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PubMed2000

Rivastigmine for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. One of the most successful therapeutic strategies for Alzheimer's disease has been the use of acetylcholinesterase inhibitors to enhance surviving cholinergic neurotransmission by inhibiting breakdown of released acetylcholine. The first generation acetylcholinesterase inhibitors, such as tacrine, revealed major limitations to use including hepatotoxicity. Several second generation acetylcholinesterase inhibitors have now been introduced, including rivastigmine, which are believed to have superior proprieties. The mode of action and metabolism of rivastigmine suggest that it is unlikely to interact significantly with other medications. This is of particular relevance in elderly AD patients, the majority of whom are likely to be receiving concomitant medication. Large multi-centre trials have been completed in the USA, Canada, Europe and South Africa. Rivastigmine has received EU approval for use in all member states. It has approval in 30 countries but not the US. It is currently under review by the Food and Drug Administration, who requested additional analyses in 1998. OBJECTIVES: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of the Alzheimer's type. SEARCH STRATEGY: The Cochrane Controlled Trials Register, the Dementia Group Register of Clinical Trials, other electronic databases and other sources of reports were searched using the terms ENA 713, EXELON, and rivastigmine in addition to the terms for controlled trials in dementia (see the Group's search strategy for full details). SELECTION CRITERIA: All unconfounded, double-blind, randomised trials in which treatment with rivastigmine was administered for more than one day and compared to placebo for patients with dementia of the Alzheimer's type. DATA COLLECTION AND ANALYSIS: Data were extracted by the reviewer (JSB) and entered into an appropriate meta-analysis. The data extracted were cross-checked by the second reviewer (VI). For each outcome measure, data were sought on every patient randomised. To allow an intention-to-treat analysis, the data were sought irrespective of compliance, whether or not the patient was subsequently deemed ineligible, or otherwise excluded from treatment or follow-up. If these data were not available, an analysis of data on patients who completed treatment was conducted. MAIN RESULTS: There are seven included trials. There are no published reports for two large phase III trials, B304 and B351, although they were completed more than 3 years ago. These are part of the Novartis ADENA programme and comprise 1379 (49%) out of 2803 phase III patients. It is unclear how missing data are replaced in ITT analyses, as reports from the ADENA programme provide no description of the use of this method. This has a profound effect on the results: if the method is substantially the same as LOCF, the benefits of treatment inferred from the analyses described in the publications as ITT, may be exaggerated. The meta-analysis reveals benefits on cognitive function as measured by ADAS-Cog test scores for the higher dose of rivastigmine compared to placebo at 26 weeks and for the lower dose. An additional analysis of ADAS-Cog dichotomised into those showing less than 4 points improvement and those showing 4 or more points improvement at 26 weeks shows benefit for cognitive function for the higher dose of rivastigmine compared to placebo and not for the lower dose. Global clinical state, dichotomised, counting those showing no change or decline, against those showing improvement shows benefit due to lower dose rivastigmine compared to placebo at 26 weeks and not for the higher dose. One trial reported results at 18 weeks and there are no significant differences between higher dose rivastigmine and placebo. One trial reported results at 13 weeks, and there are no significant differences between the 4 or 6 mg/d rivastigmine group and p

Alzheimer Disease↗
PubMedDate not supplied

Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer's disease.

Rivastigmine (ENA 713, or carbamoylatine) is an acetylcholinesterase (AChE) inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system (CNS) compartment than in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). Moreover, rivastigmine preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer's disease (AD). Evidence from animal studies also suggests that rivastigmine is a more potent inhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. Absorption of rivastigmine is rapid and almost complete (>96% of the administered dose). Extensive, saturable first-pass metabolism, however, leads to bioavailability of approximately 35% of the administered dose and nonlinear pharmacokinetics. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug. Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Although patients with AD demonstrate 30% to 50% higher plasma concentrations of rivastigmine and its principal metabolite than do healthy elderly patients, there is no evidence of drug accumulation, which is consistent with rivastigmine's short pharmacokinetic half-life. Distribution of rivastigmine into the CNS is extensive, and inhibition of AChE in the cerebrospinal fluid is detectable 1.2 hours after oral dosing in both healthy volunteers and patients with AD. Peak activity is reached somewhat more slowly in AD patients than in healthy subjects, and the inhibitory effects have a longer duration (6.0 vs 2.4 hours and 12.0 vs 8.5 hours, respectively). Rivastigmine is inactivated during the process of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine. This reduces its propensity to interact with drugs metabolized by specific CYP-450 isoenzymes. Consistent with rivastigmine's pharmacokinetic and pharmacodynamic profiles, Phase II and III trials have demonstrated that the drug is a well-tolerated and effective treatment for AD.

