Combination of eudragit EPO with poloxamers for improved solubility and dissolution of Zafirlukast: An evaluation of solid dispersion formulations.

This study investigated the effect of solid dispersions (SD) on solubility and release of Zafirlukast (ZA) by physical mixture (PM), solvent evaporation (SE) and kneading method (KM) with Eudragit EPO (EPO) as binary component and Poloxamer 188 (P188) and Poloxamer 407 (P407) as ternary components. The binary and ternary systems caused an increase of 322 folds and 356 folds in aqueous solubility of ZA, respectively. Formulations were characterized for solubility, FTIR, PXRD, DSC, SEM and dissolution studies. P407 was found to be an excellent solubility booster in combination with EPO. It was concluded that solubility and dissolution rate of ZA increased significantly when SD of the ZA was prepared by solvent evaporation method (1:7 ratio) using 15% P407 as ternary component.

The effects of oral administration of the novel muscarinic receptor antagonist DA-8010 on overactive bladder in rat with bladder outlet obstruction.

BACKGROUND: DA-8010 is a novel compound developed for the treatment of overactive bladder (OAB) and urinary incontinence. The aims of this study were to investigate the effects of DA-8010 on OAB in a rat model. METHODS: Study animals were divided into the following five groups of seven animals each: a sham-operated control group, a control group with partial bladder outlet obstruction (BOO) (OAB group), and three DA-8010 (doses of 0.3 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day, respectively) with partial BOO groups. Oral administration of the drugs was continued for 14 days after 2 weeks of partial BOO. After 4 weeks of partial BOO, cystometrography was performed in all groups. Additionally, pro-inflammatory cytokines, Rho-kinases, and histology of the bladder were analyzed. RESULTS: There was a significant increase in the contraction interval and a decrease in contraction pressure in the 3 mg/kg/day DA-8010 group versus those in the OAB group. Rho kinase was also significantly decreased in the DA-8010 3 mg/kg/day dosage treatment group. The increased ratio of collagen to smooth muscle after partial BOO was significantly attenuated in the DA-8010 3 mg/kg/day dosage group. CONCLUSIONS: Oral administration of DA-8010 at 3 mg/kg/day improved findings in an OAB rat model induced by partial BOO. Our results suggest that the novel muscarinic receptor antagonist DA-8010 may be a promising drug for treating patients with OAB.

The Impact of Multiple Rounds of Indoor Residual Spraying on Malaria Incidence and Hemoglobin Levels in a High-Transmission Setting.

BACKGROUND: Indoor residual spraying (IRS) is widely used as a vector control measure, although there are conflicting findings of its effectiveness in reducing malaria incidence. The objective of this study was to estimate the effect of multiple IRS rounds on malaria incidence and hemoglobin levels in a cohort of children in rural southeastern Uganda. METHODS: The study was based upon a dynamic cohort of children aged 0.5-10 years enrolled from August 2011 to June 2017 in Nagongera Subcounty. Confirmed malaria infections and hemoglobin levels were recorded over time for each participant. After each of 4 rounds of IRS, malaria incidence, hemoglobin levels, and parasite density were evaluated and compared with pre-IRS levels. Analyses were carried out at the participant level while accounting for repeated measures and clustering by household. RESULTS: Incidence rate ratios comparing post-IRS to pre-IRS incidence rates for age groups 0-3, 3-5, and 5-11 were 0.108 (95% confidence interval [CI], .078-.149), 0.173 (95% CI, .136-.222), and 0.226 (95% CI, .187-.274), respectively. The mean hemoglobin levels significantly increased from 11.01 (pre-IRS) to 12.18 g/dL (post-IRS). CONCLUSIONS: Our study supports the policy recommendation of IRS usage in a stable and perennial transmission area to rapidly reduce malaria transmission.

Evaluation of the residual efficacy of indoor residual spraying with bendiocarb (FICAM WP 80) in six health districts in Senegal.

