Cholinesterase Inhibitor Donepezil Research Articles

The ASCOMALVA trial: Association between the cholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate in Alzheimer's disease with cerebrovascular injury: Interim results

BackgroundCholinesterase inhibitors (ChE-Is) are among the drugs more largely used for the treatment of mild-to-moderate symptoms of Alzheimer's disease (AD), but beneficial long-term effects of these compounds on the cognitive, functional, and behavioural symptoms of the disease are small and not always apparent in practice. Preclinical investigations have suggested that association between ChE-Is and the cholinergic precursor choline alphoscerate enhances cholinergic neurotransmission more effectively than single compounds alone. The ongoing clinical trial on the “Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in Alzheimer's disease associated with cerebrovascular injury” (ASCOMALVA) was designed to assess if association of the ChE-I donepezil with choline alphoscerate has a more favourable clinical profile than monotherapy with donepezil alone. MethodsASCOMALVA is a double-blind multicentre trial that has completed the first 12months of observation of 91 patients of the 210 planned. Patients were aged between 56 and 91years (mean 75±10years) and were included in the protocol with a MMSE score between 15 and 24. Patients with AD diagnosed according to the DSM IV criteria suffer from ischemic brain damage documented by neuroimaging (MRI and CT scan), with a score≥2 in at least one subfield of the New Rating Scale for Age-Related White Matter Changes (ARWMC). Patients were randomly allotted to an active treatment group (donepezil+choline alphoscerate) or to a reference treatment group (donepezil+placebo) and were examined after 3, 6, 9 and 12months of treatment. ResultsCognitive functions, patient's daily activities and behavioural symptoms were assessed by the Mini‐Mental State Evaluation (MMSE), Alzheimer's Disease Assessment Scale Cognitive subscale (ADAS-cog), Basic Activities of Daily Living (BADL), Instrumental Activities of Daily Living (IADL) and Neuropsychiatric Inventory (NPI), of severity and of caregiver distress measures (NPI-F and NPI-D). Patients of the reference group (donepezil+placebo) showed along the course of the 12months of observation, a slight time-dependent worsening of MMSE, ADAS-cog, IADL and NPI-D scores and no changes in the BADL and NPI-F scores. Donepezil plus choline alphoscerate improved compared to donepezil alone the different items analysed except the BADL. ConclusionsThe first results of the ASCOMALVA trial suggest that association of choline alphoscerate to the standard treatment with a ChE-I may represent an option to prolong beneficial effects of cholinergic therapies in AD with concomitant ischemic cerebrovascular injury.

Drugs licensed for treating patients with alzheimer's disease.

Four drugs are licensed in the UK for the management of Alzheimer's disease. These are the cholinesterase inhibitors donepezil, rivastigmine and galantamine, and memantine, which decreases the action of the neurotransmitter glutamate. Cholinesterase inhibitors increase the availability of acetylcholine at the synaptic cleft between neurones by preventing its breakdown by the enzyme acetylcholinesterase. The four drugs are only licensed for Alzheimer's disease, with rivastigmine also licensed for Parkinson's disease. For vascular dementia they have been shown to give modest improvements in cognitive function but not for activities of living and so are not recommended.

The role of acetylcholine in drug addiction

Acetylcholine ACh, is involved in many CNS functions like sensory and motor processing, sleep, nociception, memory, mood, stress response, attention, arousal, motivation and reward. Due to the interaction with the dopaminergic reward system mainly in the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC), it is believed that ACh plays a significant role on the initiation and maintenance of the drug addiction. Substances affecting the cholinergic system by increasing the levels of ACh, like cholinesterase and butyrylcholinesterase inhibitors (donepezil, rivastigmine, physostigmine, tacrine, galantamine), reduced the symptoms of addiction in a drug-induced CPP test as well as locomotor activity caused by morphine, cocaine and heroin. Unfortunately, donepezil failed to inhibit methamphetamine-CPP as well as the locomotor sensitization caused by this drug. For comparison, it has been indicated that mice lacking M5 receptor showed a reduction in cocaine self-administration and morphine-induced CPP. The stimulation of M4 receptor decreased DA release in NAc and the administration of non-selective antagonist of mAChRs, scopolamine decreased cocaine-induced locomotor activity in rats. Moreover, mecamylamine, a noncompetitve antagonist of nAChRs, prevented the increase in cocaine consumption as well as blocked cocaine and amphetamine-induced behavioral sensitization. Thus, drugs affecting cholinergic transduction could be approached as potential therapeutic agents for patients who abuse different psychoactive substances. These issues, however, require further studies.

