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a complex consisting of an organic base in association with hydrogen chloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/16 22:21:45」(JST)

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Tacrine is a centrally acting anticholinesterase and indirect cholinergic agonist (parasympathomimetic). It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the University of Sydney. It also acts as a histamine N-methyltransferase inhibitor.^[1]

Clinical use

Tacrine was the prototypical cholinesterase inhibitor for the treatment of Alzheimer's disease. William K. Summers received a patent for this use (US Patent No. 4,816,456).^[2]^[3]^[4] Studies found that it may have a small beneficial effect on cognition and other clinical measures, though study data was limited and the clinical relevance of these findings was unclear.^[5]^[6]

Tacrine has been discontinued in the US^[7] in 2013, due to concerns over safety.^[8]

Adverse Effects

Very Common (>10% incidence) adverse effects include^[7]

Increased LFTs
Nausea
Vomiting
Diarrhea
Headache
Dizziness

Common (1-10% incidence) adverse effects include^[7]^[9]

Indigestion
Belching
Abdominal pain
Myalgia — muscle pain
Confusion
Ataxia — decreased control over bodily movements.
Insomnia
Rhinitis
Rash
Fatigue
Weight loss
Constipation
Somnolence
Tremor
Anxiety
Urinary incontinence
Hallucinatons
Agitation
Conjunctivitis (a link to tacrine treatment has not been conclusively proven)
Diaphoresis — sweating.

Uncommon/Rare (<1% incidence) adverse effects include^[9]

Hepatotoxicity (that is toxic effects on the liver)
Ototoxicity (hearing/ear damage; a link to tacrine treatment has not been conclusively proven)
Seizures
Agranulocytosis (a link between treatment and this adverse effect has not been proven) — a potentially fatal drop in white blood cells, the body's immune/defensive cells.
Taste changes

Unknown incidence adverse effects include^[9]

Urinary tract infection
Delirium
Other optic effects such as glaucoma, cataracts, etc. (also not conclusively linked to tacrine treatment)
Depression
Suicidal ideation and behaviour
Hypotension
Bradycardia

Overdose

As stated above, overdosage of tacrine may give rise to severe side effects such as nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Atropine is a popular treatment for overdose.^[9]

Pharmacokinetics

Major form of metabolism is in the liver via hydroxylation of benzylic carbon by CYP1A2. This forms the major metabolite 1-hydroxy-tacrine (velnacrine) which is still active.^[9]

References

^ Taraschenko, OD; Barnes, WG; Herrick-Davis, K; Yokoyama, Y; Boyd, DL; Hough, LB (April 2005). "Actions of tacrine and galanthamine on histamine-N-methyltransferase.". Methods and findings in experimental and clinical pharmacology 27 (3): 161–165. doi:10.1358/mf.2005.27.3.890872. PMID 15834447.
^ {US Patent No. 4,816,456} http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4,816,456.PN.&OS=PN/4,816,456&RS=PN/4,816,456
^ Waldholz M. A Psychiatrist’s work leads to a US study of Alzheimer’s drug: but Dr. Summers shuns test, seeks to widen his own; is Memory really aided; Fee-forresearch Furor. Wall Street Journal. Tuesday August 4, 1987 p A-1
^ Peacock D. New Mexico Doctor invents drugs, supplements for Alzheimer’s disease, Multiple Sclerosis. NM Bus Weekly. 25 MAR 2005
^ Qizilbash N, Whitehead A, Higgins J, et al. (1998). "Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials". Journal of the American Medical Association 280 (20): 1777–82. doi:10.1001/jama.280.20.1777. PMID 9842955.
^ Rang HP, Dale MM, Ritter JM, Moore PK (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4. .
^ ^a ^b ^c "tacrine (Discontinued) - Cognex". Medscape Reference. WebMD. Retrieved 8 October 2013.
^ Tacrine at LiverTox
^ ^a ^b ^c ^d ^e Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Oct 8]. Greenwood Village, CO: Thomsen Healthcare; 2013.

External links

Acetylcholinesterase: A gorge-ous enzyme QUite Interesting PDB Structure article at PDBe

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 認知症治療におけるコリンエステラーゼ阻害剤 cholinesterase inhibitors in the treatment of dementia
2. 認知症の治療 treatment of dementia
3. 小児および思春期における注意欠陥多動性障害治療薬の薬理学 pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents
4. 有機リン剤およびカルバメート中毒 organophosphate and carbamate poisoning
5. エストロゲンと認知機能 estrogen and cognitive function

English Journal

An electrochemical platform for acetylcholinesterase activity assay and inhibitors screening based on Michael addition reaction between thiocholine and catechol-terminated SAMs.

