| Revision as of 15:04, 17 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456671290 of page Galantamine for the Chem/Drugbox validation project (updated: 'DrugBank'). |
Latest revision as of 22:31, 22 November 2024 edit Jakespeedorg (talk | contribs)8 editsm Linking ketoconazole to its own article on Misplaced Pages |
| Line 1: |
Line 1: |
|
|
{{Short description|Neurological medication}} |
|
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
|
|
|
{{Use mdy dates|date=August 2024}} |
|
{{Drugbox |
|
|
|
{{cs1 config|name-list-style=vanc|display-authors=6}} |
|
| verifiedrevid = 443831212 |
|
|
|
{{Infobox drug |
|
| IUPAC_name = (4a''S'',6''R'',8a''S'')- 5,6,9,10,11,12- hexahydro- 3-methoxy- 11-methyl- 4a''H''- benzofuro benzazepin- 6-ol |
|
|
|
| Watchedfields = changed |
|
| image = Galantamine.svg |
|
|
|
| verifiedrevid = 461118063 |
|
| width = 175 |
|
|
|
| image = Galantamine.svg |
|
|
| alt = |
|
|
| image2 = File:Galantamine 3D.png |
|
|
| alt2 = |
|
|
|
|
|
<!--Clinical data--> |
|
<!--Clinical data--> |
|
| tradename = Razadyne |
|
| tradename = Razadyne, others |
|
| Drugs.com = {{drugs.com|monograph|razadyne}} |
|
| Drugs.com = {{drugs.com|monograph|galantamine-hydrobromide}} |
|
| MedlinePlus = a699058 |
|
| MedlinePlus = a699058 |
|
|
| DailyMedID = Razadyne |
|
| pregnancy_category = B |
|
|
|
| pregnancy_AU = B1 |
|
| legal_status = Rx |
|
|
|
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Galantamine Use During Pregnancy | website=Drugs.com | date=February 18, 2019 | url=https://www.drugs.com/pregnancy/galantamine.html | access-date=February 24, 2020 | archive-date=February 25, 2020 | archive-url=https://web.archive.org/web/20200225040154/https://www.drugs.com/pregnancy/galantamine.html | url-status=live }}</ref> |
|
| routes_of_administration = Oral |
|
|
|
| pregnancy_category = |
|
|
| routes_of_administration = ] |
|
|
| ATC_prefix = N06 |
|
|
| ATC_suffix = DA04 |
|
|
|
|
|
<!-- Legal status --> |
|
|
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
|
|
| legal_BR = C1 |
|
|
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=March 31, 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=August 3, 2023 |access-date=August 16, 2023 |publisher=] |language=pt-BR |publication-date=April 4, 2023}}</ref> |
|
|
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
|
|
| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
|
|
| legal_NZ = <!-- Class A, B, C --> |
|
|
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
|
|
| legal_US = Rx-only |
|
|
| legal_US_comment = <ref name="Razadyne FDA label">{{cite web | title=Razadyne- galantamine hydrobromide tablet, film coated | website=DailyMed | date=November 11, 2010 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e62efb5a-d2cc-4e11-9e61-10e65ef3d897 | access-date=August 5, 2024 | archive-date=April 26, 2023 | archive-url=https://web.archive.org/web/20230426034728/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e62efb5a-d2cc-4e11-9e61-10e65ef3d897 | url-status=live }}</ref> |
|
|
| legal_EU = Rx-only |
|
|
| legal_EU_comment = <ref>{{cite web | title = Active substance: galantamine | work = List of nationally authorised medicinal products, Human Medicines Evaluation Division | publisher = European Medicines Agency | date = November 12, 2020 | url = https://www.ema.europa.eu/documents/psusa/galantamine-list-nationally-authorised-medicinal-products-psusa/00001512/202003_en.pdf | access-date = December 19, 2020 | archive-date = October 31, 2021 | archive-url = https://web.archive.org/web/20211031194913/https://www.ema.europa.eu/en/documents/psusa/galantamine-list-nationally-authorised-medicinal-products-psusa/00001512/202003_en.pdf | url-status = live }}</ref> |
|
|
| legal_status = Rx-only |
|
|
|
|
|
<!--Pharmacokinetic data--> |
|
<!--Pharmacokinetic data--> |
|
| bioavailability = 80 to 100% |
|
| bioavailability = 80–100% |
|
| protein_bound = 18% |
|
| protein_bound = 18% |
|
| metabolism = ] partially ]:]/] substrate |
|
| metabolism = ] partially ]:]/] substrate |
|
