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Glutamatergic, noradrenergic, serotonergic, and cholinergic systems play a critical role in the basal ganglia circuitry. Targeting these non-dopaminergic receptors remains a focus of ongoing research to improve Parkinson's disease (PD) motor symptoms, without the potential side effects of dopamine replacement therapy. This review updates advancements in non-dopaminergic treatments for motor control in PD since 2013. To date, no non-dopaminergic selective drug has shown significant long-term efficacy as monotherapy in PD. The largest area of development in non-dopaminergic targets has been for motor complications of dopamine replacement therapy (motor fluctuations and dyskinesia). For treatment of motor fluctuations, safinamide, zonisamide, and istradefylline are currently approved, and novel glutamatergic and serotonergic drugs are in development. Long-acting formulations of amantadine are approved for treating dyskinesia. Several non-dopaminergic drugs have failed to show anti-dyskinetic efficacy, while some are still in development. Non-dopaminergic targets are also being pursued to treat specific motor symptoms of PD. For example, CX-8998 (a calcium channel modulator) is being evaluated for PD tremor and rivastigmine may improve gait dysfunction in PD. Drug repurposing continues to be a key strategy for non-dopaminergic targets in PD, but the field needs to increase discovery and availability of such drugs.

Vascular cognitive impairment (VCI) is the second most common type of dementia after Alzheimer's disease (AD). Stroke and cardiovascular risk factors have been linked to both AD and VCI and potentially can affect cognitive function in mid and later life. Various pharmacological agents, including donepezil, galantamine, and memantine, approved for the treatment of AD have shown modest cognitive benefits in patients with vascular dementia (VaD). However, their functional and global benefits have been inconsistent. Donepezil has shown some cognitive benefit in patients with VaD only, and galantamine has shown some benefit in mixed dementia (AD/VaD). The benefits of other drugs such as rivastigmine, memantine, nimodipine, and piracetam are not clear. Some other supplements and herbal therapies, such as citicoline, actovegin, huperzine A, and vinpocetine, have also been studied in patients with VaD, but their beneficial effects are not well established. Non-drug therapies and lifestyle modifications such as diet, exercise, and vascular risk factor control are important in the management of VCI and should not be ignored. However, there is a need for more robust clinical trials focusing on executive function and other cognitive measures and incorporation of newer imaging modalities to provide additional evidence about the utility of these strategies in patients with VCI.

A possible association between benzodiazepine use and Alzheimer’s disease (AD) has been hypothesized in previous studies. Using claims data from the Helsana Group, a large Swiss health insurance provider, we examined the association between previous benzodiazepine use and the risk of AD. We conducted a matched case-control study and identified 1438 incident AD cases between 2013 and 2014 based on recorded first-time use of drugs used to treat AD [i.e., acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and the N-methyl-d-aspartate receptor antagonist memantine] and matched one control to each case on age, sex, index date, and residence (canton). Because the initiation of benzodiazepine use shortly before the AD diagnosis date may occur as a result of symptomatic treatment of prodromal symptoms of early major neurocognitive disorder, we introduced an induction period of 2 years before the AD diagnosis date. Additionally, we categorized medication use by duration of use prior to the index date using prescriptions. We applied conditional logistic regression analyses to calculate odds ratios with 95% confidence intervals and adjusted for use of antidepressants. The crude odds ratio (95% confidence interval) of developing AD for patients starting benzodiazepine treatment was 1.71 (1.17–2.99) in the year before diagnosis and 1.19 (0.82–1.72) in the third year before diagnosis. After accounting for benzodiazepine use initiated during the prodromal phase, benzodiazepine use was not associated with an increased risk of developing AD; long-term benzodiazepine use (≥30 prescriptions) yielded an adjusted odds ratio of 0.78 (0.53–1.14). After taking into consideration a possible protopathic bias in the 2 years preceding the AD diagnosis date, benzodiazepine use was not associated with an increased risk of developing AD.

Alzheimer’s disease (AD) is the most common form of dementia among older persons. Pathognomonic hallmarks of the disease include the development of amyloid senile plaques and deposits of neurofibrillary tangles. These changes occur in the brain long before the clinical manifestations of AD (cognitive impairment in particular) become apparent. Nicotinic acetylcholine receptors (AChRs), particularly the α7 subtype, are highly expressed in brain regions relevant to cognitive and memory functions and involved in the processing of sensory information. There is strong evidence that implicates the participation of AChRs in AD. This review briefly introduces current strategies addressing the pathophysiologic findings (amyloid-β-peptide plaques, neurofibrillary tangles) and then focuses on more recent efforts of pharmacologic intervention in AD, specifically targeted to the α7 AChR. Whereas cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, together with the non-competitive N-methyl-d-aspartate receptor antagonist memantine are at the forefront of present-day clinical intervention for AD, new insights into AChR molecular pharmacology are bringing other drugs, directed at AChRs, to center stage. Among these are the positive allosteric modulators that selectively target α7 AChRs and are aimed at unleashing the factors that hinder agonist-mediated, α7 AChR channel activation. This calls for more detailed knowledge of the distribution, functional properties, and involvement of AChRs in various signaling cascades—together with the corresponding abnormalities in all these properties—to be able to engineer strategies in drug design and evaluate the therapeutic possibilities of new compounds targeting this class of neurotransmitter receptors. Fil: Valles, Ana Sofia. Consejo Nacional de Investigaciones Cientificas y Técnicas. Centro Científico Tecnológico Bahia Blanca. Instituto de Investigaciones Bioquímicas Bahia Blanca (i); Argentina Fil: Borroni, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Planta Piloto de Ingeniería Química (i); Argentina Fil: Barrantes, Francisco Jose. Pontificia Universidad Católica Argentina "santa María de Los Buenos Aires". Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina

