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Cholinesterase inhibitors used to treat the symptoms of Alzheimer's disease (AD) inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), albeit to different degrees. Because central and peripheral neurons, including intrinsic cardiac neurons located on the surface of the mammalian heart, express both BuChE and AChE, we studied spontaneously active intrinsic cardiac neurons in the pig as a model to assess the effects of inhibition of AChE compared to BuChE. Neuroanatomical experiments showed that some porcine intrinsic cardiac neurons expressed AChE and/or BuChE. Enzyme kinetic experiments with cholinesterase inhibitors, namely, donepezil, galantamine, (+/-) huperzine A, metrifonate, rivastigmine, and tetrahydroaminoacridine, demonstrated that these compounds differentially inhibited porcine AChE and BuChE. Donepezil and (+/-) huperzine A were better reversible inhibitors of AChE, and galantamine equally inhibited both the enzymes. Tetrahydroaminoacridine was a better reversible inhibitor of BuChE. Rivastigmine caused more rapid inactivation of BuChE as compared to AChE. Neurophysiological studies showed that acetylcholine and butyrylcholine increase or decrease the spontaneous activity of the intrinsic cardiac neurons. Donepezil, galantamine, (+/-) huperzine A, and tetrahydroaminoacridine changed spontaneous neuronal activity by about 30-35 impulses per minute, while rivastigmine changed it by approximately 100 impulses per minute. It is concluded that (i) inhibition of AChE and BuChE directly affects the porcine intrinsic cardiac nervous system, (ii) the intrinsic cardiac nervous system represents a suitable model for examining the effects of cholinesterase inhibitors on mammalian neurons in vivo, and (iii) the activity of intrinsic cardiac neurons may be affected by pharmacological agents that inhibit cholinesterases.
With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t(1/2)) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t(1/2) of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t(1/2) of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t(1/2) of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.
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Rivastigmine-treated Alzheimer's disease patients who had been maintained on a fixed regimen of twice-daily rivastigmine for >or=2 months were eligible to enter the study. Sixteen patients (seven males and nine females, age range 64-88 years, weight range 51.8-104 kg) were enrolled in this open-label, crossover study, which consisted of a 28-day screening period, a 36-hour baseline period, and a 35-day combination treatment phase. The patients spent the baseline period and day 35 at the study centre, where plasma samples for pharmacokinetic evaluation were taken at specified time intervals over a 10-hour time period. In addition, 10-hour (evening pre-dose) memantine plasma samples were taken on days 21, 34 and 35.
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To evaluate the efficacy of a NeuroPsychological Training (TNP) in patients with MCI who are treated with cholinesterase inhibitors (ChEIs), compared with patients MCI treated only with ChEIs and patients not treated, in a longitudinal, one year follow-up study.
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Aluminum, a known neurotoxin, has long been implicated in the pathogenesis of Alzheimer's disease. Its exposure is associated with impairment in the cholinergic system in the brain. In this study we investigated the behavioral effects of aluminum in rats and the possible effect of rivastigmine, a cholinesterase inhibitor, on the aluminum-induced behavioral changes. Rats were exposed to aluminum chloride (100 mg/kg/day i.p.) for 60 days before the start of behavioral tests. Rivastigmine was given in doses of 0.5, 1, 1.5 and 2.5 mg/kg i.p. 60 min before the behavioral tests. Five tests were investigated; open field test, Morris water maze, radial arm maze, passive avoidance test and rota-rod test. Results showed that aluminum exposure was associated with significant reductions in spontaneous locomotor and exploratory activities in open field test and significant impairments in learning and memory in Morris water maze, radial arm maze and passive avoidance tests. The behavioral impairments caused by aluminum were significantly improved by rivastigmine. Neither aluminum alone nor co-treatment with rivastigmine caused any significant alteration of the animals' performance in rota-rod test. The improvements in activity, learning and memory caused by rivastigmine were found to be dose-dependent, and the maximal improvement was encountered with its large dose (2.5 mg/kg). From these results we can conclude that rivastigmine can reverse behavioral deficits caused by aluminum intoxication.