| elimination_half-life = 7 hours |
|
| elimination_half-life = 7 hours |
|
| excretion = ] (95%, of which 32% unchanged), fecal (5%) |
|
| excretion = ] (95%, of which 32% unchanged), fecal (5%) |
|
|
|
|
|
<!--Identifiers--> |
|
<!--Identifiers--> |
|
|
| IUPHAR_ligand = 6693 |
|
| CASNo_Ref = {{cascite|correct|CAS}} |
|
|
| CAS_number_Ref = {{cascite|correct|??}} |
|
| CAS_number_Ref = {{cascite|correct|??}} |
|
| CAS_number = 357-70-0 |
|
| CAS_number = 357-70-0 |
|
|
| PubChem = 9651 |
|
| ATC_prefix = N06 |
|
|
|
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
|
| ATC_suffix = DA04 |
|
|
|
| DrugBank = DB00674 |
|
| PubChem = 9651 |
|
|
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
|
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
|
|
| ChemSpiderID = 9272 |
|
| DrugBank = DB00674 |
|
|
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
|
| UNII_Ref = {{fdacite|correct|FDA}} |
|
|
| UNII = 0D3Q044KCA |
|
| ChemSpiderID = 9272 |
|
|
| UNII_Ref = {{fdacite|correct|FDA}} |
|
| KEGG_Ref = {{keggcite|correct|kegg}} |
|
|
| KEGG = D04292 |
|
| UNII = 0D3Q044KCA |
|
|
| KEGG_Ref = {{keggcite|correct|kegg}} |
|
| ChEBI_Ref = {{ebicite|correct|EBI}} |
|
|
| ChEBI = 42944 |
|
| KEGG = D04292 |
|
|
| ChEBI_Ref = {{ebicite|correct|EBI}} |
|
| ChEMBL_Ref = {{ebicite|correct|EBI}} |
|
|
| ChEMBL = 659 |
|
| ChEBI = 42944 |
|
|
|
| PDB_ligand = GNT |
|
| ChEMBL_Ref = {{ebicite|correct|EBI}} |
|
|
| ChEMBL = 659 |
|
|
|
|
|
|
<!--Chemical data--> |
|
<!--Chemical data--> |
|
|
| IUPAC_name = (4a''S'',6''R'',8a''S'')-5,6,9,10,11,12-Hexahydro-3-methoxy-11-methyl-4a''H''-benzofuro benzazepin-6-ol |
|
| C=17 | H=21 | N=1 | O=3 |
|
|
|
| C = 17 |
|
| molecular_weight = 287.354 g/mol |
|
|
|
| H = 21 |
|
| smiles = O(c2c1O4C(O)/C=C\43c1c(cc2)CN(C)CC3)C |
|
|
|
| N = 1 |
|
| InChI = 1/C17H21NO3/c1-18-8-7-17-6-5-12(19)9-14(17)21-16-13(20-2)4-3-11(10-18)15(16)17/h3-6,12,14,19H,7-10H2,1-2H3/t12-,14-,17-/m0/s1 |
|
|
|
| O = 3 |
|
| InChIKey = ASUTZQLVASHGKV-JDFRZJQEBY |
|
|
|
| smiles = O(c2c1O4C(O)/C=C\43c1c(cc2)CN(C)CC3)C |
|
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
|
|
|
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
|
| StdInChI = 1S/C17H21NO3/c1-18-8-7-17-6-5-12(19)9-14(17)21-16-13(20-2)4-3-11(10-18)15(16)17/h3-6,12,14,19H,7-10H2,1-2H3/t12-,14-,17-/m0/s1 |
|
|
|
| StdInChI = 1S/C17H21NO3/c1-18-8-7-17-6-5-12(19)9-14(17)21-16-13(20-2)4-3-11(10-18)15(16)17/h3-6,12,14,19H,7-10H2,1-2H3/t12-,14-,17-/m0/s1 |
|
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
|
|
|
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
|
| StdInChIKey = ASUTZQLVASHGKV-JDFRZJQESA-N |
|
|
|
| StdInChIKey = ASUTZQLVASHGKV-JDFRZJQESA-N |
|
| melting_point = 126.5 |
|
|
|
| melting_point = 126.5 |
|
}} |
|
}} |
|
|
|
|
|
'''Galantamine''' is a type of ]. It is an ] ]ed from the bulbs and flowers of '']'' (common snowdrop), ''Galanthus caucasicus'' (Caucasian ]), '']'' (Voronov's snowdrop), and other members of the family '']'', such as ''Narcissus'' (]), '']'' (snowflake), and ''Lycoris'' including '']'' (red spider lily).<ref>{{cite web | vauthors = Theodorou M | url = http://www.nnfcc.co.uk/publications/nnfcc-project-factsheet-sustainable-production-of-the-natural-product-galanthamine-defra-nf0612 | archive-url = https://web.archive.org/web/20120314175551/http://www.nnfcc.co.uk/publications/nnfcc-project-factsheet-sustainable-production-of-the-natural-product-galanthamine-defra-nf0612 | archive-date = March 14, 2012 | work = NNFCC Project Factsheet | publisher = The National Non-Food Crops Centre (NNFCC) | title = Sustainable Production of the Natural Product Galanthamine (Defra), NF0612 }}</ref> It can also be ]. |
|
|
|
|
|
