Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

BACKGROUND: The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. OBJECTIVES: While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. METHODS: We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. RESULTS: A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. CONCLUSIONS: Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. CLINICAL TRIAL REGISTRATION: The study was pre-registered on PROSPERO (CRD42021258376).

The impact of rivastigmine on post-surgical delirium and cognitive impairment; a randomized clinical trial.

BACKGROUND: Delirium is an acute and transient disorder of brain function that often occurs in post-surgical patients. Rivastigmine is a cholinesterase inhibitor drug that has been proposed as an adjuvant drug in recent years, still, despite significant theoretical evidence, few clinical studies have been performed on its impact on delirium. AIM: Due to the widespread use of cholinesterase inhibitors in pediatric and adult surgery, the present study aims to investigate the impact of Rivastigmine as a cholinesterase inhibitor on delirium after radical surgery. METHODS: In this randomized double-blind clinical trial, a hundred recruited patients were randomly assigned to either Rivastigmine (n = 50) or placebo (n = 50) groups, and we measured post-operative impact on delirium, by Confusion Assessment Method (CAM) score, and cognitive impairment, by the Mini-Mental State Examination (MMSE). Our univariate and multivariate logistical regression models assessed this hypothesized impact. RESULTS: Treatment with Rivastigmine was significantly associated with reduced day one post-op delirium, as measured by CAM score (Odds Ratio (OR) = 0.35, 95% Confidence Interval (CI) 0.11 to 0.97, p = 0.05), and cognitive impairment, as measured by MMSE (OR = 0.25, 95% CI 0.1 to 0.59, p = 0.0022). These associations became stronger after controlling for age, blood loss, and post-op blood sodium levels: Delirium (OR = 0.23, 95% CI 0.05 to 0.92, p = 0.05), cognitive impairment (OR = 0.12, 95% CI 0.03 to 0.42, p = 0.000178). CONCLUSION: The significant result of our randomized clinical trial is that pre-op Rivastigmine treatment may be associated with a substantial drop in patients experiencing post-op delirium and post-op cognitive impairment.

Comparative Bioavailability Study of a Novel Multi-Day Patch Formulation of Rivastigmine (Twice Weekly) with Exelon® Transdermal Patch (Daily)- A Randomized Clinical Trial.

BACKGROUND: Rivastigmine, a reversible AChEI for symptomatic treatment of mild to moderately severe Alzheimer's dementia, is administered once daily transdermal patches, enabling an easier and continuous drug delivery. A novel multi-day (twice week) patch formulation was developed with greater convenience for patients' therapeutic management. OBJECTIVE: To assess the bioequivalence under SS conditions of the multiple-day rivastigmine transdermal patch (Test Product, RID-TDS) in comparison to the once-daily Exelon® transdermal patch (Reference Product), both at a release rate of 9.5 mg/24 h. DESIGN: Single-center, open-label, randomized, multiple-dose study in healthy male adults in a 2- period, 2-sequence-crossover design with multiple applications. METHODS: Patches were applied on 11 consecutive days for Exelon® and a 4-3-4-day regimen for the multiday test patch (RID-TDS), separated by a 14-day wash-out period. The safety, local tolerability and inhibitory effect of rivastigmine on plasma BuChE activity were also evaluated. RESULTS: 57 subjects completed the study according to the protocol. Calculated point estimates and 90% CI for all primary parameters (AUC96-264, Cmax96-264 and Cmin96-264) were within the predefined acceptance interval of 80.00-125.00%. They were 113.64% (107.33-120.33), 105.14% (98.38- 112.38) and 107.82% (97.78-118.89) respectively. Satisfactory adhesion (CI of mean adhesion above 90%) was demonstrated for RID-TDS but not for Exelon®. CONCLUSION: Bioequivalence was demonstrated between RID-TDS mg twice a week and Exelon® once daily in SS. Patch adhesion favored RID-TDS despite the longer dosing interval. Both products were well tolerated.