Alzheimer's disease is a chronic neurodegenerative disorder resulting in part from the degeneration of cholinergic neurons in the brain. Rivastigmine, a cholinesterase inhibitor, is commonly used as a treatment for dementia due to its ability to moderate cholinergic neurotransmission; however, treatment with oral rivastigmine can lead to gastrointestinal adverse effects such as nausea and vomiting. Transdermal administration of rivastigmine can minimize these adverse effects by providing continuous delivery of the medication, while maintaining the effectiveness of the oral treatment. While the transdermal form of rivastigmine has been found to have fewer systemic adverse effects compared with the oral form, cutaneous reactions, such as contact dermatitis, can lead to discontinuation of the drug in its transdermal form. Lack of patient compliance with regard to applying the patch to the designated site, applying the patch for the correct length of time or rotating patch application sites increases the risk of cutaneous adverse reactions. This article outlines the diagnosis and management of irritant contact dermatitis and allergic contact dermatitis secondary to transdermal rivastigmine. The large majority of reactions to transdermal patches are of an irritant type, which can be diagnosed clinically by the presence of a pruritic, erythematous, eczematous plaque strictly confined to the borders of the patch. In contrast, an allergic reaction can be differentiated by the presence of vesicles and/or oedema, erythema beyond the boundaries of the transdermal patch and lack of improvement of the lesion 48 hours after removal of the offending treatment. By encouraging the patient to follow a regular rotation schedule for the patch, and using lipid-based emollients for irritant dermatitis and pre- and post-treatment topical corticosteroids for allergic dermatitis, cutaneous reactions can often be alleviated and patients can continue with their medication regimen. Other simple changes to a patient's treatment routine, including minimizing the use of harsh soaps, avoiding recently shaven or damaged areas of skin and carefully removing the patch after use, can help to further decrease the risk of dermatitis development.

It has been shown that, during several years preceding the diagnosis of Alzheimer's disease there is a gradual cognitive decline with a continuum between the pre-dementia stage (still known as the prodromal stage but now included within the general concept of mild cognitive impairment [MCI]) and the other stages of the disease. In MCI, the use of cholinesterase inhibitors (ChEIs) is not associated with any delay in the onset of Alzheimer's disease or dementia. During the dementia stages, the three ChEIs (donepezil, galantamine and rivastigmine) are efficacious for mild to moderate Alzheimer's disease; therefore, monotherapy with a ChEI can be envisaged as initial treatment. Confirmation of the efficacy of ChEIs in the mild dementia stage is essentially based on the results from a single, randomized study carried out specifically among patients at this stage of severity. Memantine can represent an alternative to ChEIs in the moderate stage of Alzheimer's disease. At the severe stage of the disease, memantine and donepezil are currently indicated. Indeed, memantine has been approved by numerous drug regulatory agencies for use in severe stages of the disease, whereas donepezil has only been approved by the US FDA. There is currently insufficient evidence for recommending combination therapy in Alzheimer's disease.

Background: The efficacy of cholinesterase inhibitors (ChEIs), especially over the long term, is still under discussion. There is a lack of data concerning the optimal drug treatment duration and the reasons for discontinuation, particularly outside the clinical trial setting. Objective: To identify predictive factors of discontinuation and switch of ChEIs in a real-world setting. Methods: A multicentre cohort study of 686 patients with mild-to-moderate ambulatory Alzheimer’s disease who were diagnosed in 16 Alzheimer’s disease expert centres in 2000–2 and who were assessed twice yearly for 2 years. The main outcome measure was ChEI discontinuation and switch (analysed using Cox survival analyses). Results: After 2 years, of the 611 subjects treated with a ChEI at baseline, 100 subjects had switched or discontinued ChEI therapy (incidence rate 12.7 [95% CI 10.2, 15.2] per 100 person-years). The incidences of switching and discontinuation were 9.2 (95% CI 7.0, 11.3) and 3.6 (95% CI 2.3, 4.8) per 100 person-years, respectively. In the multivariate analysis, predictive factors for switching were an ineffective ChEI dose (adjusted hazard ratio [HRa] = 6.91, 95% CI 3.08, 15.49), rapid cognitive decline (HRa = 4.10, 95% CI 1.85, 9.05), hospitalization unrelated to Alzheimer’s disease (HRa = 2.33,95% CI 1.07, 5.09) and anxiety (HRa= 2.08, 95% CI 1.16, 3.73). Predictive factors of discontinuation were: hospitalization related (HRa = 9.14, 95% CI 2.69, 31.07) or unrelated (HRa = 4.23, 95% CI 1.54, 11.59) to Alzheimer’s disease, use of an anticholinergic drug (HRa = 4.26, 95% CI 1.46, 12.45) and weight loss (HRa = 3.77, 95% CI 1.15, 12.33). Conclusions: This study highlights four types of predictors of switch or discontinuation, reflecting disease progression, reconsideration of ChEI benefits, adverse drug reactions to ChEIs and inappropriate concurrent use of anticholinergic drugs. Attention should be paid to anticholinergic agents and prescribers should be given better information about these drugs.

