Transdermal Nicotine Treatment and Progression of Early Parkinson's Disease.

BACKGROUND: Epidemiologic studies show that smokers have a lower incidence of Parkinson's disease. Nicotine has been hypothesized to slow progression in early Parkinson's disease. METHODS: In a double-blind, placebo-controlled multicenter trial, we randomly assigned patients with Parkinson's disease, diagnosed within 18 months, who were in Hoehn and Yahr disease stage less than or equal to 2 (range from 0 to 5; higher scores indicate greater impairment), who were therapy naïve (except for stable monoamine-oxidase-B inhibition), and not requiring dopaminergic therapy, to transdermal nicotine or placebo. The primary end point was change in Unified Parkinson's Disease Rating Scale parts I­III (Total UPDRS) score (range from 0 to 172; higher scores indicate greater impairment) between baseline and 60 weeks (52 weeks of trial therapy, 8 weeks of washout). The first secondary end point was change in Total UPDRS from baseline to 52 weeks. Differences between groups were estimated using the Hodges­Lehmann (HL) method and tested with the exact two-sided stratified Mann­Whitney­Wilcoxon test according to the intention-to-treat principle. RESULTS: Among 163 participants, 101 were assessed for the primary end point. Mean worsening of Total UPDRS was 3.5 in the placebo versus 6.0 in the nicotine group (HL-difference with 95% CI: ­3 [­6 to 0], P=0.06). For the first secondary end point, analysis of 138 participants showed a mean worsening of 5.4 in the placebo versus 9.1 in the nicotine group (HL-difference with 95% CI: ­4 [­7 to ­1]). Dropout was mainly because of early treatment discontinuation or adverse events. Cutaneous adverse effects at the patch application site were common. In all, 34.6% of participants initiated dopaminergic therapy during participation. CONCLUSIONS: One-year transdermal nicotine treatment did not slow progression in early Parkinson's disease. (Funded by the Michael J. Fox Foundation for Parkinson's Research and others; ClinicalTrials.gov number, NCT01560754; EudraCT number, 2010-020299-42.)

Effects of rivastigmine on actigraphically monitored motor activity in severe agitation related to Alzheimer's disease: a placebo-controlled pilot study.

Acetylcholinesterase inhibitors (AChEIs) are effective in the treatment of cognitive symptoms in Alzheimer's disease (AD). Because the behavioral and psychological symptoms of dementia (BPSD) have also been attributed to central cholinergic deficits, we examined whether the AChEI rivastigmine can reduce motor activity as measured in a rater-independent manner by wrist actigraphy in agitated AD patients. A total of 20 consecutive AD inpatients (13 females, 7 males, 80.4+/-9.1 years, S.D.) were included from our geriatric psychiatry unit, all of whom were exhibiting agitated behavior not attributable to delirium. Patients were assigned randomly and in a single-blinded fashion to rivastigmine 3mg or placebo for 14 days. Motor activity levels were monitored using an actigraph worn continuously on the wrist of the non-dominant hand. At the beginning and end of the study, patients were assessed using the Neuropsychiatric Inventory (NPI) and Nurses' Observation Scale for Geriatric Patients (NOSGER). Patients in the rivastigmine group exhibited less agitation than placebo recipients on the NPI-agitation subscale, but not on NOSGER. Actigraphic measurements showed a tendency towards reduced motor activity in the rivastigmine group. Because rivastigmine usually exerts its main effects after a longer period of time, the short-term effects seen in our study justify further controlled clinical trials examining the use of rivastigmine in BPSD by means of actigraphy.

The influence of age and sex on sleep latency in the MSLT-30--a normative study.

STUDY OBJECTIVES: The Multiple Sleep Latency Test-30 (MSLT-30) is a variation of the Multiple Sleep Latency Test with a fixed duration of 30 minutes for each of 5 test sessions. It requires less effort for reliable recording and is not susceptible to on-line scoring errors. The aim of the study was to provide normative data for the clinical use of the MSLT-30 and to evaluate the influence of age, sex, and other sociodemographic variables. DESIGN: An MSLT-30, along with measures of mood, objective, and subjective sleepiness was performed in a sample of healthy subjects in a balanced quota design. SETTING: Sleep laboratory in a sleep disorders center. PARTICIPANTS: One hundred subjects with no complaint of sleep disturbance or daytime sleepiness, 10 men and 10 women each from 5 age decades from 20 to 69 years. INTERVENTIONS: None. RESULTS: Mean latency to sleep stage 1 or any other sleep stage was 13.9 +/- 6.9 minutes. The SL-30 showed a clear quadratic association with age, with the shortest latencies in the middle age groups. No correlation was found between the mean latency to sleep stage 1 or any other sleep stage and sociodemographic variables or other measures of daytime sleepiness (Epworth Sleepiness Scale, vigilance test), mood scales, sleep quality (Pittsburgh Sleep Quality Index), and amount of prior sleep. CONCLUSIONS: Sleep latencies in normal subjects are age dependent in a quadratic fashion, with a minimum in middle-aged subjects. This reconciles the findings of a long mean sleep latency in the MSLT of adolescents and of an increase on the mean sleep latency with age in adults.

