Rivastigmine patch for treatment of Alzheimer's disease in clinical practice in Thailand

Background: Rivastigmine is a cholinesterase inhibitor for treatment of mild to moderate Alzheimer's disease (AD) and dementia associated with Parkinson's disease. The new patch formulation was recently made available. We assessed the safety, tolerability, and cognitive outcome of rivastigmine patch in treatment of mild to moderate AD in clinical practice in Thailand. Methods: A multicentre, hospital‐based, prospective observational study was conducted in nine hospitals across Thailand. Patients with probable mild to moderate AD who received the rivastigmine patch were enrolled. Data were collected data at baseline, weeks 4–8 and after week16. Results: A total of 116 AD patients were screened, and three were excluded. Of 113 patients, 62.8% were women with a mean age of 73.3 ± 9.2 years; 79.7% were newly diagnosed. One‐third of all patients had been using antipsychotic or antidepressant medication. Common comorbidities were hypertension and dyslipidemia. The Thai Mental State Examination score significantly increased from 18.6 to 20.3 (weeks 4–8) and 20.4 (week 16+) (P < 0.001). Scores based on physicians’ (Clinical Global Impression) and caregivers’ (Patients’ Caregiver Global Impression of Change) impressions of improvement suggested minimal improvement. Because of adverse events, seven patients's dosages were reduced 10 cm² to 5 cm² or from 5 cm² to nothing. Itching was the most common adverse symptom. Conclusions: During the first 16 weeks after initiation of rivastigmine patch therapy, patients with probable mild to moderate AD had statistically significant improvement in cognitive function, but clinically marginal benefit. Rivastigmine was safe and well tolerated.     

Rivastigmine in Alzheimer's disease and Parkinson's disease dementia: an ADAS-cog factor analysis

Rivastigmine treatment is associated with significant improvements on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) in patients with mild-to-moderate Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Both AD and PDD are purported to have different profiles of cognitive impairment, which may respond differentially to rivastigmine treatment. This was a retrospective analysis of 3 randomized, double-blind, rivastigmine trial databases (Investigation of transDermal Exelon in ALzheimer's disease [IDEAL; AD], EXelon in PaRkinson's disEaSe dementia Study [EXPRESS; PDD], and Alzheimer's Disease with ENA 713 [ADENA; AD]). Factor analyses of the 11 baseline ADAS-cog items derived the same factors in the 2 diseases, that is, "memory" and "language". Rivastigmine-treated AD and PDD patients showed significant improvements (P < .0001 versus placebo) on both factors. For both AD and PDD, rivastigmine had a numerically greater effect on memory than language. Treatment effect sizes were numerically greater in PDD compared with AD. Rivastigmine treatment is associated with improvement in memory and language in AD and PDD. The numerically greater response in PDD is consistent with greater cholinergic deficits in this disease state.     

Rivastigmine in dementia associated with Parkinson's disease and Alzheimer's disease: similarities and differences

Parkinson's disease dementia (PDD) and Alzheimer's disease (AD) are both characterized by cognitive abnormalities, neuropsychiatric symptoms, and cholinergic deficits. We reviewed data from large, placebo-controlled clinical trials conducted with rivastigmine in patients with PDD and AD to evaluate similarities and differences in response to treatment. In placebo groups, AD patients appeared to show more rapid cognitive decline than those with PDD. Treatment effects (rivastigmine versus placebo) on cognitive performance over 6 months were quantitatively similar in both populations, but qualitatively different: in AD, cognitive abilities were stabilized by rivastigmine compared to declines in placebo groups, whereas in PDD symptomatic improvements above baseline drove treatment effects while placebo patients had limited change. On activities of daily living, stabilization (rather than improvement) was observed in both dementia types. A more aggressive course of placebo decline, and greater treatment differences (rivastigmine versus placebo), were seen in sub-populations of both PDD and AD patients with hallucinations at baseline. The safety and adverse event profiles were comparable in the two populations. In conclusion, the magnitude of effect with rivastigmine versus placebo is quantitatively comparable in patients with AD and PD, but the treatment effect tended to be one of stabilization in AD, while in PDD improvements over baseline were seen. In both populations, hallucinations may identify patients who are likely to be more treatment-responsive.     