Background: Cholinesterase inhibitors are used in Alzheimer’s disease, mostly in elderly persons with co-morbidities and receiving co-medications that could increase the risk of serious adverse reactions. Objective: To identify factors associated with serious adverse drug reactions (ADRs) in patients treated with cholinesterase inhibitors. Methods: All ADRs associated with donepezil, rivastigmine or galantamine were identified in the French pharmacovigilance database, from the launching of these drugs to January 2007. Serious ADRs (SADRs) were those that led to death, hospitalization or prolongation of hospitalization, or that were life threatening. A multiple logistic regression analysis was used to identify factors associated with seriousness in the reported adverse reactions. Results: We identified 773 reports of ADRs related to cholinesterase inhibitor use, among which 438 (57%) concerned SADRs. The median age of patients was 80 years (interquartile range: 75–84 years); 65.1% were women. The most represented ADRs were those responsible for CNS disorders (17.0%), gastrointestinal disorders (16.2%) and cardiac rhythm disorders (11.2%). Factors associated with an increased risk of SADRs were: age (odds ratio [OR] 1.92; 95% CI 1.22, 3.02 for subjects aged 85 years and over), use of atypical antipsychotics (OR 2.15; 95% CI 1.04, 4.46), use of conventional antipsychotics (OR 2.06, 95% CI 1.10, 3.85), use of antihypertensive drugs (OR 2.11; 95% CI 1.47, 3.02) and use of drugs targeting the alimentary tract and metabolism (OR 1.62; 95% CI 1.06, 2.46). The use of benzodiazepines (long-acting or others), antidepressants (tricyclic or others) or antiarrhythmic drugs was not associated with the reporting of SADRs. Conclusions: An increased risk of SADRs related to cholinesterase inhibitors was associated with the use of antipsychotics (with no difference between conventional and atypical antipsychotics), drugs targeting the alimentary tract/metabolism and antihypertensive drugs. It was not associated with the use of other psychotropic drugs, other non-psychotropic CNS drugs or with the use of antiarrhythmic agents. The association with drugs targeting the alimentary tract and metabolism could result from a protopathic bias or reflect the particular sensitivity to serious nausea and vomiting in patients already treated for gastrointestinal disorders. These results confirm that attention needs to be paid to patients receiving both cholinesterase inhibitors and antipsychotics.

▴ The cholinesterase inhibitor rivastigmine is now available as a transdermal patch for use in the treatment of mild to moderate dementia of the Alzheimer’s type. ▴ The transdermal patch gradually releases rivastigmine over the application period. There was less fluctuation between plasma peak and trough rivastigmine concentrations with the patch than with the capsule formulation. ▴ The rivastigmine 9.5 mg/24 hours patch was effective in patients with Alzheimer’s disease, according to the results of a well designed, 24-week trial. A significant improvement in Alzheimer’s Disease Assessment Scale —Cognitive subscale (ADAS-Cog) scores and significantly lower Alzheimer’s Disease Cooperative Study —Clinical Global Impression of Change scores were seen with the rivastigmine 9.5 mg/24 hours patch versus placebo. ▴ In addition, treatment with the rivastigmine 9.5 mg/ 24 hours patch was noninferior to rivastigmine 6mg twice-daily capsules, as assessed by ADAS-Cog scores. Significantly more caregivers of study patients preferred administering the patch formulation of rivastigmine than the capsule formulation. ▴ The rivastigmine 9.5 mg/24 hours patch was generally well tolerated by patients with Alzheimer’s disease. The incidence of adverse events (including nausea and vomiting) in the rivastigmine 9.5 mg/ 24 hours patch group was not significantly different to that in the placebo group. However, several adverse events such as nausea and vomiting occurred in significantly more rivastigmine capsule recipients than in placebo recipients.

Background: Alzheimer’s disease is associated with abnormalities in the levels of some brain metabolites, including decreases in N-acetyl-aspartate (NAA) and increases in myo-inositol and choline levels. Cholinesterase inhibitors have proven modest effects on cognition in patients with mild or moderate Alzheimer’s disease; however, there is little information on the effects of these drugs on metabolic parameters in the brain. Magnetic resonance spectroscopy (MRS) provides a method of determining changes in such parameters. Objective: To assess the effect of rivastigmine on metabolite levels in different areas of the brain, and whether changes in metabolite levels correlate with clinical outcome, in patients with Alzheimer’s disease compared with untreated patients with Alzheimer’s disease. Methods: Twenty-four consecutive patients with mild or moderate Alzheimer’s disease were enrolled in the study and were treated with rivastigmine at a target dosage of 12 mg/day for 4 months. A comparison group of ten consecutive untreated patients with Alzheimer’s disease with similar cognitive impairment to the treatment group were also enrolled. Each patient underwent assessment using the Mini-Mental State Examination (Spanish version), the Blessed Dementia Rating Scale, the Clinical Dementia Rating scale, the Interview for Deterioration in Daily living activities in Dementia, the Alzheimer’s Disease Assessment Scale cognitive and noncognitive subscales, and single-voxel MRS of the frontal, parietal and occipital cortices of the brain to assess levels of brain metabolites (NAA, creatine, choline and myo-inositol) and their ratios to creatine. All assessments were performed at baseline and after 4 months of treatment with rivastigmine, and at baseline and 1 month later in the comparison group. Results: Globally, although there was some mean improvement, no significant changes in the cognitive and noncognitive scale scores between baseline and post-treatment assessments were seen in patients who received rivastigmine. A significant increase in the NAA/creatine ratio in the frontal cortex (1.23 at baseline vs 1.3 after treatment; p = 0.026) and in the myo-inositol/creatine ratio in the occipital cortex (0.61 vs 0.65; p = 0.009) was seen in rivastigmine-treated patients. No other significant changes in the metabolite levels or their ratios to creatine were seen in these patients. After correction for multiple comparisons, the significant effects disappeared. Only in the frontal cortex did the changes in metabolite ratios correlate with changes on the clinical scales. In the comparison group, no significant differences between the metabolite levels or ratios to creatine seen with the two scans were detected. Conclusion: Treatment with rivastigmine showed modest neuronal functional recovery in the frontal cortex only (being able to reverse disease-related decreases in NAA/creatine ratio in this area but unable to affect the disease-related increase in myo-inositol/creatine ratio in any cortex). Since the modest clinical changes correlated with the small changes in the metabolite rates, MRS could be useful in monitoring response to current or future treatments for Alzheimer’s disease.