Risk of Serious Adverse Events Associated With Individual Cholinesterase Inhibitors Use in Older Adults With Dementia: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVE: Cholinesterase inhibitors (ChEIs) are used as first-line pharmacotherapy to manage dementia. However, there are limited data regarding their relative safety. This study evaluated the risk of serious adverse events (SAEs) associated with individual ChEIs in older adults with dementia and also examined sex-based and dose-based effects on this risk. METHODS: This was a retrospective cohort study using 2013-2015 US Medicare claims data involving Parts A, B, and D. Patients aged ≥ 65 years with a dementia diagnosis and incident use of the ChEIs, namely donepezil, galantamine, or rivastigmine, were included. The primary outcome of interest was SAEs defined as emergency department visits, inpatient hospitalizations, or death within 6 months of ChEI initiation. Multivariable Cox proportional hazards regression with propensity score (PS) as a covariate and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of SAEs across individual ChEIs. RESULTS: The study included 767,684 older adults with dementia who were incident new users of ChEIs (donepezil 79.42%, rivastigmine 17.67%, galantamine 2.91%). SAEs were observed in 15.5% of the cohort within 6 months of ChEI prescription. Cox regression model with PS as covariate found that patients prescribed rivastigmine (adjusted hazard ratio [aHR] 1.12; 95% CI 1.03-1.33) and galantamine (aHR 1.51; 95% CI 1.24-1.84) were at increased risk of SAEs compared with patients on donepezil. Stratified analyses revealed that rivastigmine was associated with an 18% increased risk for SAEs in females (aHR 1.18; 95% CI 1.06-1.31), and galantamine was associated with a 71% increased risk in males (aHR 1.71; 95% CI 1.17-2.51) compared with donepezil. High and recommended index doses of rivastigmine and galantamine were associated with an increased risk of SAEs compared with donepezil. The findings were consistent in sensitivity analyses. CONCLUSION: The study found that the risk of SAEs varied across individual ChEIs, with sex and dose moderating these effects. Therefore, these moderating effects should be carefully considered in personalizing dementia care.

Exposure to pesticides in utero impacts the fetal immune system and response to vaccination in infancy.

The use of pesticides to reduce mosquito vector populations is a cornerstone of global malaria control efforts, but the biological impact of most pesticides on human populations, including pregnant women and infants, is not known. Some pesticides, including carbamates, have been shown to perturb the human immune system. We measure the systemic absorption and immunologic effects of bendiocarb, a commonly used carbamate pesticide, following household spraying in a cohort of pregnant Ugandan women and their infants. We find that bendiocarb is present at high levels in maternal, umbilical cord, and infant plasma of individuals exposed during pregnancy, indicating that it is systemically absorbed and trans-placentally transferred to the fetus. Moreover, bendiocarb exposure is associated with numerous changes in fetal immune cell homeostasis and function, including a dose-dependent decrease in regulatory CD4 T cells, increased cytokine production, and inhibition of antigen-driven proliferation. Additionally, prenatal bendiocarb exposure is associated with higher post-vaccination measles titers at one year of age, suggesting that its impact on functional immunity may persist for many months after birth. These data indicate that in utero bendiocarb exposure has multiple previously unrecognized biological effects on the fetal immune system.

Felbamate add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: This is an updated version of the Cochrane Review previously published in 2017.Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. SEARCH METHODS: For the latest update we searched the Cochrane Register of Studies (CRS Web), MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), on 18 December 2018. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, the third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data.Only one study reported the outcome, 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate while another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were: headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants.We assessed the evidence for all outcomes using GRADE and found it as being very-low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Fenoxycarb exposure disrupted the reproductive success of the amphipod Gammarus fossarum with limited effects on the lipid profile.

Insect growth regulator insecticides mimic the action of hormones on the growth and development of insect pests. However, they can affect the development of non-target arthropods. In the present study, we tested the effects of the growth regulator insecticide fenoxycarb on several endpoints in the freshwater crustacean Gammarus fossarum (Amphipoda). Females carrying embryos in their open brood pouch were exposed to 50 µg L-1 fenoxycarb throughout the entire oogenesis (i.e. 21 days). After exposure, newborn individuals from exposed embryos were removed from the maternal open brood pouch for lipidomic analysis, while males were added to assess the reproductive success. After fertilization, the lipid profile, energy reserve content (lipids, proteins and glycogen), and activity of phenoloxidase - an enzyme involved in the immune response - were measured in females. No significant effect of fenoxycarb exposure was observed on the lipid profile of both newborn individuals and females, while reproductive success was severely impaired in exposed females. Particularly, precopulatory behavior was significantly reduced and fertilized eggs were unviable. This study highlighted the deleterious effects of the insect growth regulator fenoxycarb on gammarid reproduction, which could have severe repercussions on population dynamics.

Acute and chronic effects of exposure to the juvenile hormone analog fenoxycarb during sexual reproduction in Daphnia magna.

