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

Details

Stereochemistry RACEMIC
Molecular Formula C13H10N2O4
Molecular Weight 258.2295
Optical Activity ( + / - )
Defined Stereocenters 0 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of THALIDOMIDE

SMILES

O=C1N(C2CCC(=O)NC2=O)C(=O)C3=CC=CC=C13

InChI

InChIKey=UEJJHQNACJXSKW-UHFFFAOYSA-N
InChI=1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)

HIDE SMILES / InChI

Description
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020785s051lbl.pdf

Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. Thalidomide is racemic — it contains both left and right-handed isomers in equal amounts: one enantiomer is effective against morning sickness, and the other is teratogenic. The enantiomers are converted to each other in vivo. That is, if a human is given D-thalidomide or L-thalidomide, both isomers can be found in the serum. Hence, administering only one enantiomer will not prevent the teratogenic effect in humans. In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood. Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-a) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-a in patients with ENL, however, it has also been shown to increase plasma TNF-a levels in HIV-seropositive patients. As a cancer treatment, the drug may act as a VEGF inhibitor. Thalidomide is used for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). Also for use as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. Thalidomide is sold under the brand name Immunoprin, among others.

CNS Activity

Curator's Comment: Thalidomide, an inhibitor of TNF-α protein synthesis is readily capable of crossing the blood-brain barrier

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: Q96SW2
Gene ID: 51185.0
Gene Symbol: CRBN
Target Organism: Homo sapiens (Human)
Target ID: CHEMBL1825
200.0 µM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
THALOMID

Approved Use

THALOMID in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM). THALOMID is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.

Launch Date

9.0046077E11
Primary
THALOMID

Approved Use

THALOMID in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM). THALOMID is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.

Launch Date

9.0046077E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
2 mg/L
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
THALIDOMIDE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
19.8 mg × h/L
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
THALIDOMIDE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
6.17 h
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
THALIDOMIDE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
45%
THALIDOMIDE plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
400 mg/m2 1 times / day multiple, oral
MTD
Dose: 400 mg/m2, 1 times / day
Route: oral
Route: multiple
Dose: 400 mg/m2, 1 times / day
Co-administed with::
Carboplatin, i.v(1/21 days)
Sources: Page: p.4397
unhealthy, 11
n = 10
Health Status: unhealthy
Condition: Cancer
Age Group: 11
Sex: M+F
Population Size: 10
Sources: Page: p.4397
DLT: Somnolence...
Dose limiting toxicities:
Somnolence (20%)
Sources: Page: p.4397
400 mg/m2 1 times / day multiple, oral
MTD
Dose: 400 mg/m2, 1 times / day
Route: oral
Route: multiple
Dose: 400 mg/m2, 1 times / day
Co-administed with::
Carboplatin, i.v(1/21 days)
Sources: Page: p.4397
unhealthy, 11
n = 6
Health Status: unhealthy
Condition: Cancer
Age Group: 11
Sex: M+F
Population Size: 6
Sources: Page: p.4397
DLT: Ataxia...
Dose limiting toxicities:
Ataxia (16.7%)
Sources: Page: p.4397
150 mg 2 times / day multiple, oral
MTD
Dose: 150 mg, 2 times / day
Route: oral
Route: multiple
Dose: 150 mg, 2 times / day
Sources: Page: p.658
unhealthy, 57
n = 7
Health Status: unhealthy
Condition: Hepatocellular carcinoma
Age Group: 57
Sex: M+F
Population Size: 7
Sources: Page: p.658
200 mg 2 times / day multiple, oral
Studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources: Page: p.658
unhealthy, 57
n = 2
Health Status: unhealthy
Condition: Hepatocellular carcinoma
Age Group: 57
Sex: M+F
Population Size: 2
Sources: Page: p.658
DLT: Dyspnea...
Dose limiting toxicities:
Dyspnea (50%)
Sources: Page: p.658
400 mg 1 times / day multiple, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: multiple
Dose: 400 mg, 1 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Erythema nodosum leprosum
Sources: Page: p.1
Disc. AE: Fetal damage, Deep vein thrombosis...
AEs leading to
discontinuation/dose reduction:
Fetal damage
Deep vein thrombosis
Pulmonary embolism
Sources: Page: p.1
AEs

