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Rivastigmine (sold under the trade name Exelon) is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer's type and dementia due to Parkinson's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects,^[1] which typically include nausea and vomiting.^[2] The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions.^[2]

History

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology at the Hebrew University of Jerusalem^[3] and sold to Novartis by Yissum for commercial development. It is a semi-synthetic derivative of physostigmine.^[4] It has been available in capsule and liquid formulations since 1997.^[5] In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson's disease;^[6] and in 2007 the rivastigmine transdermal patch became the first patch treatment for dementia.

Administration

Rivastigmine tartrate is a white to off-white, fine crystalline powder that is both lipophilic (soluble in fats) and hydrophilic (soluble in water). It comes in a variety of administrations including a capsule, solution and a transdermal patch. Like other cholinesterase inhibitors, it requires doses to be increased gradually over several weeks; this is usually referred to as the titration phase.^[2] Oral doses of rivastigmine should be titrated with a 3 mg per day increment every 2 to 4 weeks. For oral dosing, an initial dose of 1.5 mg twice daily is recommended followed by an increase by 1.5 mg/dose after four weeks. The dose should increase as long as side effects are tolerable. Patients should be reminded to take with food. For the transdermal patch, an initial dose of 4.6 mg per day increases to 9.5 mg per day after four weeks if the patient is not experiencing any intolerable side effects.^[7] Patients or caregivers should be reminded to remove the old patch every day, rotate sites and place a new one. It is recommended that the patch be applied to the upper back or torso.^[8]

Rivastigmine is classified as pregnancy category B, with insufficient data on risks associated with breastfeeding. In cases of overdose, atropine is used to reverse bradycardia. Dialysis is ineffective due to the drug's half-life.

Pharmacodynamics

Rivastigmine, an acetylcholinesterase inhibitor, inhibits both butyrylcholinesterase and acetylcholinesterase (unlike donepezil, which selectively inhibits acetylcholinesterase). It is thought to work by inhibiting these cholinesterase enzymes, which would otherwise break down the brain neurotransmitter acetylcholine.^[9]

Indication

The U.S. Food and Drug Administration has approved rivastigmine capsules, liquid solution and patches for the treatment of mild to moderate dementia of the Alzheimer's type and for mild to moderate dementia related to Parkinson's disease. It has been used in more than 6 million patients worldwide.^{[citation needed]}

Rivastigmine has demonstrated significant treatment effects on the cognitive (thinking and memory), functional (activities of daily living) and behavioural problems commonly associated with Alzheimer's^[10]^[11]^[12]^[13] and Parkinson's disease dementias.^[14]

Efficacy

In patients with either type of dementia, rivastigmine has been shown to provide meaningful symptomatic effects that may allow patients to remain independent and ‘be themselves’ for longer. In particular, it appears to show marked treatment effects in patients showing a more aggressive course of disease, such as those with younger onset ages, poor nutritional status, or those experiencing symptoms such as delusions or hallucinations.^[15] For example, the presence of hallucinations appears to be a predictor of especially strong responses to rivastigmine, both in Alzheimer's and Parkinson's patients.^[16]^[17] These effects might reflect the additional inhibition of butyrylcholinesterase, which is implicated in symptom progression and might provide added benefits over acetylcholinesterase-selective drugs in some patients.^[15]^[16] Multiple-infarct dementia patients may show slight improvement in executive functions and behaviour. No firm evidence supports usage in schizophrenia patients.

Its efficacy is similar to donepezil and tacrine. Doses below 6 mg/d may be ineffective. The effects of this kind of drug in different kinds of dementia (including Alzheimer's dementia) are modest, and it is still unclear which AcCh(ButCh) esterase inhibitor is better in Parkinson's dementia, though rivastigmine is well-studied.

