Rivastigmine Therapy Research Articles

Cardiac and Blood Pressure Safety of Transdermal Rivastigmine in Elderly Patients With Dementia With Lewy Bodies.

Dementia with Lewy bodies (DLB) is the second most common dementia. Features of DLB include postganglionic cardiac sympathetic denervation and autonomic instability. Rivastigmine therapy, an acetylcholinesterase inhibitor, is widely used in the primary treatment of DLB; however, the cardiovascular safety and tolerability of transdermal rivastigmine needs to be reviewed. To evaluate whether transdermal rivastigmine has an effect on blood pressure, heart rate, and electrocardiography measurements. A total of 722 patients diagnosed with dementia were retrospectively screened. Fifty-seven of 98 DLB patients who received transdermal rivastigmine treatment with available serial electrocardiography and blood pressure measurements were included in the study. Baseline and follow-up measurements were compared for patients on the 9.5 to 13.3 mg/d rivastigmine dose for at least 4 weeks. The mean age of the patients was 80.77±6.04, and the majority were women (63%). A total of 8 cases with bradycardia and 5 with orthostatic hypotension were detected during follow-up, and rivastigmine patch was stopped in one of those 8 patients due to symptomatic bradycardia. Nonetheless, there was no difference between baseline and follow-up measurements of the patients, including heart rate, cardiac rhythm, electrocardiographic intervals, blood pressure, pulse pressure, and postural blood pressure changes. Transdermal rivastigmine therapy is not associated with arrhythmogenic or hypotensive effects in the elderly patients with DLB. However, when prescribing transdermal rivastigmine, physicians should pay attention to newly emerging orthostatic hypotension during the follow-up in these patients.

Effects of online computerized cognitive training program Beynex on the cognitive tests of individuals with subjective cognitive impairment (SCI) and Alzheimer disease on rivastigmine therapy

Background/aim Clinical trials conducted on the efficacy of computerized cognitive training (CCT) programs have not led to any important breakthroughs. CCT is a safe and inexpensive approach, but its efficacy in patients on rivastigmine therapy has not been evaluated. This study aims to compare effects of CCT and examines rivastigmine to determine whether CCT has any further contributions to make. Materials and methods Sixty individuals with subjective memory complaint (SCI) and 60 individuals with early stage Alzheimer’s dementia (AD) were subjected to the Montreal Cognitive Assessment (MoCA), Cambridge Cognition (CANTAB tests: MOT, PRM, DMS, SWM, PAL, RTI), and Bayer-ADL. After screening patients who were diagnosed with AD, we started rivastigmine patch treatment (10 cm2 = 9.5 mg). The SCI and AD groups were randomly divided, and one each of the SCI and AD groups were accessed using BEYNEX, a web-based program. After a minimum of at least 1200 min of use, the diagnostic tests were repeated.ResultsThe AD groups’ MoCA scores of the BEYNEX-practicing group demonstrated meaningfully increase, whereas they decreased in the control group, and the Bayer-ADL scores indicated improvement in ADL. The CANTAB tests both in SCI and AD and in groups using BEYNEX showed positive improvement in MOT, DMS, and PAL data.Conclusion This study is a rare example that focuses on both groups with SCI and AD. The efficacy of CCT varies across cognitive domains and shows significant efficacy for AD but small improvements in cognitively healthy older adults. In future studies, integration with a smart learning algorithm may lead to interesting observations on which parameters are more sensitive to change under long-term use of CCT in a large number of subjects.

