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Galantamine

 

Galantamine

Galantamine
Systematic (IUPAC) name
(4aS,6R,8aS)- 5,6,9,10,11,12- hexahydro- 3-methoxy- 11-methyl- 4aH- [1]benzofuro[3a,3,2-ef] [2] benzazepin- 6-ol
Clinical data
Trade names Razadyne
AHFS/Drugs.com
MedlinePlus
Pregnancy
category
  • B
Legal status
  • (Prescription only)
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 80 to 100%
Protein binding 18%
Metabolism Hepatic partially CYP450:CYP2D6/3A4 substrate
Biological half-life 7 hours
Excretion Renal (95%, of which 32% unchanged), fecal (5%)
Identifiers
CAS Registry Number  Y
ATC code N06
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
PDB ligand ID GNT (, )
Chemical data
Formula C17H21NO3
Molecular mass 287.354 g/mol
Physical data
Melting point 126.5 °C (259.7 °F)
 Y   

Galantamine (Nivalin, Razadyne, Razadyne ER, Reminyl, Lycoremine) is used for the treatment of mild to moderate Alzheimer's disease and various other memory impairments, in particular those of vascular origin. It is an alkaloid that is obtained synthetically or from the bulbs and flowers of Galanthus caucasicus (Caucasian snowdrop, Voronov's snowdrop), Galanthus woronowii (Amaryllidaceae) and related genera like Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata (Red Spider Lily).[1]

Studies of usage in modern medicine began in the Soviet Union in the 1950s. The active ingredient was extracted, identified, and studied, in particular in relation to its acetylcholinesterase (AChE)-inhibiting properties. The bulk of the work was carried out by Soviet pharmacologists M. D. Mashkovsky and R. P. Kruglikova–Lvova, beginning in 1951.[2] The work of Mashkovsky and Kruglikova-Lvova was the first published work that demonstrated the AChE-inhibiting properties of galantamine.[3]

The first industrial process was developed in Bulgaria by prof. Paskov in 1959 (Nivalin, Sopharma) from a species traditionally used as a popular medicine in Eastern Europe, and, thus, the idea for developing a medicine from these species seems to be based on the local use (i.e., an ethnobotany-driven drug discovery).[4][5]

Galantamine has been used for decades in Eastern Europe and Russia for various indications such as treatment of myasthenia, myopathy, and sensory and motor dysfunction associated with disorders of the central nervous system. In the US, it is FDA approved for the treatment of Alzheimer's disease.

It is available in both a prescription form and as an over the counter supplement.

Contents

  • Pharmacology 1
  • Pharmacokinetics 2
  • Metabolism 3
  • Clinical use 4
    • Indications 4.1
    • Available forms 4.2
    • Adverse events 4.3
  • Other uses 5
    • Supplement for lucid dream 5.1
    • Sleep aid 5.2
    • Nootropic 5.3
    • Augmentative therapy in autistic children 5.4
  • Caution 6
  • Total synthesis 7
  • References 8
  • External links 9

Pharmacology

Galantamine is a potent allosteric potentiating ligand of human nicotinic acetylcholine receptors (nAChRs) α4β2, α7/5-HT3, α3β4, and α6β4 in certain areas of the brain, as well as a weak competitive and reversible cholinesterase inhibitor in all areas of the body.[6] It increases the concentration and thereby action of acetylcholine in certain parts of the brain. It has shown activity in modulating the nicotinic cholinergic receptors on cholinergic neurons to increase acetylcholine release.[7] It is hypothesized that this action might relieve some of the symptoms of Alzheimer's.

Galantamine in its pure form is a white powder. The atomic resolution 3D structure of the complex of galantamine and its target, acetylcholinesterase, was determined by X-ray crystallography in 1999 (PDB code: 1DX6; see complex).[8] There is no evidence that galantamine alters the course of the underlying dementing process.[9]

Pharmacokinetics

Absorption of galantamine is rapid and complete and shows linear pharmacokinetics. It is well absorbed with absolute oral bioavailability between 80 and 100%. It has a half-life of seven hours. Peak effect of inhibiting acetylcholinesterase was achieved about one hour after a single oral dose of 8 mg in some healthy volunteers.

Plasma protein binding of galantamine is about 18%, which is relatively low.

Metabolism

Approximately 75% of a dose of galantamine is metabolised in the liver. In vitro studies have shown that Hepatic CYP2D6 and CYP3A4 are involved in galantamine metabolism.

For Razadyne ER (the once-a-day formulation), CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers. About 7% of the population has this genetic mutation; however, because the drug is individually titrated to tolerability, no specific dosage adjustment is necessary for this population.

Clinical use

Indications

Galantamine is indicated for the treatment of mild to moderate vascular dementia and Alzheimer's.[10][11]

Available forms

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. The tablets come in 4 mg, 8 mg, and 12 mg forms. The capsules come in 8 mg, 16 mg, and 24 mg forms.

Adverse events

In clinical trials, galantamine's side effect profile was very similar to that of other cholinesterase inhibitors, with gastrointestinal symptoms being the most notable and most commonly observed. 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.[12]

Other uses

Supplement for lucid dream

Galantamine is an oneirogen. Some people who practice lucid dream (LD) use galantamine to increase their odds to achieve LD.[13][14][15] By taking small amount of galantamine (around 4 to 8 mg) after five to six hours of deep sleep and practice an induction technique such as meditation, MILD, or WILD many people report more success with galantamine.[16]

There are also reports claiming that taking galantamine without proper induction technique will not lead to LD but will result in only a vivid dream instead. Due to a long half-life, galantamine will stay in the body for a period of up to and over 48 hours. As such, it is advisable to space out the use of galantamine over a period of three days so that the body does not build a resistance to the drug, ruining its effectiveness.[13]

Sleep aid

Galantamine has been anecdotally described both to help people fall asleep and to increase the quality of sleep. Extensive research and sleep studies have not been conducted, but initial research suggests that Galantamine does have properties that can aid patients suffering from insomnia.