Galantamine is primarily known for its potential to slow ]. It is used clinically for treating early-stage ] and ] impairments, although it has had limited success with the more advanced condition of ].<ref name="drugs">{{cite web|title=Galantamine|url=https://www.drugs.com/mtm/galantamine.html|publisher=Drugs.com|date=August 8, 2023|access-date=March 26, 2024|archive-date=October 14, 2018|archive-url=https://web.archive.org/web/20181014091614/https://www.drugs.com/mtm/galantamine.html|url-status=live}}</ref><ref name="birks">{{cite journal | vauthors = Birks J | title = Cholinesterase inhibitors for Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD005593 | date = January 2006 | volume = 2016 | pmid = 16437532 | doi = 10.1002/14651858.CD005593 | pmc = 9006343 | veditors = Birks JS }}</ref><ref name=kalola/><ref name="battle">{{cite journal |vauthors=Battle CE, Abdul-Rahim AH, Shenkin SD, Hewitt J, Quinn TJ |title=Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis |journal=The Cochrane Database of Systematic Reviews |volume=2021 |issue=2 |pages=CD013306 |date=February 2021 |pmid=33704781 |pmc=8407366 |doi=10.1002/14651858.CD013306.pub2}}</ref> |
|
|
|
|
|
It works by increasing the amount of a type of ] named ] by the inhibiting activity of an enzyme called ] known for ] acetylcholine. This elevates and prolongs acetylcholine levels boosting acetylcholine's ] functionality, subsequently enhancing functionality of the various ] that acetylcholine is involved in, such as memory processing, ], and ].<ref name=drugs/> Galantamine may cause serious ]s, such as stomach bleeding, liver injury or chest pain.<ref name=drugs/><ref name="kalola">{{cite web|vauthors=Kalola UK, Nguyen H|title=Galantamine|date=March 12, 2023|publisher=StatPearls Publishing, US National Library of Medicine|pmid=34662060 |url=https://www.ncbi.nlm.nih.gov/books/NBK574546/|accessdate=March 26, 2024|archive-date=December 26, 2023|archive-url=https://web.archive.org/web/20231226163656/https://www.ncbi.nlm.nih.gov/books/NBK574546/|url-status=live}}</ref> |
|
|
|
|
|
Galantamine was isolated for the first time from bulbs of '']'' (common snowdrop) in the Soviet Union in the 1940s.<ref>Proskurnina NF, Areshknina LY. J. Chim. Gen. USSR. Chem. Abst. 1947;1948;1742(1595h):1216. No title available.</ref> The active ingredient was extracted, identified, and studied, in particular in relation to ] (AChE)-inhibiting properties.<ref>{{cite journal | title=Snowdrops: The heralds of spring and a modern drug for Alzheimer's disease | vauthors=Heinrich M | journal=Pharmaceutical Journal | year=2004 | volume=273 | issue=7330 | pages=905–6 | oclc=98892008 | url=http://www.pharmaceutical-journal.com/pj-online-christmas-2004-snowdrops-the-heralds-of-spring-and-a-modern-drug-for-alzheimer8217s-disease/20013614.article | access-date=July 30, 2015 | archive-date=October 23, 2018 | archive-url=https://web.archive.org/web/20181023160656/https://www.pharmaceutical-journal.com/pj-online-christmas-2004-snowdrops-the-heralds-of-spring-and-a-modern-drug-for-alzheimer8217s-disease/20013614.article | url-status=dead }}</ref><ref>{{cite journal | title=On the pharmacology of the new alkaloid galantamine | vauthors = Mashkovsky MD, Kruglikova-Lvova RP | journal=Farmakologia Toxicologia | year=1951 | volume=14 | pages=27–30 }}</ref> The first industrial process was developed in 1959.<ref>{{cite journal | vauthors = Heinrich M, Lee Teoh H | title = Galanthamine from snowdrop--the development of a modern drug against Alzheimer's disease from local Caucasian knowledge | journal = Journal of Ethnopharmacology | volume = 92 | issue = 2–3 | pages = 147–162 | date = June 2004 | pmid = 15137996 | doi = 10.1016/j.jep.2004.02.012 }}</ref><ref>{{cite journal | vauthors = Scott LJ, Goa KL | title = Galantamine: a review of its use in Alzheimer's disease | journal = Drugs | volume = 60 | issue = 5 | pages = 1095–1122 | date = November 2000 | pmid = 11129124 | doi = 10.2165/00003495-200060050-00008 | s2cid = 250305879 }}</ref> However, it was not until the 1990s when full-scale synthesis was upscaled and optimized.<ref>{{Cite web|url=https://www.alzforum.org/therapeutics/galantamine|title=Galantamine|website=alzforum|access-date=November 17, 2019|archive-date=November 17, 2019|archive-url=https://web.archive.org/web/20191117153220/https://www.alzforum.org/therapeutics/galantamine|url-status=live}}</ref> |
|
|
|
|
|
== Medical uses == |