Rivastigmine for Alzheimer's Disease: Improvement Versus Reduced Worsening

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in later life. It is manifested by gradual and progressive decline in cognitive function and ability to perform activities of daily living (ADL) and the development of behavioral disturbances. Progressive reduction in functional ability reduces independence and quality of life and adversely affects caregivers and society. Therefore, benefit from any AD therapy may be obtained not only from improved function but also from stabilization or reduced worsening of function. METHOD: This retrospective study of pooled data from 3 randomized, placebo-controlled trials (N = 2126) compared the incidence of different levels of worsening between 2 rivastigmine treatment groups and a placebo group at week 26 for cognition, using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog); global functioning, using the Clinicians' Interview-Based Impression of Change-Plus (CIBIC-Plus); and ADL, using the Progressive Deterioration Scale (PDS). Categories of worsening analyzed for each scale were as follows: ADAS-Cog: any decline, >/= 4-point decline, >/= 7-point decline; CIBIC-Plus: stabilized/worsened (rating = 4, 5, 6, or 7), any worsening (rating = 5, 6, or 7); PDS: any worsening, >/= 10% worsening. RESULTS: Patients treated with rivastigmine, 6-12 mg/day, showed significantly less decline in cognition, global functioning, and ADL for all categories of worsening examined compared with patients who received placebo. The reduction in decline compared with placebo was greater in the group receiving 6-12 mg/day of rivastigmine compared with the treatment group receiving 1-4 mg/day of rivastigmine. CONCLUSION: Rivastigmine reduces the amount of worsening observed in cognition, global functioning, and ADL in a 6-month trial period.     

Rivastigmine in current clinical practice in patients with mild to moderate Alzheimer's disease

Six hundred and sixty nine out patients with mild to moderate Alzheimer's disease were enrolled by 193 French neurologists, psychiatrists and gerontologists. The patients, 38p.cent males and 62p.cent females with a mean age of 75 years were progressively titrated from 3 to 12mg by day of rivastigmine, Exelon((R)), a day, and treated for 6 months. Mean Mini-Mental State (MMS) at baseline was 18.6. Concomitant pathologies and treatments were present in 89p.cent of the patients. Safety was good though 86p.cent reported an adverse event which was mild in most of the cases. The premature drop out rate was 29p.cent. Seventy-five patients showed no change or an improvement in their 4 Instrumental Activities of Daily Living (IADL) score with no change in the MMS at the end of treatment (18.8). Four items of the Neuro-Psychiatric Inventory (NPI): delusions, anxiety, apathy, and irritability were significantly improved at week 12 and the improvement in anxiety was still significant at the end of treatment. The total score frequency X severity showed a tendency to improvement. The correlations between the sum of the 4 IADL, MMS and NPI scores were strongly significant.     

Rivastigmine in Parkinson's disease dementia

Dementia associated with Parkinson's disease (PD) ultimately develops in approximately 70% of patients with PD older than 80 years of age. The neuropathology of PD dementia (PDD) is likely multifactorial and affects several neuronal populations. There is evidence that PDD is associated with a cholinergic deficit, supporting the therapeutic role of cholinesterase inhibitors, which are already first-line agents in the treatment of Alzheimer's disease. Open-label and small controlled studies suggested a clinical efficacy of cholinesterase inhibitors in PDD. One large randomized placebo-controlled trial of 541 patients demonstrated that oral rivastigmine improved cognition, attention and executive functions, activities of daily living and behavioral symptoms after 6 months of treatment. Rivastigmine is a dual cholinesterase inhibitor, being effective on both acetylcholinesterase and butyrylcholinesterase. This paper reviews the pharmacokinetic and pharmacodynamic properties of rivastigmine (oral and transdermal administration). It also reviews evidence on clinical efficacy, safety and tolerability of the oral administration in PDD patients at doses of 3-12 mg/day.     