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We extracted data on patient population, pharmacologic agents, delirium characteristics, rescue treatment, length of stays in the ICU and hospital, and mortality. For each trial, we assessed the risk of bias domains and rated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach.
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Six impurities were detected at trace level in rivastigmine tartrate drug substance by a newly developed high performance liquid chromatography method. Three impurities were characterized rapidly and three impurities were found to be unknown. The unknown impurities were enriched and identified with a combination of semi-preparative HPLC and LC/MS/MS techniques. Proposed structures were further confirmed by characterization using NMR, FT-IR, and EA techniques of impurity standards. Based on the spectroscopic, spectrometric and elemental analysis data unknown impurities were characterized as 3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methyl carbamate N-oxide, ethyl-methyl-carbamic acid 4-(1-dimethylamino-ethyl)-phenyl ester and ethyl-methyl-carbamic acid 2-(1-dimethylamino-ethyl)-phenyl ester. A plausible mechanism for the formation of these impurities is also proposed. The method was validated according to ICH guidelines for fourteen impurities to demonstrate specificity, precision, linearity, accuracy and stability indicating nature of the method. Regression analysis showed correlation coefficient value greater than 0.999 for rivastigmine tartrate and its impurities. Accuracy of the method was established based on the recovery obtained between 93.41 and 113.33% for all impurities.
The purpose of this systematic review was to compare the safety and tolerability of the cholinesterase inhibitors (ChEIs) donepezil, rivastigmine and galantamine for treating mild to moderate Alzheimer's disease (AD) patients in routine clinical practice.
The CITIRIVAD study was a retrospective case-control study on 174 consecutive outpatients aged ≥65 years, affected with AD or MD, mean age 81.3 ± 4.5 years. Of the 174 patients, 92 had been treated with rivastigmine + citicoline 1000 mg/day given orally (group A); 82 patients had been treated with rivastigmine (group B). In both groups rivastigmine patch had been used for at least six months at the highest tolerated dosage. Group A comprised 62 patients affected with AD and 30 patients with MD. Group B comprised 53 patients affected with AD and 29 with MD. Cognitive functions had been assessed by Mini Mental State Examination (MMSE), daily life functions by activities of daily living (ADL) and instrumental activities (IADL), behavioral symptoms by neuropsychiatric inventory (NPI), comorbidities by the Cumulative Illness Rating Scale and mood by geriatric depression scale (GDS)-short form tests, which had been administered at baseline, 3 and 9 months.
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To define the actual knowledge of the impact of drugs for the treatment of dementia on the improvement of cognition in aging and mild cognitive impairment.
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The disposition of SDZ ENA 713, indicated for the treatment of Alzheimer's disease, was studied in non-pregnant, pregnant, and lactating New Zealand white rabbits. 3H-SDZ ENA 713 was administered as single oral or intravenous dose (1.09 mg kg-1) and as multiple oral doses (1.09 mg kg-1) daily for 7 days. Serial blood and milk samples, selected tissues and excreta samples were collected. Radioactivity was determined in all biological samples by liquid scintillation counting. Concentrations of unchanged SDZ ENA 713 and its phenolic metabolite, ZNS 114-666, were measured by GC-MS. Pharmacokinetic parameters were determined by model independent methods. The rate and onset of absorption were rapid (tmax 1.3 +/- 0.58 h) and the extent of absorption was essentially complete. Concentrations of SDZ ENA 713 were below the limit of quantification (0.98 ng mL-1) after oral administration. Following intravenous administration, SDZ ENA 713 was extensively distributed (Vss = 3.1 L kg-1) and rapidly cleared (Cl = 2.7 L h-1 kg-1). The radioactivity was primarily excreted via the kidneys (86% of dose). In pregnant rabbits receiving multiple oral doses, the fetus to placentae tissue ratio of radioactivity averaged 0.5. Passage of radioactivity from blood into milk was rapid (tmax = 2 h) and the milk:blood AUC ratio of radioactivity averaged 1.5. No unchanged SDZ ENA 713 was detected in the milk samples; however, there were measurable concentrations of the phenolic metabolite (Cmax = 82.9 ng mL-1). The milk to blood ratio of the phenolic metabolite averaged 2.3. In conclusion, SDZ ENA 713 underwent extensive presystemic metabolism following oral administration. There was moderate transfer of drug-related materials across the placenta. Projecting the rabbit data to humans, it is suggested that nursing neonates would not be exposed to unchanged SDZ ENA 713 following oral doses to nursing mothers.