QUETIAPINE- AND RIVASTIGMINE-INDUCED NEUROLEPTIC MALIGNANT SYNDROME IN LEWY BODY DEMENTIA

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Neuroleptic malignant syndrome (NMS) is a life threatening idiosyncratic reaction to neuroleptic medications. Quetiapine is considered a safe and common medication prescribed in patients with agitation and Lewy Body dementia (LBD). We present a case of NMS in a patient with LBD who is treated with quetiapine and rivastigmine. CASE PRESENTATION: A 66 year old man with a past medical history of LBD presents to the emergency department with a 5 day progression of altered mental status. At baseline, he is typically bed-bound but able to communicate verbally and feed independently. His LBD is managed with quetiapine and rivastigmine with recent up-titration of his quetiapine dose. His quetiapine was held 3 days prior to presentation due to concerns for sedation. In the ED, his vitals were notable for a fever of 102.4 and tachycardia of 114. Physical exam was significant for listlessness and stiff posturing. Initial labs revealed a lactic acid of 2.7 and creatinine kinase (CK) of 1,273. Head CT was unrevealing. Neurology was consulted and recommended lorazepam due to concern for NMS. Dantrolene was added the next day due to worsening rigidity, fevers and tachycardia. He was then transferred to the critical care unit and intubated for a GCS of 7. Lumbar puncture showed no source of infection and EEG monitoring demonstrated low amplitudes and generalized slowing. Bromocripitine was initiated due to limited improvement and lorazepam was discontinued due to concern of complicating delirium. His mental status improved shortly after and he was extubated at 7 days. He completed 14 days of dantrolene, 11 days of bromocriptine and was discharged home at 25 days with near baseline mental status. DISCUSSION: NMS is a life threatening idiosyncratic reaction to antipsychotic medications, characterized by altered mental status, fevers, muscle rigidity, and autonomic dysfunction1. It is often difficult to differentiate clinically from other common pathologies, such as sepsis, heat stroke, and serotonin syndrome. Incidence rates vary from 0.01% to 3.2% in patients taking neuroleptic medication2. Clinical investigation should include a septic screen, CK level, urinalysis for myoglobinuria, neuroimaging, and lumbar puncture2. Treatment strategies often include cessation of the offending agent, supportive care, and pharmacological therapy (i.e. dantrolene and bromocriptine). One case report highlighted that rivastigmine is unrecognized risk factor for the development of NMS with concomitant neuroleptic antipsychotics3. It is certainly possible in our case that with the up-titration of quetiapine and co-existing use of rivastigmine, our patient had a lowered threshold for NMS. CONCLUSIONS: NMS diagnosis requires a high index of suspicion and early identification improves outcomes. Rivastigmine use should raise suspicion of NMS with autonomic dysfunction, bland infectious work up, and concomitant neuroleptic use. Reference #1: Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. The Neurohospitalist 2011;1(1):41–47. Reference #2: Simon LV, Callahan AL. Neuroleptic Malignant Syndrome [Internet]. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2018 [cited 2019 Mar 7]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK482282/ Reference #3: Stevens DL, Lee MR, Padua Y. Olanzapine-associated neuroleptic malignant syndrome in a patient receiving concomitant rivastigmine therapy. Pharmacotherapy 2008;28(3):403–405. DISCLOSURES: No relevant relationships by Joy Ayyoub, source=Web Response No relevant relationships by Paul Kinniry, source=Web Response No relevant relationships by cyrus vahdatpour, source=Web Response

Cost-effectiveness analysis of the treatment of mild and moderate Alzheimer's disease in Brazil.

Objective:To perform a cost-effectiveness analysis of donepezil and rivastigmine therapy for mild and moderate Alzheimer’s disease (AD) from the perspective of the Brazilian Unified Health System.Method:A hypothetical cohort of 1,000 individuals of both sexes, aged >65 years, and diagnosed with AD was simulated using a Markov model. The time horizon was 10 years, with 1-year cycles. A deterministic and probabilistic sensitivity analysis was performed.Results:For mild AD, the study showed an increase in quality-adjusted life years (QALYs) of 0.61 QALY/21,907.38 Brazilian reais (BRL) for patients treated with donepezil and 0.58 QALY/BRL 24,683.33 for patients treated with rivastigmine. In the moderate AD group, QALY increases of 0.05/BRL 27,414.96 were observed for patients treated with donepezil and 0.06/BRL 34,222.96 for patients treated with rivastigmine.Conclusions:The findings of this study contradict the standard of care for mild and moderate AD in Brazil, which is based on rivastigmine. A pharmacological treatment option based on current Brazilian clinical practice guidelines for AD suggests that rivastigmine is less cost-effective (0.39 QALY/BRL 32,685.77) than donepezil. Probabilistic analysis indicates that donepezil is the most cost-effective treatment for mild and moderate AD.

A 48-Week, Multicenter, Open-Label, Observational Study Evaluating Oral Rivastigmine in Patients with Mild-to-Moderate Alzheimer's Disease in Taiwan.

