Two-Year Treatment of Alzheimer’s Disease with Eptastigmine

Impairment of the central cholinergic system has a pivotal role in the cognitive decline observed in patients with Alzheimer’s disease (AD). One of the most prominent cholinergic deficits is the reduced number of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are important for memory and learning, enhancing nicotinic neurotransmission is a promising treatment strategy for AD. The two most common approaches to correcting these cholinergic deficits are to increase the synaptic availability of acetylcholine (ACh) by inhibiting acetylcholinesterase (AChE), or to mimic the effects of ACh (nicotinic agonists) by acting directly on nicotinic receptors. Clinical studies suggest that AChE inhibitors produce only short-term symptomatic improvement. Similarly, long-term use of nicotinic agonists may induce desensitization of nicotinic receptors, leading to tolerance and therefore limiting the duration of efficacy. Allosteric modulation of nAChR is a novel approach, which circumvents the development of tolerance. Allosteric modulators bind to a site on nAChR that is different to the binding site of the natural agonist, ACh. This allosteric interaction amplifies the actions of ACh at post- and presynaptic nAChR. In particular, presynaptic nAChR are capable of modulating the release of ACh and other neurotransmitters, such as glutamate, serotonin and GABA, which may contribute to symptoms of the illness. Allosteric modulation of nAChR could therefore produce significant therapeutic benefit in AD. One of the most potent of these allosteric modulators is galantamine. As well as modulating nAChR, galantamine inhib- its AChE. The extent to which the clinical benefits of galantamine are attributable specifically to its nicotinic effects is uncertain and requires further investigation. However, galantamine maintains patients’ level of cognitive and daily function for at least 1 year, which has not been reported for other AChE inhibitors. Galantamine’s modulatory effects on nAChR may influence transcriptional regulation, resulting in an increased synthesis of nAChR. This may account for galantamine’s sustained efficacy.

Section: Galantamine: Positive Allosteric Modulation Of Nachr Activitysupporting

confidence: 53%

Allosteric Modulation of Nicotinic Receptors as a Treatment Strategy for Alzheimer’s Disease

Maelicke

2000

“…As well as producing long-term benefits on ADL, continuous treatment with galantamine 24 mg/day appears to maintain patients' cognitive function for at least 12 months [24]. This sustained level of cognitive and functional benefit has not, to date, been reported with other cholinergic treatments [22,23].…”

Section: Galantamine Preserves Activities Of Daily Living For Atmentioning

confidence: 95%

“…Current data suggest that ADAS-cog scores of patients treated with acetylcholinesterase inhibitors fall below baseline before 12 months [22,23]. To assess the longterm effects of galantamine, a further study was undertaken [24].…”

Section: Galantamine: a Novel Treatment For Admentioning

confidence: 99%

Galantamine: Therapeutic Effects beyond Cognition

Blesa

2000

Decline in cognitive function, especially memory, is the core feature of Alzheimer’s disease (AD). However, other characteristic aspects of the disease are also important. These include patients’ activities of daily living (ADL), including quality of sleep, behavioural disturbances and the impact of the disease on the caregiver. Therefore, increasing attention is being paid to clinically meaningful outcome measures, such as the Disability Assessment for Dementia (DAD) scale, the Neuropsychiatric Inventory (NPI), caregiver time and the Pittsburgh Sleep Quality Index (PSQI). Galantamine is a new treatment for AD that combines modulation of nicotinic receptors with inhibition of acetylcholinesterase. The present review outlines the positive and sustained effects of this agent on patients’ behaviour and daily functioning as well as on caregiver time. In studies of up to 5 months’ duration, galantamine-treated patients had a significantly better outcome on ADL than placebo-treated patients, and after 12 months of treatment with galantamine, patients’ functional ability was preserved. Galantamine also significantly benefits behavioural disturbances in patients with AD. These functional and behavioural benefits are associated with a decrease in the burden on caregivers, as indicated by a reduction, relative to placebo, in the time spent supervising and assisting patients. These clinical benefits are not offset by disruption of patients’ sleep, as has been reported with other cholinergic treatments.

“…6). In other long-term studies, the AChE inhibitors donepezil and eptastigmine have failed to maintain cognitive function at baseline levels for 12 months [52,53].…”

Section: The Clinical Relevance Of the Beneficial Effects Of Galantammentioning

confidence: 99%

Galantamine: Additional Benefits to Patients with Alzheimer’s Disease

Lilienfeld¹,

Parys²

2000

Galantamine, a novel treatment for Alzheimer’s disease (AD), has a dual mechanism of action, combining allosteric modulation of nicotinic acetylcholine receptors with reversible, competitive inhibition of acetylcholinesterase. In the Phase III clinical trial programme, over 3,000 patients with mild-to-moderate AD were enrolled in one of five randomized, controlled, double-blind studies. Using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) to assess memory and other cognitive functions, galantamine was found to be significantly superior to placebo in all five studies at doses of 16, 24 and 32 mg/day. In all studies, galantamine-treated patients maintained their cognitive function, whereas the placebo-treated patients experienced a significant deterioration in ADAS-cog scores. The 32-mg/day dose was not associated with any additional cognitive benefit. Pooled data from two 6-month studies (n = 1,269), which were of identical design, show that the therapeutic benefits of galantamine are sustained for the duration of treatment. The treatment effect (galantamine-placebo difference on ADAS-cog) for the pooled data was approximately 4 points. Clinical benefit was seen in all levels of disease severity, with a 7-point advantage over placebo on ADAS-cog for patients with moderately severe disease. Galantamine was well tolerated, with most patients completing the 6-month studies. The long-term effects of galantamine have been evaluated in a 12-month study. Patients who completed one of the pivotal 6-month studies (n = 353) were entered into a 6-month open-label extension. Cognitive and daily function were maintained throughout the 12 months in patients who received galantamine 24 mg/day. This sustained level of benefit may reflect galantamine’s dual effect on the cholinergic system. Data from a 5-month, placebo-controlled study have also shown that galantamine produces significant benefits on behavioural symptoms. The persistence and range of therapeutic effects produced by galantamine suggest that it may provide additional benefits for patients with AD.