The brain of mammals contains two major forms of cholinesterases (ChEs): acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and in their kinetics. Butyrylcholine is not a physiological substrate in mammalian brains which makes the function of BuChE difficult to interpret. In human brains, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in patients with Alzheimer's disease (AD). While AChE activity decreases progressively in the brain of patients with AD, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor. We found that extracellular acetylcholine levels increased 15-fold from 5 nmol/L to 75 nmol/L concentrations, with little cholinergic adverse effect in the animal. Based on these data, we postulated that two pools of ChEs may be present in the brain: one mainly neuronal and AChE dependent; and one mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of acetylcholine concentration in the brain and can be separated with selective inhibitors. The recent development of highly selective BuChE inhibitors will allow us to test these new agents in patients with AD in order to find out whether or not they represent an advantage for the treatment of patients with AD as compared with selective (donepezil) or relatively non-selective (rivastigmine, galantamine) ChE inhibitors presently in use. The association between a BuChE-K variant and AD has not been confirmed in several studies. In conclusion, additional experimental and clinical work is necessary in order to elucidate the role of BuChE in normal brain function and in the brains of patients with AD. In the future, it may be possible that selective BuChE inhibitors will have a role in treatment of patients with advanced AD.
Articles describing studies, case series, and case studies are included in this review.
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Of the 13 studies (10 prevention and three treatment) involving 5,848 patients, one multicentered randomized controlled trial on prophylactic dexamethasone made up 77% of the total sample size. The use of pharmacologic agents (dexamethasone, rivastigmine, risperidone, ketamine, dexmedetomidine, propofol, and clonidine) reduced the risk of delirium (relative risk, 0.57; 95% CI, 0.40-0.80) with quality of evidence rated as moderate. There was high quality of evidence for no increased risk of mortality (relative risk, 0.89; 95% CI, 0.57-1.38) associated with the use of prophylactic pharmacologic agents. Metaanalysis of treatment trials was not undertaken because of high heterogeneity. In two small trials (total number of patients = 133), haloperidol did not appear to be effective in treating delirium.
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Two hundred and six (n = 206) patients with probable AD and Mini-Mental State Examination (MMSE) scores of 10-20 were randomized to rivastigmine patch monotherapy or memantine plus rivastigmine patch for 24 weeks. Of the 206 patients with probable AD, 146 patients who consented to genetic testing for APOE were included and assessed for this subgroup study.
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This study suggests that specific drugs for AD, especially memantine and rivastigmine, may be effective in the improvement of BPSD in patients with mild to moderate AD, without major side effects.
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This open-label, six-month study evaluated the efficacy and safety of rivastigmine in 382 AD patients who had previously failed to benefit from treatment with donepezil (80% due to lack of efficacy, 11% due to tolerability problems, 9% both reasons).
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Until 2010, Donepezil, one of choline esterase inhibitors, was solely available for the treatment of AD. At spring 2011, new 3 anti-dementia drugs were launched. These 3 drugs are Galantamine (choline esterase inhibitor), Rivastigmine (choline esterase inhibitor), and Memantine (NMDA antagonist). Galantamine has the indication for mild to moderate AD, and Rivastigmine, which is available only in the patch formulation, also has the indication for mild to moderate AD. However, co-medication of choline esterase inhibitors is not allowed. Memantine has the indication for moderate to severe AD, and can be prescribed with one choline esterase inhibitor. From now on, we have a variety of therapeutic choices including the co-medication, resulting in the therapy best fit to individual AD patients.
To review the available pharmacokinetic data that supported the rationale behind the development of the rivastigmine transdermal patch and its clinical effects in dementia therapy. This article will also discuss how the patch may alter the treatment paradigm for patients with AD.
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Subjects with medial temporal lobe atrophy (MTLA) tended to show more decline on the MMSE after correction for age, sex, education, baseline cognitive score, and dosage at week 26 compared with subjects without MTLA (p = 0.08). A significant interaction between MTLA and dosage at week 26 existed for change on the MMSE and ADAS-Cog: subjects with MTLA showed more cognitive decline than subjects without MTLA only in the group of patients who received a low dosage at week 26. MTLA was not associated with treatment response. The APOE genotype was not associated with change on the MMSE or ADAS-Cog or with treatment response.
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Switching patients with Alzheimer's disease from one cholinesterase inhibitor to another represents a viable option for patients not responding to current therapy. The objective of this large U.S.-based study was to evaluate the safety and efficacy of a treatment switch to rivastigmine in patients not responding adequately to or declining on treatment with donepezil.
