|Systematic (IUPAC) name|
|Routes||Oral tablet, 5,10 & 23mg|
|PDB ligand ID||E20 (, )|
|Mol. mass||379.492 g/mol|
|(what is this?)|
Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, and now sold as a generic by multiple suppliers, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of Alzheimer's disease. Common side effects include gastrointestinal upset. It has an oral bioavailability of 100% and easily crosses the blood–brain barrier. Because it has a biological half-life of about 70 hours, it can be taken once a day.
Currently, no definitive proof shows the use of donepezil or other similar agents alters the course or progression of Alzheimer's disease (AD). However, 6 to 12-month controlled studies have shown modest benefits in cognition and/or behavior. Pilot studies have reported donepezil therapy may potentially have effects on markers of disease progression, such as hippocampal volume. Therefore, many neurologists, psychiatrists, and primary-care physicians use donepezil in patients with Alzheimer's disease. In 2005, the UK National Institute for Clinical Excellence (NICE) withdrew its recommendation for use of the drug for mild-to-moderate AD, on the basis of no significant improvement in functional outcome, quality of life, or behavioral symptoms. However, NICE revised its guidelines to suggest donepezil be used in moderate-stage patients for whom the evidence is strongest.
While the drug is currently indicated for mild to moderate Alzheimer's, evidence from two clinical trials also indicates it may be effective for moderate to severe disease. An example of this is a Karolinska Institute paper published in The Lancet in early 2006, which states donepezil improves cognitive function even in patients with severe AD symptoms. In Oct. 2006 the U.S. Food and Drug Administration also approved Aricept for treatment of severe dementia.
In mild to moderate Alzheimer’s Disease, a starting dose of 5 mg given once daily should be used. In a minimum of four to six weeks, an increase to 10 mg is recommended. The usual dose is 5 to 10 mg once daily. Moderate to severe AD indicates the same regimen, but in a minimum of three months, a patient may receive a dose of 23 mg once daily. Dementia patients should receive 5–10 mg once daily. The maximum daily dose is 23 mg once daily. Clinicians should use caution in prescribing the maximum daily dose as the risk of severe side effects may outweigh the unclear clinical benefits. In the UK, the maximum licensed dose is 10 mg.
Donepezil (Aricept) should be used with caution in patient with cardiac disease, cardiac conduction disturbances, chronic obstructive pulmonary disease, asthma, severe cardiac arrhythmias and sick sinus syndrome. Patients with gastrointestinal disorders should use caution because nausea or vomiting may occur. These symptoms may appear more frequent when initiating treatment or increasing the donepezil dose. Although occurrence of seizures is rare, patients who have a predisposition to seizures should be treated with caution. The British Medical Journal (BMJ) cautioned that the largest dosage, 23 mg, was crafted to extend patent protection rather than for medical reasons, and was not shown to be more effective compared to the 10 mg dose.
Donepezil has been tested (off label) in other cognitive disorders, including Lewy body dementia, and vascular dementia, but it is not currently approved for these indications. Donepezil has also been found to improve sleep apnea in Alzheimer's patients.
Donepezil has also been studied in patients with mild cognitive impairment, schizophrenia, attention deficit disorder, post-Coronary artery bypass surgery cognitive impairment, cognitive impairment associated with multiple sclerosis, CADASIL syndrome, and Down syndrome. A three-year National Institutes of Health trial in patients with mild cognitive impairment reported donepezil was superior to placebo in delaying rate of progression to dementia during the initial 18 months of the study, but this was not sustained at 36 months. In a secondary analysis, a subgroup of individuals with the apolipoprotein E4 genotype showed sustained benefits with donepezil throughout the study. At this time, though, donepezil is not indicated for prevention of dementia.
A 2001 study suggested that donepezil can improve speech in autistic children. The study found the speech of autistic children that was originally mildly to moderately affected appeared to improve with the use of donepezil.
In 2006, Eisai, the manufacturer, issued a statement that a single vascular dementia study found a difference in the percentage of study participants who died in the donepezil group (1.7%) versus the placebo group (0%). This could be due to an unusually low death rate on the placebo group. An analysis of all three vascular dementia trials, according to Eisai, "shows no statistically significant differences in observed mortality rates between the donepezil and placebo groups."
