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We investigate the behavior of stocks in daily price-limited stock markets by purposing a quantum spatial-periodic harmonic model. The stock price is presumed to oscillate and damp in a quantum spatial-periodic harmonic oscillator potential well. Complicated non-linear relations including inter-band positive correlation and intra-band negative correlation between the volatility and the trading volume of stocks are derived by considering the energy band structure of the model. The validity of price limitation is then examined and abnormal phenomena of a price-limited stock market (Shanghai Stock Exchange) of China are studied by applying our quantum model., 8 pages, 9 figures

Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenya(®), Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis. Fingolimod first-dose administration is associated with a transient, generally asymptomatic, slowing of heart rate, which may also prolong QT interval. This posthoc analysis compared cardiac outcomes in over 3300 patients with relapsing multiple sclerosis who were or were not receiving SSRIs during fingolimod treatment initiation, including a subset of patients receiving citalopram or escitalopram. Vital signs were recorded hourly for 6h, and electrocardiograms were obtained pre-dose and 6 h post-dose. Changes in mean hourly heart rate from baseline (pre-dose) to 6 h post-dose were similar among patients not receiving SSRIs (fingolimod 0.5 mg, -7.5 bpm; placebo, 0.0 bpm) and those receiving SSRIs (fingolimod 0.5 mg, -6.6 bpm; placebo, 0.3 bpm). In patients treated with fingolimod 0.5 mg, the mean change in corrected QT interval from baseline to 6 h after treatment initiation was under 10 ms, and few patients had absolute corrected QT intervals of over 450 ms (men) or 470 ms (women), calculated according to Bazett׳s or Fridericia׳s correction methods, irrespective of whether or not they were receiving an SSRI; similar findings were reported in the placebo group. Co-administration of SSRIs and fingolimod was not associated with an increased incidence of any electrocardiogram findings compared with fingolimod therapy alone, and the majority of patients receiving fingolimod (83-86%) were discharged from first-dose monitoring at 6 h irrespective of whether they were also receiving SSRIs. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation.

Advances in digital technologies have led to an increasing concern about piracy for providers of digital content (e.g., e-books, games, music, software, videos). Yet controversies exist over the influence of copyright protection on firm profitability. The objective of this paper is to provide an alternative rationale for the growing anti-protection trend and to investigate optimal copyright enforcement and quality provision in a monopoly setting. The proposed economic mechanism centers on the influence of copyright protection on consumer search when consumers can get to know the firm’s actions (e.g., price, quality) only after costly search. We show that more stringent copyright protection can induce the consumers to rationally expect lower ex post surplus, thus exerting a negative strategic effect on the consumers' willingness to search. This strategic effect may outweigh the positive main effect on the relative attractiveness of the authorized versus the pirated product, which can hence explain the optimality of incomplete and even zero copyright protection policies in markets where consumer prepurchase search is important (e.g., information goods, digital products). It is also because of this strategic effect that the firm may provide lower quality as copyright enforcement increases. Interestingly, quality unobservability can moderate this strategic effect and thus lead to an increasing incentive for copyright protection. This paper was accepted by Pradeep Chintagunta, marketing.

The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open-label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (-4.6; SD=8.7) and SIB (-7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (-3.9; SD=8.0 and -4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch.

Background In the absence of controlled, parallel-group studies, statistical methods developed to estimate treatment effects in patients receiving alternative/rescue treatment in clinical trials may be used to estimate the effects of multiple sclerosis (MS) therapy switch using available clinical trial data. Objective To use TRANSFORMS data and parametric models to assess the time to first confirmed relapse in MS patients who switched from intramuscular interferon β-1a (IFNβ-1a IM) 30 μg/mL once weekly to oral fingolimod 0.5 or 1.25 mg once daily vs. remaining on IFNβ-1a IM. Methods Post hoc analyses were conducted using data from the intent-to-treat population. The Branson and Whitehead switch model with iterative parameter estimation was used to estimate the ratio of the observed time to first confirmed relapse over the estimated time. Results Log-linear regression model results showed that fingolimod 0.5 and 1.25 mg prolonged time to relapse, with an estimated median time to first relapse of 5.07 years ( P = 0.0026 vs. IFNβ-1a IM) and 4.11 years ( P = 0.0113), respectively, versus 2.26 years with IFNβ-1a IM. The estimated ratio of observed time to first confirmed relapse to the estimated time had the patient remained on IFNβ-1a IM was 2.09 (95% CI, 1.45–3.04) for switching to fingolimod 0.5 mg and 1.84 (95% CI, 1.30–2.65) for switching to fingolimod 1.25 mg. Conclusion During the extension, time to first confirmed relapse was approximately doubled in patients switching from IFNβ-1a IM to fingolimod. These analytic methods may be useful in evaluating treatment switch effects in clinical trials with extension data.

Summary Background and objectives Rivastigmine patch is approved for the treatment of all stages of Alzheimer's disease (AD). Application site reactions may be a concern to clinicians and we used two large clinical trial databases to investigate the incidence of skin reactions in patients receiving rivastigmine patch. Methods Data from a 24-week, randomised, double-blind (DB) evaluation of 13.3 vs. 4.6 mg/24 h rivastigmine patch in severe AD (ACTION) and a 72- to 96-week study comprising an initial open-label (IOL) phase followed by a 48-week randomised, DB phase (13.3 vs. 9.5 mg/24 h rivastigmine patch) in declining patients with mild-to-moderate AD (OPTIMA) were analyzed. The incidence, frequency, severity, management and predictors of application site reactions were assessed. Results Application site reactions were mostly mild or moderate in severity and reported by similar proportions in each treatment group (ACTION: 13.3 mg/24 h, 24.5% and 4.6 mg/24 h, 24.2%; OPTIMA: IOL 9.5 mg/24 h, 22.9%; DB 13.3 mg/24 h, 11.4% and 9.5 mg/24 h, 12.0%); none were rated serious. In both studies