Side effects

Side effects may include nausea and vomiting, decreased appetite and weight loss.^[2]

The strong potency of rivastigmine, provided by its dual inhibitory mechanism, has been postulated to lead to more nausea and vomiting during the titration phase of oral rivastigmine treatment.^[2] This enforces the importance of taking oral forms of these drugs with food as prescribed.^[5] However, rates of nausea and vomiting are markedly reduced with the once-daily rivastigmine patch (which can be applied at any time of the day, with or without food). Patients and caregivers should be aware of warning signs of potential toxicities and know when to call their doctor. For the patch and oral formulations, skin rashes can occur at which time patients should contact their doctor immediately.^[7] For the patch, patients and caregivers should monitor for any intense itching, redness, swelling or blistering at the patch location. If this occurs, remove the patch, rinse the area and call the doctor immediately.^[8]

In a large clinical trial of the rivastigmine patch in 1,195 patients with Alzheimer's disease, the target dose of 9.5 mg/24-hour patch provided similar clinical effects (e.g. memory and thinking, activities of daily living, concentration) as the highest doses of rivastigmine capsules, but with one-third fewer reports of nausea and vomiting.^[1]

Pharmacokinetics

When given orally, rivastigmine is well absorbed, with a bioavailability of about 40% in the 3-mg dose. Pharmacokinetics are linear up to 3 mg BID, but nonlinear at higher doses. Elimination is through the urine. Peak plasma concentrations are seen in about one hour, with peak cerebrospinal fluid concentrations at 1.4–3.8 hours. When given by once-daily transdermal patch, the pharmacokinetic profile of rivastigmine is much smoother, compared with capsules, with lower peak plasma concentrations and reduced fluctuations.^[18] The 9.5 mg/24 h rivastigmine patch provides comparable exposure to 12 mg/day capsules (the highest recommended oral dose).^[18]

The compound does cross the blood–brain barrier. Plasma protein binding is 40%.^[19] The major route of metabolism is by its target enzymes via cholinesterase-mediated hydrolysis. Elimination bypasses the hepatic system, so hepatic cytochrome P450 (CYP) isoenzymes are not involved.^[20] The low potential for drug-drug interactions (which could lead to adverse effects) has been suggested as due to this pathway compared to the many common drugs that use the cytochrome P450 metabolic pathway.^[2]

References

^ ^a ^b Winblad, B.; Grossberg, G.; Frölich, L.; Farlow, M.; Zechner, S.; Nagel, J.; Lane, R. (2007). "IDEAL: A 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease". Neurology 69 (4 Suppl 1): S14–S22. doi:10.1212/01.wnl.0000281847.17519.e0. PMID 17646619.
^ ^a ^b ^c ^d ^e ^f Inglis, F. (2002). "The tolerability and safety of cholinesterase inhibitors in the treatment of dementia". International journal of clinical practice. Supplement (127): 45–63. PMID 12139367.
^ "Exelon". Yissum Technology Transfer. Retrieved 7 October 2010.
^ Kumar, V. (2006). "Potential medicinal plants for CNS disorders: An overview". Phytotherapy Research 20 (12): 1023–1035. doi:10.1002/ptr.1970. PMID 16909441.
^ ^a ^b Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006
^ Approves the First Treatment for Dementia of Parkinson's Disease U.S. FDA News Release
^ ^a ^b https://www.pharma.us.novartis.com/product/pi/pdf/exelon.pdf
^ ^a ^b http://www.exelonpatch.com/info/alzheimers-dementia-help/applying-exelon-patch.jsp?usertrack.filter_applied=true&NovaId=2935376991487123443
^ Camps P. Munoz-Torrero D. “Cholinergic drugs in pharmacotherapy of Alzheimer's disease”. Mini Rev Med Chem. 2002 Feb;2(1):11–25. PMID 12369954
^ Corey-Bloom J, Anand R, Veach J. “A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease”. Int J Geriatr Psychopharmacol. 1998;1:55–65.
^ Rosler, M.; Anand, R.; Cicin-Sain, A.; Gauthier, S.; Agid, Y.; Dal-Bianco, P.; Stähelin, H. B.; Hartman, R.; Gharabawi, M.; Bayer, T. (1999). "Efficacy and safety of rivastigmine in patients with Alzheimer's disease: International randomised controlled trial Commentary: Another piece of the Alzheimer's jigsaw". BMJ 318 (7184): 633–638. doi:10.1136/bmj.318.7184.633. PMC 27767. PMID 10066203.
^ Finkel, S. I. (2004). "Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease". Clinical Therapeutics 26 (7): 980–990. doi:10.1016/S0149-2918(04)90172-5. PMID 15336465.
^ Rösler, M.; Retz, W.; Retz-Junginger, P.; Dennler, H. J. (1998). "Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer's disease". Behavioural neurology 11 (4): 211–216. PMID 11568422.
^ Emre, M.; Aarsland, D.; Albanese, A.; Byrne, E. J.; Deuschl, G. N.; De Deyn, P. P.; Durif, F.; Kulisevsky, J.; Van Laar, T.; Lees, A.; Poewe, W.; Robillard, A.; Rosa, M. M.; Wolters, E.; Quarg, P.; Tekin, S.; Lane, R. (2004). "Rivastigmine for Dementia Associated with Parkinson's Disease". New England Journal of Medicine 351 (24): 2509–2518. doi:10.1056/NEJMoa041470. PMID 15590953.
^ ^a ^b Gauthier, S.; Vellas, B.; Farlow, M.; Burn, D. (2006). "Aggressive course of disease in dementia". Alzheimer's & Dementia 2 (3): 210. doi:10.1016/j.jalz.2006.03.002.
^ ^a ^b Touchon, J.; Bergman, H.; Bullock, R.; Rapatz, G. N.; Nagel, J.; Lane, R. (2006). "Response to rivastigmine or donepezil in Alzheimer's patients with symptoms suggestive of concomitant Lewy body pathology". Current Medical Research and Opinion 22 (1): 49–59. doi:10.1185/030079906X80279. PMID 16393430.
^ Burn, D.; Emre, M.; McKeith, I.; De Deyn, P. P.; Aarsland, D.; Hsu, C.; Lane, R. (2006). "Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease". Movement Disorders 21 (11): 1899–1907. doi:10.1002/mds.21077. PMID 16960863.
^ ^a ^b Cummings, J.; Lefevre, G.; Small, G.; Appel-Dingemanse, S. (2007). "Pharmacokinetic rationale for the rivastigmine patch". Neurology 69: S10. doi:10.1212/01.wnl.0000281846.40390.50.
^ Jann, M. W.; Shirley, K. L.; Small, G. W. (2002). "Clinical Pharmacokinetics and Pharmacodynamics of Cholinesterase Inhibitors". Clinical Pharmacokinetics 41 (10): 719–739. doi:10.2165/00003088-200241100-00003. PMID 12162759.
^ Jann, M. W. (2000). "Rivastigmine, a New-Generation Cholinesterase Inhibitor for the Treatment of Alzheimer's Disease". Pharmacotherapy 20 (1): 1–12. doi:10.1592/phco.20.1.1.34664. PMID 10641971.