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Most appeals were again denied after expert review. Better education concerning utilization guidelines and a platform for insurer, insuree, and physician to dialog are needed to improve the effectiveness and efficiency of the appeals system.
The ACTION trial examines the efficacy and tolerability of a 15 cm(2) rivastigmine patch over a 24-week period in patients with severe AD. This is a novel trial in the development of rivastigmine, as it uses a design that does not include a placebo arm, is recruiting patients with severe AD, and includes an ADL measure as a co-primary efficacy variable. CLINICAL REGISTRATION NUMBER: CENA713D US44.
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From a societal perspective, treatment with cholinesterase inhibitors or memantine was more effective but also more costly than standard care for mild to moderate vascular dementia. The donepezil 10 mg strategy was the most cost-effective and also dominated the other alternatives.
To investigate the clinical response to rivastigmine transdermal patch monotherapy or memantine plus rivastigmine transdermal patch therapy in AD patients based on the BCHE-K gene.
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Reduced TAS, AChE activity and learning performance was observed in old rats. Both rivastigmine and selesiline alone improved performance, although they influenced the biochemical parameters in a different way. The combination of the two drugs did not affect learning performance.
Inappropriate sexual behaviors in dementia can be difficult to treat. Frequently, multiple psychoactive medications are used and many pharmacotherapies are trialed prior to finding an effective agent. More research is needed to clarify the usefulness of these medications and to identify non-pharmacological strategies to prevent unnecessary use of medications.
This was a prospective, longitudinal, randomized, open-label, 4-arm, parallel-group, 12-month clinical trial carried out in 177 AD patients. The severity of BPSD was evaluated at baseline and after treatment with memantine (n = 48), donepezil (n = 42), rivastigmine (n = 46), and galantamine (n = 41), by using the Neuropsychiatric Inventory (NPI) and the Behavioural Pathology in Alzheimer's Disease (BEHAVE-AD) scales.
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In 2002, an estimated 3.4 million Medicare beneficiaries were diagnosed with ADRDs (8.1%), of whom 58.9% resided in the community (prevalence rate=5.1%) and 41.1% resided in LTC facilities (prevalence rate=57.2%). Use of antidementia drugs was similar across settings, with 24.7% of subjects with dementia in the community and 26.3% of those in LTC receiving prescriptions for donepezil, galantamine, or rivastigmine. Use of haloperidol was comparable (and low) in both settings. Use of atypical antipsychotics, especially risperidone, olanzapine, and quetiapine, was much higher in LTC residents (21.0%, 11.9%, and 7.1%, respectively) than in the community (5.1%, 4.0%, and 2.3%).
Three new cholinesterase inhibitors, donepezil, rivastigmine, and galantamine, all inhibit the enzyme AChE. Rivastigmine also inhibits BuChE, which could lead to additional benefits in late-stage Alzheimer's disease, but also cause more GI side effects at initiation of therapy. Galantamine is also an allosteric modulator of nicotinic receptors, which could lead to additional efficacy for attention and for behaviors mediated by neurotransmitters other than ACh. We are now entering an exciting era where the options for treating the devastating illness Alzheimer's disease are multiplying and creating a foundation upon which new therapies with new mechanisms of action can be built.
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SIB data were provided by 104 rivastigmine-treated patients and 106 patients receiving placebo (Intent-To-Treat Last Observation Carried Forward population). Significantly less decline was observed on the previously defined memory and language subscales, and the newly defined working memory/memory subscale in rivastigmine-treated patients (all P < 0.05 versus placebo). Calculation of effect sizes demonstrated numerically greater efficacy of rivastigmine versus placebo on each of the subscales, and a broad range of SIB items; greatest effect sizes were observed on SIB items assessing the current month (effect size = 0.30) and digit span series (effect size = 0.33).