Recent studies have demonstrated that insect growth regulating insecticides are able to affect reproductive endpoints in zooplankton species at very low levels. For the cyclic parthenogenetic water flea Daphnia, most of this research has focused on the asexual part of the life cycle and induction of male offspring. Even though Daphnia and many other aquatic invertebrates rely on sexual reproduction and subsequent production of dormant eggs to recover from environmentally harsh conditions, much less is known about the effects of toxicants on the sexual reproductive phase. Using fenoxycarb as a model pesticide, we exposed male and female neonate Daphnia magna, under conditions inducing a switch to sexual reproduction, and tested for effects on dormant egg (ephippia) production and sex ratio of parthenogenetic offspring. Subsequently, we assessed whether fenoxycarb exposure affected the quality of the produced dormant eggs and viability of the hatchlings. Our results showed that exposure to sub-lethal concentrations of fenoxycarb caused a sharp decrease in parthenogenetic reproduction, while inducing male offspring. Dormant egg production was marginally negatively affected, but survival and fitness of the hatched individuals were not significantly affected. This indicates that under pesticide stress, surviving adult females invested in sexual reproduction at the expense of parthenogenetic reproduction. Exposure to toxicants during the sexual reproductive phase, could affect the active aquatic phase as well as the dormant phase in natural zooplankton populations. This indicates the need for further ecotoxicological research and development of test protocols taking into account the full life cycle of zooplankton species.

Felbamate as an add-on therapy for refractory partial epilepsy.

BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and we have assessed its effects as an add-on therapy to standard drugs in this review. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. SEARCH METHODS: For the latest update we searched the Cochrane Epilepsy Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, up to 20 October 2016. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: Randomised placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: We included four randomised controlled trials with a total of 236 participants. Two trials were parallel design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. Two studies were at an unclear risk of bias for random sequence generation and allocation concealment. These two studies did not include any description of their methods for outcome assessment and performance blinding (i.e. participants or doctors). Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. Only one study reported 50% or greater reduction in seizure frequency. One study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. One study reported percentage reduction in seizure frequency compared to placebo, but there were no P values. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number of individual studies and differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Residues and dissipation kinetics of carbendazim and diethofencarb in tomato (Lycopersicon esculentum Mill.) and intake risk assessment.

Dissipation behaviors and residues of carbendazim and diethofencarb in combination in tomato were investigated. The half-lives were 2.1-3.4 days for carbendazim, and 1.8-3.2 days for diethofencarb at a dose of 1.5 times of the recommended dosage. The residues of carbendazim and diethofencarb were below the maximum residue limits (MRLs) in China one day after application of the combination. The ultimate residues were significantly lower than the maximum permissible intake (MPI) in China at the recommended high dose for both child and adult. The values of the maximum dietary exposure for carbendazim and diethofencarb were 0.26 and 0.27 mg per person per day, respectively. The theoretical maximum daily intake (TMDI) values for carbendazim and diethofencarb were 1.5 and 0.5 mg/day, respectively. The dietary exposure was lower than the MPI, which indicates the harvested tomato samples under the experimental conditions (open field) are safe for human consumption at the recommended high dosage of the wettable powder.

Evaluating the safety and efficacy of felbamate in the context of a black box warning: A single center experience.

INTRODUCTION: Felbamate was approved in 1993 to treat partial seizures with and without secondary generalization in adults and in Lennox-Gastaut Syndrome in children. Its use was later restricted when rare but fatal cases of aplastic anemia and hepatic failure were identified. METHODS: This single center analysis retrospectively evaluated the safety and efficacy of felbamate in a cohort of children, adolescents, and adults with epilepsy. RESULTS: A chart review identified 103 patients taking felbamate. The range of felbamate dose was 300-4500 mg (mean: 1800 ± 900 mg). The duration of therapy ranged from 1 month to 20 years (mean duration: 35 ± 45 months). Eighteen (17.5%) subjects experienced adverse events including insomnia, nausea, vomiting, decreased appetite, weight loss, gastric discomfort, diarrhea, mood and behavioral problems, high blood pressure, headache, and elevated liver enzymes. Out of these, 6 (5.9%) patients discontinued the therapy. No hepatic failure or agranulocytosis was observed. Fifty-nine (57.72%) patients achieved ≥ 50% reduction in seizure frequency, and 30 (29.12%) patients achieved seizure freedom. CONCLUSIONS: These findings suggest that felbamate is safe, well tolerated, and effective in treatment of various types of epilepsy syndromes.

The rise and fall of felbamate as a treatment for partial epilepsy--aplastic anemia and hepatic failure to blame?