New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs

Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop 'disease modifying drugs' hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce β amyloid (Aβ) production, drugs to prevent Aβ aggregation, drugs to promote Aβ clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. Specific problems with completed trials and hopes with ongoing trials are discussed in this review.

Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice

We have recently found that the combination of ovariectomy (OVX) and chronic restraint stress (CS) causes hippocampal pyramidal cell loss and cognitive dysfunction in female rats and that estrogen replacement prevents the OVX/CS-induced morphological and behavioral changes. In this study, to clarify the mechanisms underlying the OVX/CS-mediated memory impairment further, we examined the roles of cholinergic systems in the OVX/CS-induced memory impairment in mice. Female Slc:ICR strain mice were randomly divided into two groups: OVX and sham-operated groups. Two weeks after the operation, the mice of each group were further assigned to CS (6 h/day) or non-stress group. Following the 3-week-stress period, all mice were subjected to contextual fear conditioning, and context- and tone-dependent memory tests were conducted 1 or 24 h after the conditioning. Overburden with 3 weeks of CS from 2 weeks after OVX impaired context- and tone-dependent freezing and the OVX/CS caused significant Nissl-stained neuron-like cell loss in the hippocampal CA3 region, although OVX and CS alone did not cause such behavioral and histological changes. Replacement of 17β-estradiol for 5 weeks after OVX suppressed OVX/CS-induced memory impairment and hippocampal Nissl-positive cell loss. Furthermore, the OVX/CS mice exhibited a significant decrease in choline acetyltransferase in the hippocampus compared with other groups. The cholinesterase inhibitors donepezil and galantamine ameliorated OVX/CS-induced memory impairment. These data suggest that cholinergic dysfunction may be involved in the OVX/CS-induced conditioned fear memory impairment. Overall, our findings suggest that the OVX/CS mouse model is useful to study the mechanisms underlying estrogen loss-induced memory deficits.

Cholinergic enhancement reduces orientation-specific surround suppression but not visual crowding

Acetylcholine (ACh) reduces the spatial spread of excitatory fMRI responses in early visual cortex and receptive field size of V1 neurons. We investigated the perceptual consequences of these physiological effects of ACh with surround suppression and crowding, two phenomena that involve spatial interactions between visual field locations. Surround suppression refers to the reduction in perceived stimulus contrast by a high-contrast surround stimulus. For grating stimuli, surround suppression is selective for the relative orientations of the center and surround, suggesting that it results from inhibitory interactions in early visual cortex. Crowding refers to impaired identification of a peripheral stimulus in the presence of flankers and is thought to result from excessive integration of visual features. We increased synaptic ACh levels by administering the cholinesterase inhibitor donepezil to healthy human subjects in a placebo-controlled, double-blind design. In Experiment 1, we measured surround suppression of a central grating using a contrast discrimination task with three conditions: (1) surround grating with the same orientation as the center (parallel), (2) surround orthogonal to the center, or (3) no surround. Contrast discrimination thresholds were higher in the parallel than in the orthogonal condition, demonstrating orientation-specific surround suppression (OSSS). Cholinergic enhancement decreased thresholds only in the parallel condition, thereby reducing OSSS. In Experiment 2, subjects performed a crowding task in which they reported the identity of a peripheral letter flanked by letters on either side. We measured the critical spacing between the targets and flanking letters that allowed reliable identification. Cholinergic enhancement with donepezil had no effect on critical spacing. Our findings suggest that ACh reduces spatial interactions in tasks involving segmentation of visual field locations but that these effects may be limited to early visual cortical processing.