|
|
Galantamine, sold under the brand name '''Razadyne''' among others, is ] for the treatment of mild to moderate ] and Alzheimer's disease.<ref name=drugs/><ref name=birks/> The first person to extract galantamine and theorize its usefulness in medicine, was the Bulgarian chemist ] in 1959. In the United States, it is approved by the ] (FDA) for the treatment of mild to moderate dementia.<ref name=kalola/><ref>{{cite web|title=Galantamine hydrobromide (trademark)|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021615lbl.pdf|publisher=US Food and Drug Administration|access-date=December 17, 2017|date=2004|archive-date=July 13, 2020|archive-url=https://web.archive.org/web/20200713225426/https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021615lbl.pdf|url-status=live}}</ref> Galantamine may not be effective for treating mild cognitive impairment.<ref>{{cite journal | vauthors = Tricco AC, Soobiah C, Berliner S, Ho JM, Ng CH, Ashoor HM, Chen MH, Hemmelgarn B, Straus SE | title = Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis | journal = CMAJ | volume = 185 | issue = 16 | pages = 1393–401 | date = November 2013 | pmid = 24043661 | pmc = 3826344 | doi = 10.1503/cmaj.130451 }}</ref> |
|
|
|
|
|
===Alzheimer's disease=== |
|
|
Alzheimer's disease is characterized by the impairment of ] function.<ref name=drugs/><ref name=kalola/> 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.<ref name=drugs/><ref name=kalola/> Galantamine inhibits acetylcholinesterase, an enzyme which ] acetylcholine.<ref name=drugs/><ref name=kalola/> As a result of acetylcholinesterase inhibition, galantamine increases the availability of acetylcholine for synaptic transmission.<ref name=kalola/> Additionally, galantamine binds to the ] sites of ] receptors, which causes a conformational change.<ref name="springer">{{cite journal | vauthors = Farlow MR | title = Clinical pharmacokinetics of galantamine | journal = Clinical Pharmacokinetics | volume = 42 | issue = 15 | pages = 1383–92 | year = 2003 | pmid = 14674789 | doi = 10.2165/00003088-200342150-00005 | s2cid = 36855768 }}</ref> This allosteric modulation increases the nicotinic receptor's response to acetylcholine.<ref name=kalola/> The activation of presynaptic nicotinic receptors increases the release of acetylcholine, further increasing the availability of acetylcholine.<ref name=kalola /> Galantamine's competitive inhibition of acetylcholinesterase and allosteric nicotinic modulation serves as a dual mechanism of action.<ref name="springer" /> |
|
|
|
|
|
To reduce the prevalence of negative side effects associated with galantamine, such as ] and ], a dose-escalation scheme may be used.<ref name="direct">{{cite journal | vauthors = Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV | title = Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial | journal = Lancet | volume = 359 | issue = 9314 | pages = 1283–90 | date = April 2002 | pmid = 11965273 | doi = 10.1016/S0140-6736(02)08267-3 | s2cid = 1172847 }}</ref> The use of a dose-escalation scheme has been well accepted in countries where galantamine is used.<ref name="direct" /> 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).<ref name=drugs/> After a minimum of 4 weeks, the dosage may then be increased to 8 mg given twice a day (16 mg/day).<ref name="drugs" /> 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).<ref name="drugs" /> Dosage increases are based upon the assessment of clinical benefit as well as tolerability of the previous dosage.<ref name="drugs" /> 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.<ref name="drugs" /> It has been found that a dosage between 16–24 mg/day is the optimal dosage.<ref name="pmid24591834">{{cite journal | vauthors = Hager K, Baseman AS, Nye JS, Brashear HR, Han J, Sano M, Davis B, Richards HM | title = Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer's disease | journal = Neuropsychiatric Disease and Treatment | volume = 10 | pages = 391–401 | date = 2014 | pmid = 24591834 | pmc = 3937252 | doi = 10.2147/NDT.S57909 | doi-access = free }}</ref> |