Galantamine inhibits acetylcholinesterase (AChE) to slow acetylcholine hydrolysis, and may also modulate presynaptic nicotinic receptor activation, thereby increasing neurotransmitter concentrations in the synaptic cleft.black triangle Once-daily galantamine extended release (ER) 24 mg and twice-daily galantamine immediate release (IR) 12 mg are bioequivalent in terms of the area under the plasma concentration-time curve from time 0 to 24 hours and steady-state minimum plasma concentration.black triangle Primary endpoints indicated a significantly greater effect of galantamine ER on cognitive performance than placebo, with efficacy similar to galantamine IR, in a randomised, double-blind trial. While galantamine ER did not show a significant effect on the coprimary endpoint of global change, neither did galantamine IR in this study. Exploratory post hoc analyses of global change correcting for study centre and prognostic factors associated with response (baseline Mini-Mental State Examination, Alzheimer's Disease Assessment Scale cognitive score, prior cholinomimetic use) indicated nominal significance in the galantamine ER treatment arm. Secondary endpoints indicated an improvement in activities of daily living and memory- and nonmemory-dependent measures of cognitive performance, but not in measures of behaviour or dichotomised rating of global change. Adverse events occurred in similar proportions of galantamine ER, galantamine IR and placebo recipients.

Two of the four licensed cholinesterase inhibitors, galantamine and donepezil, have recently featured in published work showing how they act in dementia associated with cerebrovascular disease (CVD). It is timely to review this new evidence and place it within the current consensus understanding of what makes up a clearly heterogeneous dementia population. To do this, the current review explores the relationship between Alzheimer's disease, for which this group of compounds originally received licensing approval, and vascular pathology within the brain, highlighting the significant overlap in risk factors and the frequent coexistence of the two conditions in the patients that are studied. Whether they are inter-related or separate entities is discussed, followed by a description of the current classifications of Alzheimer's disease with CVD, and the three subtypes of 'pure' vascular dementia - subcortical, cortical and strategic infarct. Understanding these entities allows more accurate diagnostic and prognostic information to be given to patients, and leads towards matching the published clinical evidence discussed with more predictable clinical syndromes. This distinction is particularly relevant in terms of the studies conducted thus far. Galantamine has been studied in a placebo-controlled study of patients with Alzheimer's disease and CVD as well as patients with vascular dementia, whereas donepezil was studied exclusively in patients with vascular dementia. Differences in the way the placebo groups acted in these studies confirmed the fact that these actually are two distinct groups. Galantamine showed efficacy across the combined groups studied, with placebo deterioration similar to previous Alzheimer's disease studies, while donepezil produced a positive effect in vascular dementia - with this placebo group relatively unchanged. The symptomatic improvements seen were not really surprising, as cholinergic deficits are a common factor across all of these syndromes. Wherever this is the predominant biological finding, it would be expected that cholinesterase inhibitors would have a similar effect, whatever the condition causing it.

By some estimates moderate-to-severe Alzheimer's disease accounts for 50% of all patients with Alzheimer's disease. However, there are numerous issues that remain to be resolved in the management of patients with more advanced Alzheimer's disease. The first prospective, randomised, controlled trial of the cholinesterase inhibitor donepezil in more advanced Alzheimer's disease has reported quite encouraging results, with further studies being undertaken. Post-hoc analyses of rivastigmine and galantamine in patients with more advanced Alzheimer's disease have supported the hypothesis that acetylcholinesterase inhibitors are likely be efficacious in this subgroup. Memantine, a glutamate NMDA receptor antagonist, is newly licensed in Europe for the treatment of more advanced Alzheimer's disease and will provide the first non-cholinesterase inhibitor option for the treatment of Alzheimer's disease. The combination of donepezil and memantine has been shown to have superior efficacy than donepezil alone in this severe Alzheimer's disease subgroup, potentially supporting a role for dual treatment in more advanced Alzheimer's disease. Further studies of all aspects of more advanced Alzheimer's disease are clearly needed. The problems of translating clinical trial results to routine clinical practice are even more complex and challenging in this patient group, with the true impact of any one given treatment ranging over a spectrum of clinical domains from improved cognition to reduced caregiver burden. Increased attentiveness by clinicians to treatment response across this multidisciplinary spectrum in more advanced Alzheimer's disease is warranted.

Cholinesterase inhibitors are the only pharmacological class indicated for the treatment of mild to moderate Alzheimer's disease. These drugs are also being used off label to treat severe cases of Alzheimer's disease or vascular dementia and other disorders. The widespread use of cholinesterase inhibitors raises the possibility of their use in combination regimens, with the subsequent risk of deleterious drug-drug interactions in high-risk populations. The purpose of this review is to present the possible sources of pharmacokinetic or pharmacodynamic drug-drug interactions involving cholinesterase inhibitors. The four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) that are currently available have different pharmacological properties that expose patients to the risk of several types of drug interactions of nonequivalent clinical relevance. The principal proven clinically relevant drug interactions involve tacrine and drugs metabolised by the cytochrome P450 (CYP) 1A2 enzyme, as well as tacrine or donepezil and antipsychotics (which results in the appearance of parkinsonian symptoms). The bioavailability of galantamine is increased by coadministration with paroxetine, ketoconazole and erythromycin. It is of interest to note that because rivastigmine is metabolised by esterases rather than CYP enzymes, unlike the other cholinesterase inhibitors, it is unlikely to be involved in pharmacokinetic drug-drug interactions. Care must be taken to reduce the risk of inducing central (excitation, agitation) or peripheral (e.g. bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects via drug interactions with cholinesterase inhibitors. A review of the literature does not reveal any alarming data but does highlight the need for prudent prescription, particularly when cholinesterase inhibitors are given in combination with psychotropics or antiarrhythmics. Possible interactions involving other often coprescribed antidementia agents (e.g. memantine, antioxidants, cognitive enhancers) remain an open area requiring particularly prudent use.

