Galantamine

Galantamine (brand names Razadyne, Reminyl, and others) is used for the treatment of cognitive decline in mild to moderate Alzheimer's disease and various other memory impairments. It is an alkaloid that has been isolated from the bulbs and flowers of Galanthus caucasicus (Caucasian snowdrop), Galanthus woronowii (Voronov's snowdrop), and some other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata (red spider lily). It can also be produced synthetically. Galantamine (brand names Razadyne, Reminyl, and others) is used for the treatment of cognitive decline in mild to moderate Alzheimer's disease and various other memory impairments. It is an alkaloid that has been isolated from the bulbs and flowers of Galanthus caucasicus (Caucasian snowdrop), Galanthus woronowii (Voronov's snowdrop), and some other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata (red spider lily). It can also be produced synthetically. Studies of usage in modern medicine began in the Soviet Union in the 1950s. Galantamine was isolated for the first time from bulbs of Galanthus nivalis (common snowdrop) by the Bulgarian chemist D. Paskov and his team in 1956. The active ingredient was extracted, identified, and studied, in particular in relation to its acetylcholinesterase (AChE)-inhibiting properties. The first industrial process was developed in 1959. In Homer's Odyssey the god Hermes gives Odysseus an herb with 'a black root, but milklike flower' called 'moly', which Hermes claims will make Odysseus immune to the sorceress Circe's drugs. It is believed that moly is the snowdrop Galanthus nivalis, which is a source of galantamine. The descriptions of moly given by Greek physician and herbalist Dioscorides support moly's identity as Galanthus nivalis. It has been proposed that the drugs Circe used were an extract from Datura stramonium (also known as jimsonweed), which causes memory loss and delirium. This would give a basis for the snowdrop's use as an antidote, as Datura stramonium is anticholinergic, while galantamine is an acetylcholinesterase inhibitor. Galantamine is indicated for the treatment of mild to moderate vascular dementia and Alzheimer's. In the United States, it is approved by the Food and Drug Administration as safe and effective for the treatment of mild to moderate dementia. As with other cholinesterase inhibitors, galantamine may not be effective for treating mild cognitive impairment. Alzheimer's disease is characterized by the impairment of cholinergic function. One hypothesis is that this impairment contributes to the cognitive deficits caused by the disease. This hypothesis forms the basis for use of galantamine as a cholinergic enhancer in the treatment of Alzheimer's. Galantamine inhibits acetylcholinesterase, an enzyme which hydrolyzes acetylcholine. As a result of acetylcholinesterase inhibition, galantamine increases the availability of acetylcholine for synaptic transmission. Additionally, galantamine binds to the allosteric sites of nicotinic receptors, which causes a conformational change. This allosteric modulation increases the nicotinic receptor's response to acetylcholine. The activation of presynaptic nicotinic receptors increases the release of acetylcholine, further increasing the availability of acetylcholine. Galantamine's competitive inhibition of acetylcholinesterase and allosteric nicotinic modulation serves as a dual mechanism of action. To reduce the prevalence of negative side effects associated with galantamine, such as nausea and vomiting, a dose-escalation scheme may be used. The use of a dose-escalation scheme has been well accepted in countries where galantamine is used. A dose-escalation scheme for Alzheimer's treatment involves a recommended starting dosage of 4 mg galantamine tablets given twice a day (8 mg/day). After a minimum of 4 weeks, the dosage may then be increased to 8 mg given twice a day (16 mg/day). After a minimum of 4 weeks at 16 mg/day, the treatment may be increased to 12 mg given twice a day (24 mg/day). Dosage increases are based upon the assessment of clinical benefit as well as tolerability of the previous dosage. If treatment is interrupted for more than three days, the process is usually restarted, beginning at the starting dosage, and re-escalating to the current dose. The product is supplied in both a prescription form as well as an over the counter supplement in twice-a-day tablets, in once-a-day extended-release capsules, and in oral solution. Galantamine's side effect profile was similar to that of other cholinesterase inhibitors, with gastrointestinal symptoms being the most notable and most commonly observed. One study reports higher proportions of patients treated with galantamine experiencing nausea and vomiting as opposed to the placebo group. Another study using a dose-escalation treatment has found that incidences of nausea would decrease to baseline levels soon after each increase in administered dosage. In practice, some other cholinesterase inhibitors might be better tolerated; however, a careful and gradual titration over more than three months may lead to equivalent long-term tolerability. The U.S. Food and Drug Administration (FDA) and international health authorities have published an alert of galantamine based on data from two studies during the treatment for mild cognitive impairment (MCI); higher mortality rates were seen in drug-treated patients. On April 27, 2006, FDA approved labeling changes concerning all form of galantamine preparations (liquid, regular tablets, and extended release tablets) warning of the risk of bradycardia (slow resting heart rate), and sometimes atrioventricular block, especially in predisposed persons. At the same time, the risk of syncope (fainting) seems to be increased relative to placebo. 'In randomized controlled trials, bradycardia was reported more frequently in galantamine-treated patients than in placebo-treated patients, but was rarely severe and rarely led to treatment discontinuation' These side effects have not been reported in Alzheimer's Disease related studies.