|
|
|
|
|
In December 2023, the FDA approved a ] (NDA) for a pro-drug of galantamine called ALPHA-1062.<ref>{{cite press release | title=Alpha Cognition Announces FDA Acceptance of New Drug Application for ALPHA-1062 for Mild-to-Moderate Alzheimer's Disease | publisher=Alpha Cognition | via=Business Wire | date=December 7, 2023 | url=https://www.businesswire.com/news/home/20231207840612/en/Alpha-Cognition-Announces-FDA-Acceptance-of-New-Drug-Application-for-ALPHA-1062-for-Mild-to-Moderate-Alzheimer%E2%80%99s-Disease | access-date=August 5, 2024 | archive-date=April 16, 2024 | archive-url=https://web.archive.org/web/20240416023157/https://www.businesswire.com/news/home/20231207840612/en/Alpha-Cognition-Announces-FDA-Acceptance-of-New-Drug-Application-for-ALPHA-1062-for-Mild-to-Moderate-Alzheimer%E2%80%99s-Disease | url-status=live }}</ref> In July 2024, The FDA approved ] (Zunveyl), previously known as ALPHA-1062, to treat mild-to-moderate Alzheimer's disease.<ref>{{cite press release | title=Alpha Cognition's Oral Therapy Zunveyl Receives FDA Approval to Treat Alzheimer's Disease | publisher=Alpha Cognition | via=Business Wire | date=July 29, 2024 | url=https://www.businesswire.com/news/home/20240729327804/en/ | access-date=August 4, 2024 | archive-date=August 4, 2024 | archive-url=https://web.archive.org/web/20240804193100/https://www.businesswire.com/news/home/20240729327804/en/ | url-status=live }}</ref> |
|
|
|
|
|
== Side effects == |
|
|
The ] profile of galantamine includes potential for ], including ], swelling of the face or throat, and skin rash.<ref name=drugs/><ref name=mayo/> Using galantamine may cause chest pain, bloody urine, stomach bleeding, and liver injury, among other side effects.<ref name=drugs/><ref name=mayo/> Nausea, vomiting, diarrhea, dizziness, and headache are considered common side effects.<ref name="drugs" /> |
|
|
|
|
|
A gradual titration over more than three months may enable long-term tolerability in some people.<ref>{{cite journal | vauthors = Birks J | title = Cholinesterase inhibitors for Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD005593 | date = January 2006 | volume = 2016 | pmid = 16437532 | doi = 10.1002/14651858.CD005593 | pmc = 9006343 | veditors = Birks J }}</ref> |
|
|
|
|
|
Galantamine has a wide spectrum of ] and medical disorders, requiring close assessment between the physician and patient.<ref name="mayo">{{cite web |title=Galantamine |url=https://www.mayoclinic.org/drugs-supplements/galantamine-oral-route/precautions/drg-20067458?p=1 |publisher=Mayo Clinic |access-date=March 26, 2024 |date=2024 |archive-date=March 26, 2024 |archive-url=https://web.archive.org/web/20240326145046/https://www.mayoclinic.org/drugs-supplements/galantamine-oral-route/precautions/drg-20067458?p=1 |url-status=live }}</ref> |
|
|
|
|
|
== Pharmacology == |
|
|
Galantamine's chemical structure contains a tertiary ]. At a neutral ], this tertiary amine will often bond to a hydrogen, and appear mostly as an ammonium ion.<ref name=drugs/> |
|
|
|
|
|
Galantamine is a potent ] potentiating ] of human ] (nAChRs) ], ], and ], and chicken/mouse nAChRs ]/] in certain areas of the brain.<ref name=drugs/><ref name="metabolism">{{cite journal | vauthors = Mannens GS, Snel CA, Hendrickx J, Verhaeghe T, Le Jeune L, Bode W, van Beijsterveldt L, Lavrijsen K, Leempoels J, Van Osselaer N, Van Peer A, Meuldermans W | title = The metabolism and excretion of galantamine in rats, dogs, and humans | journal = Drug Metabolism and Disposition | volume = 30 | issue = 5 | pages = 553–63 | date = May 2002 | pmid = 11950787 | doi = 10.1124/dmd.30.5.553 | s2cid = 6795456 }}</ref> By binding to the allosteric site of the nAChRs, a conformational change occurs which increases the receptors response to acetylcholine.<ref name=kalola/> This modulation of the ]s on cholinergic neurons in turn causes an increase in the amount of acetylcholine released.<ref>{{cite journal | vauthors = Woodruff-Pak DS, Vogel RW, Wenk GL | title = Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 4 | pages = 2089–94 | date = February 2001 | pmid = 11172080 | pmc = 29386 | doi = 10.1073/pnas.031584398 | bibcode = 2001PNAS...98.2089W | jstor = 3055005 | doi-access = free }}</ref> |