Development and marketing
Research leading to the development of donepezil began in 1983 at Eisai, and the first Phase I clinical trial took place in 1989. In 1996, Eisai received approval from the United States Food and Drug Administration (USFDA) for donepezil under the brand Aricept, which it co-marketed with Pfizer. As of 2011, Aricept was the world's best-selling Alzheimer's disease treatment. The first generic donepezil became available in November 2010 with the USFDA approval of a formulation prepared by Ranbaxy Labs. In April 2011 a second generic formulation, from Wockhardt, received tentative USFDA marketing approval.
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- "Drug 'treats severe Alzheimer's'". BBC News. 2006-03-23. Retrieved 2007-07-24.
- Aricept (donepezil hydrochloride) package insert. Woodcliff Lake, NJ: Eisai Co., Ltd.; 2010 Nov.
- How the FDA forgot the Evidence: the case of Donepezil 23 mg. BMJ 2012;344:e1086
- LA Times, 2012-03-22 New Alzheimer's Pill Likely To Cause Misery
- Rojas-Fernandez CH (February 2001). "Successful use of donepezil for the treatment of dementia with Lewy bodies". Ann Pharmacother 35 (2): 202–5. doi:10.1345/aph.10192. PMID 11215841.
- Malouf R, Birks J (2004). Malouf, Reem, ed. "Donepezil for vascular cognitive impairment". Cochrane Database Syst Rev (1): CD004395. doi:10.1002/14651858.CD004395.pub2. PMID 14974068.
- Moraes W, Poyares D, Sukys-Claudino L, Guilleminault C, Tufik S (March 2008). "Donepezil improves obstructive sleep apnea in Alzheimer disease: a double-blind, placebo-controlled study". Chest 133 (3): 677–83. doi:10.1378/chest.07-1446. PMID 18198262.
- Doraiswamy PM (2007). "Donepezil for cognitive decline following coronary artery bypass surgery: a pilot randomized controlled trial.". Psychopharmacology Bulletin 40 (2): 54–62. PMID 17514186.
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- "Alzheimer's Drug Shows Promise As Treatment for Autism -- Arehart-Treichel". Psychiatric News (pn.psychiatryonline.org). 2001-11-16. Retrieved 2009-08-18.
- Donepezil hydrochloride: a double-blind study in autistic children
- Benazzi F (November 1999). "Mania associated with donepezil". J Psychiatry Neurosci 24 (5): 468–9. PMC 1189062. PMID 10586539.
- Collins C; Copeland B; Croucher M (2011). "Bipolar affective disorder, type II, apparently precipitated by donepezil.". Int Psychogeriatr 23: 503–504. doi:10.1017/s1041610210002206.
- Rao V; Ovitt L; Robbins B (2008). "Donepezil induced hypomania.". Jour Neuropsychiatry Clin Neurosci 2008; 20: 107. doi:10.1176/appi.neuropsych.20.1.107.
- Sarah Wicklund, M.D.; Mark Wright, M.D. (2012). "Donepezil-Induced Mania,". The Journal of Neuropsychiatry and Clinical Neurosciences 2012; 24 (3): E27–E27. doi:10.1176/appi.neuropsych.11070160. PMID 23037669.
- Sugimoto, Hachiro; Ogura, Hiroo; Arai, Yasuo; Iimura, Youichi; Yamanishi, Yoshiharu (25 January 2002), Research and Development of Donepezil Hydrochloride, a New Type of Acetylcholinesterase Inhibitor, The Japanese Journal of Pharmacology (2002) 89 (1): 7–20, doi:10.1254/jjp.89.7, retrieved 25 April 2011
- Kanoko Matsuyama (25 April 2011). "Eisai Aricept Patch for Alzheimer’s Isn’t Ready for Approval". Bloomberg. Retrieved 25 April 2011.
- "Ranbaxy gets FDA nod for Alzheimer's drug". The Indian Express (New Delhi, India: Indian Express Group). 30 November 2010. IndianExpress.com. Retrieved 25 April 2011.
- Staff Writer (25 April 2011). "Wockhardt Obtains US FDA Nod For Generic Version Of Aricept Tablets". RTTNews. Retrieved 25 April 2011.
- Brenner, George D.; George M., PhD. Brenner (2000). Pharmacology. Philadelphia: W. B. Saunders. ISBN 0-7216-7757-6.
- Acting Editor-in-Chief Louise Welbanks. (2000). Compendium of Pharmaceuticals and Specialities, 2000 (25th ed.). Canadian Pharmaceutical Assn. ISBN 0-919115-76-4.
- Official Aricept product site
- Aricept entry at Drugs.com
- 3D Molecular structure of Donepezil
- Acetylcholinesterase: A gorge-ous enzyme QUite Interesting PDB Structure article at PDBe