evening administration of placebo, and caused significant effects on symmetry analysis. The magnitude of the change in SDLP is highly similar to changes previously observed using on-the-road driving methods. CONCLUSIONS: Further validation of the CRCDS Mini-Sim is warranted to develop this platform for drug safety studies.

Relationship Between Obesity and Driving.

Obesity, which has become epidemic throughout many parts of the world, is known to be a risk factor for a range of diseases including hypertension, diabetes, and vascular disease. Based on this review, it also appears that obesity is associated with increased crash risk and increased risk of serious or fatal injury in a crash. The problem is particularly an issue for commercial truck drivers. Data are presented showing the high prevalence of obesity in truck drivers. Inadequate sleep, poor nutrition, lack of exercise, and the sedentary nature of driving all contribute to the risk of obesity. The obesity related condition of obstructive sleep apnea (OSA) is known to increase crash risk. Treatment of this condition has been demonstrated to improve driving performance and to reduce crash risk. Screening truck drivers for obesity related health conditions, such as OSA, would be expected to result in public safety benefits.

Early-stage comparative effectiveness: randomized controlled trial with histamine inverse agonist MK-7288 in excessive daytime sleepiness patients.

Histaminergic neurons are regulators of the sleep-wake cycle. We evaluated the alerting effects of MK-7288 (10, 20 mg), a novel histamine-3 receptor inverse agonist (H3RIA), along with modafinil (200 mg), a standard treatment, in a randomized, double-blind, placebo controlled, crossover study of 56 patients with excessive daytime sleepiness (EDS). Efficacy was assessed using maintenance of wakefulness tests (MWT) and car driving simulation tests. MK-7288 and modafinil significantly prolonged MWT sleep latency (improvements vs. placebo of 8.1 to 8.2 min for MK-7288 and 10.2 min for modafinil), and improved car driving simulation standard deviation of lane position (reduction vs. placebo of -0.1 m for each treatment). MK-7288 was associated with more insomnia (29%) than modafinil (9%) and placebo (6%). The study demonstrated the potential of the H3RIA mechanism for treating EDS, but did not show efficacy differentiation from modafinil. Early-stage comparative effectiveness can help prevent late-stage failure and increase the cost-effectiveness of drug development.

Effects of armodafinil on simulated driving and self-report measures in obstructive sleep apnea patients prior to treatment with continuous positive airway pressure.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has been associated with an increased risk of motor vehicle crashes. This driving risk can be reduced (≥ 50%) by treatment with continuous positive airway pressure (CPAP). However residual excessive daytime sleepiness (EDS) can persist for some patients who regularly use CPAP. The current study was designed to assess the effect of armodafinil on simulated driving performance and subsequent CPAP treatment compliance in newly diagnosed OSA patients with EDS during a 2-week "waiting period" prior to initiation of CPAP. METHODS: Sixty-nine newly diagnosed OSA patients, awaiting CPAP therapy, were randomized (1:1) to placebo or armodafinil (150 mg/day) treatment. Simulated driving tests and self-report measures were completed at baseline, after 2 weeks of drug treatment, and following 6 weeks of CPAP treatment. CPAP compliance was evaluated at the end of 6 weeks of CPAP. RESULTS: Compared to placebo, armodafinil improved simulated driving safety performance in OSA patients awaiting CPAP therapy (p = 0.03). Improvement was seen in lane position deviation (p = 0.002) and number of lane excursions (p = 0.02). Improvement was also observed on measures of sleepiness using the Epworth Sleepiness Scale (ESS) and sleep related quality of life. Following 6 weeks of CPAP, there was also significant improvement observed on multiple measures of simulated driving performance. CPAP compliance did not differ between armodafinil-treated and placebo-treated patients (p = 0.80). CONCLUSIONS: Armodafinil was found to improve simulated driving performance in OSA patients with EDS prior to initiation of CPAP. Treatment with armodafinil showed no effect on subsequent CPAP compliance.

Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES).

STUDY OBJECTIVE: To determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA). DESIGN, SETTING, AND PARTICIPANTS: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures. INTERVENTION: Active or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F]) RESULTS: The primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test. CONCLUSIONS: CPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship. CLINICAL TRIAL INFORMATION: Registered at clinicaltrials.gov. Identifier: NCT00051363. CITATION: Kushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.

