Galantamine Reports


Galantamine Helps Moderate-Severe and
Severe Alzheimer’s Disease

In a new Russian study, galantamine was found to reconfirm the extension of its use for moderate-severe and severe stages of Alzheimer’s disease (see “Galantamine Keeps Neurons Alive” in the March 2009 issue).1 Twenty-five patients with Alzheimer’s disease (AD) received galantamine at the dosage level of 8 mg daily during the first month, and 16 mg daily for the second month. Then out of the 25, six patients received 24 mg per day for the 3rd month, and thereafter for the duration of the study, 26 weeks.

Galantamine was found to have a positive effect on cognitive functions and psychotic symptoms of dementia, especially delusions, aggression, irritability, apathy, and aberrant motor behavior, as well as eating and sleep disorders. There was also good news for caregivers. The benefits of galantamine in the reduction of the measured disorders eased their physical and mental burden significantly. Galantamine was well tolerated, allowing the researchers to recommend its use for treating severe stages of AD.

Galantamine Protects Against Nerve Gas

In a study conducted at the Neurobehavioral Toxicology Branch of the U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground in Maryland, galantamine has once again proved its mettle (see “Galantamine Is an Antidote to Lethal Nerve Agents” in the October 2006 issue).2 The ability of galantamine hydrobromide treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic changes was assessed in guinea pigs. VX is an extremely toxic nerve agent, the only application of which is chemical warfare. Declared a weapon of mass destruction by the United Nations in its Resolution 687, the production and stockpiling of VX was outlawed in 1993. Nevertheless, VX is the most well-known of the V-series of nerve agents and due to its physical properties is considered an area denial weapon—the idea of which is to prevent an adversary from occupying or traversing an area of land.

In the study, the guinea pigs were challenged with VX and then one minute later, animals were administered atropine sulfate and pyridine-2-aldoxime methochloride (2-PAM). Also, the guinea pigs were given various doses of galantamine (either 0, 1, 2, 4, 8 or 10 mg/kg of body weight) as a post-treatment immediately prior to ATR and 2-PAM.

Post-exposure galantamine therapy produced an increase in survival from lethal VX challenge. The results were dose-dependent with optimal clinical benefits observed at the 10 mg/kg dose. This led to 100% survival of VX-challenged guinea pigs.

Muscle physiology studies found that galantamine treatment, given after exposure, protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade (action potential), and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent.

In EEG studies, galantamine did not affect seizure onset for all doses tested. However, at the 10 mg/kg dose, galantamine decreased the duration of the seizure when administered as a post-treatment 1 minute after VX. Galantamine also reduced the high correlation associated between seizure activity and lethality after VX challenge. In summary, galantamine may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease.

Galantamine Reverses Loss of Maze Memory

Researchers have known that nitric oxide (NO) plays a role in the established processes of learning and memory. In a new study, the effects of L-NAME—a nonselective inhibitor of NO synthase, the enzyme responsible for creating NO—on the performance of mice in a Y-maze task was explored.3

L-NAME noticeably impaired spontaneous alternation behavior (the ability of the mice to know right from left in the maze). However, galantamine given at 0.5 mg/kg* significantly attenuated this L-NAME-induced impairment.


* The equivalent would be 3.5 mg for a 85 kg (187 lb) human.


To clarify the underlying basis for galantamine’s protective effects against L-NAME-induced impairment of maze behavior, the researchers tested the ability of mecamylamine, an antagonist of nicotinic ACh receptors, and scopolamine, an antagonist of muscarinic ACh receptors, to reduce galantamine’s protective effects.

They found that only mecamylamine had such an ability. Galantamine also reduced L-NAME-induced decreases in NO synthase levels. However, mecamylamine obliterated galantamine’s efficacy to counter the L-NAME-induced decrease in NO synthase levels. Thus, galantamine protects maze behavior from L-NAME-induced impairment, which may be mediated by NO activation via the nicotinic ACh receptor-related pathway. Indeed, galantamine has been found to stimulate nicotinic ACh receptor activity.

Can AChEIs Prevent Age-Related,
Cognitive-Related Falls?

The older you get, the more cognitive problems you are likely to develop, and those problems are linked with a higher risk of falls. The incidence is twice as great as the number of falls in older adults who are without cognitive problems. Falls in the elderly can be very serious and fallers with cognitive problems suffer more injuries due to falls. Furthermore, they are approximately five times more likely to be admitted to institutional care.

While the mechanisms of increased fall risk in cognitively impaired people are not completely understood, it is known that impaired cognitive abilities can reduce attentional resource allocation while walking. However, cognitive enhancers, such as acetylcholinesterase inhibitors (AChEIs)—including galantamine—improve attention and executive function. Would it not be valid to think that cognitive enhancers may reduce fall risk in elderly people in the early stages of cognitive decline by improving their gait and balance performance due to an enhancement in attention and executive function? Galantamine has already shown benefit for gait in patients with Alzheimer’s disease4 and in patients with Parkinson’s disease, along with decreases in freezing of gaits and falls.5

Researchers designed a double blinded randomized controlled trial with 6 months follow-up in 140 older individuals with mild cognitive impairment (MCI) to test the hypothesis that AChEIs, such as galantamine, might be able to reduce the risk of serious falls.6 The outcomes targeted for investigation are improvements in gait velocity and reduction in gait variability. Also to be measured are changes in the balance confidence, balance sway, attention, executive function, and the number of falls. If the study succeeds in its goals, it will pave an important path for a new approach to fall prevention in the elderly, independent of disease, through AChEI use.

References

  1. Gavrilova SI, Kolykhalov IV, Kalyn IB, Selezneva ND. [Galantamine (reminyl) in the treatment of severe Alzheimer's disease.] Zh Nevrol Psikhiatr Im S S Korsakova 2009;109(7):57-61.
  2. Hilmas CJ, Poole MJ, Finneran K, Clark MG, Williams PT.Galantamine is a novel post-exposure therapeutic against lethal VX challenge. Toxicol Appl Pharmacol. 2009 Jul 30. [Epub ahead of print]
  3. Tanaka K, Yagi T, Shimakoshi R, Azuma K, Nanba T, Ogo H, Tamura A, Asanuma M. Effects of galantamine on L-NAME-induced behavioral impairment in Y-maze task in mice. Neurosci Lett 2009 Oct 25;462(3):235-8. Epub 2009 Jul 15.
  4. Assal F, Allali G, Kressig RW, Herrmann FR, Beauchet O. Galantamine improves gait performance in patients with Alzheimer’s disease. J Am Geriatr Soc 2008 May;56(5):946-7.
  5. Litvinenko IV, Odinak MM, Mogil'naya VI, Emelin AY. Efficacy and safety of galantamine (reminyl) for dementia in patients with Parkinson’s disease (an open controlled trial). Neurosci Behav Physiol 2008 Nov;38(9):937-45.
  6. Montero-Odasso M, Wells JL, Borrie MJ, Speechley M. Can cognitive enhancers reduce the risk of falls in older people with Mild Cognitive Impairment? A protocol for a randomised controlled double blind trial. BMC Neurol 2009 Aug 12;9(1):42.

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