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. 脳血管性認知症の治療および予防 treatment and prevention of vascular dementia
3. レビー小体型認知症の予後および治療 prognosis and treatment of dementia with lewy bodies
4. 認知症の治療 treatment of dementia
5. 前頭側頭型認知症：治療 frontotemporal dementia treatment

English Journal

CHRNA7 Polymorphisms and Response to Cholinesterase Inhibitors in Alzheimer's Disease.

Weng PH1, Chen JH2, Chen TF3, Sun Y4, Wen LL5, Yip PK6, Chu YM7, Chen YC8.Author information 1Department of Family Medicine, Taiwan Adventist Hospital, Taipei, Taiwan ; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.2Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan ; Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan.3Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.4Department of Neurology, En Chu Kong Hospital, Taipei, Taiwan.5Department of Laboratory Medicine, En Chu Kong Hospital, Taipei, Taiwan.6Center of Neurological Medicine, Cardinal Tien Hospital, Taipei, Taiwan ; School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan.7Department of Laboratory Medicine, Cardinal Tien Hospital, Taipei, Taiwan.8Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan ; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan ; Research Center for Genes, Environment and Human Health, College of Public Health, National Taiwan University, Taipei, Taiwan.AbstractBACKGROUND: CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response.
PloS one.PLoS One.2013 Dec 31;8(12):e84059. doi: 10.1371/journal.pone.0084059.
BACKGROUND: CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response.METHODS: Mild to moderate AD
PMID 24391883

Rivastigmine in moderately severe-to-severe Alzheimer's disease: Severe Impairment Battery factor analysis.

Ferris S, Karantzoulis S, Somogyi M, Meng X.AbstractINTRODUCTION: The Severe Impairment Battery (SIB) is validated for assessing cognition in patients with severe dementia. The current analysis aimed to further investigate the cognitive efficacy of rivastigmine capsules, as assessed by SIB factor scores, in patients with moderately severe-to-severe Alzheimer's disease (AD).
Alzheimer's research & therapy.Alzheimers Res Ther.2013 Dec 18;5(6):63. [Epub ahead of print]
INTRODUCTION: The Severe Impairment Battery (SIB) is validated for assessing cognition in patients with severe dementia. The current analysis aimed to further investigate the cognitive efficacy of rivastigmine capsules, as assessed by SIB factor scores, in patients with moderately severe-to-severe A
PMID 24351447

Pharmacological treatment for memory disorder in multiple sclerosis.