Rivastigmine is a cholinesterase inhibitor, approved for the treatment of mild-to-moderate dementia of Alzheimer's type. This study assessed the short- and long-term effectiveness and safety of rivastigmine in patients with mild-to-moderate Alzheimer's disease (AD) in a real-world clinical setting in Taiwan. This was a 48-week, single-arm, open-label, prospective, observational, post-marketing surveillance, multicenter study. The primary outcomes were change from baseline to week 48 in the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scores. One-year persistence to treatment, effect on activities of daily living, and incidence of adverse events (AEs) were also assessed. Overall, 151 patients were enrolled in the study, of which 91 (60.26%) completed this study. At the end of the study, the mean rivastigmine dose received by the patients was 6.59mg/day. At week 48, the changes in mean [standard deviation (SD)] MMSE and CDR scores in the intent-to-treat (ITT) population from baseline were -1.00 (3.8; p = 0.0344) and 0.07 (0.29; p = 0.0403), respectively. The most frequently reported AEs by preferred term were dizziness (12.58%) and nausea (9.27%). No new or unexpected AEs were observed, and 30 (20.13%) patients in the ITT population were on rivastigmine therapy for 1year without treatment discontinuation. Despite the low 1-year persistence rate, rivastigmine showed a stabilizing effect on declining cognition in patients with mild-to-moderate AD in a real-world scenario. Rivastigmine is well tolerated at 6.0-9.0mg/day with no unexpected safety concerns. Novartis Co. Ltd., Taipei, Taiwan.

Rivastigmine decreases brain damage in HIV patients with mild cognitive deficits.

Rivastigmine has been shown to improve cognition in HIV+ patients with minor neurocognitive disorders; however, the mechanisms underlying such beneficial effect are currently unknown. To assess whether rivastigmine therapy is associated with decreased brain inflammation and damage, we performed T1/T2* relaxometry and magnetization transfer imaging in 17 aviremic HIV+ patients with minor neurocognitive disorders enrolled on a crossed over randomized rivastigmine trial. Rivastigmine therapy was associated with changes in MRI metrics indicating a decrease in brain water content (i.e., edema reabsorption) and/or reduced demyelination/axonal damage. Furthermore, MRI changes correlated with cognitive improvement on rivastigmine therapy.

Pharmacogenetic Study on the Impact of Rivastigmine Concerning Genetic Variants of A2M and IL-6 Genes on Iranian Alzheimer's Patients.

Alzheimer's disease (AD) is a polygenic and multifactorial disease with a complex inheritance caused by the formation of amyloid plaques and neurofibrillary tangles in the brain. Increasing evidence indicates that many genes including interleukin-6 (IL-6) and alpha 2-macroglobulin (A2M) may contribute to the pathogenesis of AD. The A2M gene encodes α2-macroglobulin which specifically binds with the beta-amyloid peptides and prevents fibril formation. Protein of the IL-6 gene linked to beta-amyloid (βA) aggregation was detected in βA plaques in the brain of AD patients. The aim of the present study is to investigate the relationship of the IL-6 and A2M gene polymorphisms with AD and also the impact of rivastigmine on AD patients regarding their genotypes on IL-6 and A2M genes in 150 Iranian AD patients under rivastigmine therapy and 150 matched healthy controls. The results indicated that IL-6 G and C alleles had significant positive and negative association with AD, respectively, (P = 0.0001, relative risks (RR) = 1.39) and frequency of AD patients carrying IL-6 GG genotype was significantly in higher proportion in familial Alzheimer's disease (FAD) patients compared to controls (P = 0.02, RR = 2.25), and the IL-6 CC genotype was significantly protective against AD (P = 0.0003, RR = 0.65). Genotype analysis of A2M gene showed a significant positive correlation between A2M AA genotype and the AD patients (sporadic Alzheimer's disease (SAD) and FAD) (P = 0.001, RR = 1.56), proposing it as a possible risk factor for AD. Drug response from pharmacogenetic viewpoint after 3-year follow-up of AD patients and Clinical Dementia Rating (CDR) analysis demonstrated that AD patients carrying bigenic genotype IL-6 CC-A2M AG (ΔCDR = 4.5) and male patients with IL-6 CC genotype (ΔCDR = 3.83) provided the best response and the A2M GG genotype (ΔCDR = 7.97) and bigenic genotype IL-6 GG-A2M GG (ΔCDR = 8.5) conferred the worst response to the rivastigmine, suggesting likely involvement of genotype-specific response to rivastigmine therapy in AD patients. The results also propose that in view of the fact that C and G alleles created by nucleotide changes in the promoter region of IL-6 gene and this may affect the expression of the IL-6 gene and, hence, susceptible and protective role of GG and CC genotype in AD might be caused by higher and lower expression of IL-6 cytokine, respectively.