Summary Aims To identify factors predicting improvement/stabilization on the Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) and investigate whether early treatment responses can predict long-term outcomes, during a trial of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). Methods Logistic regression was used to relate Week 24 ADCS-CGIC score to potential baseline predictors. Additional analyses based on receiver-operating characteristic curves were performed using Week 8/16 ADCS-CGIC scores to predict response (13.3 mg/24 h patch) at Week 24. ADCS-CGIC score of (1) 1–3 = “improvement,” (2) 1–4 = “improvement or no change”. Results “Treatment” (13.3 mg/24 h patch) and increased age were significant predictors of “improvement” (P = 0.01 and P = 0.003, respectively), and “treatment” (P = 0.001), increased age (P = 0.002), and prior AD treatment (P = 0.03) for “improvement or no change”. At Week 8 and 16, ADCS-CGIC scores of 4 and 5 were optimal thresholds in predicting “improvement,” and “improvement or no change,” respectively, at Week 24. Conclusions A significant therapeutic effect of high-dose rivastigmine patch on ADCS-CGIC response was observed. The 13.3 mg/24 h patch was identified as a predictor of “improvement” or “improvement or no change”. Patients with minimal worsening/improvement/no change after treatment initiation may be more likely to respond following long-term therapy.

Objective: To describe secondary analyses from a 12-week, randomized, open-label trial where adult schizophrenia outpatients receiving risperidone, olanzapine, or aripiprazole were switched to iloperidone. Methods: Patients were randomized into two groups: one where the antecedent antipsychotic dose was titrated downwards to zero over 2 weeks (n=240), and the other group where the antecedent antipsychotic was abruptly stopped (n=260). Adaptations of the Clinical Global Impression scale were used to evaluate clinical changes. Other assessments included the reporting of adverse events (AEs), study discontinuation, body weight, and metabolic variables. Results: Improvement was steady throughout the study for both gradual- and immediate-switch groups starting at Week 1 and continuing through Week 12. Discontinuations due to AEs in the first 2 weeks of treatment were higher for the immediate-switch group compared with the gradual-switch group (10.8% vs. 5.4%, NNT 19, 95% CI 10–151). Fewer patients in the gradualswitch group experienced dizziness as an AE, whereas a higher percentage of patients in the immediate-switch group exhibited earlier onset of a therapeutic response within the first 2 weeks; both groups were comparable thereafter with low rates of dizziness and similar efficacy outcomes. Conclusions: Switching to iloperidone can be accomplished either with a gradual crossover or immediate discontinuation of the prior antipsychotic; however, the immediate-switch method is associated with greater proportion of initial dizziness. The observed outcomes are consistent with what has been previously reported regarding iloperidone’s favorable akathisia/EPS profile and modest impact on somnolence/ sedation, body weight, and metabolic variables.

Objective: In relapsing–remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon β-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFERMS, a randomized, parallel-group, active-controlled, open-label, 48-week study. Methods: Patients were included if they had RRMS, were aged 18–65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function. Results: Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4–57.8%; p < 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment. Conclusions: In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes.

By introducing a non-fullerene small molecule acceptor as a third component to typical polymer donor: fullerene acceptor binary solar cells, we demonstrate that the short circuit current density (Jsc), open circuit voltage (Voc), power conversion efficiency (PCE) and thermal stability can be enhanced simultaneously. The different surface energy of each component causes most of the non-fullerene acceptor molecules to self-organize at the polymer/fullerene interface, while the appropriately selected oxidation/reduction potential of the non-fullerene acceptor enables the resulting ternary junction to work through a cascade mechanism. The cascade ternary junction enhances charge generation through complementary absorption between the non-fullerene and fullerene acceptors and aids the efficient charge extraction from fullerene domains. The bimolecular recombination in the ternary blend layer is reduced as the ternary cascade junction increases the separation of holes and electrons during charge transportation and the trap assistant recombination induced by integer charge transfer (ICT) state potentially reduced due to the smaller pinning energy of inserted non-fullerene acceptor, leading to an unprecedented increase in the open circuit voltage beyond the binary reference values.

Polymer self-assembly in solution prior to film fabrication makes solution-state structures critical for their solid-state packing and optoelectronic properties. However, unraveling the solution-state supramolecular structures is challenging, not to mention establishing a clear relationship between the solution-state structure and the charge-transport properties in field-effect transistors. Here, for the first time, it is revealed that the thin-film morphology of a conjugated polymer inherits the features of its solution-state supramolecular structures. A "solution-state supramolecular structure control" strategy is proposed to increase the electron mobility of a benzodifurandione-based oligo(p-phenylene vinylene) (BDOPV)-based polymer. It is shown that the solution-state structures of the BDOPV-based conjugated polymer can be tuned such that it forms a 1D rod-like structure in good solvent and a 2D lamellar structure in poor solvent. By tuning the solution-state structure, films with high crystallinity and good interdomain connectivity are obtained. The electron mobility significantly increases from the original value of 1.8 to 3.2 cm2 V-1 s-1 . This work demonstrates that "solution-state supramolecular structure" control is critical for understanding and optimization of the thin-film morphology and charge-transport properties of conjugated polymers.

Transportation plays a critical role in shaping urbanization paths and outcomes. This study investigates the interplay between transit and urban spatial development by looking at housing market performance related to different transit technologies. The study examines the capitalization of transit access in property values and compares variations in transit access premiums among bus rapid transit (BRT), light rail transit (LRT) and metro rail transit (MRT). A sample of 8601 housing sales in Beijing was used to estimate hedonic price models for the region and for market segments along 11 transit lines. Results show that the impact zone extends to one mile from stations for MRT but only to half a mile for LRT. For BRT, the impact zone is indiscernible. On average, homes near MRT enjoy a proximity premium of 248.31 yuan (or US$39.41)/m2 for every 100 m closer to the station. For LRT, the premium is 110.71 yuan (or US$17.57). The study concludes that technologies play a role. Technological features of transit should be taken into consideration when delineating transit districts. The potential for future development or redevelopment in addition to capital costs should be considered when choosing transit technologies, especially when cities or regions are in the mid-process of urbanization and spatial growth. Nevertheless, development context is still critical for realizing and maximizing access benefits regardless of rail or bus.