Alzheimer Disease↗
PubMed2006

Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease.

We aimed to determine prospectively whether rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, provided benefits in patients with and without visual hallucinations in a population with dementia associated with Parkinson's disease (PDD). This was a 24-week double-blind placebo-controlled study. Primary efficacy measures were the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary efficacy measures included activities of daily living, behavioral symptoms, and executive and attentional functions. Patients were stratified according to the presence of visual hallucinations at baseline. The study included 188 visual hallucinators (118 on rivastigmine, 70 on placebo) and 348 nonvisual hallucinators (239 on rivastigmine, 109 on placebo). Rivastigmine provided benefits in both visual hallucinators and nonvisual hallucinators. Absolute responses to rivastigmine on the ADAS-cog were comparable over 6 months, although rivastigmine-placebo differences tended to be larger in visual hallucinators (4.27; P = 0.002) than in nonhallucinators (2.09; P = 0.015). On the ADCS-CGIC, differences between rivastigmine and placebo were 0.5 in visual hallucinators (P = 0.030) and 0.3 in nonhallucinators (P = 0.111). Rivastigmine provided benefits on all secondary efficacy measures, and placebo declines and treatment differences were more marked in visual hallucinators. Adverse events were reported more frequently by rivastigmine-treated patients, although this difference was less marked in visual hallucinators. Visual hallucinations appear to predict more rapid decline and possibly greater therapeutic benefit from rivastigmine treatment in PDD.

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PubMed2004

A 12-month study of the efficacy of rivastigmine in patients with advanced moderate Alzheimer's disease.

The efficacy of a centrally active cholinesterase inhibitor, rivastigmine tartrate (ENA 713), in patients with advanced moderate Alzheimer's disease (AD) was evaluated in a 12-month placebo-controlled study. We aimed to investigate whether there was any evidence for the benefits of rivastigmine in patients with severe disease. These patients were compared with matched controls. In this study, 24 patients with advanced moderate AD received rivastigmine for 12 months. Another 20 patients received placebo. Mean daily doses of rivastigmine in the higher-dose group at 3, 6, 9, and 12 months were 6.1 +/- 1.0, 8.3 +/- 1.2, 8.9 +/- 1.3, and 10.7 +/- 1.6 mg/day, respectively. Cognitive abilities were assessed using the 11-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). Forty-five percent of placebo-treated patients declined by at least 4 points on the ADAS-cog. Conversely, only 18.3% of patients treated with rivastigmine declined by 4 or more points. Functional disabilities, as assessed using the Disability Assessment for Dementia Scale, remained significantly superior in rivastigmine-treated patients compared with placebo-treated patients. Patients benefited from high-dose rivastigmine treatment on all outcome measures, including the Mini-Mental State Examination, Progressive Deterioration Scale, as well as the Global Deterioration Scale. Patients receiving rivastigmine for 12 months significantly improved compared with placebo-treated patients (p < 0.001). By 52 weeks, patients originally treated with 6-12 mg/day rivastigmine had a significantly better cognitive function than patients originally treated with placebo. Long-term rivastigmine treatment appeared to be well tolerated in patients with advanced moderate AD and significantly benefits the cognitive and functional symptoms of AD.

Aged↗
PubMed2001

Review of rivastigmine and its clinical applications in Alzheimer's disease and related disorders.