Domperidone effective in preventing rivastigmine-related gastrointestinal disturbances in patients with Alzheimer's disease

ObjectiveWhile acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastig-mine, are beneficial in treating behavioral symptoms of patients with Alzheimer’s disease (AD), their dose-limiting effects include gastrointestinal disturbances, such as nausea, vomiting, and diarrhea. We aimed to predict the occurrence of these gastrointestinal disturbances with rivastigmine therapy for optimal drug choice and improved compliance.Materials and methodsThirty patients with mild-to-moderate AD (scores 10–22 on the MiniMental State Examination) were administered a rivastigmine 18 mg patch with domperidone 30 mg (RWD) and without domperidone (RWOD; n = 15 each) for 20 weeks. Gastrointestinal disturbances were evaluated using a frequency scale for symptoms of gastroesophageal reflux disease (FSSG), Bristol stool form scale, laboratory data (hemoglobin, albumin, total cholesterol), body weight, and amount of food intake.ResultsAfter 12 weeks, FSSG scores were higher in the RWOD group compared to baseline scores; however, no significant differences were noted between the RWD and RWOD groups. We then subdivided each group based on high and low baseline scores; the RWOD high-score (≥4) subgroup showed increased FSSG after 12 weeks compared with the baseline score. In both RWD and RWOD groups, the low-score (≤3) subgroups showed no changes during the dose-escalation phase.ConclusionFor AD patients with higher FSSG scores at baseline, domperidone was effective in preventing rivastigmine-related gastrointestinal disturbances.

Pharmacogenetic Study on the Effect of Rivastigmine on PS2 and APOE Genes in Iranian Alzheimer Patients

Background/Aims: Alzheimer disease (AD) is a complex and genetically heterogeneous disorder, and certain genes such as PS2 and APOE4 contribute to the development of AD. Due to its heterogeneity, AD-predisposing genes could vary in different populations. Moreover, not all AD patients will respond to the same therapy. We specifically investigated the effect ofrivastigmine (Exelon) on PS2 and APOE genes in Iranian AD patients. Methods: A total of 100 AD patients, 67 patients with sporadic AD (SAD) and 33 patients with familial AD (FAD), receiving rivastigmine therapy and 100 healthy controls were studied.PCR-RFLP was used for genotyping of PS2 and APOE. Results: We found a positive association between the PS2 –A allele and SAD patients (p^c = 0.01), and the PS2 +A/–A genotype was significantly more frequent in SAD than FAD patients (p^c = 0.009). The APOE4 allele was associated with total AD, SAD and FAD (p^c = 0.000002). Patients with the PS2 +A/–A genotype and bigenic genotypes of +A/–A·Ε3/Ε3 and +A/–A·Ε3/Ε4 were the best responders to Exelon therapy, and those with the PS2 +A/+A and APOE Ε3/Ε4 genotypes were the worst responders. Conclusion: Our findings suggest that the PS2 and APOE4 alleles and genotypes affect both AD risk and response to rivastigmine therapy.

Rivastigmine-Induced REM Sleep Behavior Disorder (RBD) in a 88-Year-Old Man with Alzheimer's Disease

We report the case of an 88-year-old man with Alzheimer's disease (AD) of 8 years duration (emerging shortly after the de novo onset of sleeptalking) who developed REM sleep behavior disorder (RBD) after increasing the nightly dose of rivastigmine, an acetylcholinesterase inhibitor, from 1.5 mg to 3 mg (total daily dose, 4.5 mg), as therapy for his dementia. His family then became aware of recurrent nocturnal episodes arising from sleep of his leaving bed, and he sustained multiple abrasion injuries from falling down. Polysomnography (PSG), utilizing a seizure montage with fast paper speed, conducted with the patient taking rivastigmine 3 mg at bedtime, documented 3 abrupt episodes of bilateral arm-waving with moaning and shouting that emerged exclusively during each of the 3 REM sleep periods, with the duration of the episodes lasting 8 to 25 seconds. No epileptiform discharge appeared with the onset of these REM sleep behaviors. Therapy with clonazepam, 0.5 mg at bedtime (with ongoing 3 mg bedtime and 4.5 mg total daily rivastigmine therapy), fully suppressed the sleep-related events, with prompt relapse whenever clonazepam was not taken. This is the second reported case (both males with AD) of rivastigmine-induced RBD, and the oldest reported case of RBD; and it represents reversible, medication-induced, acute RBD.