He D, Zhang Y, Dong S, Wang D, Gao X, Zhou H.Author information Department of Neurology, Affiliated Hospital of Guiyang Medical College, No. 28, Gui Yi Street, Guiyang, Guizhou Province, China, 550004.AbstractBACKGROUND: This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10).Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent.
The Cochrane database of systematic reviews.Cochrane Database Syst Rev.2013 Dec 17;12:CD008876. doi: 10.1002/14651858.CD008876.pub3.
BACKGROUND: This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10).Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the centr
PMID 24343792

Japanese Journal

抗認知症薬の最近の動向 (特集認知症最前線)

中村祐
Monthly book medical rehabilitation (127), 65-69, 2011-01
NAID 40018281974

リバスチグミン--経皮吸収型製剤への期待 (特集アルツハイマー病治療薬の現状と期待される治療薬)

中村祐
老年精神医学雑誌 21(12), 1336-1347, 2010-12
NAID 40017427216

Related Pictures

★リンクテーブル★

リンク元	「リバスチグミン」
拡張検索	「rivastigmine tartrate」

「リバスチグミン」

Rivastigmine
Systematic (IUPAC) name
	(S)-3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate
Clinical data
Trade names	Exelon
AHFS/Drugs.com	monograph
MedlinePlus	a602009
Pregnancy; category	US: B (No risk in non-human studies);
Legal status	US: ℞-only;
Routes of; administration	Oral, Transdermal
Pharmacokinetic data
Bioavailability	60 to 72%
Protein binding	40%
Metabolism	Hepatic, via pseudocholinesterase
Biological half-life	1.5 hours
Excretion	Renal, 97%
Identifiers
CAS Registry Number	123441-03-2
ATC code	N06DA03
PubChem	CID: 77991
IUPHAR/BPS	6602
DrugBank	DB00989
ChemSpider	70377
UNII	PKI06M3IW0
KEGG	D03822
ChEBI	CHEBI:8874
ChEMBL	CHEMBL636
Chemical data
Formula	C14H22N2O2
Molecular mass	250.337 g/mol
	SMILES O=C(Oc1cc(ccc1)[C@@H](N(C)C)C)N(CC)C ;
	InChI InChI=1S/C14H22N2O2/c1-6-16(5)14(17)18-13-9-7-8-12(10-13)11(2)15(3)4/h7-11H,6H2,1-5H3/t11-/m0/s1 ; Key:XSVMFMHYUFZWBK-NSHDSACASA-N ;
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　　[★]

英: rivastigmine
化: 酒石酸リバスチグミン rivastigmine tartrate
商: イクセロン、リバスタッチ
関: 抗認知症薬。その他の中枢神経系用薬

アセチルコリンエステラーゼとブチリルコリンエステラーゼ BuChEを両方共に阻害する。
BuChEは海馬に多く存在。AChEは神経に多く存在、BuChEは神経細胞やグリア細胞、血管内皮細胞にも存在。(週刊医学会新聞 2011/5/23)
副作用(消化器症状)が多いので、パッチ剤のみ存在。
維持量は18mg。4.5mgから開始して4週毎に4.5mgずつ増量する。18mg未満では薬効がないため、18mgに達するまで増量させる。それまでに悪心・嘔吐などの副作用が出現しないか慎重に経過をみる。

「rivastigmine tartrate」

　　[★] 酒石酸リバスチグミン

[Winblad-1] Winblad, B.; Grossberg, G.; Frölich, L.; Farlow, M.; Zechner, S.; Nagel, J.; Lane, R. (2007). "IDEAL: A 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease". Neurology 69 (4 Suppl 1): S14–S22. doi:10.1212/01.wnl.0000281847.17519.e0. PMID 17646619.

[Inglis-2] ^ ^a ^b ^c ^d ^e ^f Inglis, F. (2002). "The tolerability and safety of cholinesterase inhibitors in the treatment of dementia". International journal of clinical practice. Supplement (127): 45–63. PMID 12139367.

[3] "Exelon". Yissum Technology Transfer. Retrieved 7 October 2010.