Rivastigmine (Exelontrade mark, Novartis) is a novel intermediate-acting reversible and non-competitive carbamate acetylcholinesterase (AChE) that was recently introduced for the treatment of Alzheimer's disease (AD). Preclinical studies have shown that rivastigmine has many similarities to other currently available cholinesterase inhibitors (ChEIs) and some important differences. The drug has been evaluated for this use in two well designed, published, adequately powered, Phase III, 26 week clinical trials that included a total of more than 1500 rivastigmine and 700 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. These studies indicate that rivastigmine (6 - 12 mg/day) usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild-to-moderate AD, with higher doses producing more benefits. Rivastigmine is beneficial in all three domains (namely cognition, daily activities and behaviour) of AD. Data on long-term efficacy support continued benefits of rivastigmine beyond 6 months. Rivastigmine is generally well-tolerated with no requirement for routine electrocardiogram (ECG) or blood monitoring. Rivastigmine causes adverse events that are generally those expected from a ChEI and mainly involve gastrointestinal system. They are usually mild-to-moderate, of short duration and responsive to dosage reduction. They occur mostly during the dosage titration phase and decrease during the maintenance phase. Clinically significant drug-drug interactions are unlikely. The consistent efficacy in treating all three domains (cognition, daily functioning and behaviour) and good tolerability, particularly with slow titration, makes rivastigmine a good first-line ChEI therapy for the treatment of AD. Therapeutic dose range is 6 - 12 mg/day. Rivastigmine should be started at 1.5 mg b.i.d. with meals and increased at 2 - 4 week intervals to achieve the highest tolerated dose.

Alzheimer Disease↗
PubMed2001

Response of patients with Alzheimer disease to rivastigmine treatment is predicted by the rate of disease progression.

BACKGROUND: Evidence suggests that disease severity predicts the response of patients with Alzheimer disease (AD) to cholinesterase inhibitor treatment, raising the question of whether disease progression also predicts response to this treatment. OBJECTIVE: To evaluate retrospectively whether rate of disease progression during placebo treatment affects response to subsequent rivastigmine tartrate therapy for patients with mild to moderately severe AD. DESIGN: A 26-week, open-label extension study following a 26-week, double-blind, randomized, placebo-controlled trial. SETTING: Outpatient research centers at 22 sites in the United States. PATIENTS: We studied 187 of 235 patients originally randomized to receive placebo treatment in the double-blind phase of the trial who continued with open-label (rivastigmine) extension therapy. INTERVENTION: Placebo treatment for 26 weeks followed by rivastigmine treatment, 2 to 12 mg/d, for 26 weeks. MAIN OUTCOME MEASURES: Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), Progressive Deterioration Scale, Mini-Mental State Examination, and Global Deterioration Scale scores. RESULTS: Rivastigmine administration during open-label extension therapy benefited patients who had progressed slowly and those who had progressed rapidly during initial double-blind placebo treatment. Slowly progressive patients responded with a mean 1.03-point improvement in the week 26 (ie, start of open-label rivastigmine treatment) ADAS-Cog score at 12 weeks of rivastigmine treatment (week 38 of treatment; P =.02 vs week 26). However, more rapidly progressive patients had a significantly larger mean 4.97-point improvement from the week 26 ADAS-Cog score at 12 weeks (with respect to week 26 of treatment and slowly progressive patient scores, P<.001 for both). Thus, a more rapid disease progression rate while receiving placebo treatment was predictive of a significantly stronger patient response to rivastigmine therapy. This relation also was observed with the other 3 outcome measures and was still apparent when accounting for disease severity. CONCLUSIONS: Rate of disease progression for patients with mild to moderate AD seems to predict response to rivastigmine treatment. Patients with more rapidly progressive disease might be particularly likely to benefit from rivastigmine therapy.

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PubMed2003

Analysis of outcome in retrieved dropout patients in a rivastigmine vs placebo, 26-week, Alzheimer disease trial.