Rivastigmine (Exelon) for dementia in patients with Parkinson's disease

OBJECTIVES: To study the efficacy of cholinesterase inhibitors in the treatment of dementia in patients with Parkinson's disease (PD). METHODS: We treated twenty-eight demented patients with PD openly for 26 weeks with rivastigmine (mean daily dose 7.2 +/- 3.3 mg/day). Baseline scores were compared with those at weeks 12, 26 and after 8 weeks of washout. RESULTS: Twenty patients completed 26 weeks of treatment and eight dropped out because of side effects. The Unified Parkinson's Disease Rating Scale mental subscore improved significantly at week 26 (P < 0.01) while the motor score (part III) did not change. The mean ADAScog total score improved by 7.3 points at week 26 (P < 0.002). The subscores for recognition, word finding, remembering instructions and concentration items of the ADAScog improved significantly as well (P < 0.02, P < 0.05, P < 0.005 and P < 0.003, respectively). CONCLUSIONS: Rivastigmine may improve the cognitive functions in PD patients with dementia with no worsening of motor function.     

Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer's disease

Objective

To evaluate the efficacy and safety of rapidly titrated rivastigmine administered twice (BID) or three times (TID) daily in patients with mild to moderate Alzheimer''s disease (AD).

Methods

This was a 26 week international, randomised, double blind, placebo controlled study in which 678 patients with probable AD received placebo or rivastigmine 2–12 mg/day BID or TID. Primary outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS‐cog) and categorical analysis of the Clinician Interview Based Impression of Change incorporating caregiver information (CIBIC‐Plus). Secondary outcomes were the CIBIC‐Plus change from baseline, Progressive Deterioration Scale, ADAS‐cogA, Mini‐Mental State Examination and Global Deterioration Scale.

Results

At week 26, mean rivastigmine dose was 9.6 (2.76) mg/day in the TID group and 8.9 (2.93) mg/day in the BID group. Mean ADAS‐cog changes from baseline in the TID and BID rivastigmine treated groups were −0.2 (SD 7.3) and 1.2 (SD 7.2) versus 2.8 (SD 7.2) for the placebo group (p<0.05). Differences between rivastigmine TID and placebo on the CIBIC‐Plus categorical responder analysis were significant (31% vs 19%; p<0.05, intention to treat). No significant differences were seen between BID and placebo for this outcome measure. Adverse events were predominantly gastrointestinal, occurring mainly during dose titration. Withdrawal because of adverse events accounted for 17% of BID, 11% of TID and 9% of placebo patients.

Conclusions

Rivastigmine administered as a BID or TID regimen significantly benefited cognitive, function and global performances in AD patients. The TID regimen showed a tendency for superior tolerability and permitted titration to higher doses, an outcome that is significant as the efficacy of rivastigmine is dose related.Alzheimer''s disease (AD) is characterised by a loss of cholinergic neurons and their cortical projections from the nucleus basalis and associated areas in the basal forebrain.¹ Progressive deterioration of the widespread and dense cholinergic innervation of the human cerebral cortex contributes to the symptoms of AD and is associated with decreased levels of the neurotransmitter acetylcholine (ACh). Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) appear to be simultaneously active in the synaptic hydrolysis of ACh, terminating its neurotransmitter action, and co‐regulating ACh levels.² The use of cholinesterase inhibitors (ChE‐Is) has been directed at increasing and maintaining synaptic ACh to improve cholinergic neurotransmission.Three regulatory approved ChE‐Is (rivastigmine, donepezil and galantamine) are widely used for the symptomatic treatment of AD. These drugs have demonstrated efficacy in treating cognitive and global functioning, while stabilising functional abilities, over at least 6 months during clinical trials in patients with mild to moderate AD.^3,4 Although the currently used ChE‐Is have the same treatment indication, they differ pharmacologically.⁵ Rivastigmine induces a slowly reversible inhibition of both AChE and BuChE that is sustained for at least 12 months of repeated administration.⁶ Metabolism of rivastigmine occurs by its target enzymes (AChE and BuChE), independent of hepatic drug metabolising cytochrome enzymes. Its pharmacodynamic half life is 1.6 h following a 6 mg dose,⁷ although both AChE and BuChE activity are inhibited for about 8–10 h, with maximum inhibition of about 60% 5 h after dosing.⁸Previous placebo controlled, randomised controlled trials (RCTs) with rivastigmine clearly demonstrated a dose–response relationship with best efficacy reported for doses between 6 and 12 mg daily.^9,10 However, too rapid titration to optimal recommended doses can be associated with intolerance, particularly nausea and vomiting, which are attributed to centrally mediated cholinergic effects.^11,12 Clinically, 4 weekly titration on a twice daily (BID) dosing basis with 3 mg dose increments is recommended to achieve a therapeutic response, although titration with smaller increments has been suggested to minimise side effects.¹³ To allow for more rapid titration, three times daily (TID) dosing, which might be associated with lower peak plasma levels, could be a useful therapeutic approach.¹⁴The aim of this study was to evaluate the safety and efficacy of rapidly titrated rivastigmine BID or TID for 26 weeks, in patients with mild to moderately severe AD.     