Cholinesterase Inhibitors Improve Both Memory and Complex Learning in Aged Beagle Dogs

Similar to patients with Alzheimer's disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 μg/kg; SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Aβ pathology, and cognitive decline.

Disease progression and costs of care in Alzheimer’s disease patients treated with donepezil: a longitudinal naturalistic cohort

Improved data and methods are needed for modeling disease progression in Alzheimer's disease (AD) for economic evaluation of treatments. The aim is to estimate prediction models for long-term AD progression and subsequently economic outcomes. Three-year follow-up data on 435 patients treated with the cholinesterase inhibitor donepezil in clinical practise were analyzed. Regression models were estimated for long-term prediction of decline in cognitive function (ADAS-cog) and activities in daily living (ADL) ability, risk of institutionalization and costs of care. The cognitive deterioration was estimated at between 1.6 and 4 ADAS-cog points per every 6months, increasing with disease severity. Cognitive function was an important predictor of ADL-ability, which itself was the most important predictor of the risk of institutionalization and costs of care. Combining all models in a cross-validation process generated accurate predictions of costs of care at each 6months follow-up. The proposed methods for representing AD progression and economic outcomes can be used in micro-simulation models for the economic evaluation of new treatments.

Editorial: New drugs for Alzheimer's disease in Japan

Editorial: New drugs for Alzheimer's disease in Japan

Cognitive Impairment and MS: Searching for Effective Therapies

Introduction: Cognitive impairment can be a significant disabling symptom in many people with multiple sclerosis (MS) leading to poor quality of life and social and economic burdens [1–3]. Prevalence of cognitive impairment in MS varies from 40% to 65% [1] and can affect people even in early MS [4–6]. The cognitive domains commonly affected in MS include short-term memory, information processing speed, and attention [1, 7]. Despite availability of disease-modifying therapies (DMTs) such as interferon β, glatiramer acetate, natalizumab, and fingolimod for relapsing forms of MS, the beneficial effect on cognitive improvement of these therapies remains far from being clear. In theory, controlling the MS disease activity with use of such therapies should slow the cognitive impairment but this has not been studied well in the completed clinical trials of the DMTs. In addition, none of these therapies seem effective at reversing established cognitive impairment, and symptomatic therapies for this MS problem are needed. In recent years, researchers have tested several therapies aimed specifically at improving cognition in MS. These therapies have included dietary supplements, such as gingko biloba [8, 9], and drugs used in treatment of cognitive dysfunction in Alzheimer’s disease (AD) such as the cholinesterase inhibitors donepezil hydrochloride [10, 11] and rivastigmine [12–14], in which the preliminary studies showed mixed results. We describe here two recent large trials that tested memantine and donepezil for treatment of MS-related cognitive dysfunction and showed them to be ineffective [15, 16]. Donepezil hydrochloride (marketed in the United States as Aricept®; Eisai, Tokyo, Japan) is a centrally acting cholinesterase inhibitor that is US Food and Drug Administration (FDA) approved for symptomatic treatment of mild to moderate dementia in AD [17]. Donepezil’s mechanism of action involves increasing acetylcholine in the neuronal pathways affected in AD. Donepezil is administered in a dose of 5 to 10 mg per day. Memantine (marketed in United States as Namenda®; Forest Pharmaceuticals, St. Louis, MO), conversely, is an N-methyl-Daspartate (NMDA) receptor antagonist that is FDA approved for symptomatic treatment of moderate to severe dementia in AD [18] and can be given in doses up to 5 to 20 mg per day. NMDA receptors with glutamate as their key neurotransmitter have an important role in learning and memory function of the brain; and by blocking the actions of glutamate, memantine is thought to improve some aspects of cognitive dysfunction in AD. This editorial revisits the limitations that exist currently in the treatment of cognitive dysfunction in MS. The first study that we discuss here was conducted by Krupp et al. [16] studying the effects of donepezil on memory function in MS. The second study was conducted by Lovera et al. V. Yadav (*) :D. N. Bourdette Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHS-42, Portland, OR 97239, USA e-mail: yadavv@ohsu.edu