Cognitive effects of oxybutynin chloride topical gel in older healthy subjects: a 1-week, randomized, double-blind, placebo- and active-controlled study.

BACKGROUND AND OBJECTIVE: Oxybutynin is a common antimuscarinic therapy for overactive bladder. Transdermally administered oxybutynin chloride topical gel 10% (OTG) has a low propensity for anticholinergic adverse effects and possibly also a low risk of cognitive impairment. A randomized, double-blind, placebo- and active-controlled study evaluated the effects of OTG on cognitive and psychomotor functions in older healthy adults. METHODS: Healthy adults aged 60-79 years were assigned randomly (1:1:1) to 1-week's treatment with OTG (1 g [100 mg oxybutynin] applied once daily on rotating sites of upper arms/shoulders, abdomen or thighs) plus oral placebo, immediate-release oxybutynin (OXB-IR; 5 mg capsule three times/day) plus placebo gel, or double placebo. Delayed recall Name-Face Association Test (NFAT) score was the primary end point. Treatments were compared by analysis of covariance. RESULTS: Of 152 participants (mean age, 68 years), 49 received OTG, 52 OXB-IR and 51 placebo. NFAT Delayed Recall tests revealed no significant treatment differences (overall, p = 0.2733; OTG vs placebo, p = 0.1551; OXB-IR vs placebo, p = 0.1767). However, a significant effect (p = 0.0294) was noted for the Misplaced Objects Test, with scores declining only for OXB-IR. Approximately twice as many participants receiving OXB-IR (n = 10) as those receiving OTG (n = 5) or placebo (n = 6) showed a significant decline (≥6 points) in Total Recall score for the Hopkins Verbal Learning Test-Revised. No significant effects on psychomotor reaction time were observed. The most common adverse event, dry mouth, occurred in 6.1%, 73.1% and 7.8% of participants receiving OTG, OXB-IR and placebo, respectively. CONCLUSIONS: OTG applied for 1 week had no clinically meaningful effect on recent memory or other cognitive functions in healthy, older adults. CLINICAL TRIAL REGISTRATION: Registered as NCT00752141 at www.clinicaltrials.gov.

Evaluation of cognitive function in healthy older subjects treated with fesoterodine.

OBJECTIVE: To evaluate the cognitive effects of fesoterodine 4 and 8 mg versus placebo in healthy older adults. METHODS: This was an active- and placebo-controlled, double-blind, double-dummy crossover study conducted using healthy volunteers (aged 65-85 years) with baseline Mini-Mental State Examination score ≥ 26. The study comprised 4 treatment periods: fesoterodine 4 mg for 6 days; fesoterodine 4 mg for 3 days followed by fesoterodine 8 mg for 3 days; placebo for 6 days; and placebo for 6 days with alprazolam 1 mg on day 6. The treatment sequence was randomized, with a 3- to 6-day washout between periods. Subjects completed computer-based cognitive assessments and the Rey Auditory Verbal Learning Test on day 1 (before dosing) and day 6 (after dosing) of each period. The primary endpoint was the Detection task; secondary endpoints were the Identification task, 1-card learning task, Continuous Paired Associate Learning task, Groton Maze Learning Task, and the Rey Auditory Verbal Learning Test. RESULTS: Among 18 subjects in the per protocol set, changes from baseline to day 6 with fesoterodine 4 and 8 mg were not significantly different from placebo for any endpoint (P > 0.05); alprazolam produced significant impairment in all endpoints versus placebo (P < 0.05). No serious adverse events were reported; the most common adverse events were dry mouth for fesoterodine and sedation for alprazolam. No sedation was reported with fesoterodine. CONCLUSION: In healthy older adults, fesoterodine 4 and 8 mg once daily had no statistically significant effects versus placebo on any cognitive function assessed, including memory; alprazolam 1 mg produced statistically significant deterioration.

Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder.