P03-49 - Efects of rivastigmine tartrate in therapy of schizophrenic patients

ObjectivesExelon (ravastigmine tartrate) is dual, reversible cholinesterase inhibitor. FDA has approved its use in treatment of Alchaimer dementia and Dementia combinated with Parkison disease. In addition to this, results based on small clinical studies and case reports showed positive efects of rivastigmin tartrate in therapy applied in numerous pyschiatric disorders.MethodsIn this study 15 patients have been observed. According to ICD 10 they all satisfied criteria for diagnosis of residual schizophrenia and had a score of below 24 at MMSE and high scores at NPI 12 and BPRS. During the period of 60 days, apart from antipsychotics and anxiolitics or psychostabilisers, patients also received rivastigmin tartrate in their therapy.ResultsThe study showed that rivastigmine therapy produced significant improvements when it comes to cognition and reduction of disorders in the sphere of afective-behavioristic functioning of patients with residual schizophrenia. However, this interpretation cannot be confirmed to be completely valid due to the size of treated group, the absence of the control group, and the length of the observing period.ConclusionsDual cholinesterase inhibitors (Acetilcholine and Butirilcholine) may produce improvement in cognition and behavioural performances, as well as the general quality of life of patients diagnosed with residual schizophrenia. Future studies applied on this kind of patients should precisely explain the basic pharmachological mechanisams of rivastigmin tartrate, and approve/disapprove the results of clinical studies and case reports that have been preformed so far.

Safety and tolerability of transdermal and oral rivastigmine in Alzheimer's disease and Parkinson's disease dementia

Importance of the field: Cholinesterase inhibitors are the mainstay of symptomatic therapy for Alzheimer's disease (AD). Rivastigmine, an inhibitor of both acetylcholinesterase and butyrylcholinesterase, is available as a transdermal patch and in oral forms. It is also approved for the treatment of Parkinson's disease dementia (PDD) in many countries. The objective of this article is to review the safety and tolerability profile of transdermal and oral rivastigmine in AD and PDD patients.Areas covered in this review: Articles were identified by searching MEDLINE in July 2009 using the terms rivastigmine, Exelon, ENA 713 and clinical trial. All double-blind, placebo-controlled randomized trials in which rivastigmine monotherapy was administered to AD or PDD patients for longer than 2 weeks were included.What the reader will gain: This article provides a comprehensive summary of currently available safety data on rivastigmine.Take home message: The main adverse events reported with rivastigmine therapy are gastrointestinal in nature. However, the transdermal patch appears to reduce these side effects, allowing more patients to access higher therapeutic doses. Overall, the safety profile of rivastigmine is favorable and the improved tolerability offered by the rivastigmine patch suggests that transdermal delivery may be the best way to deliver this drug in AD and PDD patients.

Evp-6124: Safety, Tolerability And Cognitive Effects Of A Novel A7 Nicotinic Receptor Agonist In Alzheimer'S Disease Patients On Stable Donepezil Or Rivastigmine Therapy