BACKGROUND: Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease (AD). In studies designed with a washout period at the end of the study, after treatment with a cholinesterase inhibitor is discontinued, the cognitive benefits of therapy are no longer apparent following washout. The rivastigmine trials discussed in this article were not designed with a posttreatment washout period at the end of the study. Therefore, to evaluate the effect of discontinuing treatment, we analyzed the retrieved dropout (RDO) population. OBJECTIVE: To evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine. DESIGN AND METHODS: Eligible patients with AD (Mini-Mental State Examination [MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week, double-blind, placebo-controlled studies (Novartis US Pivotal [dose-range] Trial, US fixed-dose study, and a Global Pivotal [dose-range] Trial) that compared rivastigmine therapy with placebo. Patients who discontinued study participation (for any reason) (considered to be the RDO population) were encouraged to return for their scheduled week 26 efficacy evaluations. Effects on cognition were assessed using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). RESULTS: The results for the Novartis US Pivotal Trials and for the 3 studies combined (Novartis studies B352, B351, and B303) are reported. In the US pivotal trial, RDO patients in the 6- to 12-mg/d group had been not receiving the drug (to be called "off drug") for 102 (57.7) days (mean [SD]) compared with 68 (51.7) days in the RDO placebo group. In these RDO analyses, a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group (n = 17) compared with the rivastigmine 6- to 12-mg/d group (n = 33) at week 26 (MMSE score, -8.2 vs -3.0; P =.009). In the pooled studies, the mean (SD) number of days off treatment was 95 (52.0) days for the rivastigmine 6- to 12-mg/d group and 66 (52.7) days for the placebo group. The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group (n = 38) compared with the rivastigmine 6- to 12-mg/d group (n = 88) at week 26 (MMSE score, -5.69 vs -2.5; P =.004). A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials (P =.007, P =.009) and the pooled studies (P =.002, P =.017). CONCLUSIONS: After discontinuation of therapy, rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients. The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression.

Adult↗
PubMed2007

Identification of responders and reactive domains to rivastigmine in Alzheimer's disease.

PURPOSE: Presently, it is unclear which patients suffering from Alzheimer's Disease (AD) respond to rivastigmine and if rivastigmine acts on specific cognitive domains. The aims of this study are thus to investigate treatment effects of rivastigmine on specific cognitive domains and to find possible responsive subpopulations to rivastigmine cognitive effects. METHODS: Mini Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG) were administered at baseline and after 6 months in 83 rivastigmine users and 96 historical controls, representing natural decline. Treatment effects on different subsections of the CAMCOG and in different subpopulations were investigated by linear regression analyses. RESULTS: Rivastigmine showed effectiveness on total CAMCOG (p < 0.001), CAMCOG non-memory subsection (p < 0.001) and subscales of language (p = 0.002), attention/calculation (p = 0.043), abstract thinking (p < 0.001) and perception (p = 0.031). In patients with baseline MMSE < or =19 rivastigmine showed significant and favourable effects compared to historical controls on total CAMCOG (p < 0.001) and both non-memory (p < 0.001) and memory subsections (p = 0.002). CONCLUSION: Rivastigmine showed primarily effectiveness on the non-memory section of the CAMCOG and patients with a baseline MMSE < or = 19 appeared to show greater responses to rivastigmine compared to patients with baseline MMSE > or = 20.

Aged↗
PubMed2005

Rivastigmine is a potent inhibitor of acetyl- and butyrylcholinesterase in Alzheimer's plaques and tangles.

Acetylcholinesterase and butyrylcholinesterase activities emerge in association with plaques and tangles in Alzheimer's disease. These pathological cholinesterases, with altered properties, are suggested to participate in formation of plaques. The present experiment assessed the ability of rivastigmine, a clinically utilized agent that inhibits acetylcholinesterase and butyrylcholinesterase activities, to inhibit cholinesterases in plaques and tangles. Cortical sections from cases of Alzheimer's disease were processed using cholinesterase histochemistry in the presence or absence of rivastigmine. Optical densities of stained sections were utilized as a measure of inhibition. The potency of rivastigmine was compared with those of other specific inhibitors. Optimum staining for cholinesterases in neurons and axons was obtained at pH 8.0. Cholinesterases in plaques, tangles and glia were stained best at pH 6.8. Butyrylcholinesterase-positive plaques were more numerous than acetylcholinesterase-positive plaques. Rivastigmine inhibited acetylcholinesterase in all positive structures in a dose-dependent manner (10(-6)-10(-4) M). However, even at the highest concentration, faint activity remained. In contrast, rivastigmine resulted in complete inhibition of butyrylcholinesterase in all structures at 10(-5) M. Rivastigmine was equipotent to the specific acetylcholinesterase inhibitor BW284C51 and more potent than the butyrylcholinesterase inhibitors iso-OMPA and ethopropazine. In conclusion, rivastigmine is a potent inhibitor of acetylcholinesterase and a more potent inhibitor of butyrylcholinesterase in plaques and tangles. Unlike other cholinesterase inhibitors tested, rivastigmine inhibited cholinesterases in normal and pathological structures with the same potency. Thus, at the therapeutic concentrations used, rivastigmine is likely to result in inhibition of pathological cholinesterases, with the potential of interfering with the disease process.