Overactive bladder (OAB) is a common condition, particularly in the elderly. Anticholinergic agents are the mainstay of pharmacological treatment of OAB; however, many anticholinergics can cross the blood-brain barrier (BBB) and may cause central nervous system (CNS) effects, including cognitive deficits, which can be especially detrimental in older patients. Many anticholinergics have the potential to cause adverse CNS effects due to muscarinic (M(1)) receptor binding in the brain. Of note, permeability of the BBB increases with age and can also be affected by trauma, stress, and some diseases and medications. Passive crossing of a molecule across the BBB into the brain is dependent upon its physicochemical properties. Molecular characteristics that hinder passive BBB penetration include a large molecular size, positive or negative ionic charge at physiological pH, and a hydrophilic structure. Active transport across the BBB is dependent upon protein-mediated transporter systems, such as that of permeability-glycoprotein (P-gp), which occurs only for P-gp substrates, such as trospium chloride, darifenacin and fesoterodine. Reliance on active transport can be problematic since genetic polymorphisms of P-gp exist, and many commonly used drugs and even some foods are P-gp inhibitors or are substrates themselves and, due to competition, can reduce the amount of the drug that is actively transported out of the CNS. Therefore, for drugs that are preferred not to cross into the CNS, such as potent anticholinergics intended for the bladder, it is optimal to have minimal passive crossing of the BBB, although it may also be beneficial for the drug to be a substrate for an active efflux transport system. Anticholinergics demonstrate different propensities to cross the BBB. Darifenacin, fesoterodine and trospium chloride are substrates for P-gp and, therefore, are actively transported away from the brain. In addition, trospium chloride has not been detected in cerebrospinal fluid assays and does not appear to have significant CNS penetration. This article reviews the properties of anticholinergics that affect BBB penetration and active transport out of the CNS, discusses issues of increased BBB permeability in patients with OAB, and examines the clinical implications of BBB penetration on adverse events associated with anticholinergics.

A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: This study provides antimuscarinic agents for overactive bladder (OAB) display variable association with side effects mediated by the central nervous system (CNS), which may be of particular concern in the elderly. Adverse effects on CNS functioning are related to muscarinic receptor subtype selectivity and the ability of the agent to cross the blood-brain barrier, where P-gp plays a role in limiting permeability. WHAT THIS STUDY ADDS: This study provides a parallel investigation of CNS penetration of antimuscarinic OAB agents in vivo and assessment of physical properties and permeability in cell monolayers in vitro. It adds further understanding of the roles of passive transcellular permeability and P-gp in determining CNS penetration of antimuscarinic OAB agents. It also enables a comparison of CNS side-effect profiles of OAB agents with preclinical CNS penetration data. AIMS: To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents. METHODS: Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTS: Oxybutynin displayed extensive CNS penetration, with brain:plasma ratios (B:P), unbound brain:unbound plasma ratios (Kp,free) and CSF:free plasma ratios each >1. Tolterodine (B:P = 2.95, Kp,free = 0.23 and CSF:free plasma = 0.16) and solifenacin (B:P = 3.04, Kp,free = 0.28 and CSF:free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B:P (0.03-0.16), Kp,free (0.01-0.04) and CSF:free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10(-6) cm s(-1) ), moderate for 5-HMT (11.7 × 10(-6) cm s(-1) ) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 × 10(-6) cm s(-1) ). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONS: Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.

The association between obstructive sleep apnea and neurocognitive performance--the Apnea Positive Pressure Long-term Efficacy Study (APPLES).

STUDY OBJECTIVES: To determine associations between obstructive sleep apnea (OSA) and neurocognitive performance in a large cohort of adults. STUDY DESIGN: Cross-sectional analyses of polysomnographic and neurocognitive data from 1204 adult participants with a clinical diagnosis of obstructive sleep apnea (OSA) in the Apnea Positive Pressure Long-term Efficacy Study (APPLES), assessed at baseline before randomization to either continuous positive airway pressure (CPAP) or sham CPAP. MEASUREMENTS: Sleep and respiratory indices obtained by laboratory polysomnography and several measures of neurocognitive performance. RESULTS: Weak correlations were found for both the apnea hypopnea index (AHI) and several indices of oxygen desaturation and neurocognitive performance in unadjusted analyses. After adjustment for level of education, ethnicity, and gender, there was no association between the AHI and neurocognitive performance. However, severity of oxygen desaturation was weakly associated with worse neurocognitive performance on some measures of intelligence, attention, and processing speed. CONCLUSIONS: The impact of OSA on neurocognitive performance is small for many individuals with this condition and is most related to the severity of hypoxemia.