The disease characteristics of multiple sclerosis (MS) appear to differ between Hispanic and Caucasian patients, with Hispanic patients having a younger age at onset, and a higher prevalence of optic nerve and spinal cord involvement. Fingolimod, the first-in-class oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing MS, has been shown to significantly reduce annualized relapse rates (ARRs), lesion-based magnetic resonance imaging (MRI) activity, confirmed disability, and brain volume loss, compared with placebo or intramuscular interferon beta-1a (IFNβ-1a IM) in randomized, double-blind, controlled clinical studies. Here, the efficacy and safety profile of fingolimod in Hispanic patients was compared to that observed in the overall study populations.This was a post hoc analysis of relapses and safety data for Hispanic patients with relapsing-remitting MS (RRMS) randomized to receive daily fingolimod 0.5 mg, weekly IFNβ-1a IM (30 mg) or placebo, in the phase 3, controlled FREEDOMS, FREEDOMS II, and TRANSFORMS fingolimod studies. The ARR was estimated for each treatment group; only relapses that were confirmed by an independent examining neurologist were included in these analyses. Safety assessments included the incidence of adverse events and serious adverse events.Eligible Hispanic patients aged 18-55 years (n=181) had been treated as follows: fingolimod 0.5 mg (n=89), IFNβ-1a IM (n=65), and placebo (n=27). Hispanic patients treated with fingolimod for up to 2 years had lower ARRs (ARR: 0.22, 95% confidence interval [CI]: 0.14-0.35) than those receiving placebo (ARR: 0.46, 95% CI: 0.24-0.88) or IFNβ-1a IM (ARR: 0.34, 95% CI: 0.18-0.63), with relative reductions of 52% and 35%, respectively. A transient decrease in heart rate that started to attenuate 6 h after fingolimod administration was observed, consistent with the well-characterized pharmacologic effect following fingolimod treatment initiation. No cases of symptomatic bradycardia were reported in Hispanic patients. The incidence of first-degree atrioventricular block was low and similar across all treatment groups (3.1-4.5%). The safety profile of fingolimod in Hispanic patients was consistent with that reported in the overall population of each study.Overall, this study demonstrates that fingolimod is efficacious and well tolerated in Hispanic patients with RRMS.

Background Fingolimod is a once-daily, oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing multiple sclerosis. Objective This post-hoc analysis of phase 3 FREEDOMS data assessed whether the effects of fingolimod are consistent among subgroups of patients defined by prior treatment history. Methods Annualized relapse rate and safety profile of treatment with fingolimod 0.5 mg, 1.25 mg, or placebo once-daily for 24 months were analyzed in 1272 relapsing multiple sclerosis patients, by subgroups based on disease-modifying therapy history (treatment-naive; prior interferon-β or glatiramer acetate), reason for discontinuation of prior disease-modifying therapy (unsatisfactory therapeutic response or adverse events), and prior disease-modifying therapy duration. Results Both fingolimod doses significantly reduced annualized relapse rate in patients that received prior interferon-β or glatiramer acetate, discontinued prior disease-modifying therapy owing to unsatisfactory therapeutic effect, were treatment-naive, or had prior disease-modifying therapy duration of >1–3 years (P≤0.0301 for all comparisons vs placebo). Fingolimod 1.25 mg resulted in greater reductions in annualized relapse rate in patients that discontinued prior disease-modifying therapy for adverse events or had prior disease-modifying therapy duration of ≤1 year or >3 years (P≤0.0194 vs placebo). Conclusions Fingolimod demonstrated similar efficacy in relapsing multiple sclerosis patients regardless of prior treatment history. Clinicaltrials.gov identifier: NCT00289978.

Objective Rivastigmine displays dose-dependent efficacy on cognition in patients with Alzheimer's disease (AD), as measured by the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-cog). Subanalysis of the OPTIMA (OPtimising Transdermal Exelon In Mild-to-moderate Alzheimer's disease) study aimed to define ADAS-cog domains by factor analysis of individual items. Efficacy of 13.3 mg/24 h versus 9.5 mg/24 h rivastigmine patch on individual items and newly derived domains was assessed. Methods OPTIMA was a 48-week, double-blind (DB) study in patients with mild-to-moderate AD. Patients meeting pre-defined decline criteria during open-label treatment with 9.5 mg/24 h patch were randomized in the DB phase to 13.3 mg/24 h (n = 280) or 9.5 mg/24 h (n = 287) patch. ADAS-cog change from baseline was a co-primary outcome measure. Factor analysis categorized ADAS-cog items into newly derived domains. Change from DB-baseline was calculated for domains and individual items. Results Numerically, less decline was displayed with 13.3 mg/24 h versus 9.5 mg/24 h patch in the total ADAS-cog score at all time points (significant at Week 24, p = 0.027). Factor analysis identified two domains: memory and language. Significantly, less decline was observed on the memory domain with 13.3 mg/24 h versus 9.5 mg/24 h patch at Weeks 12, 24, and 48 (p

The impact of government structure on citizen welfare remains an open question. This study uses a repeated cross-section data (China General Social Survey) of Chinese urban households to test the hypothesis that fiscal decentralization increases individual welfare. The data used were collected in 2003, 2005 and 2006 and covered most of the provinces in China. We construct two measures of fiscal decentralization: one is based on revenue and the other on expenditure. Then we apply ordered Probit regression to investigate the impact of decentralization on individual life satisfaction after controlling a rich set of individual characteristics and several important macroeconomic factors. We find that greater revenue decentralization increases life satisfaction, a finding that is quite robust across different specifications. We also find that revenue decentralization is more important to the underdeveloped western region, the private sector employees and homeowners. In terms of income distribution, both the rich and the poor gain from revenue decentralization.