Rivastigmine versus placebo in hyperhomocysteinemic Parkinson's disease dementia patients

The effects of rivastigmine versus placebo in Parkinson's disease dementia (PDD) patients with elevated or normal/low plasma homocysteine were determined. In this prospective analysis of a 24‐week, randomly assigned, placebo‐controlled study of rivastigmine in PDD, subpopulations comprised patients with plasma homocysteine ≥14 μmol/L (elevated) or <14 μmol/L (normal/low). Coprimary outcomes were the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS‐cog) and Alzheimer Disease Cooperative Society–Clinical Global Impression of Change (ADCS‐CGIC). Secondary outcomes included additional measures of cognition, including attention and executive function, daily function, and neuropsychiatric symptoms. Adverse events (AEs) were monitored. In total, 342 of 541 patients provided samples for analysis, from which 72% had elevated plasma homocysteine. Hyperhomocysteinemic patients showed treatment differences (rivastigmine vs. placebo) of 4.0 on ADAS‐cog and 0.7 on ADCS‐CGIC (both P < 0.01), and significant treatment differences on secondary outcomes. Rivastigmine‐ and placebo‐treated hyperhomocysteinemic patients (16.5% and 14.6%) discontinued the study because of AEs. Patients with normal/low homocysteine showed no treatment differences on primary or secondary outcomes (1.4 on the ADAS‐cog and 0.1 on ADCS‐CGIC, both P = ns); 16.7% and 10.3% rivastigmine‐ and placebo‐treated patients discontinued because of AEs. Elevated homocysteine was associated with greater rivastigmine treatment differences than normal/low homocysteine. © 2008 Movement Disorder Society     

Biomarkers for Alzheimer's disease

The development and validation of biomarkers for the latent, prodromal and dementia stages of Alzheimer's disease (AD) is a pressing issue because of their high prevalence and an emerging set of experimental therapeutics that will soon force decisions regarding risk versus benefit. While genetic risk factors and neuroimaging will certainly have important roles to play, here we have focused on biomarkers assayed in body fluids. There is developing consensus for a central role for cerebrospinal fluid amyloid-beta (Abeta)42 and tau species to aid in the diagnosis of AD at different stages; plasma-based assays for Abeta species show some promise, but the picture is much less clear than in the cerebrospinal fluid. Biomarkers of different pathogenic steps thought to contribute to AD will also be important in assessing pharmacologic mechanisms of new therapies. Discovery approaches now underway may develop novel panels of biomarkers for AD. The next 5 years will see standardization of more established approaches, and the combination of different modalities into the most effective means for assessing different stages of AD.     

Immunotherapy for Alzheimer's disease

Recent studies in murine models of Alzheimer's disease (AD) have found that active immunisation with amyloid-beta peptide (Abeta) or passive immunisation with Abeta antibodies can lessen the severity of Abeta-induced neuritic plaque pathology through the activation of microglia. These antibodies can be detected in the serum and CSF. Whether they slow down or speed up the development and progression of AD has not been determined. Furthermore, the conditions that induce formation of such antibodies are unknown, or how specific they are to AD. However, the evidence suggests at least a potential beneficial role for some features of neuroinflammation in AD. A clinical phase II study of an active immunisation approach with AN1792 was started in 2001, but was recently suspended after some patients developed serious adverse events. These were most likely caused by the activation of the proinflammatory cascade. Immunotherapy approaches represent fascinating ways to test the amyloid hypothesis and may offer genuine opportunities to modify disease progression. This review focuses on immunisation strategies and details of the pathways involved in antibody clearance of Abeta.