RIVASTIGMINE TARTRATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C14H22N2O2.C4H6O6
Molecular Weight	400.4235
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O[C@H]([C@@H](O)C(O)=O)C(O)=O.CCN(C)C(=O)OC1=CC(=CC=C1)[C@H](C)N(C)C

InChI

InChIKey=GWHQHAUAXRMMOT-MBANBULQSA-N

InChI=1S/C14H22N2O2.C4H6O6/c1-6-16(5)14(17)18-13-9-7-8-12(10-13)11(2)15(3)4;5-1(3(7)8)2(6)4(9)10/h7-11H,6H2,1-5H3;1-2,5-6H,(H,7,8)(H,9,10)/t11-;1-,2-/m01/s1

HIDE SMILES / InChI

Molecular Formula	C4H6O6
Molecular Weight	150.0868
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	C14H22N2O2
Molecular Weight	250.3367
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020823s035,021025s023lbl.pdf

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. 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. Rivastigmine capsules, liquid solution, and patches are used for the treatment of mild to moderate dementia of the Alzheimer's type and for mild to moderate dementia related to Parkinson's disease. Rivastigmine has demonstrated treatment effects on the cognitive (thinking and memory), functional (activities of daily living) and behavioral problems commonly associated with Alzheimer's and Parkinson's disease dementia. In people 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 the disease, such as those with younger-onset ages, poor nutritional status, or those experiencing symptoms such as delusions or hallucinations. Side effects may include nausea and vomiting, decreased appetite and weight loss.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Acetylcholinesterase 209 Target ID: CHEMBL220 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26159481	Inhibitor 8504		54.0 nM [IC50]
Butyrylcholinesterase 45 Target ID: CHEMBL1914 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25226236	Inhibitor 8504		30.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Mild to moderate dementia of the Alzheimer’s type 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020823s035,021025s023lbl.pdf	Primary	Approved 8583	EXELON Approved Use EXELON PATCH is an acetylcholinesterase inhibitor indicated for treatment of: Mild, moderate, and severe dementia of the Alzheimer’s type (1.1) Mild to moderate dementia associated with Parkinson’s disease (1.2) 1.1 Alzheimer’s Disease EXELON PATCH is indicated for the treatment of dementia of the Alzheimer’s type (AD). Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease. 1.2 Parkinson’s Disease Dementia EXELON PATCH is indicated for the treatment of mild to moderate dementia associated with Parkinson’s disease (PDD). Launch Date 2007
Mild to moderate dementia associated with Parkinson’s disease 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020823s035,021025s023lbl.pdf	Primary	Approved 8583	EXELON Approved Use EXELON PATCH is an acetylcholinesterase inhibitor indicated for treatment of: Mild, moderate, and severe dementia of the Alzheimer’s type (1.1) Mild to moderate dementia associated with Parkinson’s disease (1.2) 1.1 Alzheimer’s Disease EXELON PATCH is indicated for the treatment of dementia of the Alzheimer’s type (AD). Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease. 1.2 Parkinson’s Disease Dementia EXELON PATCH is indicated for the treatment of mild to moderate dementia associated with Parkinson’s disease (PDD). Launch Date 2007
Alzheimer’s disease 278 Sources: https://clinicaltrials.gov/ct2/show/NCT00731224	Primary	Phase IV 63	EXELON Approved Use EXELON PATCH is an acetylcholinesterase inhibitor indicated for treatment of: Mild, moderate, and severe dementia of the Alzheimer’s type (1.1) Mild to moderate dementia associated with Parkinson’s disease (1.2) 1.1 Alzheimer’s Disease EXELON PATCH is indicated for the treatment of dementia of the Alzheimer’s type (AD). Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease. 1.2 Parkinson’s Disease Dementia EXELON PATCH is indicated for the treatment of mild to moderate dementia associated with Parkinson’s disease (PDD). Launch Date 2007