Alzheimer's disease · Parkinson's disease dementia · Rivastigmine · Alzheimer's Disease Assessment Scale-cognitive subscale · Alzheimer's Disease Cooperative Study-Activities of Daily Living scale · 10-item Neuropsychiatric Inventory · Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Abstract Background: Greater understanding of differences in baseline impairment and disease pro- gression in patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies. Methods: This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS- ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Im- pression of Change (CGIC) was compared (standardized difference (Cohen's d), similar if

Summary Aims The 24-week, prospective, randomized, double-blind ACTION study investigated the efficacy, safety, and tolerability of 13.3 versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). Methods Patients had probable AD and Mini–Mental State Examination scores ≥3–≤12. Primary outcome measures were as follows: Severe Impairment Battery (SIB) and AD Cooperative Study–Activities of Daily Living scale–Severe Impairment Version (ADCS-ADL-SIV). Secondary outcomes were as follows: ADCS-Clinical Global Impression of Change (ADCS-CGIC), 12-item Neuropsychiatric Inventory (NPI-12), and safety/tolerability. Results Of 1014 patients screened, 716 were randomized to 13.3 mg/24 h (N = 356) or 4.6 mg/24 h (N = 360) patch. Baseline characteristics/demographics were comparable. Completion rates were as follows: 64.3% (N = 229) with 13.3 mg/24 h and 65.0% (N = 234) with 4.6 mg/24 h patch. The 13.3 mg/24 h patch was significantly superior to 4.6 mg/24 h patch on cognition (SIB) and function (ADCS-ADL-SIV) at Week 16 (P

The potential for iloperidone, a D2/5-HT2A antipsychotic, to affect the heart rate-corrected QT interval (QTc) was assessed in the absence and presence of metabolic inhibitors in a randomized, open-label, multicenter study. QT interval prolongation by medications, including both conventional and atypical antipsychotic drugs, can predispose patients to cardiac arrhythmias and result in sudden death. Adults with schizophrenia or schizoaffective disorder and normal electrocardiograms at baseline (N = 188) were randomized 1:1:1:1:1 to iloperidone, 8 mg twice daily (BID), 12 mg BID, 24 mg once daily (QD); quetiapine, 375 mg BID; or ziprasidone, 80 mg BID during period 1 (no metabolic inhibitors present). Iloperidone BID produced mean changes in QTc Fridericia correction (QTcF) interval (8.5-9.0 milliseconds [ms]) similar to those produced by ziprasidone (9.6 ms) and higher than those produced by quetiapine (1.3 ms). Iloperidone, 24 mg QD, produced a mean QTcF change of 15.4 ms. Coadministration of metabolic inhibitors with iloperidone during periods 2 (paroxetine) and 3 (paroxetine and ketoconazole) resulted in greater increases in the QTc interval. Increased QTc was observed in individuals with specific cytochrome P450 2D6 polymorphisms. Up to 10% of patients on iloperidone experienced QTc intervals of 60 ms or longer in the presence of metabolic inhibition and QD dosing. However, no patients experienced QTc changes of clinical concern (QTc ≥ 500 ms). The most common adverse events with iloperidone were headache, anxiety, and dyspepsia. The only cardiovascular adverse events with iloperidone were non-concentration-dependent tachycardia that was mild in most patients and did not lead to further sequelae. Pharmacogenetics and recommendations are discussed.

Introduction/ObjectiveLong-term use of the atypical antipsychotic iloperidone has not been investigated at doses above 16 mg/d. This article describes safety and tolerability results from the 25-week open-label extension of a 4-week placebo- and ziprasidone-controlled clinical trial of iloperidone.MethodsPatients received a dose of 24 mg/d (given as 12 mg twice daily; mean dose = 21.6 mg) that could be reduced to 12 mg/d (given once daily at bedtime) any time after day 35 at the investigator's discretion.ResultsA total of 72/173 patients (41.6%) completed the open-label extension. Treatment-emergent adverse events (TEAEs), most mild to moderate in severity, included headache (13.9%), weight increase (9.2%), dizziness (6.9%), nausea (6.4%), sedation (6.4%), and insomnia (5.2%). The only notable dose-related TEAEs were increased weight and headache. Levels of serum glucose, lipids, and prolactin were essentially unchanged or decreased during treatment. In general, akathisia and extrapyramidal symptoms (EPS) improved or were unchanged during treatment. There was no signal of worsening of efficacy based on changes from baseline in the Positive and Negative Syndrome Scale-Total.Discussion/ConclusionThis study further supports the long-term safety and tolerability of iloperidone for the treatment of schizophrenia, including iloperidone's favorable effect on metabolic laboratory parameters and low propensity to cause akathisia or EPS.

Cherry is an important fruit tree with delicious taste and high economic value, which have been planted worldwide. However, this species cannot withstand the presence of excessive amount of water; submergence injury sometimes occurs during cultivation of cherry and results in severe economic losses. By using a submergence-tolerant germplasm Prunus serrulata “Yimeng” and a submergence-sensitive germplasm Prunus pseudocerasus “Aihua” as test materials, this study cloned PsERF and PsCIPK, which are related to submergence tolerance in cherry, and analyzed the expression of PsERF and PsCIPK in submergence-tolerant and submergence-sensitive germplasms under submergence stress; moreover, the consistency and correlation of such expression with carbohydrate metabolism and plant growth-related genes (PsPDC, PsSUS, PsRAMY, and PsEXP) were analyzed. The results showed that PsERF and PsCIPK influence the expression of PsPDC, PsSUS, PsRAMY, and PsEXP at different extents under submergence and during recovery to systematically improve the submergence resistance of P. serrulata “Yimeng”. This study lays the important theoretical and practical foundation for molecular improvement and germplasm innovation in submergence tolerance in cherry through genetic engineering.

Growing interests have been devoted to the design of polymer acceptors as potential replacement for fullerene derivatives for high-performance all polymer solar cells (all-PSCs). One key factor that is limiting the efficiency of all-PSCs is the low fill factor (FF) (normally

Two new conjugated polymers are synthesized based on a novel donor-acceptor-acceptor (D-A-A) design strategy with the intention of attaining lower lowest unoccupied molecular obital levels compared to the normally used D-A strategy. By coupling two thieno-benzo-isoindigo units together via the phenyl position to give a new symmetric benzene-coupled di-thieno-benzo-isoindigo (BdiTBI) monomer as an A-A acceptor and thiophene (T) or bithiophene (2T) as a donor, two new polymers PT-BdiTBI and P2T-BdiTBI are synthesized via Stille coupling. The two polymers are tested in top gate and top contact field effect transistors, which exhibit balanced ambipolar charge transport properties with poly(methyl methacrylate) as dielectric and a high hole mobility up to 1.1 cm(2) V-1 s(-1) with poly(trifluoroethylene) as dielectric. The polymer films are investigated using atomic force microscopy, which shows fibrous features due to their high crystallinity as indicated by grazing incidence wide-angle X-ray scattering. The theoretical calculations agree well with the experimental data on the energy levels. It is demonstrated that the D-A-A strategy is very effective for designing low band gap polymers for organic electronic applications. Refereed/Peer-reviewed