Acetylcholinesterase↗
PubMed2006

Antipsychotic drug use among nursing home residents taking rivastigmine.

OBJECTIVE: To evaluate whether or not rivastigmine use is associated with a decrease in the initiation of antipsychotic drug therapy among nursing home residents in the United States. METHODS: A retrospective analysis was performed using Minimum Data Set data and physician order files for newly admitted residents of 452 US nursing facilities from 2000 through 2002. The rivastigmine group included those who were diagnosed with Alzheimers disease (AD) and began rivastigmine treatment within 30 days of diagnosis. Patients were required to be on treatment for a minimum of 30 days. The control group included those who were diagnosed with AD, but did not receive a cholinesterase inhibitor. All subjects were antipsychotic drug-naive within 30 days of baseline (initiation of rivastigmine or initial AD diagnosis). A Cox proportional hazards model was used to estimate predicted risk of antipsychotic drug use. RESULTS: This study included 845 patients in the rivastigmine group and 517 patients in the control group. The rivastigmine group had fewer female patients, was younger, and had more verbal distress, sleep issues, sadness, loss of interest, and behavioral symptoms at baseline compared with the control group (P < .01). Overall initiation of antipsychotics was lower in the rivastigmine group (8.6%) compared with the control group (17.0%). Patients in the control group were almost 2 times more likely (relative risk = 1.86; P < .001) to take antipsychotics compared with patients taking rivastigmine, after adjusting for demographic covariates and mental health conditions or behavioral symptoms at baseline. Patients with baseline mental health conditions or behavioral symptoms were more likely to start antipsychotics than those without such conditions (P < .001). CONCLUSIONS: Study results suggest that nursing home residents with Alzheimers disease treated with rivastigmine have a reduced risk of initiating therapy with an antipsychotic drug compared with residents who do not receive cholinesterase inhibitor treatment.

Aged↗
PubMed2004

Co-administration of memantine has no effect on the in vitro or ex vivo determined acetylcholinesterase inhibition of rivastigmine in the rat brain.

Rivastigmine, a cholinesterase inhibitor, is successfully used for the symptomatic therapy of Alzheimer's disease (AD) in the clinic. The drug has a very low potential for drug-drug interactions, as has been demonstrated within large clinical trials. Memantine, recently approved by the FDA for the treatment of moderate to severe AD, acts as a low affinity, non-competitive NMDA-antagonist, on a completely different neurotransmitter system, the glutamatergic system. Given the different sites of action, the possibility to combine a cholinergic with a glutamatergic intervention as potentially superior AD therapy has recently been proposed. In vitro studies have demonstrated that memantine, when added to reversible AChE inhibitors, such as tacrine, donepezil or galantamine, did not interfere with the inhibitory action of any of these drugs. The results from the present study provide evidence that rivastigmine as a pseudo-irreversible (or slow-reversible) AChE inhibitor shares this property described for reversible inhibitors, since memantine (1-100 microM), irrespective of whether given prior to or after rivastigmine did not influence rivastigmine's AChE inhibition in vitro. A similar observation was also made under in vivo conditions (ex vivo measurements): following a 21 day chronic, oral administration of 6 micromol/kg rivastigmine alone or of a combination of rivastigmine plus memantine (6 micromol/kg p.o. of either of the two compounds), an identical degree of AChE inhibition was observed. The concentrations of rivastigmine, its metabolite NAP 226-90 and memantine were measured in the brain of the same animals. Following an equimolar oral dose (6 micromol/kg) of both compounds, the brain level of memantine exceeded that of rivastigmine + metabolite, by a factor of around 30, when measured 2 h after the final dosing, irrespective of the duration of treatment (acute, for 3 or 21 days). This indicates that neither of the two drugs showed accumulation but also, and more importantly, that memantine does not modulate the prime therapeutic action of rivastigmine (AChE inhibition) in vitro or in vivo. Clinical trials using a combination of both drugs will provide a final proof of whether a combination therapy would lead to an increased efficacy in AD patients.