C_max

Value	Dose	Co-administered	Analyte	Population
37.23 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28670911	6 mg single, oral dose: 6 mg route of administration: Oral experiment type: SINGLE co-administered:		RIVASTIGMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
129.46 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28670911	6 mg single, oral dose: 6 mg route of administration: Oral experiment type: SINGLE co-administered:		RIVASTIGMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
1.76 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28670911	6 mg single, oral dose: 6 mg route of administration: Oral experiment type: SINGLE co-administered:		RIVASTIGMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
60% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020823s032%2C021025s022lbl.pdf			RIVASTIGMINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
12 mg single, oral Overdose Dose: 12 mg Route: oral Route: single Dose: 12 mg Sources: https://pubmed.ncbi.nlm.nih.gov/28328690	healthy, 3 years Health Status: healthy Age Group: 3 years Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/28328690	Other AEs: Cholinergic syndrome... Other AEs: Cholinergic syndrome (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/28328690
90 mg single, oral Overdose Dose: 90 mg Route: oral Route: single Dose: 90 mg Sources: https://pubmed.ncbi.nlm.nih.gov/16373816	unknown, 38 years Health Status: unknown Age Group: 38 years Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/16373816	Other AEs: Respiratory depression, Dizziness... Other AEs: Respiratory depression (1 patient) Dizziness (1 patient) Nausea (1 patient) Vomiting (1 patient) Sweating (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/16373816
288 mg single, oral Overdose Dose: 288 mg Route: oral Route: single Dose: 288 mg Sources: https://pubmed.ncbi.nlm.nih.gov/16440521	unknown, 59 years Health Status: unknown Age Group: 59 years Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/16440521	Other AEs: Cholinergic syndrome... Other AEs: Cholinergic syndrome (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/16440521
9.5 mg 6 times / day multiple, transdermal Overdose Dose: 9.5 mg, 6 times / day Route: transdermal Route: multiple Dose: 9.5 mg, 6 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22663954	unhealthy, 87 years Health Status: unhealthy Age Group: 87 years Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/22663954	Other AEs: Nausea, Vomiting... Other AEs: Nausea (grade 5) Vomiting (grade 5) Renal failure (grade 5) Sources: https://pubmed.ncbi.nlm.nih.gov/22663954
17.4 mg 1 times / day multiple, transdermal Highest studied dose Dose: 17.4 mg, 1 times / day Route: transdermal Route: multiple Dose: 17.4 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022083lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022083lbl.pdf	Disc. AE: Vomiting, Nausea... AEs leading to discontinuation/dose reduction: Vomiting (1.7%) Nausea (1.7%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022083lbl.pdf
10 mg 1 times / day multiple, oral MTD Dose: 10 mg, 1 times / day Route: oral Route: multiple Dose: 10 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10362894	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/10362894	Other AEs: Nausea, Vomiting... Other AEs: Nausea (58%) Vomiting (38%) Dizziness (27%) Anorexia (18%) Headache (16%) Sources: https://pubmed.ncbi.nlm.nih.gov/10362894
6 mg 1 times / day multiple, oral Recommended Dose: 6 mg, 1 times / day Route: oral Route: multiple Dose: 6 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20823lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20823lbl.pdf	Disc. AE: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Nausea (8%) Vomiting (4%) Anorexia (2%) Dizziness (2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20823lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252	inhibitor 2438	inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2153 CYP2C8 1057 CYP2C19 2057 CYP3A5 136	esterase 74	P-gp 301 BCRP 101

Drug as perpetrator

Target	Modality	Activity
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022083s000_ClinPharmR_P1.pdf#page=38 Page: 38.0	no
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022083s000_ClinPharmR_P1.pdf#page=38 Page: 38.0	no
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022083s000_ClinPharmR_P1.pdf#page=38 Page: 38.0	no
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022083s000_ClinPharmR_P1.pdf#page=38 Page: 38.0	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022083s000_ClinPharmR_P1.pdf#page=38 Page: 38.0	no
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022083s000_ClinPharmR_P1.pdf#page=38 Page: 38.0	no
CYP3A5 201	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022083s000_ClinPharmR_P1.pdf#page=38 Page: 38.0	no
BCRP 985	inducer 1966 Sources: https://www.sciencedirect.com/science/article/pii/S0378517320309960	yes
P-gp 1932	inducer 1966 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788561/	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
esterase 74	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022083s000_ClinPharmR_P1.pdf#page=38 Page: 38.0	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:8874	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:8874
ChemicalBook	CB92656938	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB92656938
eMolecules	902424	https://www.emolecules.com/cgi-bin/more?vid=902424
MolPort	MolPort-003-666-662	https://www.molport.com/shop/molecule-link/MolPort-003-666-662
ZINC	ZINC000000004413	http://zinc15.docking.org/substances/ZINC000000004413