Objective: To determine the impact of iloperidone treatment on metabolic parameters. Methods: Data were analyzed from 3210 patients who received iloperidone and 587 patients who received placebo for up to 2 years during 9 Phase II and Phase III studies (integrated safety database). Patients were pooled by most frequent iloperidone dose into 3 groups: 4 - 8 mg/d, 10 - 16 mg/d, and 20 - 24 mg/d. Laboratory data from 8 studies were random (fasting and nonfasting) while patients from 1 study (n = 447) were all sampled at fasting. Results: Mean (standard deviation [SD]) weight gain from baseline to endpoint was 2.1 (6.8) kg for all patients on iloperidone. Fasting mean (SD) total cholesterol changes from baseline to end of study were 8.2 (31.6) for iloperidone and -2.2 (35.2) mg/dL for placebo. Fasting mean (SD) triglyceride changes during this period were iloperidone: -0.83 (82.3); placebo: 16.5 (113.1) mg/dL. Fasting mean (SD) glucose changes were iloperidone: 6.6 (24.0); placebo: -0.05 (17.0) mg/dL from baseline to end of study. Glycosylated hemoglobin levels were unchanged following iloperidone treatment. Conclusion: These data suggest a metabolic profile for iloperidone of modest weight gain accompanied by small changes in lipids and glucose that are unlikely to be of clinical concern.

Objectives The efficacy and tolerability characteristics of an antipsychotic are difficult to determine from a single registration study. We thus conducted an analysis that assessed key efficacy and tolerability outcomes post hoc from four pooled short-term (4–6 weeks) phase III studies that evaluated iloperidone versus placebo in patients with schizophrenia or schizoaffective disorder. Methods Patient-level data were pooled from four prospective, randomized, double-blind, placebo-controlled and active-controlled, multicenter trials of iloperidone in patients with schizophrenia or schizoaffective disorder aged 18–65 years. Iloperidone 4–8, 10–16, and 20–24 mg/day (all dosed twice daily) were compared with placebo. Active controls used for assay sensitivity included risperidone 4–8 mg/day, haloperidol 15 mg/day, and ziprasidone 160 mg/day. Outcomes of interest were change from baseline to endpoint in the Brief Psychiatric Rating Scale (derived) (BPRSd), Positive and Negative Syndrome Scale (PANSS)-total (PANSS-T) score, and PANSS-positive (PANSS-P) and PANSS-negative (PANSS-N) subscale scores. An analysis of covariance (with treatment and study as factors, baseline as a covariate) was performed to compare changes between the iloperidone treatment groups versus placebo, on the basis of a last-observation-carried-forward approach for the intent-to-treat (ITT) populations. Tolerability outcomes were obtained from spontaneously reported adverse events (AEs), and number needed to harm was calculated for each antipsychotic versus placebo for the total population. Results The ITT population included both schizoaffective and schizophrenia patients (N = 2401): n = 370, n = 494, and n = 424 for iloperidone 4–8, 10–16, and 20–24 mg/day, respectively; n = 294 for risperidone; n = 114 for haloperidol; n = 144 for ziprasidone; and n = 561 for placebo. Treatment with iloperidone 10–16 mg/day or 20–24 mg/day was associated with significantly improved BPRSd, PANSS-T, PANSS-P, and PANSS-N scores versus treatment with placebo. When only patients with schizophrenia were included (n = 1941), the pattern of results was essentially unchanged. The active controls confirmed assay sensitivity. Across all iloperidone dose groups, the incidences of extrapyramidal disorders and akathisia were similar to those observed with placebo. AEs for which the frequency was greater for iloperidone than placebo and for which the 95% confidence interval for number needed to harm did not contain infinity were dizziness, dry mouth, somnolence, nasal congestion, fatigue, sedation, and tachycardia; in general, for these AEs, frequency was higher with higher doses, resulting in a lower number needed to harm. Conclusions Consistent with product labeling, iloperidone 10–16 mg/day or 20–24 mg/day demonstrated significant improvement over placebo on BPRSd and PANSS-T scores, as well as on PANSS-P and PANSS-N subscale scores over 6 weeks of treatment in patients with schizophrenia and in the ITT population, which includes patients with schizoaffective disorder. Iloperidone did not differ from placebo in terms of extrapyramidal disorders and akathisia. Copyright © 2011 John Wiley & Sons, Ltd.

Rivastigmine treatment is associated with significant improvements on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) in patients with mild-to-moderate Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD). Both AD and PDD are purported to have different profiles of cognitive impairment, which may respond differentially to rivastigmine treatment. This was a retrospective analysis of 3 randomized, double-blind, rivastigmine trial databases (Investigation of transDermal Exelon in ALzheimer's disease [IDEAL; AD], EXelon in PaRkinson's disEaSe dementia Study [EXPRESS; PDD], and Alzheimer's Disease with ENA 713 [ADENA; AD]). Factor analyses of the 11 baseline ADAS-cog items derived the same factors in the 2 diseases, that is, “memory” and “language”. Rivastigmine-treated AD and PDD patients showed significant improvements ( P < .0001 versus placebo) on both factors. For both AD and PDD, rivastigmine had a numerically greater effect on memory than language. Treatment effect sizes were numerically greater in PDD compared with AD. Rivastigmine treatment is associated with improvement in memory and language in AD and PDD. The numerically greater response in PDD is consistent with greater cholinergic deficits in this disease state.

