U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C13H16ClNO
Molecular Weight 237.7257
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ESKETAMINE

SMILES

CN[C@@]1(CCCCC1=O)c2ccccc2Cl

InChI

InChIKey=YQEZLKZALYSWHR-ZDUSSCGKSA-N
InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3/t13-/m0/s1

HIDE SMILES / InChI
Esketamine is an S(+)-enantiomer of ketamine. It is a nonselective, noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor. A nasal spray, containing esketamine, was approved in 2019 for the treatment of treatment-resistant depression in adults, in conjunction with an oral antidepressant, and is marketed under tradename SPARAVATO. Esketamine is a schedule III drug product in the USA.

Approval Year

Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
153 ng/mL
0.7 mg/kg single, respiratory
dose: 0.7 mg/kg
route of administration: Respiratory
experiment type: SINGLE
co-administered:
NORKETAMINE, (S)- plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
52 ng/mL
0.35 mg/kg single, respiratory
dose: 0.35 mg/kg
route of administration: Respiratory
experiment type: SINGLE
co-administered:
NORKETAMINE, (S)- plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
97 ng/mL
0.5 mg/kg single, respiratory
dose: 0.5 mg/kg
route of administration: Respiratory
experiment type: SINGLE
co-administered:
NORKETAMINE, (S)- plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
2277.6 ng/mL
0.5 mg/kg single, intramuscular
dose: 0.5 mg/kg
route of administration: Intramuscular
experiment type: SINGLE
co-administered:
ESKETAMINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
128 ng/mL
0.35 mg/kg single, respiratory
dose: 0.35 mg/kg
route of administration: Respiratory
experiment type: SINGLE
co-administered:
ESKETAMINE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
180 ng/mL
0.5 mg/kg single, respiratory
dose: 0.5 mg/kg
route of administration: Respiratory
experiment type: SINGLE
co-administered:
ESKETAMINE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
227 ng/mL
0.7 mg/kg single, respiratory
dose: 0.7 mg/kg
route of administration: Respiratory
experiment type: SINGLE
co-administered:
ESKETAMINE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
475.2 ng × h/mL
0.5 mg/kg single, intramuscular
dose: 0.5 mg/kg
route of administration: Intramuscular
experiment type: SINGLE
co-administered:
ESKETAMINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
7.5 h
single, respiratory
NORKETAMINE, (S)- plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
287.5 min
0.5 mg/kg single, intramuscular
dose: 0.5 mg/kg
route of administration: Intramuscular
experiment type: SINGLE
co-administered:
ESKETAMINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
11.1 h
single, respiratory
ESKETAMINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
56%
ESKETAMINE plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Other AEs: Vomiting...
Other AEs:
Vomiting (3%)
Sources:
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Other AEs: Dissociation, Dizziness...
Other AEs:
Dissociation (17%)
Dizziness (3%)
Dry mouth (7%)
Headache (23%)
Nasopharyngitis (7%)
Nausea (10%)
Oropharyngeal pain (3%)
Paresthesia (7%)
Vertigo (7%)
Sources:
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Disc. AE: Depression, Blood pressure increased...
AEs leading to
discontinuation/dose reduction:
Depression (0.9%)
Blood pressure increased (0.6%)
Dizziness (0.6%)
Suicidal ideation (0.5%)
Dissociation (0.4%)
Nausea (0.4%)
Vomiting (0.4%)
Headache (0.3%)
Muscular weakness (0.3%)
Vertigo (0.2%)
Hypertension (0.2%)
Panic attack (0.2%)
Sedation (0.2%)
Sources:
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant(oral)
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Disc. AE: Anxiety...
AEs leading to
discontinuation/dose reduction:
Anxiety (1.2%)
Sources:
10 mg 1 times / day multiple, oral (starting)
Dose: 10 mg, 1 times / day
Route: oral
Route: multiple
Dose: 10 mg, 1 times / day
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: adult
Sex: M+F
Sources:
28 mg single, intravenous
Dose: 28 mg
Route: intravenous
Route: single
Dose: 28 mg
Sources: Page: p. 43
unhealthy|healthy
n = 18
Health Status: unhealthy|healthy
Condition: treatment-resistant depression
Population Size: 18
Sources: Page: p. 43
84 mg single, oral
Dose: 84 mg
Route: oral
Route: single
Dose: 84 mg
Sources: Page: p. 43
unhealthy|healthy
n = 14
Health Status: unhealthy|healthy
Condition: treatment-resistant depression
Sex: M+F
Population Size: 14
Sources: Page: p. 43
AEs