PubMed

Title	Date	PubMed
Evaluation of cholinergic treatment in demented patients by P300 evoked related potentials.	2001	12001652
A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase.	2001	11900310
[Perspectives for drug treatment in Alzheimer's disease].	2001 Dec	11937989
[Alzheimer dementia. Comparison of the effectiveness of cholinesterase inhibitors and gingko].	2001 Dec 13	11824165
Testosterone mediates sex difference in hypothermia and cholinesterase inhibition by rivastigmine.	2001 Dec 14	11755136
Rivastagmine-induced agitation following transient recollection of autobiographical memory.	2001 Jun	11731885
Rivastigmine in the treatment of parkinsonian psychosis and cognitive impairment: preliminary findings from an open trial.	2001 Nov	11748755
Erythematous maculopapular eruption due to rivastigmine therapy.	2001 Nov	11705442
[A comparison of cholinesterase inhibitors and ginkgo extract in treatment of Alzheimer dementia].	2001 Nov 29	11789125
[Risperidone in the ambulatory treatment of behavior disorders in demented patients of Alzheimer's type: a retrospective analysis].	2001 Nov-Dec	11877883
Dementia with Lewy bodies treated with rivastigmine: effects on cognition, neuropsychiatric symptoms, and sleep.	2001 Sep	11768375
Rivastigmine for the treatment of dementia and visual hallucinations associated with Parkinson's disease: a case series.	2002	12240787
Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis.	2002	12207957
Galantamine for Alzheimer's disease.	2002	12137632
Cutaneous drug reaction case reports: from the world literature.	2002	11978142
Estimation of the absolute bioavailability of rivastigmine in patients with mild to moderate dementia of the Alzheimer's type.	2002	11929322
Effects of rivastigmine on cognitive function in dementia with lewy bodies: a randomised placebo-controlled international study using the cognitive drug research computerised assessment system.	2002	11893841
Advances in the treatment of Alzheimer's disease: benefits of dual cholinesterase inhibition.	2002	11803198
The clinical benefits of rivastigmine may reflect its dual inhibitory mode of action: an hypothesis.	2002 Apr	12018828
A pilot, randomized, open-label trial assessing safety and pharmakokinetic parameters of co-administration of rivastigmine with risperidone in dementia patients with behavioral disturbances.	2002 Apr	11994888
SL65.0155, a novel 5-hydroxytryptamine(4) receptor partial agonist with potent cognition-enhancing properties.	2002 Aug	12130738
Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months.	2002 Aug 27	12196650
AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease.	2002 Aug-Oct	12212772
An open-label study to evaluate the safety, tolerability and efficacy of rivastigmine in patients with mild to moderate probable Alzheimer's disease in the community setting.	2002 Feb	11859291
Synthesis and cholinesterase activity of phenylcarbamates related to Rivastigmine, a therapeutic agent for Alzheimer's disease.	2002 Feb	11858843
Cerebral blood flow and cognitive responses to rivastigmine treatment in Alzheimer's disease.	2002 Jan 21	11924899
[Rivastigmine for Alzheimer disease; evaluation of preliminary results and of structured assessment of efficacy].	2002 Jan 5	11802333
Effect of subchronic administration of metrifonate, rivastigmine and donepezil on brain acetylcholine in aged F344 rats.	2002 Jul	12111444
Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit.	2002 Jul	12111443
Correlates of dropout, efficacy, and adverse events in treatment with acetylcholinesterase inhibitors in Korean patients with Alzheimer's disease.	2002 Jun	12243209
Evidence that the clinical effects of cholinesterase inhibitors are related to potency and targeting of action.	2002 Jun	12139368
Donepezil and rivastigmine in the treatment of Alzheimer's disease: a best-evidence synthesis of the published data on their efficacy and cost-effectiveness.	2002 Jun	12117079
[Nicotinic Receptor, galantamine and Alzheimer disease].	2002 Jun 1-15	12134305
Guidelines for managing Alzheimer's disease: Part II. Treatment.	2002 Jun 15	12086242
[Cognitive rehabilitation in Alzheimer's disease patients: multidisciplinary team report].	2002 Mar	11965412
Rivastigmin and impaired motor function.	2002 Mar	11951151
Understanding changes in cholinergic function: implications for treating dementia.	2002 Mar	11926730
Switching cholinesterase inhibitor therapy in Alzheimer's disease--donepezil to rivastigmine, is it worth it?	2002 Mar	11921158
Rivastigmine in outpatient services: experience of 114 neurologists in Austria.	2002 Mar	11890189
Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine.	2002 Mar 19	11888271
[Rivastigmine for Alzheimer disease; evaluation of preliminary results and of structured assessment of efficacy].	2002 Mar 9	11913117
Centrally acting antiemetics mitigate nausea and vomiting in patients with Alzheimer's disease who receive rivastigmine.	2002 Mar-Apr	11981242
In vitro toxicity of rivastigmine and donepezil in cells of epithelial origin.	2002 Mar-Apr	11914613
Impact of Alzheimer's disease and rivastigmine treatment on activities of daily living over the course of mild to moderately severe disease.	2002 May	12188104
Long-term effects of rivastigmine in moderately severe Alzheimer's disease: does early initiation of therapy offer sustained benefits?	2002 May	12188103
Pharmacologic treatments of dementia.	2002 May	12171061
Electrocardiographic effects of rivastigmine.	2002 May	12017350
Prolonged QT interval with rivastigmine.	2002 May	11983648
The nicotinic allosteric potentiating ligand galantamine facilitates synaptic transmission in the mammalian central nervous system.	2002 May	11961141
[Dementing disorders. What benefits do the new anti-dementia drugs have?].	2002 May 6	12070846