Felbamate has been approved for refractory partial seizures since the early nineties. Due to safety concerns regarding its use, namely, in aplastic anemia and hepatic failure, felbamate's use has been restricted and a 'Black Box' warning has been inserted. Nonetheless, it is a useful drug in refractory cases of partial epilepsy. There are certain precautions which can prevent and minimize the serious idiosyncratic reactions associated with felbamate, thereby providing an option in refractory cases where no other drug works.

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.

Risk of pneumonia in new users of cholinesterase inhibitors for dementia.

OBJECTIVES: To compare the risk of pneumonia in older adults receiving donepezil, galantamine, or rivastigmine for dementia. DESIGN: Retrospective cohort study. SETTING: Nationally representative 5% sample of Medicare databases. PARTICIPANTS: Medicare beneficiaries aged 65 and older who newly initiated cholinesterase inhibitor therapy between 2006 and 2009. MEASUREMENTS: Pneumonia, defined as the presence of a diagnosis code for pneumonia as the primary diagnosis on an inpatient claim or on an emergency department claim followed by dispensing of appropriate antibiotics. Cox proportional hazards models were used to estimate the risk of pneumonia. Subgroup analyses and sensitivity analyses were conducted using alternative pneumonia definitions and adjustments using high-dimensional propensity scores to test the robustness of the results. RESULTS: The mean age of 35,570 new users of cholinesterase inhibitors (30,174 users of donepezil, 1,176 users of galantamine, 4,220 users of rivastigmine) was 82; 75% were women, and 82% were white. The cumulative incidence of pneumonia was 51.9 per 1,000 person-years. The risk of pneumonia for rivastigmine users was 24% lower than that of donepezil users (hazard ratio (HR)=0.75, 95% confidence interval (CI)=0.60-0.93). Risk in galantamine users (HR=0.87, 95% CI=0.62-1.23) was not significantly different from risk in donepezil users. Results of subgroup and sensitivity analyses were similar to the primary results. CONCLUSION: The risk of pneumonia was lower in individuals receiving rivastigmine than in those receiving donepezil. Additional studies are needed to confirm the findings of pneumonia risk between the oral and transdermal forms of rivastigmine and in users of galantamine.

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.

Cognitive function in early clinical phase huntington disease after rivastigmine treatment.

BACKGROUND: In Huntington disease (HD) patients receiving rivastigmine treatment improvement of behavioral symptoms and of cognitive function (assessed with screening diagnostic instruments) has been reported. The aim of the present study was to verify such improvement in cognitive function by cognitive function assessment with a detailed neuropsychological battery covering all relevant cognitive systems expected to be impaired in early phase HD. SUBJECTS AND METHODS: Eighteen (18) HD patients entered the study and were randomly allocated to the rivastigmine and placebo group. All subjects underwent neuropsychological assessment at baseline. Follow-up neuropsychological assessment was applied after 6 months of rivastigmine or placebo treatment. Eighteen (18) healthy controls entered the study to control for practice effect and underwent neuropsychological assessment at baseline and after 6 months, without treatment. The neuropsychological battery consisted of assessment tools that are sensitive to cognitive impairment seen in early phase HD: CTMT, SDMT, Stroop (attention and information control), RFFT, TOL, Verbal fluency (executive functioning), CVLT-II, RCFT (learning and memory). Effect of rivastigmine and possible effect of practice was assessed using the mixed ANOVA model. RESULTS: No statistically significant effect of rivastigmine treatment on cognitive function in HD patients was detected. There was no evidence for practice or placebo effect. CONCLUSIONS: Detailed neuropsychological assessment did not confirm previously reported effect of rivastigmine treatment on cognitive function in HD patients. The limitations of our study are, in particular, small sample size and the lack of a single measure of relevant cognitive functioning in HD patients. Instead of focusing solely on statistical significance, a clinical relevance study is proposed to clarify the issue of rivastigmine effects in HD.

Transdermal rivastigmine in the treatment of Alzheimer's disease: current and future directions.

Despite the fact that the prevalence of Alzheimer's disease (AD) is exponentially increasing, we have not yet been able to develop a new treatment to modify the course of the disease. This vacuum makes the traditional cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist the only accessible pharmacotherapy options for the treatment of this disease. Among these medications, the only available transdermal patch at this time is the rivastigmine patch. This patch provides significantly lower gastrointestinal adverse effects. A higher tolerability rate provides the option for physicians to continue treatment with higher doses of rivastigmine in advanced stages of AD. Moreover, ease of use, easy-to-follow schedule, less administration time spent by the caregiver result in greater adherent to the treatment. This article aims to provide a comprehensive drug profile for transdermal rivastigmine, to review currently available treatment options, and to try to anticipate future treatment directions for AD.