Background: Vascular risk factors (VRF) may influence response to rivastigmine in Alzheimer’s disease (AD). Methods: AD patients who participated in a randomized, double-blind, placebo-controlled trial of rivastigmine patch and capsule treatment were stratified by baseline VRF status. Treatment response was evaluated using the AD Assessment Scale-cognitive subscale (ADAS-cog), AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Results: ADAS-cog scores significantly improved in all rivastigmine-treated patients (p < 0.05 vs. placebo), except 9.5 mg/24 h patch-treated patients with VRF, and were significantly affected by VRF status in the study population as a whole. Significant benefits were seen on the ADCS-ADL in 9.5 mg/24 h patch- and capsule-treated patients with, but not without, VRF. The ADCS-CGIC significantly improved in capsule-treated patients with, and patch-treated patients without VRF. Although non-significant, patients without VRF showed an apparent faster rate of placebo decline. Conclusion: VRF may influence AD progression and response to rivastigmine.

China's rural village elections have been acclaimed as a crucial step in China's democratization and a success in improving villagers' welfare and self-governance. Around 2002 the central government implemented another influential reform: the Tax-for-Fee reform. Using a unique two-year panel of village data from rural China covering more villages than the previous literature and spanning over these two reforms, our dual-goal in this paper is, first to evaluate the impact of village election on local governance, and second to examine the potential interplay between the Tax-for-Fee reform and the village election. We show empirically that village elections do bring about positive consequences, including the enhancement of public expenditure and the improvement in efficiency in public administration, through the check and balances provided by the villagers' representatives meetings. However, the improvement in administrative efficiency has been partly unexpectedly attenuated by the Tax-for-Fee reform. We argue that this conflict is possibly due to the Tax-for-Fee reform's tightening up the villages' budget and that with sticky administration costs, the reduction of administrative share in total expenditure has been weakened. Therefore the tax reform undermines the functioning of village democracy.

Summary Aim: The cholinesterase inhibitor rivastigmine is available in both oral and transdermal forms. The efficacy of oral rivastigmine appears to be dose-dependent. The current analysis investigates the effect of dose on the efficacy of the rivastigmine transdermal patch. Methods: This was a retrospective analysis of a large, international, 24-week, randomised, placebo- and active-controlled trial (IDEAL, CENA713D2320) of rivastigmine in patients with mild-to-moderate Alzheimer’s disease (AD). Patients received the 9.5 mg/24 h rivastigmine patch, the 17.4 mg/24 h rivastigmine patch, 12 mg/day rivastigmine capsules or placebo. Changes from baseline at week 24 on the AD Assessment Scale–cognitive subscale (ADAS-cog), AD Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) and the AD Cooperative Study–Activities of Daily Living (ADCS-ADL) scale were calculated based on the patient’s mode and last prescribed patch dose. The analysis included the 4.6 mg/24 h and 13.3 mg/24 h patch doses, for which efficacy data have not previously been reported. Results: Significant differences (p

Background: Rivastigmine patches provide similar efficacy to rivastigmine capsules with a lower incidence of gastrointestinal side effects in patients with probable Alzheimer’s disease (AD). Methods: Post hoc analysis of a 24-week, prospective, international, randomized, double-blind, placebo- and active-controlled trial. Patients (n = 892) with probable AD received rivastigmine transdermal patches (9.5 mg/24 hours [10 cm2]), rivastigmine capsules (6 mg twice daily), or placebo, and impact on activities of daily living (ADLs) was assessed utilizing 3 subscales: basic, high-level function, and autonomy. Results: At week 24, both rivastigmine groups demonstrated significantly superior performance in Alzheimer’s Disease Cooperative Study—Activities of Daily Living (ADCS-ADL) Total Score versus placebo (rivastigmine patch, P = .013; capsules, P = .039). Overall, both rivastigmine formulations provided benefits in ADL subscales. For basic ADLs, rivastigmine capsules performed significantly better than placebo (P = .012). For high-level function ADLs, rivastigmine patch performed better than placebo (P = .056). For autonomy ADLs, rivastigmine patch performed significantly better than placebo (P = .017). Conclusion: Rivastigmine patches and capsules provide significant effects in both total and subscale ADLs in patients with probable AD.

Objectives The cholinesterase inhibitor rivastigmine is approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). This exploratory, hypothesis-forming analysis assessed response to rivastigmine according to severity of dementia at baseline. Methods This was a retrospective analysis of a large randomized, placebo-controlled trial (ENA713D2320). AD patients treated with 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, rivastigmine capsule (12 mg/day), or placebo were stratified according to baseline Mini-Mental State Examination (MMSE) scores: ≥7 to ≤12 (severe disease), ≥13 to ≤15 (moderately severe), ≥16 to ≤18 (moderate), or ≥19 to ≤25 (mild to moderate). Changes from baseline at Week 24 on Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC), and Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) were assessed. Results Based on baseline MMSE scores, 141, 228, 333, and 348 patients had severe, moderately severe, moderate, and mild to moderate dementia. Worsening of ADAS-cog, ADCS-CGIC, and ADCS-ADL scores in patients receiving placebo were greater in patients with more severe dementia. Significant improvements versus placebo were seen with rivastigmine patch and/or capsule on ADAS-cog, ADCS-CGIC, and ADCS-ADL scores in patients with severe, moderately severe, and moderate AD (all p

Alzheimer’s disease (AD) patients treated with rivastigmine transdermal patch have shown statistically significant differences versus placebo on the AD Assessment scale-cognitive subscale (ADAS-cog). In this retrospective analysis of a double-blind, placebo- and active-controlled, 24-week clinical trial, the specific effects of rivastigmine patch on individual ADAS-cog items and cognitive domains (memory, language, and praxis) were explored. The mean baseline to week 24 changes were calculated for each ADAS-cog item and domain in this exploratory, hypothesis-generating analysis. Patients on 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, and 3 to 12 mg/d rivastigmine capsules showed improvements over placebo on the memory and praxis ADAS-cog subscales. The rivastigmine patch groups also showed improvements on the language subscale. Significant differences versus placebo were seen on several individual item scores in the rivastigmine-treated groups. Rivastigmine patch was associated with improvements on the memory, praxis, and language domains of cognition in patients with mild-to-moderate AD.