Approved symptomatic therapies for Alzheimer's disease (AD) provide modest relief. In the future, it is likely that symptomatic treatments will be utilized with AD modifying therapies, the development of which are currently a primary focus of research. The nicotinic a-7 receptor agonist may be an attractive drug candidate to potentially improve cognition in Alzheimer's disease patients either as a stand-alone therapy or in combination with other symptomatic treatments. EVP-6124 is a novel, potent, and selective alpha7 nicotinic receptor agonist. EVP-6124 has an excellent brain to plasma ratio and has shown excellent efficacy and potency in a number of animal models of cognition. Four clinical studies in healthy normal human subjects have been completed with EVP 6124. EVP-6124 exhibited linear kinetics over the range of 1 to 180mg and demonstrated a half-life suitable for once daily dosing. EVP 6124 appears to be safe and well-tolerated for up to 21 days as measured by adverse events, vital signs, continuous cardiac monitoring, physical examination, and clinical laboratory evaluations. In addition, in normal volunteers, EVP-6124 demonstrated pro-cognitive effects (CogState testing) in various cognitive domains including executive function. The safety and efficacy of EVP-6124 was assessed in a Phase 1b study of 48 mild to moderate AD patients 60-80 years of age, on stable donepezil or rivastigmine therapy. Patients were dosed with placebo or two different doses of EVP-6124 (0.3 or 1.0mg/d) for 28 days. Cognitive effects were measured by CogState computerized cognitive testing and a subset of NTB scales (category fluency, Trails A and B). EVP-6124 appeared to be safe and well tolerated with no significant adverse events reported more frequently in treated versus placebo patients; there were no SAEs reported. Subjects exposed to EVP-6124 in addition to donepezil or rivastigmine showed an increase in cognitive function, primarily in the domains of non-verbal learning, memory, and executive function. These data suggest that EVP-6124 administered to AD subjects on cholinesterase inhibitor therapies, may have a potential benefit. Larger phase II studies are currently being initiated in both Alzheimer's disease and schizophrenia.

Efficacy of Rivastigmine for Cognitive Symptoms in Parkinson Disease With Dementia

Impairment of multiple neurotransmitter networks, including acetylcholine, may contribute to the cognitive impairment in patients with Parkinson disease with dementia (PDD). Therefore, cholinesterase inhibitors might improve cognitive function in PDD. On the other hand, enhancing cholinergic function could plausibly worsen features of parkinsonism. To determine if oral cholinesterase inhibitors improve measures of cognitive outcome and are tolerated by people with PDD. We addressed the question through the development of a critically appraised topic. Participants included consultant and resident neurologists, clinical epidemiologists, a medical librarian, and behavioral neurology and movement disorder specialists. Participants began with a structured clinical question, devised search strategies, compiled the best evidence, performed a critical appraisal, summarized the evidence, provided commentary, and declared bottom-line conclusions. A randomized controlled trial (n = 541) showed that, compared with placebo, rivastigmine (mean, 8.6 mg/d) significantly improved scores on 2 coprimary cognitive outcome scales in PDD, including the Alzheimer disease Cooperative Study-Clinician's Global Impression of Change. When dichotomized to evaluate clinically significant benefit (moderate or marked improvement), this outcome was not significant (risk difference = 5.3%; 95% confidence interval (CI) = -1.6 to 12.1). The number needed to treat (NNT) to avoid clinically significant worsening of cognition was 10 (95% CI = 6-28). The NNT for the combined outcome of either achieving clinically significant benefit or avoiding significant worsening was 7. The numbers needed to harm for cholinergic side effects were 9 (95% CI = 5-24) for parkinsonian symptoms and 11 (95% CI = 6-32) for rivastigmine discontinuation due to any side effect. Rivastigmine therapy for PDD is associated with significant tradeoffs in efficacy and adverse effects. Carefully monitored trials of rivastigmine may provide meaningful benefits for a minority of PDD patients.

P01-28 Rivastigmine in treatment of alcohol - induced persisting dementia

Alcohol- Induced Persisting Dementia (AIPD) can occur because of both the direct effects of alcohol and specific vitamin deficiencies, and the indirect influence of genetic or neurochemical predisposition.Aim of this study was to ascertain the efficiency of the rivastigmine therapy in the treatment of AIPD.Methods:The prospective clinical study included 101 patients diagnosed in accordance with DSM IV criteria for AIPD. Patients were monitored for 3 months in hospital and outpatient conditions, according to specially designed protocol, which included MMSE, BPRS, CGI1-4 scales, and clock drawing test (CDT). Both the control and the experimental groups were treated with conventional therapy and in addition the experimental group treatment was supplemented with rivastigmine (3-12 mg/24 h).Results:The participants were in the same age range, predominantly male, with an similar average illness duration. Average daily rivastigmine dose was 9.76±2.014 mg. An average pretrial MMSE score was around 19, BPRS score was around 50, CGI1 score was around 4.6, and CDT score around 5. Statistically significant differences among the C and E group begin to show after 14th (in BPRS scores)and 28th day of therapy(in MMSE,CDT,and CGI1 scores) (p>0.1) and to become more apparently significant after two and three months of treatment (p>0.5).Conclusion:MMSE and CDT scores are significantly higher, and BPRS, CGI1-3 scores significantly lower in rivastigmine group from 14th and 28thday of treatment. Rivastigmine has statistically significant effect in treatment of AIPD.