Nootropic

Along with other cholinergics or acetylcholinesterase inhibitors such as huperzine A, galantamine also has been used as nootropic or "brain enhancer" to enhance memory in brain-damaged adults.[17]

Augmentative therapy in autistic children

Galantamine given in addition to risperidone to autistic children has been shown to improve some of the symptoms of autism (irritability, lethargy, and social withdrawal).[18]

Caution

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.[19][20] 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"[21] These side effects have not been reported in Alzheimer's Disease related studies.[22]

Total synthesis

Galantamine is produced from natural resources and a patented total synthesis process. Many other synthetic methods exist but have not been implemented on an industrial scale.

References

  1. ^ NNFCC Project Factsheet: Sustainable Production of the Natural Product Galanthamine (Defra), NF0612
  2. ^ Heinrich, M. (2004). "Snowdrops: The heralds of spring and a modern drug for Alzheimer's disease". Pharmaceutical Journal 273 (7330): 905–6.  
  3. ^ Mashkovsky, MD; Kruglikova–Lvova, RP (1951). "On the pharmacology of the new alkaloid galantamine". Farmakologia Toxicologia 14: 27–30. 
  4. ^ Heinrich, M.; Teoh, H.L. (2004). "Galanthamine from snowdrop – the development of a modern drug against Alzheimer's disease from local Caucasian knowledge". Journal of Ethnopharmacology 92 (2–3): 147–162.  
  5. ^ Scott, LJ; Goa, KL (2000). "Galantamine: a review of its use in Alzheimer's disease". Drugs 60 (5): 1095–122.  
  6. ^ Samochocki, Marek; Höffle, Anja; Fehrenbacher, Andreas; Jostock, Ruth; Ludwig, Jürgen; Christner, Claudia; Radina, Martin; Zerlin, Marion; Ullmer, Christoph; Pereira, Edna F. R.; Lübbert, Hermann; Albuquerque, Edson X.; Maelicke, Alfred (2003). "Galantamine Is an Allosterically Potentiating Ligand of Neuronal Nicotinic but Not of Muscarinic Acetylcholine Receptors". Journal of Pharmacology and Experimental Therapeutics 305 (3): 1024–36.  
  7. ^ Woodruff-Pak, Diana S.; Vogel, Richard W.; Wenk, Gary L. (2001). "Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning". Proceedings of the National Academy of Sciences 98 (4): 2089–94.  
  8. ^ Greenblatt, H.M.; Kryger, G.; Lewis, T.; Silman, I.; Sussman, J.L. (1999). "Structure of acetylcholinesterase complexed with (−)-galanthamine at 2.3 Å resolution". FEBS Letters 463 (3): 321–6.  
  9. ^ Ortho-McNeil Neurologics, "Razadyne ER US Product Insert", May 2006
  10. ^ Galantamine Benefits Both Alzheimer's Disease and Vascular Dementia
  11. ^ Galantamine Improves Attention in Alzheimer's
  12. ^ Birks, J; Birks, Jacqueline (2006). Birks, Jacqueline, ed. "Cholinesterase inhibitors for Alzheimer's disease". Cochrane database of systematic reviews (Online) (1): CD005593.  
  13. ^ a b Thomas Yuschak (2006). Advanced Lucid Dreaming (1st ed.). Lulu Enterprises.  
  14. ^ Thomas Yuschak (2007). Pharmacological Induction of Lucid dreams (PDF). 
  15. ^ "Substances that enhance recall and lucidity during dreaming". Stephen LaBerge - US Patent. Retrieved 2007-10-29. 
  16. ^ "Galantamine LDS Profile". Yuschak LDS Profiles. Retrieved 2007-10-29. 
  17. ^ Galantamine Protects Neurons and Memory Following Brain Injury
  18. ^ Ghaleiha, A; Ghyasvand, M; Mohammadi, M. R.; Farokhnia, M; Yadegari, N; Tabrizi, M; Hajiaghaee, R; Yekehtaz, H; Akhondzadeh, S (2013). "Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial". Journal of Psychopharmacology 28 (7): 677–685.  
  19. ^ "FDA ALERT: Galantamine hydrobromide (marketed as Razadyne, formerly Reminyl) - Healthcare Professional Sheet" (PDF). Postmarket Drug Safety Information for Patients and Providers.  
  20. ^ "Safety Alerts for Human Medical Products > Reminyl (galantamine hydrobromide)". # MedWatch The FDA Safety Information and Adverse Event Reporting Program.  
  21. ^ "Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)". MedWatch, The FDA Safety Information and Adverse Event Reporting Program.  
  22. ^ "Safety information from Investigational Studies with REMINYL (galantamine hydrobromide) in Mild Cognitive Impairment". Janssen-Ortho Inc. 2005-04-22. Retrieved 29 August 2012. 

External links

  • Razadyne ER (manufacturer's website)
  • Proteopedia 1dx6
  • AChE inhibitors and substrates (Part II)
  • Acetylcholinesterase: A gorge-ous enzyme PDB Structure article at PDBe
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