Adding memantine to rivastigmine therapy in patients with mild-to-moderate alzheimer's disease: results of a 12-week, open-label pilot study.

OBJECTIVE: At present, inhibition of cholines-terase is the treatment of choice for subjects with mild-to-moderate Alzheimer's disease (AD). Memantine, a noncompetitive antagonist at N-methyl-d-aspartate receptors, is currently used to treat subjects with moderate-to-severe AD. The goal of this multicenter, open-label pilot study was to investigate whether combination therapy with memantine added to rivastigmine is safe and beneficial in subjects with mild-to-moderate AD. METHOD: Patients with a DSM-IV diagnosis of dementia of the Alzheimer's type (N = 95), who were treated with rivastigmine (6-12 mg/day) for a maximum duration of 24 weeks prior to baseline, received memantine (5-20 mg/day) in combination with rivastigmine for 12 weeks. The primary efficacy variable was the change in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) total score at the end of 12 weeks compared with baseline. The study was conducted between September 15, 2003, and May 27, 2004. RESULTS: There was a statistically significant difference between baseline and week 12 for the ADAS-cog total score, showing a positive effect of combination therapy. Combination therapy did not evidence any unexpected safety concerns and was well-tolerated by most patients. CONCLUSION: Memantine in combination with rivastigmine appears to be safe and beneficial in patients with mild-to-moderate AD. Our results need to be confirmed in a large, long-term, randomized, double-blind, placebo-controlled clinical trial.

The influence of polysomnography on the Multiple Sleep Latency Test and other measures of daytime sleepiness.

INTRODUCTION: According to its guidelines, the Multiple Sleep Latency Test (MSLT) should be performed following an all-night polysomnography (PSG). However, the sleep quality and consequently the MSLT results may be affected by PSG and by the fact that a subject sleeps under unfamiliar conditions. The aim of this study was to examine whether PSG performed in a sleep laboratory has any influence on the MSLT and other measures of daytime sleepiness. METHODS: Twenty healthy subjects with a mean age of 35.9+/-10.1 years underwent two MSLT examinations, and the 2 examination days were at least 4 weeks apart. In addition, on each occasion a monotonous vigilance task (VT) was performed and the subjects were asked to fill out the Epworth Sleepiness (ESS) and Visual Analogue Scales (VAS). In a cross-over design, a group of 10 subjects underwent a MSLT (MSLT-P) following a PSG and, on a second occasion, a MSLT (MSLT-N) was performed without a prior PSG. Vice versa, a second group of 10 subjects underwent first MSLT-N and then MSLT-P. RESULTS: None of the MSLT parameters differed significantly between MSLT-P and MSLT-N. The other measures of daytime sleepiness (VT, ESS, VAS) also showed no evidence of significant differences between days with and without a prior PSG. CONCLUSIONS: The results of MSLT and other measures of daytime sleepiness in healthy subjects are not influenced by the fact whether or not the subjects had a PSG the night prior to MSLT.

Effectiveness and tolerability of transdermal rivastigmine in the treatment of Alzheimer's disease in daily practice.

BACKGROUND: Oral cholinesterase inhibitors at doses efficacious for the treatment of Alzheimer's disease (AD) are often prematurely discontinued due to gastrointestinal side effects. In controlled clinical trials, transdermal rivastigmine demonstrated less such effects at similar efficacy. The current study aimed to verify the validity of this data in daily practice. METHODS: This was a prospective, multicenter, observational study on transdermal rivastigmine in Germany. Eligible patients were those with AD who had not yet been treated with rivastigmine. Outcome measures were changes in clock-drawing test, Mini-Mental State Examination (MMSE), Caregiver Burden Scale, Clinical Global Impression (CGI), physicians' assessments of tolerability, and the incidence of adverse events (AEs) over 4 months of treatment. RESULTS: In 257 centers 1113 patients were enrolled; 614 women and 499 men, mean age 76.5 years. In 58% of patients AD was treated for the first time and in 42% therapy was switched to transdermal rivastigmine, mostly due to lack of tolerability (13.6%) or effectiveness (26.9%). After 4 months, 67.4% of patients were on the target dose of 9.5 mg/day and 21.8% were still on 4.6 mg/day. MMSE significantly improved in patients with and without pretreatment (ΔMMSE, 0.9 ± 3.4 and 0.8 ± 3.4, respectively, both P < 0.001); the CGI score improved in 60.9% and 61.3% of patients, respectively. Overall 11.7% of patients had AEs, mainly affecting the skin or the gastrointestinal tract; in 1.1% of cases AEs were serious; 14.7% of patients discontinued therapy, 6.0% due to AEs. With rivastigmine treatment the percentage of patients taking psychotropic comedication decreased, particularly in first-time treated rivastigmine patients (from 27.1% to 22.6%; P < 0.001). CONCLUSION: Results were in line with data from controlled clinical trials. Switching from any other oral acetylcholinesterase inhibitor to transdermal rivastigmine may improve cognition.