Studies have examined the effects of anti-dementia drugs on gait performance. No structured critical evaluation of these studies has been done so far. The objectives of this study were (1) to perform a qualitative analysis of all published studies on changes in stride time variability (STV) with anti-dementia drugs among patients with Alzheimer disease through a systematic review, and (2) to quantitatively synthesize anti-dementia drug-related changes in STV.An English and French MEDLINE search was conducted on November 2013, with no limit of date, using the Medical Subject Headings term "pharmaceutical preparations" combined with "delirium", "dementia", "amnestic", "cognitive disorders" AND "gait" OR "gait disorders, neurologic" OR "gait apraxia". Fixed-effects meta-analyses were performed to compare STV before and after the use of anti-dementia drugs, and to compare the final STV among participants in intervention and control groups.Of the 110 originally identified abstracts, four studies (i.e., one assessing galantamine, one donepezil, one memantine, and one memantine and acetylcholinesterase inhibitors) were included in the qualitative review, and three studies in the quantitative synthesis. Results were mixed, as two studies showed significant between-visit improvements (i.e., decrease in mean value) in STV, while one study did not, and the last one reported mixed results. In the meta-analysis, there was no difference between intervention and control groups (summary mean difference of final STV = -0.38 % [95 % confidence interval -1.14 to 0.37]) and no before-after difference in the intervention group (summary mean difference of STV = 0.66 [95 % confidence interval -0.17 to 1.49]).Our findings showed inconclusive effects of anti-dementia drugs on STV.

Contains fulltext : 136470.pdf (Publisher’s version ) (Closed access) BACKGROUND: There is no consensus on when and how to discontinue cholinesterase inhibitors (ChEI). Predictors of non-persistency of antidementia drugs have been poorly investigated, mostly during short-term periods and using administrative data. OBJECTIVE: The aim of this study was to investigate the incidence and predictors of ChEI switch and discontinuation among subjects with ascertained Alzheimer's disease (AD). METHODS: A total of 557 community-dwelling, mild-to-moderate AD subjects initiating ChEIs in 29 European clinic centres were assessed twice-yearly for 2 years. Antidementia drug exposure was recorded through a physician-administered structured questionnaire to document any change in drug therapy (start and stop dates, reasons). Discontinuation was defined as >35 days without any antidementia drug. Switch was defined as a change for any antidementia drug strategy within 35 days after ChEI cessation. Two separate time-dependent multivariate Cox survival analyses were conducted to identify predictors of discontinuation and switch. RESULTS: The incidences of discontinuation and switch were 9.65 and 12.47/100 person-years, respectively. Behavioural disturbances, low body mass index, falls, decline in Mini-Mental State Examination (MMSE) score, and AD-related hospitalization predicted discontinuation. MMSE score, decline in activities of daily living score, aberrant motor behaviour, shorter AD duration and higher nurse resource use predicted a switch. An ineffective ChEI dose and clinic specialty predicted both outcomes. Sensitivity analyses using a 60-day cut-off provided stable results. CONCLUSION: Several predictors were identified: adverse drug events and their predisposing factors, perceived loss of efficacy or disease progression on cognitive or functional scales, behavioural disturbances, hospitalization and professional practices. The latter implies a need for harmonization in AD drug prescription practice.

During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) has resulted in drugs being registered for the first time in the US and Europe for this specific indication. The 3 agents registered are cholinesterase inhibitors (ChEIs). The major therapeutic effect of ChEIs in patients with AD is the maintenance of cognitive function, as compared with placebo, during a 6-month to 1-year period of treatment. Additional drug effects that may occur are the slowing of cognitive deterioration and improvement of behaviour and daily living activities. Comparison of clinical effects of 6 ChEIs demonstrates a rather similar magnitude of improvement in cognitive outcome measures. For some drugs, this level may represent an upper limit, while for others it may be possible to increase the benefit further. In order to maximise and prolong positive drug effects it is important to start treatment early and adjust the dosage during treatment. Recent studies that used this administration strategy have shown that in many patients, the stabilisation effect produced by ChEIs can be prolonged for as long as 36 months. This long-lasting effect suggests mechanisms of action other than symptomatic ones. In this article, the effects of ChEIs on beta-amyloid metabolism are postulated to explain the stabilising (i.e. disease-modifying) effects of the drugs. Evidence for such a mechanism is available at the experimental but not yet at the clinical level.