SUMMARY Background and objective: Rivastigmine is approved in the USA for the treatment of mild to moderate Alzheimer's disease and Parkinson's disease dementia (PDD). Executive function (EF) deficits are a core symptom of PDD. The current objective was to investigate the effects of rivastigmine capsules versus placebo on EF in PDD, focusing on secondary outcome measures from a large, international, randomized, double-blind, placebo-controlled, 24-week trial (EXPRESS, CENA713B2311). Methods: Secondary outcomes included Delis–Kaplan Executive Function System (D-KEFS) measures of EF. Data from three D-KEFS subtests (Card Sorting, Letter Fluency, Color–Word Interference), plus the Symbol Digit Modalities Test were analyzed in the observed case (OC) population. Changes from baseline in the rivastigmine versus placebo groups were evaluated using the van Elteren test blocking for country. Results: Of 541 patients in the EXPRESS study, 402, 71, 97, and 65 patients provided data for Letter Fluency, Card Sorting and Color-Word Interference subtests, and the Symbol Digit Modalities Test, respectively. On Letter Fluency, rivastigmine was associated with improvements in correct responses, set loss errors, and responses made (all P < 0.05), but not repetition errors. Higher Card Sorting recognition description score (P= 0.03), and more correct substitutions on the Symbol Digit Modalities Test (P= 0.02) were also recorded. Conclusion: Rivastigmine was associated with significant improvements over placebo on EF tests evaluating flexibility of thinking, problem solving and planning in patients with PDD. These findings support the hypothesis that rivastigmine may affect frontal subcortical circuits, which potentially contributes to observed clinical improvement associated with EF.

Background: Investigate the safety and tolerability of rivastigmine capsules and transdermal patch in patients with moderate Alzheimer's disease receiving concomitant memantine.Methods: Safety data from two prospective, open-label, multicenter trials were analyzed. Study US32: patients received rivastigmine capsules (3–12 mg/day) plus memantine (20 mg/day). Study US38: patients switched from donepezil to rivastigmine patches (4.6 mg/24 hours) immediately or following 7 days' withdrawal; ∼50% received concomitant memantine (20 mg/day).Results: The rivastigmine patch demonstrated more favorable tolerability than rivastigmine capsules, being associated with fewer adverse events (AEs) (73% versus 83%), serious AEs (10% versus 23%) and gastrointestinal symptoms (4% versus 26% for nausea; 4% versus 11% for vomiting). Application site reactions occurred in 17% of patients.Conclusion: Concomitant memantine treatment with rivastigmine patch and capsule is generally well tolerated. The favorable tolerability and safety profile of rivastigmine transdermal patch is not further improved with concomitant memantine. Recommendations to minimize application site reactions are provided.

Background Adherence to multiple sclerosis (MS) disease-modifying therapy (DMT) is commonly assessed through patient reporting, but patient-reported adherence is rarely studied. Objective To determine rates of DMT adherence reported from patient to clinician, reasons for nonadherence, and relationships between adherence and outcomes. Methods We identified relapsing–remitting MS patients on DMT for ≥3 months. DMT adherence was defined as taking ≥80% of doses. Linear and logistic regression models were created used to determine the association of baseline adherence with several patient reported outcomes and the timed 25-foot walk at 6 months, 1 year, 2 years, and 3 years after the index visit. Results The analysis included 1148 patients, of whom 501 had data at 6 months, 544 at 1 year, 331 at 2 years, and 247 at 3 years. Baseline adherence was 94.9% and overall adherence was 93.1%. Forgetting was the most common reason for missed doses. In the adjusted models, adherence was not associated with the outcomes. Conclusions Higher than expected adherence and a lack of association between adherence and outcomes suggests patient reported adherence may not be reliable. Further research is needed to clarify the relationship between patient-reported adherence and relapses or new lesion formation.

Rivastigmine has been shown to improve cognition in patients with Parkinson’s disease dementia (PDD). To further explore the impact of anticholinesterase therapy on PDD, Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) items were assessed in a retrospective analysis of a 24-week, double-blind, placebo-controlled trial of rivastigmine. Mean changes from baseline at week 24 were calculated for ADAS-cog item scores and for 3 cognitive domain scores. A total of 362 patients were randomized to 3 to 12 mg/d rivastigmine capsules and 179 to placebo. Patients with PDD receiving rivastigmine improved versus placebo on items: word recall, following commands, ideational praxis, remembering test instructions, and comprehension of spoken language (P < .05), with standardized mean differences ranging from 0.04 to 0.30. Rivastigmine also showed significant effects versus placebo on all domains: memory, language, and praxis. The ADAS-cog is sensitive to broad cognitive changes in PDD. Overall, rivastigmine was associated with improvements on individual cognitive items and general cognitive domains.

Due to the attraction of optimizing the electronic structure beyond chemical synthesis, molecular doping has recently aroused wide interest in the field of organic solar cells. However, the selecti ...

Background: The Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale is widely used in Alzheimer trials. It assesses cognition, activities of daily living (ADLs), behavior and global functioning. To advance the understanding of relationships between the ADCS-CGIC and scores from other commonly used tools, this analysis investigated the ability of each domain to measure change. This was a hypothesis-forming study, designed to provide a basis for possible future research. Methods: This retrospective analysis used data from a 24-week, randomized, placebo-controlled trial [study ENA713D2320 (IDEAL)] that evaluated rivastigmine patches and capsules in AD patients. Results: At week 24, significant treatment effects versus placebo were seen on the ADCS-CGIC cognitive domain with rivastigmine 17.4 mg/24 h patch (p < 0.01), 9.5 mg/24 h patch (p = 0.02) and capsules (p < 0.01); similarly on the ADCS-CGIC ADL domain. The cognition portion of the CGIC correlated with the Alzheimer’s Disease Assessment Scale cognitive subscale and the ADL section with the ADCS-ADL trial measures. Variance ascribable to these tools was small, indicating that CGIC detects changes not measured by the domain-specific tools. Conclusions: The results of this post hoc analysis suggest that the ADCS-CGIC accurately reflects changes in cognitive and functional domains measured by other tools; it captures changes not assessed by domain-specific instruments. Cognitive alterations show greatest correlation with total CGIC. These results may assist in analyzing and interpreting CGIC results in other trials.