Acetylcholinesterase↗
PubMed2006

Are cholinergic enhancers beneficial for memory in schizophrenia? An event-related potentials (ERPs) study of rivastigmine add-on therapy in a crossover trial.

Studies have reported beneficial effects of cholinergic enhancers, e.g., rivastigmine, on memory in schizophrenia but others have not. Possibly, these discrepancies are related to the lack of specificity of the tests used. This study investigated the effect of rivastigmine on memory in schizophrenia using event-related potentials (ERPs). Eighteen patients treated with atypical antipsychotic received rivastigmine adjuvant therapy in a randomized, crossover design. They were assessed at baseline (T1) and on two subsequent occasions (T2 and T3), where one half of the subjects were taken rivastigmine and the other half not. ERPs were recorded during a recognition memory task on each session. Behavioral and ERP data were analyzed using mixed ANOVA models first at T1 to detect potential group differences and for the trial (T1-T2) to determine the influence of rivastigmine, i.e., sessionxgroup interactions. The results showed no group difference at T1 except a trend for one group to be less efficient than the other on RT measures. When controlling for this difference the results on the trial data showed a trend for a benefit of rivastigmine on the RT memory effect. ERP analysis revealed that rivastigmine affects the amplitudes of two components elicited within 150-300 ms over posterior (reduced N2b) and frontal sites (enhanced P2a). It also enhances the magnitude of the memory (old/new) effect on two later components over posterior (N400) and frontal sites (F-N400). These results suggest that rivastigmine improves selective attention by enhancing interference inhibition processes (P2a) and lowering the reactivity to incoming stimulus (N2b). It also improves the integration of information with knowledge (N400) and with its context (F-N400). Generally, this study showed that the beneficial effect of rivastigmine on memory is not unitary but rather comes from its action at different time points within information processing cascade.

Adult↗
PubMed2002

Donepezil and rivastigmine in the treatment of Alzheimer's disease: a best-evidence synthesis of the published data on their efficacy and cost-effectiveness.

BACKGROUND: Various drugs have been approved for the treatment of Alzheimer's disease (AD) in the United States and Canada, including donepezil and rivastigmine, although questions remain as to their efficacy, effectiveness, and long-term benefits. OBJECTIVE: The goal of this study was to conduct a best-evidence synthesis of data on the efficacy and cost-effectiveness of donepezil and rivastigmine in the treatment of AD. METHODS: Relevant published randomized controlled trials (RCTs) and Phase IV open-label extension studies (excluding abstracts) were identified through searches of MEDLINE, HealthSTAR, and PsycINFO for the period January 1984 to October 2001. The bibliographies of retrieved articles were searched for additional publications. For inclusion in the best-evidence synthesis, clinical trials had to pass a blinded quality assessment (score > or =5 on the Jadad scale) and use National Institute of Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria. Economic studies were selected using National Health Service Centre for Reviews and Dissemination criteria for reporting critical summaries of economic evaluations. RESULTS: Nine RCTs of donepezil and 2 of rivastigmine were identified and met inclusion criteria for the best-evidence synthesis. Eight donepezil trials and both rivastigmine trials included patients with mild AD (Mini-Mental State Examination [MMSE] score, 15-27) or moderate AD (MMSE score, 8-14); 1 donepezil trial included patients with moderate or severe AD (MMSE score, 0-7). In the RCTs of donepezil, the mean decrease in scores on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was greater with active treatment than with placebo (lower scores indicate less cognitive deterioration). In the RCTs of rivastigmine, ADAS-cog scores decreased over the follow-up period with both active treatment and placebo; however, scores decreased more with active treatment. Three Phase IV studies of donepezil and I Phase IV study of rivastigmine were identified. Their results were consistent with those of the RCTs. Ten economic studies (7 donepezil, 3 rivastigmine) were identified and reviewed. In 4 of the donepezil studies and all 3 rivastigmine studies, use of the drug cost less than a no-drug strategy. CONCLUSIONS: The efficacy data indicate that both donepezil and rivastigmine can delay cognitive impairment and deterioration in global health for at least 6 months in patients with mild to moderate AD. Patients receiving active treatment will have more favorable ADAS-cog scores for at least 6 months, after which their scores will begin to converge with those of patients receiving placebo. Differences in methodology, types of direct or indirect costs included, and sources of cost data made it difficult to compare and synthesize findings of the economic studies; therefore, the cost-effectiveness data are inconclusive.