Complete atrioventricular block associated with rivastigmine therapy

A case of complete atrioventricular block associated with rivastigmine use is presented. A 67-year-old Turkish woman with Alzheimer's disease was admitted to the hospital because of dizziness and syncope. Her medical history included diagnoses of hypertension (treated with amlodipine 5 mg daily) and diabetes mellitus (treated with nateglinide 120 mg daily). She had been taking both drugs for over five years. She had also been taking rivastigmine 6 mg p.o. daily for five months for the treatment of Alzheimer's disease. She had experienced dizziness since the onset of rivastigmine therapy but had not reported it to any health care provider. On admission, she had a blood pressure measurement of 90/60 mm Hg and a pulse rate of 34 beats/min. A 12-lead electrocardiogram revealed complete atrioventricular block. Echocardiography results, blood electrolyte levels, and cardiac biochemical markers were normal. After initial evaluation, a temporary transvenous pacemaker was implanted via the right femoral vein. Amlodipine and rivastigmine were discontinued. On the first day of hospitalization, a coronary angiogram revealed normal coronary anatomy. Two days later, the complete atrioventricular block resolved spontaneously to sinus rhythm. Rivastigmine 6 mg p.o. daily was reinitiated, and complete atrioventricular block recurred on the fourth day of therapy. A VVI permanent pacemaker was implanted on the fifth day of hospitalization. Amlodipine and rivastigmine were reinitiated. The patient continued rivastigmine 6 mg p.o. daily after permanent pacemaker implantation. A three-month follow-up appointment revealed that no further syncope episodes or dizziness had occurred. A 67-year-old woman developed complete atrioventricular block after receiving rivastigmine for the treatment of Alzheimer's disease.

Olanzapine‐Associated Neuroleptic Malignant Syndrome in a Patient Receiving Concomitant Rivastigmine Therapy

Neuroleptic malignant syndrome (NMS) is an idiosyncratic and uncommon but serious adverse effect that has been reported with both typical and atypical antipsychotic agents. We describe a 58-year-old man with Down syndrome and dementia who was receiving low-dose olanzapine and rivastigmine therapy; he developed NMS 4 months after starting olanzapine. The patient presented with altered mental status, rigidity, fever, diaphoresis, and tremor, and his creatine kinase level was elevated. Olanzapine was discontinued, and the patient fully recovered; antipsychotic therapy was not restarted. Based on the Naranjo adverse drug reaction probability scale, olanzapine was the probable cause of the patient's NMS. In addition, use of rivastigmine in combination with olanzapine may have placed the patient at greater risk for NMS, possibly due to an acetylcholine-dopamine imbalance. Clinicians should be aware of the potential for NMS even with low doses of antipsychotics, particularly in patients who have a limited ability to communicate. Concomitant administration of cholinesterase inhibitors such as rivastigmine may represent an unrecognized risk factor for NMS development.

Patient and caregiver outcomes after 6 ± 1.5-months of rivastigmine therapy for mild-to-moderate Alzheimer's disease:the Belgian FExT study