Simulated driving changes in young adults with ADHD receiving mixed amphetamine salts extended release and atomoxetine.

BACKGROUND: Psychostimulant treatment may improve simulated driving performance in young adults with attention-deficit/hyperactivity disorder (ADHD). METHOD: This was a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with mixed amphetamine salts-extended release (MAS XR) 50 mg/day (Cohort 1) and atomoxetine 80 mg/day (Cohort 2) in young adults with ADHD. RESULTS: Adults aged 19 to 25 years with AD/HD (N = 19) who were administered MAS XR significantly improved overall simulated driving performance versus placebo up to 12 hours after dosing. In contrast, there were no statistically significant differences in simulated-driving-performance scores between atomoxetine and placebo. At endpoint, MAS XR reduced ADHD Rating Scale scores > or = 30% in 80% of subjects, whereas atomoxetine achieved this level of improvement for 40%. LIMITATIONS: Small sample size and use of simulated driving may limit generalizability of the findings. CONCLUSION: MAS XR in young adults with ADHD yields significant improvements in simulated driving performance and ADHD symptoms.

Pharmacodynamic effects of darifenacin, a muscarinic M selective receptor antagonist for the treatment of overactive bladder, in healthy volunteers.

OBJECTIVE: To evaluate the pharmacodynamic effects of darifenacin (a muscarinic M(3) selective receptor antagonist) and dicyclomine (an M(1) selective receptor antagonist) in healthy male volunteers. SUBJECTS AND METHODS: In this double-blind, four-way crossover study, 27 healthy men (aged 19-44 years) were randomized to receive darifenacin 7.5 mg or 15 mg once daily, dicyclomine 20 mg four times daily or matching placebo. Each 7-day treatment period was separated by a 7-day washout. Multiple assessments of cognitive function, quantitative electroencephalogram (EEG) recordings, salivation, visual nearpoint, heart rate and heart rate variability were made on day 7 in each treatment period. RESULTS: Compared with placebo, neither dose of darifenacin affected cognitive function, whereas dicyclomine impaired performance on five of the 12 variables 2 h after dosing; simple reaction time (P = 0.009), speed of numeric (P = 0.012) and spatial (P = 0.048) working memory, and speed (P = 0.04) and sensitivity (P = 0.03) of picture recognition. These cognitive changes were accompanied by slowing of the EEG for dicyclomine. Darifenacin showed no clinically relevant effect on EEG. Darifenacin 7.5 and 15 mg once daily did not differ from placebo in effects on visual nearpoint, heart rate or heart rate variability. By contrast, dicyclomine significantly increased the maximum visual nearpoint, decreased heart rate and increased heart rate variability, relative to placebo. Both agents decreased salivary flow rate vs placebo. Treatment-related adverse events were comparable in all groups, the most common being dry mouth; none led to treatment discontinuation. CONCLUSIONS: Darifenacin did not affect cognitive, cardiac or visual function in healthy volunteers, a profile that may reflect its relative M(3) receptor selectivity and M(1)/M(2) sparing properties.

Antimuscarinic agents: implications and concerns in the management of overactive bladder in the elderly.