Aged↗
PubMed2004

Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease.

BACKGROUND: The presence of certain behavioral and psychological symptoms (eg, paranoia, hallucinations, aggression, activity disturbances) in Alzheimer's disease (AD) may predict faster cognitive and functional decline; therefore, such symptoms represent an important treatment target. Behavioral and psychological symptoms of dementia (BPSD) may be caused at least in part by cholinergic deficits. Regulatory studies of rivastigmine in AD were not designed to evaluate effects on BPSD, but further investigation of rivastigmine in AD was prompted by later studies demonstrating behavioral benefits in other types of dementia. OBJECTIVE: The primary aim of this article was to review available data on the behavioral benefits of rivastigmine in patients with AD. METHODS: Relevant data were identified through a MEDLINE search for studies published in peer-reviewed journals through January 2004. The search terms were Alzheimer, behavior, psychosis, and rivastigmine. Data presented at international scientific congresses were also reviewed to ensure that the most recent data were considered. RESULTS: A meta-analysis of three 6-month, placebo-controlled trials of rivastigmine in mild to moderate AD indicated that rivastigmine 6 to 12 mg/d may improve or prevent disruptive BPSD (P < 0.05 vs placebo). In patients with more advanced AD, 2 open-label studies of up to 12 months' duration found that improvements in BPSD were accompanied by a decrease in the use of psychotropic medications. Rivastigmine demonstrated behavioral benefits in patients with dementia with Lewy bodies (DLB) in a double-blind, placebo-controlled study (P < 0.05). In open-label extension studies, rivastigmine provided sustained effects (up to 2 years) in patients with mild to moderate AD or DLB. CONCLUSIONS: The available dats suggest that rivastigmine may be a well-tolerated treatment option for improving or preventing psychotic and nonpsychotic symptoms associated with AD. Prospective, double-blind studies are needed to evaluate these preliminary findings.

Alzheimer Disease↗
PubMed2004

Rivastigmine for dementia associated with Parkinson's disease.

BACKGROUND: Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. METHODS: Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. RESULTS: A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). CONCLUSIONS: In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.

Aged↗
PubMed1999

Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans.

This study sought to examine the feasibility of prolonged assessment of acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that rivastigmine (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of rivastigmine (3 mg). CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for rivastigmine and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal rivastigmine plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of rivastigmine in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only minimal inhibition of erythrocyte AChE activity (approximately 3%) was observed. Inhibition of AChE in the CSF after rivastigmine administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours. Plasma BuChE activity was significantly lower after rivastigmine than after placebo, but this was not clinically relevant. BuChE activity in CSF was significantly lower after rivastigmine than after placebo for up to 3.6 hours after dosing, but this difference was not sustained. This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that rivastigmine markedly inhibits CSF AChE after a single oral dose of 3 mg, and that the inhibition of central AChE is substantially greater than that of peripheral AChE or BuChE.

Acetylcholinesterase↗
PubMedDate not supplied

The reduced release of GH by GHRH in 8 subjects aged 65-69 years is augmented considerably by rivastigmine, a drug for Alzheimer's disease.