ABSTRACTObjective: Despite response variability, cholinesterase inhibitors are recommended in mild to moderate Alzheimer's disease. Dose titration is common; however randomized controlled trials (RCTs) have mainly investigated fixed-dose regimens. We examined practice patterns and outcomes of 6 ± 1.5-month rivastigmine therapy.Methods: Prospective, pharmacoepidemiologic, naturalistic study of 175 evaluable patients with mild to moderate Alzheimer's disease (+ 151 caregivers) from 52 centers in Belgium on 6 ± 1.5 month (titrated) rivastigmine treatment.Main outcome measures: Measured at baseline (enrollment) and follow-up (6 ± 1.5 months). For patients: Mini-Mental State Exam (MMSE), Activities of Daily Living (ADL), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS) scores; treatment response (improvement, maintenance, or decline less than normative slope). For caregivers: hours/week spent caring; Zarit Caregiver Burden Scale (ZCBS), 12‐item version of General Health Questionnaire (GHQ‐12), Instrumental Activities of Daily Living (IADL) scores.Results: Patients’ MMSE and NPI scores ( p < 0.001) improved from baseline to follow-up, but not ADL and GDS scores. Treatment response was 89.1% of patients for MMSE (including 60.6% with improvement) and 77.7% for NPI (including 57.1% with improvement). Quadratic curves were fitted for the average daily dose and the MMSE and NPI scores; with a trend towards average daily dose of 6.0 ± 3.0 mg/day. Caregivers’ ZCBS ( p = 0.036) and GHQ‐12 ( p = 0.029) scores improved, but not IADL scores and time spent caring.Conclusions: Patients’ MMSE and ADL scores confirmed the meta-analyses of rivastigmine efficacy trials, while NPI scores exceeded efficacy results. Proportionately more patients responded to (titrated) treatment than in fixed-dose RCTs. Caregivers reported less burden (similar to meta-analysis) and better general health over the study period. Where efficacy and effectiveness results diverge, the benefit is in ‘real-world’ effectiveness. Large sample, multi-country replications, less sensitive to censoring secondary to missing data and powered to permit advanced modeling, as well as RCTs with adaptive designs to accommodate titration, are needed. The profile of patients most likely to benefit from treatment or most vulnerable to treatment outcome must be studied, as must the impact of physician- and center-related variables on outcomes.

EXACT: rivastigmine improves the high prevalence of attention deficits and mood and behaviour symptoms in Alzheimer's disease*

The objective of this study was to investigate the impact of rivastigmine therapy on attention, apathy, anxiety and agitation in patients with mild-to-moderate Alzheimer's disease (AD) in a real-world clinical setting. Patients with mild-to-moderate AD were enrolled in the study by physicians across Canada. They were treated with open-label rivastigmine (dose at the discretion of the prescribing physicians) for a period of 6 months. Changes from baseline in attention, apathy, anxiety and agitation were assessed using an abbreviated Clinician's Global Impression of Change at 3- and 6-month visits. The Mini Mental State Examination (MMSE) was also used at these visits. Use and changes in use of psychotropic medications were recorded, as were changes in caregiver burden. Analyses of subgroups (outpatients vs. institutionalised patients) were also performed. A total of 2119 patients were enrolled in the study by 375 physicians. At baseline, 91% had deficits in attention, 85.4% had symptoms of anxiety, 78.5% exhibited apathy and 70.1% showed agitation. At 6 months, 67.5% of evaluable patients had improved on the symptom of attention, while 62.3%, 62.6% and 56.0% had improvements in anxiety, apathy and agitation respectively. The percentages with improvements were higher in the institutional subgroup than among outpatients. There was an overall mean improvement of 1.1 points on the MMSE at 6 months. Approximately four times as many caregivers reported a reduced burden than an increased burden at 6 months (40.3% vs. 10.3%). The majority of patients treated with rivastigmine experienced improvements in attention, anxiety, apathy and agitation. These real-life findings further demonstrate the proven efficacy of rivastigmine in patients with mild-to-moderate AD.

Adding memantine to rivastigmine therapy in patients with mild-to-moderate alzheimer's disease: results of a 12-week, open-label pilot study.

At present, inhibition of cholines-terase is the treatment of choice for subjects with mild-to-moderate Alzheimer's disease (AD). Memantine, a noncompetitive antagonist at N-methyl-d-aspartate receptors, is currently used to treat subjects with moderate-to-severe AD. The goal of this multicenter, open-label pilot study was to investigate whether combination therapy with memantine added to rivastigmine is safe and beneficial in subjects with mild-to-moderate AD. Patients with a DSM-IV diagnosis of dementia of the Alzheimer's type (N = 95), who were treated with rivastigmine (6-12 mg/day) for a maximum duration of 24 weeks prior to baseline, received memantine (5-20 mg/day) in combination with rivastigmine for 12 weeks. The primary efficacy variable was the change in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) total score at the end of 12 weeks compared with baseline. The study was conducted between September 15, 2003, and May 27, 2004. There was a statistically significant difference between baseline and week 12 for the ADAS-cog total score, showing a positive effect of combination therapy. Combination therapy did not evidence any unexpected safety concerns and was well-tolerated by most patients. Memantine in combination with rivastigmine appears to be safe and beneficial in patients with mild-to-moderate AD. Our results need to be confirmed in a large, long-term, randomized, double-blind, placebo-controlled clinical trial.