Effects of oxcarbazepine and carbamazepine on driving ability: a double-blind, randomized crossover trial with healthy volunteers.

RATIONALE: Carbamazepine (CBZ) is known to produce cognitive side effects being at least partly relevant for driving. In contrast to this, the cognitive effects of oxcarbazepine (OXC) are suspected to be less pronounced. OBJECTIVE: This study aimed to test 900 mg/day OXC as compared to 600 mg/day CBZ with respect to driving. METHODS: Driving performance of 27 healthy volunteers under subchronic treatment of OXC and CBZ was assessed in a driving simulator with a double-blind, randomized, crossover design including a baseline measurement. The test course contained a representative set of scenarios. Lane-keeping performance, driving mistakes, and eyelid closure (as a behavioral measure of sleepiness) were analyzed. In addition, subjects were asked to assess their driving performance, effort, attention, and sleepiness subjectively. RESULTS: Both drugs had negative effects on driving as reflected in poorer lane-keeping performance, higher rate of driving mistakes, increased sleepiness, and worse subjective ratings. These effects were most obvious in monotonous situations and could be compensated in situations challenging to cognitive and motor driving skills. With respect to all considered parameters, CBZ did more often differ significantly from baseline than OXC. CONCLUSIONS: Under both drugs, driving performance was worse than at baseline. Even though deterioration of driving performance was only slightly less pronounced under OXC than under CBZ, it might be recommended as more appropriate than CBZ for epileptic patients who need to drive a car.

A double-blind, randomized, placebo/active controlled crossover evaluation of the efficacy and safety of Ritalin ® LA in children with attention-deficit/hyperactivity disorder in a laboratory classroom setting.

OBJECTIVES: The primary objective of this study was to demonstrate efficacy of Ritalin(®) LA 20 mg by showing superiority to placebo and noninferiority to Medikinet(®) Retard in a laboratory classroom setting. Secondary objectives included safety/tolerability and further efficacy parameters. METHODS: A total of 147 children with attention-deficit/hyperactivity disorder (ADHD) diagnosed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and aged 6-14 (81% males) and known to be methylphenidate (MPH) responders were enrolled in this multicenter, double-blind, randomized, placebo/active-controlled, three-period (7 days each) crossover study. The Swanson, Kotlin, Agler, M-Flynn, and Pelham (SKAMP) scale was used for efficacy ratings. The mean of SKAMP Combined ratings performed at 10:30 a.m., at 12:00 a.m., and at 1:30 p.m. was defined as the primary parameter. RESULTS: In all, 146 patients completed all treatment periods. Intensity and frequency of adverse events were comparable between the two formulations. Ritalin(®) LA demonstrated superiority compared to placebo (p<0.0001). The observed difference in the SKAMP scores between Ritalin(®) LA and Medikinet(®) Retard between the hours 1.5 until 4.5 did not exceed the noninferiority margin (p=0.0003); therefore, the difference is regarded as not clinically relevant. Similar results were obtained for the secondary efficacy variables. CONCLUSION: Ritalin(®) LA is an efficacious, well-tolerated treatment option for children aged 6-14 with ADHD.

Domain-specific improvement of cognition on memantine in patients with Alzheimer's disease treated with rivastigmine.

OBJECTIVE: Cholinergic therapy is used in mild-to-moderate Alzheimer's disease (AD) and antiglutamatergic therapy in moderate-to-severe AD. Global scales, as commonly used in clinical trials, blur specifics of disease progression and drug effects. The objective was to assess combination therapy of rivastigmine plus memantine by specific neuropsychological tests in patients with mild-to-moderate AD. METHODS: 12-week-short multicenter open-label pilot study. Ninety patients with mild-to-moderate AD already on stable medication with rivastigmine (3-6 mg b.i.d.) additionally received memantine for 12 weeks. Subscales of the Alzheimer's Disease Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE) and additional neuropsychological tests (e.g. span tasks, semantic fluency) were assessed. RESULTS: The scores in the ADAS-cog memory subscale, the MMSE score, and digit span and semantic fluency significantly improved on combination therapy. CONCLUSION: Memory improvement was correlated with ADAS-cog memory score at baseline and inversely with age at onset of treatment. The data suggest that improvement on combination therapy results from an improvement of attention/executive function with secondary memory improvement, which will need to be confirmed in a subsequent double-blind study on a larger number of patients.