The social recognition test of memory in the rat: A reliable primary in-vivo cognition assay for guiding drug discovery/development decision-making relevant to neuropsychiatric diseases

The social recognition test of memory in the rat: A reliable primary in-vivo cognition assay for guiding drug discovery/development decision-making relevant to neuropsychiatric diseases

Critical appraisal and role of memantine extended-release in the management of Alzheimer’s disease

Correspondence: indrapal Singh Department of Neurology and Psychiatry, Division of Geriatric Psychiatry, Saint Louis University School of Medicine, 1438 South Grand Blvd, St Louis, MO 63108, USA Tel +1 314 977 4829 Fax +1 314 977 4878 email isingh2@slu.edu Abstract: Alzheimer’s disease (AD) is a progressive, degenerative brain disease. Currently available US FDA-approved pharmacological management options for AD are cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and the N-methyl-D-aspartate receptor antagonist (memantine). These treatment options may provide symptomatic benefits. Medication adherence is one of the many problems faced by the caregivers of patients with dementia. The currently available FDA-approved memantine immediate-release (IR) has been found safe and efficacious at a dose of 10 mg twice daily (20 mg/day) both as monotherapy and in combination with cholinesterase inhibitors in moderate to severe dementia. Memantine extended-release (ER) 28 mg, a new once-daily form at a higher dose, has also been found to be safe and well tolerated in 2 studies: one in 24 healthy volunteers which showed relatively minor fluctuation in plasma levels of memantine during the steady-state dosing interval and second, a multinational multi-center study, comparing memantine ER 28 mg and placebo in patients with moderate to severe AD stable on concurrent cholinesterase inhibitor (ChEI). In this study, memantine ER was found to be an efficacious drug with a good safety and tolerability profile. Both memantine IR 20 mg and memantine ER 28 mg are now FDA-approved for the treatment of moderate to severe AD, either alone, or in combination with a ChEI. Both are efficacious, safe, and well tolerated. Medication adherence with the ER preparation should improve because of once-daily dosing. There is a possibility of superior efficacy of the higher dose memantine ER (28 mg) over the currently approved dosage of memantine IR (20 mg). However, further randomized, controlled, double-blind comparator studies of memantine ER 28 mg vs memantine IR 20 mg and/or 30 mg in single and/or divided doses are required to assess the possible benefits of memantine ER over memantine IR.

Impaired Attention in the 3xTgAD Mouse Model of Alzheimer's Disease: Rescue by Donepezil (Aricept)

Several mouse models of Alzheimer's disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.

Effectiveness of Adding Memantine to an Alzheimer Dementia Treatment Regimen Which Already Includes Stable Donepezil Therapy

Alzheimer dementia (AD) is a major cause of debility and economic strain in aging societies around the world. The only 2 medication classes approved specifically for the treatment of AD are the cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and memantine. Evidence that the use of memantine in a patient already on cholinesterase inhibitor therapy can provide a clinically significant benefit is limited. To review the evidence supporting the addition of memantine therapy in patients with moderate-to-severe AD who are already receiving treatment with a cholinesterase inhibitor. The objective was addressed through the development of a critically appraised topic which included a clinical scenario, structured question, search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Included were neurology consultants and residents, a medical librarian, clinical epidemiologists, and content experts in the field of behavioral neurology. One article was selected for review. Patients receiving memantine for 24 weeks experienced a statistically significant change from baseline on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (P=0.03) and on the Severe Impairment Battery (P=0.001) when compared with placebo. The change in mean scores in the memantine group versus placebo on the 19-item AD Cooperative Study-Activities of Daily Living Inventory were -2.0 versus -3.4 and on the Severe Impairment Battery 0.9 versus -2.5 which indicate improved performance or reduced deterioration in the memantine group. The number needed to treat and the effect size could not be calculated from the data provided. The addition of memantine to donepezil in patients with moderate-to-severe AD provides a statistically significant improvement in several AD-oriented outcome measures, however, the clinical relevance of this benefit remains unclear.