|
|
However, recent studies suggest that Galantamine does not functionally act at human nAChRs ] or ] as a positive allosteric modulator.<ref>{{cite journal | vauthors = Moerke MJ, McMahon LR, Wilkerson JL | title = More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder | journal = Pharmacological Reviews | volume = 72 | issue = 2 | pages = 527–557 | date = April 2020 | pmid = 32205338 | pmc = 7090325 | doi = 10.1124/pr.119.018028 | url = https://pharmrev.aspetjournals.org/content/72/2/527/tab-article-info | access-date = October 24, 2020 | archive-date = October 8, 2021 | archive-url = https://web.archive.org/web/20211008220759/https://pharmrev.aspetjournals.org/content/72/2/527/tab-article-info | url-status = live }}</ref><ref name="pmid29669164">{{cite journal |vauthors=Kowal NM, Ahring PK, Liao WY, Indurti DC, Harvey BS, O'Connor SM, Chebib M, Olafsdottir ES, Balle T |title=Galantamine is not a positive allosteric modulator of human α4β2 or α7 nicotinic acetylcholine receptors |journal=] |volume=175 |issue=14 |pages=2911–2925 |date=July 2018 |pmid=29669164 |pmc=6016680 |doi=10.1111/bph.14329 |url= |issn=}}</ref> |
|
|
|
|
|
Galantamine also works as a weak ] and ] ] in all areas of the body.<ref name="drugs" /> By inhibiting acetylcholinesterase, it increases the concentration and thereby action of ] in certain parts of the brain. Galantamine's effects on nAChRs and complementary acetylcholinesterase inhibition make up a dual mechanism of action. 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 ] in 1999 (PDB code: ; ).<ref>{{cite journal | vauthors = Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL | title = Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution | journal = FEBS Letters | volume = 463 | issue = 3 | pages = 321–6 | date = December 1999 | pmid = 10606746 | doi = 10.1016/S0014-5793(99)01637-3 | s2cid = 573270 | doi-access = free | bibcode = 1999FEBSL.463..321G }}</ref> There is no evidence that galantamine alters the course of the underlying dementing process.<ref>{{Cite web |url=http://www.ortho-mcneilneurologics.com/ortho-mcneilneurologics/shared/pi/razadyne.pdf |title=Ortho-McNeil Neurologics, "Razadyne ER US Product Insert", May 2006 |access-date=December 21, 2009 |archive-url=https://web.archive.org/web/20091222071643/http://www.ortho-mcneilneurologics.com/ortho-mcneilneurologics/shared/pi/razadyne.pdf |archive-date=December 22, 2009 |url-status=dead }}</ref> |
|
|
|
|
|
== Pharmacokinetics == |
|
|
|
|
|
Absorption of galantamine is rapid and complete and shows linear pharmacokinetics. It is well absorbed with absolute oral ] between 80 and 100%. It has a terminal elimination half-life of seven hours. Peak effect of inhibiting ] was achieved about one hour after a single oral dose of 8 mg in some healthy volunteers. |
|
|
|
|
|
The coadministration of food delays the rate of galantamine absorption, but does not affect the extent of absorption.<ref name="springer" /> |
|
|
|
|
|
] 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 ] and ] are involved in galantamine metabolism. Within 24 hours of intravenous or oral administration approximately 20% of a dose of galantamine will be excreted unreacted in the urine.<ref name="springer" /> |
|
|
|
|
|
In humans, several metabolic pathways for galantamine exist.<ref name=metabolism/> These pathways lead to the formation of a number of different metabolites.<ref name=metabolism/> One of the metabolites that may result can be formed through the ] of galantamine.<ref name=metabolism/> Additionally, galantamine may undergo ] or ] at its nitrogen atom, forming two other possible metabolites.<ref name=metabolism/> Galantamine can undergo demethylation at its oxygen atom, forming an intermediate which can then undergo glucuronidation or sulfate conjugation.<ref name=metabolism/> Lastly, galantamine may be oxidized and then reduced before finally undergoing demethylation or oxidation at its nitrogen atom, or demethylation and subsequent glucuronidation at its oxygen atom.<ref name=metabolism/> |