BACKGROUND: From 2011 to 2014, an indoor residual spray (IRS) programme for malaria vectors control was implemented in six health districts in Senegal. The main objective of the present study was to evaluate the efficacy of bendiocarb (FICAM WP 80) sprayed on different wall surfaces and its impact on malaria vectors. The entomological monitoring activities were carried out monthly in five treated sentinel villages and one control untreated village in each district. METHODS: The residual efficacy of bendiocarb applied at a dosage of 0.4 g/sq m was monitored for a period up to 9 months post-IRS using WHO cone bioassay method. This assay consisted to expose 2-5 days old unfed susceptible Anopheles coluzzii females to sprayed walls for a period of 30 min. The mortality rates after 24 h post-exposure were estimated and compared between the different types of walls sprayed in each sentinel village. RESULTS: The results showed that the residual efficacy varied between the different sprayed walls, from one sentinel village to another and between the different campaigns. The FICAM had a residual efficacy of 3-6 months post-IRS on mud and cement wall surfaces. In some cases, the observed mortality rates were much higher than those reported elsewhere particularly during the first campaign in all the six districts. CONCLUSIONS: The FICAM was found to be effective with a residual efficacy varying from 3 to 6 months. If the quality of the IRS application is excluded as a possible explanation of the short efficacy duration, the results suggest at least two rounds of treatments in order to cover the rainy season that lasts 5 to 6 months in the area. Such treatments could be carried out before the intensification of the rains in July and August in order to better cover the transmission period that occurs between late August and October in the area.

An observational analysis of the impact of indoor residual spraying with non-pyrethroid insecticides on the incidence of malaria in Ségou Region, Mali: 2012-2015.

BACKGROUND: Ségou Region in Central Mali is an area of high malaria burden with seasonal transmission, high access to and use of long-lasting insecticidal nets (LLINs), and resistance to pyrethroids and DDT well documented in Anopheles gambiae s.l. (the principal vector of malaria in Mali). Ségou has recently received indoor residual spraying (IRS) supported by Mali's collaboration with the US President's Malaria Initiative/Africa Indoor Residual Spraying programme. From 2012 to 2015, two different non-pyrethroid insecticides: bendiocarb in 2012 and 2013 and pirimiphos-methyl in 2014 and 2015, were used for IRS in two districts. This report summarizes the results of observational analyses carried out to assess the impact of these IRS campaigns on malaria incidence rates reported through local and district health systems before and after spraying. METHODS: A series of retrospective time series analyses were performed on 1,382,202 rapid diagnostic test-confirmed cases of malaria reported by district routine health systems in Ségou Region from January 2012 to January 2016. Malaria testing, treatment, surveillance and reporting activities remained consistent across districts and years during the study period, as did LLIN access and use estimates as well as An. gambiae s.l. insecticide resistance patterns. Districts were stratified by IRS implementation status and all-age monthly incidence rates were calculated and compared across strata from 2012 to 2014. In 2015 a regional but variable scale-up of seasonal malaria chemoprevention complicated the region-wide analysis; however IRS operations were suspended in Bla District that year so a difference in differences approach was used to compare 2014 to 2015 changes in malaria incidence at the health facility level in children under 5-years-old from Bla relative to changes observed in Barouéli, where IRS operations were consistent. RESULTS: During 2012-2014, rapid reductions in malaria incidence were observed during the 6 months following each IRS campaign, though most of the reduction in cases (70% of the total) was concentrated in the first 2 months after each campaign was completed. Compared to non-IRS districts, in which normal seasonal patterns of malaria incidence were observed, an estimated 286,745 total fewer cases of all-age malaria were observed in IRS districts. The total cost of IRS in Ségou was around 9.68 million USD, or roughly 33.75 USD per case averted. Further analysis suggests that the timing of the 2012-2014 IRS campaigns (spraying in July and August) was well positioned to maximize public health impact. Suspension of IRS in Bla District after the 2014 campaign resulted in a 70% increase in under-5-years-old malaria incidence rates from 2014 to 2015, significantly greater (p = 0.0003) than the change reported from Barouéli District, where incidence rates remained the same. CONCLUSIONS: From 2012 to 2015, the annual IRS campaigns in Ségou are associated with several hundred thousand fewer cases of malaria. This work supports the growing evidence that shows that IRS with non-pyrethroid insecticides is a wise public health investment in areas with documented pyrethroid resistance, high rates of LLIN coverage, and where house structures and population densities are appropriate. Additionally, this work highlights the utility of quality-assured and validated routine surveillance and well defined observational analyses to rapidly assess the impact of malaria control interventions in operational settings, helping to empower evidence-based decision making and to further grow the evidence base needed to better understand when and where to utilize new vector control tools as they become available.

Deltamethrin resistance in Aedes aegypti results in treatment failure in Merida, Mexico.

