| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
|
||
|
||
| |
||
| |
|
|
|
||
Cholinesterase Inhibitors
Galantamine
Galantamine (previously Reminyl™ now Razadyne ER™), an alkaloid found in the bulbs of snowdrops and several Amaryllidaceae plants, is a novel treatment for AD because of a dual mechanism of action on the cholinergic system.15a.. It is the fourth acetylcholinesterase inhibitor approved by the US FDA as of March 2001, and has already secured approval in several European countries. It competitively and reversibly inhibits acetylcholinesterase as well as allosterically modulates presynaptic nicotinic acetylcholine receptors 15b. One of the most prominent cholinergic deficits in AD 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 AD15b..
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. 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 AD illness15b. Allosteric modulation of nAChR could therefore produce significant therapeutic benefit in AD.
|
Galantamine
Mechanisms of Action
|
||
 |
 |
|
For more information on pharmacology and pharmacokinetics, see https://www.razadyne.com/html/raz/pd_common.xml?article=prescribing.jsp
Two recent studies 15c, 15d speak to the benefits of galantamine in randomized, placebo-controlled trials evaluating different dosages of the compound in mild to moderate AD patients.
A 6-month (The Galantamine USA-1 Study Group)15c multicenter double-blind trial was undertaken in 636 patients with mild to moderate AD and patients were randomly assigned to placebo or galantamine and escalated to maintenance doses of 24 or 32 mg/d. Primary efficacy measures were the Alzheimer’s Disease Assessment Scale, Cognitive Subsection (ADAS-Cog)and the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). The Disability Assessment for Dementia (DAD) scale was a secondary efficacy variable. In this study, galantamine significantly improved cognitive function relative to placebo; the treatment effects were 3.9 points (lower dose) and 3.8 points (higher dose) on the ADAS-Cog scale at 6 months (p < 0.001 in both cases). In addition, both doses of galantamine produced a better outcome on CIBIC-plus than placebo (p < 0.05). At 12 months (open-label phase), mean ADAS-Cog and DAD scores had not significantly changed from baseline for patients who received galantamine 24mg/d throughout the 12 months. The most common adverse events were predominantly gastrointestinal, and decreased in frequency during long-term treatment.
| Galantamine Long-term Cognitive Function Over 12 Months |
 |
The Galantamine USA-10 Study Group 15d investigated the efficacy and tolerability of galantamine, using a slow dose escalation schedule of up to 8 weeks, in 978 patients with mild to moderate AD. Following a 4-week placebo run-in, patients were randomized to one of four treatment arms: placebo or galantamine escalated to final maintenance doses of 8, 16, or 24mg/day. Outcome measures included the ADAS-Cog, the CIBIC-plus, the AD Cooperative Study Activities of Daily Living inventory, and the Neuropsychiatric Inventory (NPI). After 5 months, the galantamine-placebo differences on ADAS-Cog were 3.3 points for the 16 mg/day group and 3.6 points for the 24 mg/day group (p < 0.001 versus placebo, both doses).
Compared with placebo, the galantamine 16- and 24-mg/day groups also had a significantly better outcome on CIBIC-plus, activities of daily living, and behavioral symptoms. The incidence of GI adverse events in the galantamine groups, was low and mild.
| Function Galantamine ADL's Over 5 Months VS Placebo |
 |
| Behavior Galantamine Results Over 5 Months vs Placebo |
 |
Recently,
galantamine's benefits were 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 are important quality of life (QOL) measures for caregivers
that often spend increasing amount of unpaid time taking care
of their loved ones as the disease progresses. These clinical
benefits also help delay institutionalization of AD patients,
thereby indirectly affecting cost of care associated with AD.
The two slides below demonstrate the results from a 6-month, placebo-controlled study of galantamine evaluating caregiver burden in AD.15e.
| Caregiver Burden:
Reduction of Supervising Time —Galantamine vs Placebo |
 |
| Caregiver Burden:
Reduction of Time Spent Assisting With ADL — Galantamine vs Placebo |
 |