An Evidence-based Critical Appraisal of a Topic:: Effectiveness of High Dose Donepezil for Advanced Alzheimer's Disease

Cholinesterase inhibitors (ChEIs) have become the main approach to symptomatic treatment in mild to moderate Alzheimer's disease. Unfortunately, there is no evidence that these drugs impact clinical progression. The objective of this article is to determine whether the newly released higher dose of ChEI donepezil (23 mg/d) provides improved therapeutic benefit over the standard dose (10 mg/d). The clinical question is addressed through an evidence-based process that includes developing a clinical scenario, forming a guiding clinical question and search strategy, selecting published evidence, devising an evidence summary, performing a critical appraisal, and analyzing the results.

Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons

Effects of estrogen therapy on cognitive performance appear to diminish with age and time following the loss of ovarian function. We hypothesize that this is due to a reduction in basal forebrain cholinergic function and that treatment with a cholinergic enhancer can reverse the effect. This study tested whether combining the cholinesterase inhibitor donepezil with estradiol treatment can enhance/restore estradiol effects on cognitive performance in young ovariectomized rats with selective lesions of septal cholinergic neurons. 192IgG-saporin was injected directly into the medial septum to produce selective cholinergic lesions. Rats were then treated with donepezil (Don, daily injections of 3 mg/kg/day, i.p.) or vehicle, and then with 17β-estradiol (E2, administered by silastic capsule implanted s.c.) or an empty capsule. Rats were trained on a delayed matching-to-position (DMP) T-maze task which previous studies have shown is sensitive to ovariectomy and estrogen replacement. Results show that neither estradiol nor donepezil alone significantly enhanced acquisition of the DMP task in rats with cholinergic lesions. Combination therapy was effective, however, depending on the severity of the lesion. Don + E2 significantly enhanced acquisition of the task in rats with partial lesions (< 50% loss of cholinergic neurons), but not in rats with severe lesions. This effect was due largely to a reduction in perseverative behavior. Don + E2 also improved working memory in rats with partial lesions, as evidenced by significantly better performance than controls during increased intertrial delays. These findings suggest that even partial loss of septal cholinergic neurons can reduce effects of estrogen therapy on cognitive performance, and demonstrate that combining a cholinesterase inhibitor with estrogen therapy can help to restore beneficial effects on performance. We propose that combination therapy may have similar beneficial effects in women, particularly in older women who have not used estrogen therapy for many years and are beginning to show signs of cognitive impairment or early Alzheimer's disease.

Cognitive Enhancers in Moderate to Severe Alzheimer's Disease

The treatment of moderate to severe Alzheimer's disease is reviewed with regard to mechanisms of action, pharmacokinetics, metabolism, safety/tolerability, and efficacy in reducing cognitive, behavioral/psychiatric, functional and global symptoms. The cholinesterase inhibitors donepezil, rivastigmine and galantamine and the N-methyl-d-aspartate receptor channel blocker memantine are moderately beneficial. Small improvements over a few months are followed by slowed mental decline. Concerning cognitive, functional and global functions, these drugs are similarly effective. Cholinesterase inhibitors also reduce apathy, memantine counteracts agitation and aggression. Serious adverse effects are rare with all four drugs. Cholinesterase inhibitors bear a risk for patients with cardiac diseases. Adverse emetic events are typical for oral formulations of these drugs, but less for rivastigmine transdermal patches. Other routes of administration and use of a galantamine prodrug are currently investigated. The superiority of combination therapies over monotherapies requires further support. Promising investigational drugs include the copper/zinc ionophore PBT2 and multifunctional hybrid molecules.