The operational impact of deltamethrin resistance on the efficacy of indoor insecticide applications to control Aedes aegypti was evaluated in Merida, Mexico. A randomized controlled trial quantified the efficacy of indoor residual spraying (IRS) against adult Ae. aegypti in houses treated with either deltamethrin (to which local Ae. aegypti expressed a high degree of resistance) or bendiocarb (to which local Ae. aegypti were fully susceptible) as compared to untreated control houses. All adult Ae. aegypti infestation indices during 3 months post-spraying were significantly lower in houses treated with bendiocarb compared to untreated houses (odds ratio <0.75; incidence rate ratio < 0.65) whereas no statistically significant difference was detected between the untreated and the deltamethrin-treated houses. On average, bendiocarb spraying reduced Ae. aegypti abundance by 60% during a 3-month period. Results demonstrate that vector control efficacy can be significantly compromised when the insecticide resistance status of Ae. aegypti populations is not taken into consideration.

PUGNAc treatment provokes globotetraosylceramide accumulation in human umbilical vein endothelial cells.

PUGNAc is a well-investigated inhibitor for protein-O-GlcNAcase, whereas recent investigations showed that PUGNAc had a broad range as inhibitor for cellular ß-hexosaminidases. Here we report that PUGNAc treatment provokes globotetraosylceramide (Gb4Cer) accumulation in human umbilical vein endothelial cells (HUVEC). HPLC analysis and a quantitative ELISA using newly developed anti-Gb4Cer monoclonal antibody revealed that PUGNAc treatment specifically increased the expression of Gb4Cer among glycosphingolipids expressed in HUVEC. Although the effect was weaker than PUGNAc, an O-GlcNAcase selective inhibitor (Thiamet-G) treatment also increased Gb4Cer levels in HUVEC. Furthermore, both of PUGNAc and Thiamet-G treatment up-regulated the expression levels of α-1,4-galactosyltransferase/Gb3Cer synthase gene which encodes a key enzyme in Gb4Cer synthesis. These results indicate that protein-O-GlcNAcylation can regulate the expression levels of cellular Gb4Cer.

Effects of Different Surfaces and Insecticide Carriers on Residual Insecticide Bioassays Against Bed Bugs, Cimex spp. (Hemiptera: Cimicidae).

The performance of five insecticides (bendiocarb, deltamethrin, DDT, malathion, and imidacloprid) using three application methods (oil-based insecticide films on filter paper, and acetone-based insecticide deposits on two substrates: filter paper and glass) was assessed against a susceptible strain of Cimex lectularius (L.) and two resistant strains of Cimex hemipterus (F.). Substrate type significantly affected (P < 0.05) the insecticide knockdown response of the susceptible strain in acetone-based insecticide bioassays, with longer survival time on filter paper than on the glass surface. With the exception of deltamethrin, the different diluents (oil and acetone) also significantly affected (P < 0.05) the insecticide knockdown response of the susceptible strain in the filter paper-based insecticide bioassays, with longer survival time with acetone as the diluent. For both strains of C. hemipterus, there were no significant effects with the different surfaces and diluents for all insecticides except for malathion and imidacloprid, which was largely due to high levels of resistance. The lower effectiveness for the insecticide acetone-based treatment on filter paper may be due to crystal bloom. This occurs when an insecticide, dissolved in a volatile solvent, is applied onto absorptive surfaces. The effect is reduced on nonabsorptive surfaces and slowed down with oil-based insecticides, whereby the oil forms a film on absorptive surfaces. These findings suggest that nonabsorptive surfaces should be used in bioassays to monitor insecticide resistance. If absorptive surfaces are used in bioassays for testing active ingredients, then oil-based insecticides should be preferably used.

Antiepileptic dosing for critically ill adult patients receiving renal replacement therapy.

OBJECTIVES: The aim of this review was to evaluate current literature for dosing recommendations for the use of antiepileptic medications in patients receiving renal replacement therapy (RRT). DATA SOURCES: With the assistance of an experienced medical librarian specialized in pharmacy and toxicology, we searched MEDLINE, EMBASE, CINAHL, Web of Science, WorldCat, and Scopus through May 2016. STUDY SELECTION AND DATA EXTRACTION: Four hundred three articles were screened for inclusion, of which 130 were identified as potentially relevant. Micromedex® DRUGDEX as well as package inserts were used to obtain known pharmacokinetic properties and dosage adjustment recommendations in RRT if known. DATA SYNTHESIS: Data regarding antiepileptic drug use in RRT are limited and mostly consist of case reports limiting our proposed dosing recommendations. Known pharmacokinetic parameters should guide dosing, and recommendations are provided where possible. CONCLUSION: Additional studies are necessary before specific dosing recommendations can be made for most antiepileptic drugs in critically ill patients receiving RRT, specifically with newer agents.

A cluster randomized trial comparing deltamethrin and bendiocarb as insecticides for indoor residual spraying to control malaria on Bioko Island, Equatorial Guinea.