Aims: To investigate the effects of rivastigmine capsule 3–12 mg/day over 24 weeks on activities of daily living (ADLs) in patients with dementia associated with Parkinson’s disease (PDD). Methods: Post hocanalysis of a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with PDD (≧50 years) randomized to rivastigmine 3–12 mg/day (capsules bid) or placebo over 24 weeks. This analysis was carried out with three subscales derived from a factor analysis of the 23 items in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scale. These subscales were basic ADLs (10 items), high-level function ADLs (eight items) and autonomy ADLs (five items). Results: 541 patients were randomized (362 to rivastigmine, 179 to placebo) and 410 (75.8%) completed the study. Rivastigmine was associated with significantly better outcomes in basic ADLs (–0.5 ± 6.19 vs. –1.7 ± 5.46; p = 0.025; effect size 22.1%) and high-level function ADLs (0.1 ± 4.95 vs. –1.0 ± 4.49; p = 0.017; effect size 22.9%) compared with placebo, at week 24. Conclusion: In patients with PDD, treatment with rivastigmine may show beneficial effects on overall ADLs, as well as modest, statistically significant improvements in basic ADLs and high-level function ADLs.

Summary Objectives: To compare the safety and tolerability of switching patients with mild-to-moderate Alzheimer’s disease from donepezil to either rivastigmine capsule or transdermal patch. Methods: Three studies investigated the switch from donepezil to rivastigmine; study US13 was a 26-week, single-arm, immediate-switch study; US18 was a 26-week, sequential cohort study (both studies evaluated rivastigmine capsules 3–12 mg/day); study US38 was a 25-week, randomised, parallel-group, open-label study which investigated switch (immediate or after 7 days’ withdrawal) from donepezil to rivastigmine transdermal patch (4.6 mg/24 hr). Safety outcomes included adverse events (AEs), discontinuations caused by AEs and serious AEs (SAEs). Results: Patient groups receiving rivastigmine patch (n = 261) or capsules (n = 331) had mean ± SD ages of 77.3 ± 8.0 and 78.1 ± 7.8 years, dementia durations of 3.9 ± 2.6 and 3.6 ± 2.2 years and Mini-Mental State Examination scores of 18.3 ± 4.00 and 17.9 ± 4.4 respectively. Overall, 184 (70.5%) and 276 (83.4%) patients experienced at least one AE, and 23 (8.8%) and 55 (16.6%) patients experienced an SAE with the rivastigmine patch and capsules respectively. Of the patients who experienced an AE, 10 (3.8%) and 109 (32.9%) experienced nausea, and 11 (4.2%) and 80 (24.1%) experienced vomiting with the rivastigmine patch and capsules respectively. Discontinuations because of AEs occurred in 64 (19.3%) patients receiving capsules and 38 (14.6%) patients in the transdermal patch group. The most common reasons for discontinuation with the transdermal patch were application site reaction and disease progression, and nausea and vomiting with the capsules. Conclusions: The rivastigmine transdermal patch appears to have better tolerability than rivastigmine capsules, with fewer gastrointestinal AEs and discontinuations because of these AEs. Simple daily rotation of patch location will likely reduce the frequency of skin reactions. This post hoc analysis was carried out by Novartis Pharmaceuticals Corporation. Data for the analysis were collected from the US13 study (CENA713B US13), the US18 study (CENA713B US18) and the US38 study (CENA713D US38).

To investigate the tolerability and efficacy of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease receiving concomitant memantine.Post hoc analysis of a 25-week, randomized, prospective, open-label, parallel-group study. Patients receiving donepezil were switched to rivastigmine patches (4.6 mg/24 h) immediately or following a 7-day withdrawal for 4 weeks (core phase), before titrating up to 9.5 mg/24 h for a further 20-week extension phase. Prior memantine therapy was continued throughout.Tolerability (adverse events [AEs], serious AEs [SAEs] and discontinuations) and efficacy (cognition, global functioning and activities of daily living [ADLs]) were assessed for the rivastigmine transdermal patch, with or without concomitant memantine.Overall, 135 and 126 patients received rivastigmine with and without memantine, respectively. Of these, 122 (90.4%) and 118 (93.7%) patients with and without memantine, respectively, completed the core phase; 120 and 114 patients, respectively, entered the extension phase, and 90 (75.0%) and 86 (75.4%) completed the study. The incidences of AEs (73.3 vs. 67.5%) and SAEs (10.4 vs. 7.1%) were both slightly larger in patients receiving concomitant memantine, but the differences were not statistically significant (95% CIs: -5.2, 16.9 and -3.6, 10.1 for AEs and SEAs, respectively). The incidence of gastrointestinal AEs was low in both groups. Discontinuation due to AEs was higher in patients who received memantine (17.0 vs. 11.9%). Changes in cognitive and global function were similar between groups. ADL scores worsened in both groups; significantly more in those treated with memantine.Use of the rivastigmine transdermal patch in patients on established memantine appears to be well-tolerated, with only modest, non-significant increases in AEs compared with monotherapy, and did not seem to affect cognition or global functioning adversely.

To investigate the safety, tolerability and efficacy of rivastigmine capsules (3-12 mg/day) in a 26-week, multi-centre, open-label extension of a double-blind study.Patients with traumatic brain injury (TBI) and persistent cognitive impairment who had received rivastigmine (3-6 mg/day) or placebo for 12 weeks could enter the extension study and receive rivastigmine (or =12 mg/day). Patients were assessed using a range of cognitive tests including the Hopkins Verbal Learning Test (HVLT) and the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information Processing (CANTAB RVIP) A' sub-test. Safety measures included monitoring of adverse events.In the extension study (n = 127), the mean duration of rivastigmine treatment was 23.8 weeks and the mean final dosage was 7.9 mg/day. Approximately 40% of patients were responders (or =1.0 SD improvement from baseline) on CANTAB RVIP A' or HVLT total score at week 38 or endpoint. Statistically significant changes from week 12 at week 38 were observed for CANTAB-RVIP A' and HVLT-total word recall for the sub-group of ex-placebo patients with greater severity of initial impairment. The safety profile of rivastigmine capsules was consistent with the label.Treatment with rivastigmine for up to 38 weeks was safe in patients with TBI and cognitive impairment.