|
|
|
|
|
] |
|
|
|
|
|
==Drug interactions== |
|
|
Since galantamine is metabolized by CYP2D6 and CYP3A4, inhibiting either of these ] will increase the cholinergic effects of galantamine.<ref name="springer" /> Inhibiting these enzymes may lead to adverse effects.<ref name="springer" /> It was found that ], an inhibitor of CYP2D6, increased the ] of galantamine by 40%.<ref name="springer" /> The CYP3A4 inhibitors ] and ] increased the ] of galantamine by 30% and 12%, respectively.<ref name="springer" /> |
|
|
|
|
|
== Extraction and synthesis == |
|
|
{{main|Galantamine total synthesis}} |
|
|
Since the alkaloid is isolated from botanical sources containing low amounts (0.1%) by weight, extraction yields are low.<ref name="pmid28337117">{{cite journal | vauthors = Kim JK, Park SU | title = Pharmacological aspects of galantamine for the treatment of Alzheimer's disease | journal = EXCLI Journal | volume = 16 | pages = 35–39 | date = 2017 | pmid = 28337117 | pmc = 5318685 | doi = 10.17179/excli2016-820 }}</ref> Although galantamine can be produced from natural resources, it also has many industrial syntheses, such as by ], ], ], and ].<ref>{{cite journal | vauthors = Mucke HA | title = The case of galantamine: repurposing and late blooming of a cholinergic drug | journal = Future Science OA | volume = 1 | issue = 4 | pages = FSO73 | date = November 2015 | pmid = 28031923 | pmc = 5137937 | doi = 10.4155/fso.15.73 }}</ref> |
|
|
|
|
|
==Research== |
|
|
|
|
|
===Organophosphate poisoning=== |
|
|
The toxicity of ]s results primarily from their action as irreversible inhibitors of acetylcholinesterase.<ref name = "organo" /> Inhibiting acetylcholinesterase causes an increase in acetylcholine, as the enzyme is no longer available to catalyze its breakdown.<ref name = "organo" /> In the peripheral nervous system, acetylcholine accumulation can cause an overstimulation of muscarinic receptors followed by a desensitization of nicotinic receptors.<ref name = "organo" /> This leads to severe skeletal muscle fasciculations (involuntary contractions).<ref name = "organo" /> The effects on the central nervous system include ], restlessness, ], ], ]s, ], cardiorespiratory paralysis, and ].<ref name = "organo" /> As a reversible acetylcholinesterase inhibitor, galantamine has the potential to serve as an effective organophosphate poisoning treatment by preventing irreversible acetylcholinesterase inhibition.<ref name = "organo" /> Additionally, galantamine has ] properties which may make it even more desirable as an antidote.<ref name = "organo" /> |
|
|
|
|
|
Research supported in part by the ] has led to a ] application for the use of galantamine and/or its derivatives for treatment of ].<ref name = "organo">{{cite journal | vauthors = Albuquerque EX, Pereira EF, Aracava Y, Fawcett WP, Oliveira M, Randall WR, Hamilton TA, Kan RK, Romano JA, Adler M | title = Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 35 | pages = 13220–5 | date = August 2006 | pmid = 16914529 | pmc = 1550772 | doi = 10.1073/pnas.0605370103 | bibcode = 2006PNAS..10313220A | doi-access = free }}</ref> The indications for use of galantamine in the patent application include poisoning by ]s "including but not limited to ], ], and ], ], and ]s". Galantamine was studied in the research cited in the patent application for use along with the well-recognized nerve agent antidote ]. According to the investigators, an unexpected synergistic interaction occurred between galantamine and atropine in an amount of 6 mg/kg or higher. Increasing the dose of galantamine from 5 to 8 mg/kg decreased the dose of atropine needed to protect experimental animals from the toxicity of soman in dosages 1.5 times the dose generally required to kill half the experimental animals.<ref name="Albuquerque_patent">{{cite web |url=http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090023706.PN.&OS=PN/20090023706&RS=PN/20090023706 |title=United States Patent Application 20090023706 |publisher=US Patent and Trademark Office |date=January 22, 2009 |access-date=May 27, 2016 |vauthors=((Albuquerque, Edson X)), ((Adler, Michael)), ((Pereira, Edna F.R.)) |archive-date=July 13, 2020 |archive-url=https://web.archive.org/web/20200713225511/http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090023706.PN.&OS=PN%2F20090023706&RS=PN%2F20090023706 |url-status=dead }}</ref> |