BACKGROUND: Indoor residual spraying (IRS) has been used on Bioko for malaria control since 2004. In 2013 the insecticide was changed from bendiocarb to deltamethrin. Shortly after this change, there was a marked increase in malaria prevalence on the island. This trial was carried out to compare the effectiveness of bendiocarb and deltamethrin for use in IRS on Bioko. METHODS: Twenty-four clusters of houses were randomized to receive IRS with either bendiocarb or deltamethrin. Approximately 3 months after the intervention, the prevalence of malaria and levels of haemoglobin were measured in children aged 2-14 years in each cluster. RESULTS: Prevalence of malaria in 2-14 year olds was lower in the bendiocarb arm (16.8, 95 % CI 11.1-24.7, N = 1374) than in the deltamethrin arm (23.2, 95 % CI 16.0-32.3, N = 1330) but this difference was not significant (p = 0.390), even after adjusting for covariates (p = 0.119). Mean haemoglobin in children was marginally higher in the bendiocarb clusters (11.6 g/dl, 95 % CI 11.5-11.8, N = 1326) than in the deltamethrin clusters (11.5 g/dl, 95 % CI 11.3-11.7, N = 1329). This difference was borderline significant after adjusting for covariates (p = 0.049). CONCLUSIONS: The results are suggestive of bendiocarb being more effective at preventing malaria on Bioko although evidence for this was weak. The results are likely due to the fact that local vectors remain fully susceptible to bendiocarb whereas subsequent tests have shown resistance to deltamethrin.

First evaluation of bendiocarb in experimental huts using different substrates in Madagascar.

BACKGROUND: Indoor residual spraying with insecticide is recommended for malaria control in high-transmission settings. Determination of residual activity of insecticides is essential for the selection of appropriate indoor spraying policy. The present study was undertaken to evaluate the residual effect of bendiocarb, a carbamate insecticide used in Madagascar, on different indoor surfaces in order to elaborate future vector control interventions. METHODS: The residual activity of bendiocarb was evaluated in both experimental huts and houses. Tests in experimental huts on different substrates represented a small scale-field trials. The houses IRS performed in parallel of experimental huts IRS, was done to compare semi-field results and field results. Bioassays according to the World Health Organization (WHO) standard protocol were carried out on different substrates impregnated with bendiocarb using susceptible strains of Anopheles arabiensis and Aedes albopictus. RESULTS: Bendiocarb induced significantly high mortality in treated huts against exposed mosquito (p < 0.005) compared to untreated huts. The mortality is up to the WHO threshold of 80 % during 5 months post-treatment. Using a multivariate analysis, Ae. albopictus mortality decreased significantly from the 3rd month post-treatment. However, An. arabiensis mortality decreased significantly from the 4th month after treatment. Comparing mosquito mortality results from the mud experimental huts and the mud houses showed no significant difference regarding the persistence of bendiocarb on wall. CONCLUSIONS: Current data suggest variable persistence of bendiocarb according to the type of wall surfaces, highlighting the importance of testing insecticide for IRS in local context before using them in large scale. Data from this study validate also the importance of using experimental huts as representative tool to evaluate the effectiveness of an insecticide.

Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group.

Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.

Combination of Insecticide Treated Nets and Indoor Residual Spraying in Northern Tanzania Provides Additional Reduction in Vector Population Density and Malaria Transmission Rates Compared to Insecticide Treated Nets Alone: A Randomised Control Trial.

Indoor residual spraying (IRS) combined with insecticide treated nets (ITN) has been implemented together in several sub-Saharan countries with inconclusive evidence that the combined intervention provides added benefit. The impact on malaria transmission was evaluated in a cluster randomised trial comparing two rounds of IRS with bendiocarb plus universal coverage ITNs, with ITNs alone in northern Tanzania. From April 2011 to December 2012, eight houses in 20 clusters per study arm were sampled monthly for one night with CDC light trap collections. Anopheles gambiae s.l. were identified to species using real time PCR Taq Man and tested for the presence of Plasmodium falciparum circumsporozoite protein. ITN and IRS coverage was estimated from household surveys. IRS coverage was more than 85% in two rounds of spraying in January and April 2012. Household coverage with at least one ITN per house was 94.7% after the universal coverage net campaign in the baseline year and the proportion of household with all sleeping places covered by LLIN was 50.1% decreasing to 39.1% by the end of the intervention year. An.gambiae s.s. comprised 80% and An.arabiensis 18.3% of the anopheline collection in the baseline year. Mean An.gambiae s.l. density in the ITN+IRS arm was reduced by 84% (95%CI: 56%-94%, p = 0.001) relative to the ITN arm. In the stratum of clusters categorised as high anopheline density at baseline EIR was lower in the ITN+IRS arm compared to the ITN arm (0.5 versus 5.4 per house per month, Incidence Rate Ratio: 0.10, 95%CI: 0.01-0.66, p-value for interaction <0.001). This trial provides conclusive evidence that combining carbamate IRS and ITNs produces major reduction in Anopheles density and entomological inoculation rate compared to ITN alone in an area of moderate coverage of LLIN and high pyrethroid resistance in An.gambiae s.s.