BACKGROUND: Overactive bladder (OAB) is a widespread problem that has a negative effect on quality of life, particularly among the elderly. Antimuscarinic agents are the only drug class with broad, accepted efficacy in the treatment of OAB. Their clinical usefulness, however, is limited by dose-dependent adverse effects. In the elderly, the most serious of these is central nervous system (CNS) dysfunction, including cognitive impairment. OBJECTIVE: This article examines currently available antimuscarinic agents for the treatment of OAB in terms of their likelihood of causing CNS dysfunction by crossing the blood-brain barrier (BBB) and blocking muscarinic type 1 (Ml) receptor sites in the brain. METHODS: Pertinent studies were selected from a comprehensive review of the OAB literature with a focus on muscarinic receptor-associated mechanisms leading to CNS adverse effects and their potential impact on elderly patients. MEDLINE was searched for articles published in the past 10 years, and additional articles were obtained from the reference lists of identified publications. Also searched were abstracts of recent meetings of the International Consultation on Incontinence, International Continence Society, American Urological Association, and European Association of Urology. RESULTS: Antimuscarinic agents control involuntary detrusor muscle contractions through cholinergic blockade at the muscarinic receptors. The prevalence of OAB is highest in the elderly, the population most likely to be taking multiple anticholinergic medications and most vulnerable to the CNS adverse effects of these agents. Nonselective antimuscarinic agents that bind to the Ml receptor are most likely to cause significant cognitive adverse effects compared with the more selective antimuscarinic agents for the treatment of OAB. CONCLUSIONS: When considering use of an antimuscarinic agent for the treatment of OAB in elderly patients, prescribers should routinely consider the agent's receptor selectivity and ability to cross the BBB. The medical history should include all current medications that may contribute to the anticholinergic burden and cognitive impairment. Patients and caregivers should be educated to recognize anticholinergic adverse effects.

Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients.

Antimuscarinic agents are the predominant pharmacological treatment for patients with overactive bladder (OAB). These drugs are thought to act primarily through antagonism at muscarinic M3 receptors located at neuromuscular junctions in the human bladder detrusor muscle. Several of these drugs have been shown to be efficacious in ameliorating the symptoms of OAB in older patients, but most currently available agents lack selectivity for the M3 receptor subtype, and interaction with other muscarinic receptor subtypes throughout the body may adversely affect a variety of physiological functions and result in unwanted side effects, including cognitive dysfunction. With the recent availability of antimuscarinic agents that show increased selectivity for M3 receptors relative to other muscarinic subtypes, an invitational expert panel meeting was convened to review not only the mechanisms by which antimuscarinic agents could affect cognitive function, but also the published literature on cognitive adverse events. A review of the literature shows that the cholinergic system in the central nervous system (CNS) exerts a major influence on cognitive processes, in particular memory via M1 cholinergic receptors. In addition, recent evidence suggests a role for M2 receptors in mediating cognitive function. Thus, cognitive dysfunction (including memory loss) during treatment with nonselective antimuscarinic agents for OAB is of growing concern, particularly in older patients and those with mild cognitive impairment or dementia. Increased blood-brain barrier permeability, which can occur with advanced age and certain comorbidities, may also facilitate CNS access of antimuscarinic agents (regardless of their physiochemical properties) and add to antimuscarinic burden. On the basis of available evidence, antimuscarinic agents with selectivity for M3 over M1 and M2 receptors, limited CNS penetration, or both may therefore offer a favorable balance of efficacy in treating OAB together with a reduced risk of adverse cognitive events in the older population.

Human exposure to the jet fuel, JP-8.

INTRODUCTION: This study investigates anecdotal reports that have suggested adverse health effects associated with acute or chronic exposure to jet fuel. METHODS: JP-8 exposure during the course of the study day was estimated using breath analysis. Health effects associated with exposure were measured using a neurocognitive testing battery and liver and kidney function tests. RESULTS: Breath analysis provided an estimate of an individual's recent JP-8 exposure that had occurred via inhalation and dermal routes. All individuals studied on base exhaled aromatic and aliphatic hydrocarbons that are found in JP-8. The subject who showed evidence of the most exposure to JP-8 had a breath concentration of 11.5 mg x m(-3) for total JP-8. This breath concentration suggested that exposure to JP-8 at an Air Guard Base is much less than exposure observed at other Air Force Bases. This reduction in exposure to JP-8 is attributed to the safety practices and standard operating procedures carried out by base personnel. The base personnel who exhibited the highest exposures to JP-8 were fuel cell workers, fuel specialists and smokers, who smoked downwind from the flightline. DISCUSSION: Although study-day exposures appear to be much less than current guidelines, chronic exposure at these low levels appeared to affect neurocognitive functioning. JP-8-exposed individuals performed significantly poorer than a sample of non-exposed age- and education-matched individuals on 20 of 47 measures of information processing and other cognitive functions.