Patents

Sample Use Guides

In Vivo Use Guide

Oral (Indicated for mild-to-moderate dementia of the Alzheimer's type): Initial: 1.5 mg PO q12hr; Increase by 1.5 mg/dose q2Weeks; not to exceed 6 mg PO q12hr; Maintenance: 3-6 mg PO q12hr (higher end may be more beneficial); Transdermal (Indicated for mild, moderate, and severe dementia of the Alzheimer's type): Initial: Apply 4.6 mg q24hr; Dose titration: May increase dose to 9.5 mg q24hr after a minimum 4 weeks if well tolerated; after an additional 4 weeks, may further increase to 13.3 mg patch if needed; Mild-to-moderate Alzheimer disease: Effective dosage range is 9.5-13.3 mg/24 hr; Moderate-to-severe Alzheimer disease: Effective dose is 13.3 mg/24 hr; Replace with new patch q24hr

Route of Administration: Other

In Vitro Use Guide

The cytotoxicity of empty and Rivastigmine-loaded PHEA-EDASq17-PS80 micelles was evaluated on mouse neuroblastoma (Neuro2a) cell lines. cCells were seeded in 96 well plate at a density of 5×104 cells/well and grown in Minimum Essential Medium (MEM) with 10% FBS (fetal bovine serum) and 1% of penicillin/streptomycin (10,000U mL−1 penicillin and 10mg mL−1 streptomycin) at 37°C in 5% CO2 humidified atmosphere. After 72h of incubation, cells were treated with Riv-loaded micelles solutions in bidistilled water, having micelle concentrations of 1, 0.5 and 0.25mg/mL. Aliquots of micelle solutions (10 µL) were added to the cells in 100 µL fresh medium and incubated for 6, 24 and 48h. After incubation, 20 µL of MTT reagent solution [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide, Sigma; 0.5mg mL−1)] were added to each well and plates were incubated at 37°C for 2h; the absorbance was then measured by a multiwell plate reader (Multiskan Ex, Thermo absystems, Finland), at 490nm after background correction. Cells treated with Riv (Rivastigmine) solutions in DMSO, with drug concentration of 0.1, 0.2 and 0.05mg/mL, were used as positive control

Substance Class	Chemical Created by `admin` on `Mon Mar 31 17:59:23 GMT 2025` Edited by `admin` on `Mon Mar 31 17:59:23 GMT 2025`
Record UNII	9IY2357JPE
Record Status	`Validated (UNII)`
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Name

Type

Language

RIVASTIGMINE TARTRATE

Common Name

English

RIVASTIGMINE HYDROGEN TARTRATE

Preferred Name

English

RIVASTIGMINE (AS HYDROGEN TARTRATE)

Common Name

English

CARBAMIC ACID, N-ETHYL-N-METHYL-, 3-((1S)-1-(DIMETHYLAMINO)ETHYL)PHENYL ESTER, (2R,3R)-2,3-DIHYDROXYBUTANEDIOATE (1:1)

Common Name

English

RIVASTIGMINE HYDROGEN TARTRATE [MART.]

Common Name

English

SDZ-ENA-713

Code

English

RIVASTIGMINE TARTRATE [ORANGE BOOK]

Common Name

English

RIVASTIGMINE TARTRATE [USP MONOGRAPH]

Common Name

English

ENA-713

Code

English

RIVASTIGMINE HYDROGEN TARTRATE [EMA EPAR]

Common Name

English

RIVASTIGMINE HYDROGENTARTRATE

Common Name

English

RIVASTIGMINE HYDROGEN TARTRATE [EP MONOGRAPH]

Common Name

English

RIVASTIGMINE HYDROGEN TARTRATE [MI]

Common Name

English

SDZ-ENA 713

Common Name

English

RIVASTIGMINE TARTRATE [USP-RS]

Common Name

English

ENA 713

Code

English

RIVASTIGMINE ACTAVIS

Brand Name

English

Rivastigmine hydrogen tartrate [WHO-DD]

Common Name

English

RIVASTIGMINE BITARTRATE

Common Name

English

RIVASTIGMINE TARTRATE [VANDF]

Common Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

RIVASTIGMINE ACTAVIS (AUTHORIZED: PARKINSON DISEASE)