AEs

AESignificanceDosePopulation
Vomiting 3%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Nausea 10%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Dissociation 17%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Headache 23%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Dizziness 3%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Oropharyngeal pain 3%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Dry mouth 7%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Nasopharyngitis 7%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Paresthesia 7%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Vertigo 7%
40 mg/kg 2 times / week multiple, intravenous
Dose: 40 mg/kg, 2 times / week
Route: intravenous
Route: multiple
Dose: 40 mg/kg, 2 times / week
Sources:
unhealthy, 41.8 years (range: 11 - 63 years)
n = 11
Health Status: unhealthy
Condition: treatment resistant depression
Age Group: 41.8 years (range: 11 - 63 years)
Sex: M+F
Population Size: 11
Sources:
Hypertension 0.2%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Panic attack 0.2%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Sedation 0.2%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Vertigo 0.2%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Headache 0.3%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Muscular weakness 0.3%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Dissociation 0.4%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Nausea 0.4%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Vomiting 0.4%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Suicidal ideation 0.5%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Blood pressure increased 0.6%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Dizziness 0.6%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Depression 0.9%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
Anxiety 1.2%
Disc. AE
56 mg 2 times / week steady, intranasal (starting)
Recommended
Dose: 56 mg, 2 times / week
Route: intranasal
Route: steady
Dose: 56 mg, 2 times / week
Co-administed with::
antidepressant(oral)
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: major depressive disorder
Age Group: adult
Sex: M+F
Sources:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
modest
no (co-administration study)
Comment: administration with bupropion (substrate): activity of hepatic CYP2B6 was not altered
Page: 33,34
modest
weak (co-administration study)
Comment: twice-a-week dosing of nasal esketamine (84 mg) reduced the AUClast and AUC?? of probe CYP3A substrate Reference ID: 4397019 35 midazolam by a mean of 18% and 16%, respectively;
Page: 33,35
no
no
no
no
no
no
no
no
no
no
no
no
yes [IC50 1.92 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
weak (co-administration study)
Comment: pretreatment with ticlopidine (inhibitor) had no effect on the mean esketamine Cmax following a 56-mg nasal dose, whereas the AUC of esketamine was increased by 29%; Cmax, AUClast, and AUCinf of esketamine were approximately 17%, 31%, and 28% lower, respectively, when subjects were pretreated with rifampicin (inducer);
Page: 33,36,37
major
weak (co-administration study)
Comment: esketamine Cmax and AUCinf were increased by 11% and 4%, respectively, when coadministered with clarithromycin; Cmax, AUClast, and AUCinf of esketamine were approximately 17%, 31%, and 28% lower, respectively, when subjects were pretreated with rifampicin (inducer);
Page: 33,36,37
minor
minor
no
no
no
no
no
no
no
no
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Determination of absolute configuration of ketamine enantiomers by HPLC-CD-UV technique.
1999
Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells.
1999 Jan
Name Type Language
ESKETAMINE
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
JNJ-54135419
Common Name English
KETAMINE, S-
Common Name English
(2S)-2-(2-CHLOROPHENYL)-2-(METHYLAMINO)CYCLOHEXANONE
Systematic Name English
ESKETAMINE [WHO-DD]
Common Name English
CYCLOHEXANONE, 2-(O-CHLOROPHENYL)-2-(METHYLAMINO)-, (-)-
Common Name English
ESKETAMINE [USAN]
Common Name English
KETAVED
Brand Name English
S-KETAMINE
Common Name English
(-)-KETAMINE
Common Name English
L-KETAMINE
Common Name English
CYCLOHEXANONE, 2-(2-CHLOROPHENYL)-2-(METHYLAMINO)-, (2S)-
Systematic Name English
CYCLOHEXANONE, 2-(2-CHLOROPHENYL)-2-(METHYLAMINO)-, (S)-
Systematic Name English
S-(-)-KETAMINE
Common Name English
KETA-S
Brand Name English
ESKETAMINE [INN]
Common Name English
KETAMINE, (S)-
Common Name English
(S)-2-(O-CHLOROPHENYL)-2-(METHYLAMINO)CYCLOHEXANONE
Common Name English
Classification Tree Code System Code
WHO-ATC N01AX14
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
NCI_THESAURUS C245
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
WHO-VATC QN01AX14
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
Code System Code Type Description
WIKIPEDIA
ESKETAMINE
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
LACTMED
Esketamine
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
DRUG CENTRAL
4468
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
RXCUI
2119365
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
INN
7884
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
DRUG BANK
DB11823
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
EVMPD
SUB25825
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
EPA CompTox
33643-46-8
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
FDA UNII
50LFG02TXD
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
ChEMBL
CHEMBL395091
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
CAS
33643-46-8
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
PUBCHEM
182137
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY
NCI_THESAURUS
C81400
Created by admin on Fri Jun 25 23:18:26 UTC 2021 , Edited by admin on Fri Jun 25 23:18:26 UTC 2021
PRIMARY