The prevalence of ADRDs in LTC settings is much larger than in the community, but there is little difference in the proportions receiving antidementia drugs, although LTC residents are more likely to be treated with atypical antipsychotics (risperidone, olanzapine, and quetiapine), presumably for behavioral symptoms.
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Following oral administration of a single 6 mg capsule, rivastigmine is rapidly absorbed with an average time to peak plasma concentration of about 1 hour and an average peak concentration of about 25.6 g/L. By a noncompartmental approach, the absolute bioavailability of the 6 mg oral dose of rivastigmine was 71.7% when compared with a 2mg intravenous infusion normalised for dose. By using a population pharmacokinetic model with Michaelis-Menten elimination, absolute bioavailability was estimated at 60.2%. The average terminal elimination half-life of rivastigmine ranged from 1.4 to 1.7 hours for both treatments. Plasma concentrations of the major metabolite, NAP 226-90, formed by the hydrolysis of rivastigmine by cholinesterase are lower than those of the parent compound following oral and intravenous administration.
Out of the 433 patients, 11 patients (2.54%) suffered serious adverse events. Non-serious adverse events were reported in 179 patients (41.34%). As adverse event is defined as any untoward medical occurrence that may present during treatment with a pharmaceutical product but that does not necessarily have a causal relationship with this treatment. The most common adverse event in the present study was a decline in the Mini-Mental State Examination score in 97 patients (22.40%). The second most common non-serious adverse event was a skin reaction in 61 patients (14.09%). Treatment with rivastigmine continued in 139 cases (32.10%) and was discontinued in 40 cases (9.24%). The median Mini-Mental State Examination score observed at the time of inclusion was 21.0, and after 6 months, it was 22.0 (W 63441; P < 0.001). Because of several limitations, the open-label design of the present study necessitates caution when interpreting the results.
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The modalities for anti-dementia drugs' discontinuation are not consensual.
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A multicentre, hospital-based, prospective observational study was conducted in nine hospitals across Thailand. Patients with probable mild to moderate AD who received the rivastigmine patch were enrolled. Data were collected data at baseline, weeks 4-8 and after week16.
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Three donepezil, two galantamine, one rivastigmine, and two memantine trials, comprising 3093 patients on the study drugs and 2090 patients on placebo, met the selection criteria. Trials were of 6-month duration with similar vascular dementia criteria and outcome measures. Cognitive effects on the Alzheimer's Disease Assessment scale were significant for all drugs, ranging from a -1.10 point mean difference (95% CI -2.15 to -0.05) for rivastigmine to -2.17 for 10 mg daily donepezil (95% CI -2.98 to -1.35). Only 5 mg daily donepezil had an effect on the Clinicians' Global Impression of Change scale (odds ratio 1.51 [95% CI 1.11-2.07]). No behavioural or functional benefits were observed, except for a -0.95 point difference (95% CI -1.74 to -0.16) with 10 mg daily donepezil on the Alzheimer's Disease Functional Assessment and Change Scale. Compared with placebo, more dropouts and adverse events (anorexia, nausea, vomiting, diarrhoea, and insomnia) occurred with the cholinesterase inhibitors, but not with memantine.
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Patients stabilized on an AChEI did not differ significantly from drug naïve patients in relation to the concentrations of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha (p = 0.874, 0.225, and 0.978, respectively). Within the group taking AChEIs, the levels of cytokines did not differ between those taking donepezil, rivastigmine, or galantamine (p = 0.368, 0.851, and 0.299, respectively).
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Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, improvements were seen in the rate of decline of cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg. Adverse events were consistent with the cholinergic actions of the drug. A transdermal patch has been tested in one trial, and there is evidence that the lower dose smaller patch is associated with fewer side effects than the capsules or the higher dose larger patch and has comparable efficacy to both. This review has not examined economic data.
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Caregivers of AD patients undergoing donepezil monotherapy seem to be more satisfied with treatment than those of patients receiving the other usual AD treatments in this study, particularly due to the ease and convenience of use of this drug. The higher level of satisfaction of these caregivers could be explained by the fact that, within the donepezil group, a high percentage of patients were treated with orally disintegrating tablets, which are easier for the patient to swallow.