Tian Y, Ye S, Shi X, Jing L, Liang C, Xian Y.SourceDepartment of Chemistry, East China Normal University, Shanghai 200062, China. yzxian@chem.ecnu.edu.cn.
The Analyst.Analyst.2011 Dec 7;(23):5084-90. Epub 2011 Oct 13.
An electrochemical platform for acetylcholinesterase (AChE) activity assay and its inhibitors screening is developed based on the Michael addition reaction of thiocholine, the hydrolysis product of acetylthiocholine (AsCh) in the presence of AChE, with the electrogenerated o-quinone of catechol-term
PMID 21994917

Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues.

Martins C, Carreiras MC, León R, de Los Ríos C, Bartolini M, Andrisano V, Iriepa I, Moraleda I, Gálvez E, García M, Egea J, Samadi A, Chioua M, Marco-Contelles J.SourceResearch Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
European journal of medicinal chemistry.Eur J Med Chem.2011 Dec;46(12):6119-30. Epub 2011 Sep 29.
The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1-11 and 12-16 by Friedländer-type reaction of readily available o-amino(furano/pyrrolo)ni
PMID 22000936

Japanese Journal

Research and Development of Donepezil Hydrochloride : a New Type of Acetylcholinesterase Inhibitor

Sugimoto Hachiro,Ogura Hiroo,Arai Yasuo [他],IIMURA Youichi,YAMANISHI Yoshiharu
The Japanese journal of pharmacology 89(1), 7-20, 2002-05-01
… The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. … However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. … After four years of exploratory research, we found donepezil hydrochloride (donepezil). …
NAID 10008430837

アルツハイマー病治療薬塩酸ドネペジル (Aricept^R) の薬理学的特性

小倉博雄,小笹貴史,荒木伸,山西嘉晴
日本薬理学雑誌 115(1), 45-51, 2000-01-01
… Donepezil hydrochloride (DPZ), a novel class of cholinesterase (ChE) inhibitors, inhibits degradation of acetylcholine (ACh) and activates central cholinergic system. … In in vitro studies, DPZ more selectively inhibited acetylcholinesterase (IC50: 6.7 nM) than butyrylcholinesterase (IC50: 7400 nM), while tacrine inhibited both acetylcholinesterase (IC50: 77 nM) and butyrylcholinesterase (IC50: 69 nM). …
NAID 10005705427

Effect of Donepezil Hydrochloride (E2020) on Extracellular Acetylcholine Concentration in the Cerebral Cortex of Rats

Kosasa Takashi,Kuriya Yuka,Yamanishi Yoshiharu
The Japanese journal of pharmacology 81(2), 216-222, 1999-10-00
… Donepezil hydrochloride (donepezil), a potent and selective acetylcholinesterase inhibitor, has been developed for the treatment of Alzheimer's disease. … Other cholinesterase inhibitors, tacrine, ENA-713 and TAK-147, were used as reference drugs. … Tacrine, ENA-713 and TAK-147 also elevated the extracellular concentration of ACh. … The minimum effective doses of donepezil, tacrine, ENA-713 and TAK-147 were ≤2.5, 10, 10 and ≤10 mg/kg, respectively. …
NAID 10008196948

Related Pictures

★リンクテーブル★

リンク元	「塩酸タクリン」「tetrahydroaminoacridine」
関連記事	「hydrochloride」

「塩酸タクリン」

Tacrine
Systematic (IUPAC) name
	1,2,3,4-tetrahydroacridin-9-amine
Clinical data
Trade names	Cognex
AHFS/Drugs.com	monograph
MedlinePlus	a693039
Pregnancy; category	AU: C; US: C (Risk not ruled out); ;
Legal status	AU: S4 (Prescription only); UK: POM (Prescription only); US: ℞-only;
Routes of; administration	Oral, rectal
Pharmacokinetic data
Bioavailability	2.4–36% (oral)
Protein binding	55%
Metabolism	Hepatic (CYP1A2)
Biological half-life	2–4 hours
Excretion	Renal
Identifiers
CAS Number	321-64-2
ATC code	N06DA01
IUPHAR/BPS	6687
DrugBank	DB00382
ChemSpider	1859
UNII	4VX7YNB537
ChEBI	CHEBI:45980
ChEMBL	CHEMBL95
PDB ligand ID	THA (PDBe, RCSB PDB)
Chemical data
Formula	C13H14N2
Molecular mass	198.264 g/mol
	SMILES n1c3c(c(c2c1cccc2)N)CCCC3 ;
	InChI InChI=1S/C13H14N2/c14-13-9-5-1-3-7-11(9)15-12-8-4-2-6-10(12)13/h1,3,5,7H,2,4,6,8H2,(H2,14,15) ; Key:YLJREFDVOIBQDA-UHFFFAOYSA-N ;
Physical data
Melting point	183 °C (361 °F)
Boiling point	358 °C (676 °F)
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