|
|
|
|
|
===Autism=== |
|
|
Galantamine given in addition to ] to autistic children has been shown to improve some of the symptoms of autism such as irritability, lethargy, and social withdrawal.<ref>{{cite journal | vauthors = Ghaleiha A, Ghyasvand M, Mohammadi MR, Farokhnia M, Yadegari N, Tabrizi M, Hajiaghaee R, Yekehtaz H, Akhondzadeh S | title = Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial | journal = Journal of Psychopharmacology | volume = 28 | issue = 7 | pages = 677–85 | date = July 2014 | pmid = 24132248 | doi = 10.1177/0269881113508830 | s2cid = 206491732 }}</ref> Additionally, the cholinergic and nicotinic receptors are believed to play a role in attentional processes.<ref name="aut">{{cite journal | vauthors = Nicolson R, Craven-Thuss B, Smith J | title = A prospective, open-label trial of galantamine in autistic disorder | journal = Journal of Child and Adolescent Psychopharmacology | volume = 16 | issue = 5 | pages = 621–9 | date = October 2006 | pmid = 17069550 | doi = 10.1089/cap.2006.16.621 }}</ref> Some studies have noted that cholinergic and nicotinic treatments have improved attention in autistic children.<ref name="aut" /> As such, it is hypothesized that galantamine's dual action mechanism might have a similar effect in treating autistic children and adolescents.<ref name="aut" /> |
|
|
|
|
|
===Anesthesia=== |
|
|
Galantamine may have some limited use in reducing the side-effects of anesthetics ] and ]. In one study, a control group of patients were given ] and ] and underwent ] and surgery.<ref name="anesth">{{cite journal | vauthors = Chakalova E, Marinova M, Srebreva M, Anastasov D, Ploskov K | title = | language = bg | journal = Akusherstvo I Ginekologiia | volume = 26 | issue = 3 | pages = 28–31 | date = 1987 | pmid = 3631427 }}</ref> The experimental group was given ], ], and nivalin (of which the active ingredient is galantamine).<ref name="anesth" /> The degree of drowsiness and disorientation of the two groups was then assessed 5, 10, 15, 30 and 60 minutes after surgery.<ref name="anesth" /> The group that had taken nivalin were found to be more alert 5, 10, and 15 minutes after the surgery.<ref name="anesth" /> |
|
|
|
|
|
=== Oneirogen === |
|
|
|
|
|
Galantamine is known to have ] properties. Research has demonstrated its potential to increase ], dream self-awareness and dream vividness. The enhancement of such ] properties can facilitate the induction of ].<ref name="Tan Fan 2023 p. ">{{cite journal | vauthors = Tan S, Fan J | title = A systematic review of new empirical data on lucid dream induction techniques | journal = Journal of Sleep Research | volume = 32 | issue = 3 | pages = e13786 | date = June 2023 | pmid = 36408823 | doi = 10.1111/jsr.13786 }}</ref><ref name="Sparrow Hurd Carlson Molina 2018 pp. 74–88">{{cite journal | vauthors = Sparrow G, Hurd R, Carlson R, Molina A | title = Exploring the effects of galantamine paired with meditation and dream reliving on recalled dreams: Toward an integrated protocol for lucid dream induction and nightmare resolution | journal = Consciousness and Cognition | volume = 63 | pages = 74–88 | date = August 2018 | pmid = 29960246 | doi = 10.1016/j.concog.2018.05.012 | publisher = Elsevier BV }}</ref> |
|
|
|
|
|
== References == |
|
|
{{Reflist}} |
|
|
|
|
|
{{Antidementia}} |
|
|
{{Acetylcholine metabolism and transport modulators}} |
|
|
{{Nicotinic acetylcholine receptor modulators}} |
|
|
{{Portal bar | Medicine}} |
|
|
|
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |