Galantamine is US-Food and Drug Administration FDA-approved for mild-to-moderate Alzheimer’s disease. However, its unique pharmacological portfolio speaks to the idea of a pluripotent agent with a broad therapeutic potential. Here, authors briefly discuss these off-label clinical indications synthesizing the extant evidence.

Research into Gingko biloba extract EGb 761® has been ongoing for many years. Early studies showed that the extract was superior to placebo in improving symptoms of dementia, and this has been confirmed by more recent research. The GINDEM-NP, GOTADAY and GOT-IT! studies showed that 240 mg/day EGb 761® improved cognitive function, neuropsychiatric symptoms, activities of daily living, and quality of life in patients with mild to moderate dementia compared with placebo, with results reproducible in independent trials. The strength of the effect in terms of improvements in neurosensory symptoms associated with old age and dementia was strong enough to be detected by caregivers and independent clinicians. A combination of 240 mg/day EGb 761® and 10 mg/day (initially 5 mg/day) donepezil was also more effective than either drug alone. Regarding the improvement of neuropsychiatric symptoms, a cross-comparison of studies with different antidementia agents suggests that EGb 761® is at least as effective as memantine, galantamine, and donepezil. Safety data revealed no important safety concerns with EGb 761®.

Background: Cholinesterase inhibitors (ChEIs) represent the mainstay of symptomatic treatment in Alzheimer's disease. Three medications belonging to this class are presently widely available. These agents differ in their individual mechanisms of action and pharmacokinetic properties. Switching ChEIs can be a reasonable option in cases of intolerance or lack of clinical benefit.

Methods: A systematic literature search of switching ChEIs was conducted, and all studies specifically evaluating this issue were identified. Published consensus guidelines were also searched for recommendations on ChEI switching.

Results: Eight clinical studies are summarized and discussed. All of these studies are open-label or retrospective and they cannot be readily compared because of heterogeneity in design, number of patients, agents used, and endpoints. Switching in most of these studies was done for both “lack of benefit” or “loss of response” after up to 29 months of treatment. Nevertheless, the majority of studies did not include individuals switched for lack of response after several years of treatment. Lack of satisfactory response or intolerance with the initial agent was not predictive of similar results with the second agent.

Conclusions: In light of these findings, we propose the following practical approach to switching ChEIs: (1) in the case of intolerance, switching to a second agent should be done only after the complete resolution of side-effects following discontinuation of the initial agent; (2) in the case of lack of efficacy, switching can be done overnight, with a quicker titration scheme thereafter; (3) switching ChEIs is not recommended in individuals who show loss of benefit several years after initiation of treatment.

Background: This study sought to examine the trends in the prescribing of subsidized and unsubsidized cognition enhancing drugs (CEDs) in Australia over five years from 2002 to 2007. Subsidized cholinesterase inhibitor medication could be prescribed to people with mild to moderate Alzheimer's disease (AD) once a specialist physician had confirmed this diagnosis. Memantine was available for use in moderately severe AD but not subsidized.

Methods: We analyzed the Medicare Australia and Drug Utilisation Sub-Committee databases for CED prescription data, 2002–2007, by gender, age and prescriber class. Aggregated prescription data for each medication were converted to defined daily doses (DDD) per 1000 persons per day using national census data.

Results: There were 1,583,667 CED prescriptions dispensed during the study period. CED use increased 58% from 0.91 to 1.56 DDD/1000 persons/day between 2002 and 2007. Peak use was in those aged 85–89 years. Age-adjusted utilization was slightly higher in females than males. Donepezil was the most widely used CED (66%), followed by galantamine (27%) then memantine (4%). General practitioners prescribed the majority of CEDs. Geriatricians exhibited a greater preference for galantamine than other prescribers. CED dispensing peaked towards the end of each calendar year, reflecting stockpiling by patients under the influence of a federal safety net subsidy.

Conclusions: Despite subsidized access to CEDs in Australia, only a minority of people with AD was prescribed these drugs during the period of the study. It is likely that the combination of complex prescribing rules and negative perceptions about efficacy or cost-effectiveness might have contributed to these findings.

Background: Insulin resistance (IR) may play a role in most pathogenic processes that promote the development of late onset Alzheimer's disease (LOAD). This study was designed to evaluate whether galantamine influenced peripheral IR in LOAD.

Methods: Ninety-five consecutive elderly patients, 40 LOAD and 55 non-demented patients were evaluated. IR was calculated with HOMA and modified-HOMA. All the patients were evaluated through comprehensive geriatric assessments at baseline and at 6, 12 and 18 months.

Results: Over three 6-month periods of galantamine treatment, compared to the baseline values, there was a significant increase at 6 and 12 months in the MMSE and at 6 months in the IADL scores (t = 3.25, p = 0.002 and t = 2.69, p = 0.011 for MMSE; t = 2.03, p = 0.049; for IADL, respectively). Although, there was an improvement in MMSE and IADL scores of galantamine-treated patients, there was no significant change in IR indexes and correlation between IR indexes and cognitive status in both groups during the treatment period.

Conclusions: This study showed no relation between cognitive improvement and IR by galantamine therapy in AD. In conclusion, peripheral IR and central nervous system IR may be different, and galantamine itself may show its effects without affecting the insulin-signaling pathway.

Acetylcholine (ACh) esterase inhibitors like galantamine and donepezil have been tested as adjunct treatment in schizophrenia. Although ACh esterase inhibition might confer some antipsychotic activity, the role of allosteric potentiation of nicotinic ACh receptors (nAChRs), which is an additional mechanism of galantamine, remains elusive. Therefore, the potential antipsychotic-like effects of galantamine and donepezil, respectively, alone, and in combination with the dopamine D2/3 receptor antagonist, raclopride, were tested in the conditioned avoidance response (CAR) test and extrapyramidal side-effect liability was assessed with the catalepsy test. Neither galantamine nor donepezil alone suppressed CAR selectively. Galantamine, but not donepezil, enhanced the raclopride-induced suppression of CAR, predicting augmentation of antipsychotic activity. In contrast to donepezil, galantamine did not increase catalepsy, alone or combined with raclopride. These data suggest that allosteric potentiation of nAChRs may mediate the antipsychotic-like effect of adjunctive galantamine and provide support for the development of α7 nAChR-selective allosteric potentiators for schizophrenia.

Background: Decreased initiation of activities is a common symptom in Alzheimer's disease (AD) and creates significant burden for carers, yet little is known about how patients, carers and treating physicians describe this problem.

Methods: This is a secondary, qualitative analysis of video-recorded, semi-structured and open-ended interviews with the 130 community-dwelling patients with mild-to-moderate AD from the Video-Imaging Synthesis of Treating Alzheimer's Disease (VISTA) study – a four-month, randomized, placebo-controlled trial of galantamine. Interviews were coded and organized using Atlas.ti. By applying a framework analysis approach, patient/carer descriptions of dementia-related decreased initiation of usual tasks and activities were categorized and summarized.

Results: Decreased initiation of instrumental activities of daily living (IADLs) and/or leisure and social activities was reported in 85/130 patients at baseline, 71 (84%) of whom specifically targeted increased initiation as a goal of treatment. The most common manifestations of decreased initiation were initiating only with prompting (55%), and no longer initiating but willing to engage in the activity (42%; note that these groups can overlap). Many patients were also described as having less interest (44%) or impaired performance (34%) in the activity in which decreased initiation was noted. Coping strategies were employed by 69/85 carers, most commonly verbal prompts to begin an activity.

Conclusion: Decreased initiation is a common and problematic symptom in people with mild-to-moderate Alzheimer's disease who seek treatment for dementia. Information offered voluntarily about interest in or ability to perform activities which are initiated less often gives additional data compared with routine questioning about initiation of function. This is a potentially rich area for the elucidation of disease and treatment effects.

Alzheimer's disease (AD) is characterized by deterioration in the ability to perform activities of daily living (ADL) in addition to loss of cognitive function and behavioral changes. This decline in day-to-day functioning is increasingly recognized as a source of considerable social, health, and economic costs. Inability to perform ADL results in growing caregiver burden and may lead to the eventual need for alternative care or nursing home placement. The measurement of ADL, which enables monitoring of the effectiveness of therapeutic interventions, can be performed using a number of inventories including the Progressive Deterioration Scale (PDS), the Disability Assessment for Dementia (DAD), and the Alzheimer Disease Cooperative Study ADL (ADCS/ADL) assessment scale. Clinical studies using these and other scales have indicated that cholinesterase (ChE) inhibitors offer an effective approach to treating the functional decline of AD. Donepezil, rivastigmine, and galantamine have been shown in some studies to prevent or slow decline in ADL over treatment periods of one to two years. For instance, in a 24-week study in subjects with moderate to severe AD, donepezil-treated patients remained stable compared with the placebo-treated patients. Rivastigmine has shown improvement or stabilization of PDS scores in patients with mild to moderate disease following 26 weeks of treatment and slowed deterioration in patients with more severe disease. Evidence to date suggests that these agents may not be equally effective at slowing or stabilizing loss in ADL over time and that these differences may reflect differences in pharmacology. In addition to inhibition of acetylcholinesterase (AChE), these compounds have other putative differences in mechanisms of action. Galantamine allosterically modulates the nicotinic receptor and may prevent the loss of ADL. Rivastigmine robustly inhibits butyrylcholinesterase in addition to AChE and therefore acts as a dual ChE inhibitor. Comparative studies evaluating the differential effects of these ChE inhibitors on ADL are awaited.

This review provides an overview of the three most widely used cholinesterase (ChE) inhibitors: donepezil, rivastigmine, and galantamine. Differences in pharmacologic profiles will be discussed, and consideration will be given to how such differences may relate to and influence the clinical efficacy and tolerability of the various agents. In addition to providing cognitive benefits in patients with Alzheimer's disease (AD), growing clinical evidence also suggests that ChE inhibitors can produce favorable and clinically relevant effects on neuropsychiatric/behavioral disturbances and activities of daily living. Furthermore, recent data indicate that these agents may be effective at all levels of disease severity and for all rates of disease progression. The clinical utility of ChE inhibitors in a wider spectrum of dementias which share a common cholinergic deficit, such as Lewy body dementia, Parkinson's disease dementia, and vascular dementia, is currently under investigation. Beyond symptomatic relief, data suggest that ChE inhibitors may also slow the underlying disease process. As clinical and research experience with these agents continues to accumulate, the differences in their effects will become more apparent and will help physicians tailor ChE inhibition treatment to the needs of the individual patient.

Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (ACh) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. Recent evidence suggests that both AChE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options.