According to the cholinergic hypothesis, the impairment of cognitive function and the behavioural disturbances that affect patients with Alzheimer's disease are mainly due to cortical deficiencies in cholinergic transmission. Numerous cholinesterase inhibitors have been investigated for treatment of this disease, the rationale being to support the cholinergic system by blocking the degradation of acetylcholine released from presynaptic neurons. These drugs can be classified as reversible (tacrine, donepezil and galantamine), pseudo-reversible (physostigmine, eptastigmine and rivastigmine) or irreversible (metrifonate) enzyme inhibitors. This article reviews efficacy and tolerability results from 6-month placebo-controlled studies of 7 cholinesterase inhibitors: tacrine (80 to 160 mg/day), donepezil (5 to 10 mg/day), rivastigmine (1 to 12 mg/day), metrifonate (30 to 80 mg/day), eptastigmine (30 to 60 mg/day), physostigmine (30 to 36 mg/day) and galantamine (8 to 32 mg/day). All these agents have demonstrated a statistically significant, although modest, effect versus placebo on the cognitive and global performance of patients with Alzheimer's disease. Dramatic clinical response has been seen in only 3 to 5% of patients. There are no major differences in terms of efficacy between the different drugs. The mean difference between drug and placebo effects on standardised psychometric scales is about 2 to 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog; a 70-point cognitive scale) and 0.2 to 0.5 points on the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus; a 7-point global scale), or 5 to 14% of the average value of the scales. The most common adverse effects observed after administration of cholinesterase inhibitors are nausea, vomiting, diarrhoea, dizziness, asthenia and anorexia, all symptoms linked to cholinergic overstimulation. These effects are dose related and largely depend on the degree of cholinesterase inhibition. Also important is the rate of onset of cholinesterase inhibition, which depends on the kinetics of enzyme inhibition, the presence and rate of titration, and the pharmacodynamic peak-to-trough fluctuations. A model predicting the incidence of nausea based on acetylcholinesterase inhibition and the half-life of acetylcholinesterase recovery is proposed. In conclusion, cholinesterase inhibitors are the only pharmacological agents proved to be effective for the treatment of Alzheimer's disease in large, long term, double-blind, placebo-controlled trials. While the efficacy of different cholinesterase inhibitors is similar, their tolerability profiles differ. For example, the incidence of nausea (in excess of that seen with placebo) at cognitively effective dosages ranges from 1% with eptastigmine 60 mg/day to 53% with physostigmine 30 mg/day. Differences in tolerability profile may be due to the extent of peripheral acetylcholinesterase inhibition needed to reach clinical efficacy. Other contributing pharmacodynamic factors are the rate of onset of and fluctuations in acetylcholinesterase inhibition at steady state.

Alzheimer’s disease is a dementing illness, the risk of which increases markedly with age. It is estimated that it consumes $US90 billion annually. Alzheimer’s disease is marked by an expanding cholinergic deficit, with a direct relationship between the degree of cholinergic dysfunction and the cognitive impairment. Substantial research continues to be focused on the development of newer and better medications, in particular acetylcholinesterase inhibitors (AChEIs), to compensate for the cholinergic deficit. Trial observations over the past several years suggest that in addition to positive effects on cognitive function, AChEIs may be able to decrease and ameliorate the neuropsychiatric symptoms frequently associated with Alzheimer’s disease. These observations have also shown that the instrumentation used can significantly influence the interpretation and outcome of a study. Typically the individual subscores of the noncognitive component of the Alzheimer’s Disease Assessment Scale (ADAS-noncog) and the Neuropsychiatric Inventory (NPI) scale have most consistently reflected the ability of AChEIs to improve the noncognitive behavioural problems and neuropsychiatric symptoms. Apathy and visual hallucinations are the symptoms that respond most positively to AChEIs. These agents may have the potential to decrease polypharmacy in this elderly population by achieving symptom reduction without additional use of antipsychotic medication.

The deterioration in cognitive function that is characteristic of Alzheimer’s disease is related to a reduction in cholinergic transmission in the basal forebrain, and the appearance of neurofibrillatory tangles and plaques containing β-amyloid (Aβ). Some plaques are neurotoxic and contain acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). AChE consists of different molecular forms: G1, G2 and G4. In the cortex and hippocampus, G4 is located presynaptically and comprises about 70 to 80% of the AChE present. The remainder is in the G1 form which is present in postsynaptic neurons. G4 is the predominant type of AChE that is reduced in Alzheimer’s disease. Skeletal muscle contains mainly G4 and G2. Eight cholinesterase inhibitors that reduce the inactivation of acetylcholine (ACh) have been tested in placebo-controlled trials in patients with Alzheimer’s disease. All these agents were found to improve cognitive function, or delay its rate of decline, in a significant proportion of patients. Tacrine, eptastigmine and rivastigmine also significantly improved activities of daily living. Furthermore, most of these drugs increased cerebral blood flow and glucose metabolism, parameters that are decreased in the basal forebrain of individuals with Alzheimer’s disease. This latter effect may contribute to the therapeutic effect of cholinesterase inhibitors and may delay the formation of Aβ. Currently available cholinesterase inhibitors differ in the incidence and severity of adverse effects produced at clinical doses. Reversible liver damage, seen with tacrine and velnacrine, and cholinergic hyperactivity, such as nausea, vomiting and muscle cramps, with these and other drugs can prevent the attainment of an optimum dose. The selectivity of cholinesterase inhibitors for AChE versus BuChE, and for the different molecular forms of AChE, may have an influence on both therapeutic and adverse effects. Donepezil and galantamine (galanthamine) are selective inhibitors of AChE, while the other agents also inhibit BuChE. The adverse effects associated with cholinergic hyperactivity are not due to blockade of BuChE as previously suggested, since they are seen with the AChE-selective inhibitors and not with those inhibitors that only inhibit BuChE. The advantage of nonselective inhibitors is that they may also increase ACh levels by inhibiting BuChE in glial cells. Selective inhibitors of the G1 form of AChE, such as rivastigmine, are more likely to elevate ACh levels in the brain of patients with Alzheimer’s disease and may be less likely to cause skeletal muscle cramps than nonselective inhibitors such as metrifonate.

The cholinesterase inhibitors are the only available scientifically proven symptomatic treatments for dementia of the Alzheimer’s type. The guidelines we present summarise the current updated knowledge on the available drugs, including tacrine, donepezil, rivastigmine, metrifonate and galantamine (galanthamine). Each of these drugs have been proven to be more effective than placebo in improving symptoms in well designed, double-blind, placebo-controlled studies. Although tacrine was the first drug approved by the US Food and Drug Administration, it needs frequent monitoring of alanine amino transferase levels. Hence, donepezil emerged as a frequently prescribed drug for dementia of the Alzheimer’s type, secondary to its ease of use and lack of significant adverse effects. More studies are needed regarding long term efficacy, head-to-head comparisons and effects upon behavioural disturbances in dementia of the Alzheimer’s type. These guidelines will provide the starting point for a wider clinical use because, although available and clinically effective, the cholinesterase inhibitors are under-prescribed by clinicians in the pharmacological treatment of Alzheimer’s disease.

The impairment of cognitive function that is seen in patients with Alzheimer’s disease is widely considered to be a consequence of cortical deficiencies in cholinergic transmission. Numerous cholinesterase inhibitors have been investigated for treatment of the disease, aiming to bolster the cholinergic system by blocking the degradation of acetylcholine and prolonging its ability to transmit a signal.

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.

Background: Cognitive deficits have been described in patients with schizophrenia from the first descriptions of dementia praecox to current concepts of cognitive dysmetria. Nevertheless, little is known about how to deal with them. In Alzheimer disease, cholinergic deficit is found and cholinesterase inhibitors have been used to delay the progression of memory and cognitive dysfunction. Several lines of evidence suggest that the cholinergic system may be disrupted in schizophrenia. Objective: To evaluate cognitive and clinical effects of adjunctive cholinesterase inhibitors in patients with schizophrenia and schizoaffective disorder. Method: We conducted a literature search on PubMed and EMBASE (up to December 2008) for articles that investigated adjunctive cholinesterase inhibitors in patients with schizophrenia. The terms ‘schizophrenia’, ‘acetylcholinesterase inhibitors’, ‘rivastigmine’, ‘donepezil’, ‘galantamine’ and ‘cognitive deficit’ were searched with restriction for English language and without a year limit. All articles that presented original data from randomized, double-blind, placebo-controlled trials with donepezil, rivastigmine or galantamine in patients with schizophrenia or schizoaffective disorder were included in the meta-analysis. Studies were excluded for the following reasons: (i) case study/letter/correspondence/review; (ii) animal study; (iii) molecular/genetic investigation; and (iv) inclusion of patients with schizophrenia and co-morbid dementia. Few appropriate data for meta-analysis were found because of the large heterogeneity of the assessment instruments used. Nevertheless, effects of cholinesterase inhibitors in some cognitive domains (executive function, memory and language), psychopathology (using the Positive and Negative Syndrome Scale) and extrapyramidal symptoms could be analysed. Results: Six open-label and 24 double-blind studies were found. In five open-label studies there was an improvement in memory, attention and executive functions. Thirteen double-blind studies (four with rivastigmine, six with donepezil and three with galantamine) contributed to the meta-analysis. Significant improvement was found in this analysis for memory and the Trail Making test part A. Conclusions: The reviewed studies suggest that specific cognitive deficits (memory, and the motor speed and attention part of executive function) of patients with schizophrenia and schizoaffective disorder are responsive to rivastigmine, donepezil and galantamine as adjunctive therapy. Confirmatory studies are needed to determine the clinical utility of this treatment strategy.

Acetylcholinesterase inhibitors (AChEIs) have been used to improve cognitive status and disability in patients with mild to moderate Alzheimer's disease (AD). However, while the efficacy of AChEIs (i.e. how they act in randomized controlled trials) in this setting is widely accepted, their effectiveness (i.e. how they behave in the real world) remains controversial. To compare the effects of three AChEIs, donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon), in an Italian national, prospective, observational study representative of the 'real world' clinical practice of AChEI treatment for AD. 938 patients with mild to moderate AD collected within the framework of the Italian National Cronos Project (CP), involving several UVAs (AD Evaluation Units) spread over the entire national territory, who were receiving donepezil, galantamine or rivastigmine were followed for 36 weeks by measuring: (i) function, as determined by the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales; (ii) cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [primary outcome measures]; and (iii) behaviour, as measured on the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) scale. Moreover, all patients were genotyped for apolipoprotein E (apoE) genetic variants. No statistically significant improvement in the primary outcome measures (MMSE and ADAS-Cog) was observed with drug therapy at 36 weeks, at which point all groups had lost, on average, 1 point on the MMSE and gained 2-3 points on the ADAS-Cog scale compared with baseline. On the secondary outcome measures at week 36, all treatment groups showed a significant worsening on the ADL and IADL scales compared with baseline, while on the NPI scale there were no significant differences from baseline except for the galantamine-treated group which worsened significantly. Moreover, patients receiving galantamine worsened significantly compared with the donepezil-treated group on the IADL scale. ApoE epsilon4 allele did not influence the effect of drug therapy. Over a 36-week follow-up period, no significant difference in the effects of donepezil, galantamine and rivastigmine on a variety of functional and cognitive parameters was observed in a large number of apoE-genotyped patients with mild to moderate AD recruited within the framework of a national project representative of the scenario usually encountered in actual clinical practice in Italy. The limitations (possibility of administration of lower drug doses than are used in clinical trials, relatively short follow-up period and the lack of randomization) and strengths (large number of patients, concomitant observation of the three drugs and the number of parameters assessed, including apoE genotype) of the present study are acknowledged. Our type of naturalistic study should complement clinical trials because 'real world' practice operates in the face of the numerous variables (e.g. health status and co-morbidities) associated with a complex disease such as AD in elderly people.

The mainstay of current management of patients with Alzheimer’s disease involves drugs that provide symptomatic therapy. Research approaches for future therapy of Alzheimer’s disease are focusing on disease modifying and/or preventive approaches. Two classes of medications have been approved by the US FDA for the treatment of Alzheimer’s disease: the cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine), mostly for mild to moderate Alzheimer’s disease, and the noncompetitive NMDA receptor antagonist memantine for the moderate to severe stages of Alzheimer’s disease. Management of comorbid medical problems can be more complex in patients with dementia than in those without dementia. Unfortunately, medication adherence in Alzheimer’s disease is low and good adherence is essential for attempting to slow disease progression and improve or stabilize quality of life. Simplifying treatment regimens and providing more caregiver- and patient-friendly modes of administration that fit in better with daily routines can ease caregiver stress which, in turn, may have a favourable impact on the patient’s condition. To overcome problems of medication adherence in the elderly, simple, user-friendly dosage regimens should be prescribed for all medications; thus the need for novel regimens and delivery systems in the pharmacological treatment of Alzheimer’s disease, such as once-daily done-pezil, memantine and galantamine, and transdermal rivastigmine

Britain’s National Institute for Health and Clinical Excellence (NICE) has recently issued guidance that restricts the use of cholinesterase inhibitors and memantine for the treatment of Alzheimer’s disease in the National Health Service. This stance contains lessons for designers of trials, drug regulators, health economists and those developing clinical guidelines for dementia care. The debates that took place around and within NICE were about identifying the benefits of these medicines and the beneficiaries, clarifying the costs of the medication and whom bears them, the methods of weighing benefit against cost, and the consequences of using different approaches to cost-benefit analysis. This article discusses each of these themes and outlines the changes in research and clinical practice and policy making that might flow from NICE’S decisions on medication use. Outcome measures that capture changes in dementia syndromes need further development. Cost-benefit analysis needs refinement with better tools than quality-adjusted life-years, and the policy implications of restricting treatments in a progressive neurodegenerative disorder need more careful consideration.

Rivastigmine is a carbamate-type dual inhibitor of brain acetyl- and butyrylcholinesterases that has been evaluated in the symptomatic treatment of patients with mild to moderate dementia associated with idiopathic Parkinson's disease. Oral rivastigmine 3-12 mg/day for 24 weeks was significantly more effective than placebo in ameliorating cognitive and functional decline, including attentional deficits, in patients with Parkinson's disease dementia in a randomised, double-blind trial. The beneficial effects of rivastigmine observed in the double-blind trial were generally maintained in a 24-week extension of this study in which all patients received active treatment; placebo recipients who switched to rivastigmine also experienced improvements in their cognitive and functional symptoms at week 48. Rivastigmine appeared to be generally well tolerated, with the most common adverse events being mild to moderate in intensity and cholinergic in nature. Parkinsonian symptoms (mainly tremor) were more common in rivastigmine than placebo recipients.

The most prevalent cause of dementia--Alzheimer's disease--is characterised by an early cholinergic deficit that is in part responsible for the cognitive deficits, especially memory and attention defects, seen with this condition. Three cholinesterase inhibitors (ChEIs), namely donepezil, rivastigmine and galantamine, are widely used for the symptomatic treatment of patients with Alzheimer's disease. Placebo-controlled, randomised clinical trials have shown significant effects of these drugs on global function, cognition, activities of daily living (ADL) and behavioural symptoms in patients with this disorder. These trials have been conducted for up to 12 months and were followed by open-label extension studies. One placebo-controlled, randomised clinical trial followed patients for up to 4 years. Both retrospective and prospective follow-up studies suggest a treatment effect for ChEIs that lasts for up to 5 years. Studies have shown comparable effects for ChEIs in patients with moderate-to-severe Alzheimer's disease or mild Alzheimer's disease. Clinically relevant responses consist not only of improvement over 3-6 months but also stabilisation and possibly slower than expected decline. Lack of overt clinical improvement in one domain (e.g. global function, cognition, ADL or behaviour) does not preclude clinically relevant benefit(s) in other domains. If it is judged that the patient has experienced a treatment effect from ChEI therapy during the first 6 months, it is recommended that treatment be continued for at least 1 year before discontinuation is considered again. On average, patients will return to their pre-treatment status between 9 and 12 months of initiation of treatment. However, this return to pre-treatment level does not mean that the treatment effect has disappeared. At this point in time, the patient may still function better than he or she would have without treatment. Setting a fixed measurement, e.g. a Mini-Mental State Examination score, as a 'when to stop treatment limit' is not clinically rational. The length of treatment should depend on several individual patient factors. The earlier the diagnosis is made and the slower the rate of disease progression, the longer the treatment period will tend to be. Treatment duration must therefore be evaluated on an individual basis, and the patient's status compared with what would have been expected without treatment. If a clinical evaluation is conducted with a view to stopping or switching treatment, it is crucial that all domains are evaluated and that the patient is evaluated at more than one point in time before the decision is made.

Within the last few years, research into the cause and progression of Alzheimer's disease has made significant advances. Although there is still no preventative treatment or cure for this neurodegenerative illness, the development of drugs that may alleviate some of the cognitive symptoms associated with it is advancing. Cholinesterase inhibitors are at present the most effective form of treatment and have shown significant overall response rates in clinical trials. However, although some patients show substantial improvement when treated with this class of drugs, there is considerable variability in the amount of benefit gained in different individuals in terms of their cognitive and behavioural functioning. Furthermore, unfortunately some patients gain little or no benefit from these drugs. It would therefore be of great advantage to explore alternative therapeutic possibilities. This article reviews the potential involvement of the nicotinic cholinergic system in Alzheimer's disease and discusses the possibility of nicotinic pharmacotherapy. Substantial evidence indicates the involvement of the nicotinic cholinergic system in the pathology of Alzheimer's disease. Drugs targeting these sites may not only have a positive effect on cognitive function, but also have additional therapeutic benefits in terms of restoring the hypoactivity in the excitatory amino acid pyramidal system and even slowing the emergence of Alzheimer's disease pathology. The conclusion of this review is that nicotinic treatments are an important potential source of new therapeutic interventions in Alzheimer's disease.