BACKGROUND: The growth hormone (GH) secretion declines by 14% with each decade of adult life. Several attempts have been made to reverse the manifestations of the senile GH deficiency, termed somatopause, but GH substitution treatment in old age has not yet developed an established regimen. Cholinesterase inhibitors like pyridostigmine are able to elicit GH secretion when administered alone and to enhance the GH response to growth hormone releasing hormone (GHRH), but its clinical use is limited due to the strong peripheral cholinergic side effects. OBJECTIVE: The aims of our experiments were to find out whether the GH response to GHRH can be augmented by rivastigmine, a new orally applicable and well-tolerated selective inhibitor of cerebral acetylchoinesterase. METHODS: Eight healthy volunteers (age range 65-69 years) were studied. After an overnight fast, GHRH tests were done: 1 microg/kg GHRH was injected as an intravenous bolus. Blood samples for an immunoradiometric GH assay were taken at the time of GHRH injection (time 0) and after 15, 30, 45, 60, and 120 min. First, the baseline experiment was done: it consisted of two subsequent GHRH tests which were carried out within an interval of 120 min. Four weeks later the rivastigmine experiment was done identically, but 60 min before performing the second GHRH test, rivastigmine (4.5 mg) was administered orally. The GH secretory responses were expressed as areas under the curve (AUC; median, interquartile range), Wilcoxon's signed-rank test was used for statistical comparisons. RESULTS: Baseline experiment: The GH AUC of the first GHRH test was 1040 (range 420-1250) ng/ml/h. The repeated GHRH stimulation after 120 min (second GHRH test) showed a 13-fold decrease to 80 (range 60-130) ng/ml/h. Rivastigmine experiment: The GH AUC of the first GHRH test was 950 (range 540-1430) ng/ml/h and, therefore, similar to that of the baseline experiment. 60 min after ingestion of the single oral dose of rivastigmine (4.5 mg), the following GHRH stimulation (second GHRH test) nearly doubled the GH AUC to 1580 (range 860-3330) ng/ml/h. Comparing the DeltaGH AUC values (DeltaGH AUC = GH AUC of the first GHRH test minus GH AUC of the second GHRH test), baseline experiment versus rivastigmine experiment, there was a 20-fold (p = 0.018) increase in GH AUC after rivastigmine pretreatment. CONCLUSIONS: Rivastigmine is a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. Future investigations are necessary to find out whether rivastigmine can restore the senile decline of the circadian GH secretion in the long term and, therefore, has new implications for patient treatment.

Aged↗
PubMed2005

Drug persistency patterns for patients treated with rivastigmine or donepezil in usual care settings.

OBJECTIVE: To compare levels of persistency with 2 cholinesterase (ChE) inhibitors--rivastigmine and donepezil--for the treatment of Alzheimer's disease (AD) through the use of administrative claims data. METHODS: This retrospective cohort study identified treatment-naive, community-based AD patients having an initial prescription (index event) for rivastigmine or donepezil between June and December 2000, in the United States, from pharmacy claims in a proprietary administrative claims database. Patients were excluded if they received either drug during the 180 days prior to their index prescription or if they did not have continuous plan enrollment during this period and for at least 90 days following the index date. The probability of treatment discontinuation within the first 60 days of treatment was estimated. Time to treatment discontinuation was analyzed for the cohort of patients that remained on therapy > or =60 days as well as for subgroups of the cohort reaching either approved or maximum recommended doses of donepezil or rivastigmine. Treatment discontinuation was defined as either a stop of therapy (no prescription refill within 60 days of estimated completion of prior prescription) or a switch to an alternative AD drug. Kaplan-Meier survival and proportional hazard model analyses were performed. Proportion of days covered (PDC) by an AD therapy was also evaluated in each quarter during the first year of follow-up. RESULTS: Of the newly treated AD study population, 30.4% (171/563) of rivastigmine patients and 31.2% (583/1,871) of donepezil patients discontinued treatment within 60 days of starting therapy (P = 0.72). For the cohort of patients that remained on therapy > or =60 days, the mean time to treatment discontinuation was 331 days (95% confidence interval [CI], 307-355) for rivastigmine patients (n = 392) versus 337 days (95% CI, 322-352) for donepezil patients (n = 1288). The proportion of patients with a PDC > or =80% after 12 months of follow-up was 23% for the donepezil group and 19% for the rivastigmine group (P = 0.34). For the cohort subgroup that reached an approved dose, the mean time to treatment discontinuation was 346 days (95% CI, 318-374) for rivastigmine patients (n = 282) versus 338 days (95% CI, 323-353) for donepezil patients (n = 1,283). For the cohort subgroup that reached the maximum recommended dose, the mean time to treatment discontinuation was 396 days (95% CI, 343-449) for rivastigmine patients (n = 61) versus 364 days (95% CI, 344-384) for donepezil patients (n = 712). CONCLUSION: Newly treated AD patients in a usual care setting who initiate therapy with either rivastigmine or donepezil have similar levels of persistency with treatment.

Aged↗