[4] Kumar, V. (2006). "Potential medicinal plants for CNS disorders: An overview". Phytotherapy Research 20 (12): 1023–1035. doi:10.1002/ptr.1970. PMID 16909441.

[ProductInsert-5] Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006

[6] Approves the First Treatment for Dementia of Parkinson's Disease U.S. FDA News Release

[pharma.us.novartis.com-7] ttps://www.pharma.us.novartis.com/product/pi/pdf/exelon.pdf

[exelonpatch.com-8] ttp://www.exelonpatch.com/info/alzheimers-dementia-help/applying-exelon-patch.jsp?usertrack.filter_applied=true&NovaId=2935376991487123443

[9] Camps P. Munoz-Torrero D. “Cholinergic drugs in pharmacotherapy of Alzheimer's disease”. Mini Rev Med Chem. 2002 Feb;2(1):11–25. PMID 12369954

[10] Corey-Bloom J, Anand R, Veach J. “A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease”. Int J Geriatr Psychopharmacol. 1998;1:55–65.

[11] Rosler, M.; Anand, R.; Cicin-Sain, A.; Gauthier, S.; Agid, Y.; Dal-Bianco, P.; Stähelin, H. B.; Hartman, R.; Gharabawi, M.; Bayer, T. (1999). "Efficacy and safety of rivastigmine in patients with Alzheimer's disease: International randomised controlled trial Commentary: Another piece of the Alzheimer's jigsaw". BMJ 318 (7184): 633–638. doi:10.1136/bmj.318.7184.633. PMC 27767. PMID 10066203.

[12] Finkel, S. I. (2004). "Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease". Clinical Therapeutics 26 (7): 980–990. doi:10.1016/S0149-2918(04)90172-5. PMID 15336465.

[13] Rösler, M.; Retz, W.; Retz-Junginger, P.; Dennler, H. J. (1998). "Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer's disease". Behavioural neurology 11 (4): 211–216. PMID 11568422.

[14] Emre, M.; Aarsland, D.; Albanese, A.; Byrne, E. J.; Deuschl, G. N.; De Deyn, P. P.; Durif, F.; Kulisevsky, J.; Van Laar, T.; Lees, A.; Poewe, W.; Robillard, A.; Rosa, M. M.; Wolters, E.; Quarg, P.; Tekin, S.; Lane, R. (2004). "Rivastigmine for Dementia Associated with Parkinson's Disease". New England Journal of Medicine 351 (24): 2509–2518. doi:10.1056/NEJMoa041470. PMID 15590953.

[ReferenceA-15] Gauthier, S.; Vellas, B.; Farlow, M.; Burn, D. (2006). "Aggressive course of disease in dementia". Alzheimer's & Dementia 2 (3): 210. doi:10.1016/j.jalz.2006.03.002.

[ReferenceB-16] Touchon, J.; Bergman, H.; Bullock, R.; Rapatz, G. N.; Nagel, J.; Lane, R. (2006). "Response to rivastigmine or donepezil in Alzheimer's patients with symptoms suggestive of concomitant Lewy body pathology". Current Medical Research and Opinion 22 (1): 49–59. doi:10.1185/030079906X80279. PMID 16393430.

[17] Burn, D.; Emre, M.; McKeith, I.; De Deyn, P. P.; Aarsland, D.; Hsu, C.; Lane, R. (2006). "Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease". Movement Disorders 21 (11): 1899–1907. doi:10.1002/mds.21077. PMID 16960863.

[Cummings-18] Cummings, J.; Lefevre, G.; Small, G.; Appel-Dingemanse, S. (2007). "Pharmacokinetic rationale for the rivastigmine patch". Neurology 69: S10. doi:10.1212/01.wnl.0000281846.40390.50.

[19] Jann, M. W.; Shirley, K. L.; Small, G. W. (2002). "Clinical Pharmacokinetics and Pharmacodynamics of Cholinesterase Inhibitors". Clinical Pharmacokinetics 41 (10): 719–739. doi:10.2165/00003088-200241100-00003. PMID 12162759.

[20] Jann, M. W. (2000). "Rivastigmine, a New-Generation Cholinesterase Inhibitor for the Treatment of Alzheimer's Disease". Pharmacotherapy 20 (1): 1–12. doi:10.1592/phco.20.1.1.34664. PMID 10641971.

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rivastigmine