Successful Treatment of Electrographic Status Epilepticus of Sleep With Felbamate in a Patient With SLC9A6 Mutation.

BACKGROUND: Mutations of SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999 in which affected males exhibited profound intellectual disability, autism, drug-resistant epilepsy, ophthalmoplegia, mild craniofacial dysmorphism, microcephaly, and ataxia. METHODS: We describe a child with an SLC9A6 mutation and an electroencephalographic pattern consistent with electrographic status epilepticus of sleep. RESULTS: Our patient's electrographic status epilepticus of sleep resolved after treatment with felbamate. Following treatment, he remained seizure-free but did not make significant or lasting gains in language. CONCLUSION: Our report extends the clinical epilepsy phenotype in children with SLC9A6 mutations to include electrographic status epilepticus of sleep. In addition, felbamate was an effective treatment for electrographic status epilepticus of sleep in our patient.

A Case Report on Dyskinesia Following Rivastigmine Patch 13.3 mg/24 hours for Alzheimer's Disease: Perspective in the Movement Disorders Spectrum Following Use of Cholinesterase Inhibitors.

Current reports on movement disorder adverse effects of acetylcholinesterase inhibitors only include extrapyramidal symptoms and myoclonus.Here is a case of an 81-year-old female Filipino with dementia who presented with first-onset generalized choreiform movements.The etiology of the clinical finding of dyskinesia was investigated through laboratories, neuroimaging, and electroencephalogram, all of which yielded negative results. Review of her medications included the rivastigmine (Exelon) patch, which had just been increased to 13.3 mg/24-hour-dose 3 months prior. With all other possible causes excluded, a trial discontinuation of rivastigmine, showed decreased frequency of the dyskinesia 48 hours after, with complete resolution after 6 days, and no recurrence since then.This case thus presents a probable association or causality between the choreiform movement and rivastigmine at 13.3 mg/24-hour-dose patch because of clear temporal proximity, lack of alternative explanations, and a reversal of the dyskinesia upon medicament discontinuation.

Rivastigmine for Alzheimer's disease.

BACKGROUND: Alzheimer's disease is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and lower risk of adverse effects have since been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA. OBJECTIVES: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources. SELECTION CRITERIA: We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared. DATA COLLECTION AND ANALYSIS: One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data. MAIN RESULTS: A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies). AUTHORS' CONCLUSIONS: Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.

Evaluating high-dose rivastigmine patch in severe Alzheimer's disease: analyses with concomitant memantine usage as a factor.

BACKGROUND: ACTION, a 24-week, prospective, randomized, parallel-group, double-blind study in patients with severe Alzheimer's disease (AD), demonstrated significant efficacy of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch on the Severe Impairment Battery (SIB) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Overall, 61% of the study population received at least 1 dose of concomitant memantine, regardless of dose or duration. This retrospective analysis investigated the effects of concomitant memantine on the efficacy, safety and tolerability of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch. METHODS: Patients were stratified according to whether or not they received at least one dose of concomitant memantine during the double-blind phase. Changes from baseline on the SIB and ADCS-ADL-SIV were compared using analysis of covariance (ANCOVA) with treatment, pooled center, memantine usage and treatment-by-memantine as factors, and baseline as a covariate. Safety and tolerability were assessed. RESULTS: Memantine-treated patients were younger than those not receiving memantine (mean 75.9 and 78.8 years, respectively), with a lower screening Mini-Mental State Examination (8.6 and 9.2, respectively). ANCOVA confirmed there was no significant interaction (p>0.1) between study treatment and memantine use on the SIB or ADCS-ADL-SIV. The incidence of adverse events was: 71.4%, 13.3 mg/24 h patch with memantine; 79.7%, 13.3 mg/24 h patch alone; 74.7%, 4.6 mg/24 h patch with memantine; and 71.1%, 4.6 mg/24 h patch alone. CONCLUSION: These data suggest benefit of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch, regardless of concomitant memantine use. The incidence of adverse events with highdose patch was similar in memantine-treated patients and those not receiving memantine.