Owing to the neuro-vascular coupling, measurement of changes in regional cerebral blood flow and blood volume (rCBV) can be used as surrogates reflecting the effects of central nervous system active drugs on neural transmission. As most such drugs are administered orally or intramuscularly and, in many cases, beneficial effects due to drug treatment can be observed only after chronic administration for days or weeks, the evaluation of drug efficacy requires the development of acquisition and analysis tools that allow for comparison of imaging data sets obtained in multiple sessions and for multiple subjects. In the present study, high-resolution susceptibility contrast MR perfusion imaging using a super-paramagnetic contrast agent (CA) was applied to study the effect of a single oral administration of the acetylcholine-esterase inhibitor rivastigmine (Exelon) on rCBV in rats. rCBV maps were calculated from two T2-weighted three-dimensional fast-spin-echo scans recorded before and after the injection of the CA, respectively. All MRI data sets were mapped to a reference data set obtained from a normal male Sprague-Dawley rat using an automated co-registration procedure prior to the analysis for drug effects. Rivastigmine was orally administered at doses of 2, 4 or 8 mg/kg 1 h prior to the rCBV measurement. Rivastigmine increased rCBV in several brain areas including cortex, caudate putamen and hippocampus. The observed effects were dose-dependent and the changes reached the order of 5-12% as compared with baseline levels. Vehicle-treated animals showed no significant alterations of blood volume, demonstrating the reproducibility and stability of rCBV measurements.
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The clinical course of AD patients treated with rivastigmine was compared with a prediction of their course derived by a baseline-dependent historical model of disease progression developed from data in untreated AD patients. Rivastigmine efficacy data came from four 6-month, placebo-controlled, randomized, controlled trials (RCTs) and two open-label extension studies. Cognitive performance was assessed by various clinician- and caregiver-rated measures.
Published data provide evidence for the clinical efficacy of donepezil, galantamine and rivastigmine in patients with mild to moderate AD. There is no indication that these results are critically influenced by the origin or a bias of the publication.
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Neurologists, psychiatrists and geriatricians collected sociodemographic and clinical data from 1,078 patients and administered the Treatment Satisfaction with Medicines (SATMED-Q) and the Morisky-Green questionnaires to their caregivers at outpatient consultations.
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none (observational study).
According to the findings, while rivastigmine could not induce significant improvement of positive and negative symptoms of schizophrenia, it caused significant enhancement of cognitive function in this group of patients.
BZYX was designed as a dual-binding-site acetylcholinesterase (AChE) inhibitor and selected from series of indanone derivatives. The present study was designed to examine the cognition-enhanced, anti-cholinesterase, and neuroprotective effects of BZYX. In the passive avoidance performance and radial arm maze, BZYX showed a comparable effect to donepezil and rivastigmine on memory deficits in different stages induced by scopolamine, NaNO(2) and ethanol, respectively. Ellman's assay indicated BZYX exhibited high inhibition on AChE activity. IC(50) values for BZYX: 0.058+/-0.022 microM; donepezil: 0.019+/-0.004 microM; rivastigmine: 3.81+/-2.81 microM; glantamine: 3.01+/-1.85 microM and huperzine A: 0.053+/-0.016 microM. BZYX also presented great neuroprotecive function from apoptosis induced by hydrogen peroxide(H(2)O(2)) in PC12 cells. MTT assay and Annexin V-FITC Apoptosis Detection showed the viability of PC12 cells remarkably decreased with 400 microM H(2)O(2), while it significantly increased when the cells were pretreated with 0.1-1.0 microM BZYX. BZYX pretreatment remarkably reversed the loss of mitochondria membrane potential (DeltaPsim), scavenged reactive oxygen species formation induced by H(2)O(2) and resulted in up-regulation of procaspase3 and xIAP protein level and down-regulation of phosphorylated JNK protein, p53 protein level and cleavage of caspase 3. It is speculated that the mitochondrial pathway, mediated by Bcl-2 family and Mitogen-Activated Protein Kinases (MAPKs), might involved in the neuroprotection of BZYX. These results first demonstrated that BZYX had neuroprotective effects as well as cognition enhancement and acetylcholinesterase inhibition. It is hopeful that BZYX becomes a potential candidate for use in the intervention for neurodegenerative diseases.
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Cholinergic deficits, leading to cognitive impairment, are a significant aspect of neurodegeneration in AD. AChEIs reduce the degradation of acetylcholine, thus enhancing cholinergic transmission. In addition to the two agents approved by the Food and Drug Administration, tacrine and donepezil, six other compounds of diverse chemical structure and mechanism of inhibition including physostigmine, metrifonate, rivastigmine, and galantamine are under investigation as potential therapy for AD. These compounds are structurally diverse, possess unique patterns of specificities for the various forms of cholinesterase enzymes, use distinct mechanisms of enzyme inhibition, present unique adverse event profiles, and offer relatively similar mean gains in cognitive abilities to patients with AD in controlled clinical trials.
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To determine the frequency of treatment with antidementia drugs in patients in primary care, and the socio-demographic and clinical variables associated with antidementia drug treatment.