Pharmacokinetic and Pharmacodynamic Properties of Cholinesterase Inhibitors Donepezil, Tacrine, and Galantamine in Aged and Young Lister Hooded Rats

Physiological alterations that may change pharmacological response accompany aging. Pharmacokinetic/pharmacodynamic properties of cholinesterase inhibitors (ChEIs) used in the treatment of Alzheimer's disease, donepezil, tacrine, and galantamine, were investigated in an aged Lister hooded rat model. Intravenous and oral 6-h blood sampling profiles in old (30 months old) and young (7 months old) rats revealed pharmacokinetic changes similar to those in humans with an approximately 40% increase in C(max) of galantamine and prolonged t(1/2) (1.4-fold) and mean residence time (1.5-fold) of donepezil. Tacrine disposition was maintained with age, and area under the concentration-time curve and clearance in old rats were similar to those in young rats for all drugs tested as was bioavailability. Old rats showed a trend of increased pharmacodynamic sensitivity (<20%) to ChEIs in cholinesterase activity assays, which was attributed to pharmacokinetic effects because a trend of higher blood and brain concentrations was seen in the old rats although brain/blood ratios remained unaffected. Enhanced cholinergic-mediated behaviors such as tremor, hypothermia, salivation, and lacrimation were also observed in the old rats, which could not be accounted for by a similar magnitude of change in pharmacokinetics. A decrease in expression of muscarinic acetylcholine receptor subtype 2 detected in old rat brains was postulated to play a role. Greater age effects in both pharmacokinetics and pharmacodynamics of donepezil and tacrine were seen in previous studies with Fischer 344 rats, indicating a potential risk in overreliance on this rat strain for aging studies.

Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology

The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review and revise its first (2006) Guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A to D, with A having the strongest evidence base (from randomized controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and brain imaging can improve diagnostic accuracy (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for mild to moderate Alzheimer's disease (A) and memantine for moderate to severe Alzheimer's disease (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer's disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), especially for neuropsychiatric symptoms (A). Cholinesterase inhibitors and memantine can produce cognitive improvements in DLB (A). There is no clear evidence that any intervention can prevent or delay the onset of dementia. Although the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition are in progress. Although results of pivotal studies are awaited, results to date have been equivocal and no disease-modifying agents are either licensed or can be currently recommended for clinical use.

The Pharmacoeconomics of Cognitive Enhancers in Moderate to Severe Alzheimerʼs Disease

Alzheimer's disease is associated with a substantial economic impact on patients, their caregivers and society. Due to the current rise in the aging population, the prevalence and impact of Alzheimer's disease are expected to increase greatly. The cost of caring for someone with Alzheimer's disease is magnified in the more severe stages of the disease. There are four cognitive enhancers commonly used for the treatment of Alzheimer's disease: three cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and one NMDA receptor antagonist (memantine). Of these, donepezil and memantine have been approved in many countries as pharmacological treatments for moderate to severe Alzheimer's disease, while donepezil, rivastigmine and galantamine are approved treatments for mild to moderate Alzheimer's disease. While cost effectiveness has been well studied in mild to moderate Alzheimer's disease, the cost-benefit information for drug therapy in moderate to severe Alzheimer's disease is less clear. This article reviews the pharmacoeconomic data available on these four drugs, with a specific focus on moderate to severe Alzheimer's disease, including economic burden, cost drivers, clinical outcomes and pharmacoeconomic studies. A key driver of the cost of Alzheimer's disease is the severity of the disease, indicating that the ability to stabilize the disease state is a potential source of cost savings. Drug therapies that can limit increases in behavioural problems and cognitive and functional impairment, and postpone institutionalization without an increase in longevity may serve to reduce the economic burden on Alzheimer's disease patients. The data suggest that, while the available, approved agents offer only modest improvements in clinical outcomes, they could be cost-effective treatments for moderate to severe Alzheimer's disease when viewed from the societal perspective. For memantine and donepezil, data are available that suggest that the cost of these drugs is offset by the clinical and societal benefits provided by slowing the progression of Alzheimer's disease. While there are few head-to-head comparison trials, the similarity in costs of the treatments and efficacy against placebo suggest that cost effectiveness will not be substantially different among treatments. More studies that examine longitudinal resource utilization and its relationship to drug treatment in the moderate to severe stages are needed to clarify cost benefit in this population and possibly differentiate between individual medications.