AEs

AESignificanceDosePopulation
Somnolence 20%
DLT
400 mg/m2 1 times / day multiple, oral
MTD
Dose: 400 mg/m2, 1 times / day
Route: oral
Route: multiple
Dose: 400 mg/m2, 1 times / day
Co-administed with::
Carboplatin, i.v(1/21 days)
Sources: Page: p.4397
unhealthy, 11
n = 10
Health Status: unhealthy
Condition: Cancer
Age Group: 11
Sex: M+F
Population Size: 10
Sources: Page: p.4397
Ataxia 16.7%
DLT
400 mg/m2 1 times / day multiple, oral
MTD
Dose: 400 mg/m2, 1 times / day
Route: oral
Route: multiple
Dose: 400 mg/m2, 1 times / day
Co-administed with::
Carboplatin, i.v(1/21 days)
Sources: Page: p.4397
unhealthy, 11
n = 6
Health Status: unhealthy
Condition: Cancer
Age Group: 11
Sex: M+F
Population Size: 6
Sources: Page: p.4397
Dyspnea 50%
DLT
200 mg 2 times / day multiple, oral
Studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources: Page: p.658
unhealthy, 57
n = 2
Health Status: unhealthy
Condition: Hepatocellular carcinoma
Age Group: 57
Sex: M+F
Population Size: 2
Sources: Page: p.658
Deep vein thrombosis Disc. AE
400 mg 1 times / day multiple, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: multiple
Dose: 400 mg, 1 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Erythema nodosum leprosum
Sources: Page: p.1
Fetal damage Disc. AE
400 mg 1 times / day multiple, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: multiple
Dose: 400 mg, 1 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Erythema nodosum leprosum
Sources: Page: p.1
Pulmonary embolism Disc. AE
400 mg 1 times / day multiple, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: multiple
Dose: 400 mg, 1 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Erythema nodosum leprosum
Sources: Page: p.1
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Lack of in vitro antimicrosporidian activity of thalidomide.
1999 Sep
Thalidomide neuropathy: role of F-wave monitoring.
2000 Aug
Thalidomide for treatment of patients with chronic graft-versus-host disease.
2000 Dec 1
Thalidomide in gastrointestinal disorders.
2001
A cybernetic theory of morality and moral autonomy.
2001 Apr
Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma.
2001 Apr
Treatment of Behçet's disease--an update.
2001 Apr
Pharmacotherapeutic options in inflammatory bowel disease: an update.
2001 Feb
Thalidomide.
2001 Feb
[Suppression of synthesis of tumor necrosis factor].
2001 Jan
Safety profile of thalidomide after 53 weeks of oral administration in beagle dogs.
2001 Jan
Treatment strategies for recurrent oral aphthous ulcers.
2001 Jan 1
Clinical aspects and management of AIDS-related Kaposi's sarcoma.
2001 Jul
Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma.
2001 Jul 1
Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.
2001 Jul 15
Thalidomide and prednisolone inhibit growth factor-induced human retinal pigment epithelium cell proliferation in vitro.
2001 Jul-Aug
Thalidomide dose proportionality assessment following single doses to healthy subjects.
2001 Jun
Color Doppler ultrasonography of the superior mesenteric artery for prenatal ultrasonographic diagnosis of a left-sided congenital diaphragmatic hernia.
2001 Jun
Effectors of inflammation in actinic prurigo.
2001 Jun
Deep venous thrombosis and thalidomide therapy for multiple myeloma.
2001 Jun 21
[Thalidomide and thrombosis: three observations].
2001 Jun 9
Prognostic factors and current practice in treatment of myelofibrosis with myeloid metaplasia: an update anno 2000.
2001 Mar
Cutaneous lupus erythematosus.
2001 Mar
Anti-tumor necrosis factor monoclonal antibody therapy for gastrointestinal Behçet's disease: a case report.
2001 Mar
Embryonic mouse submandibular salivary gland morphogenesis and the TNF/TNF-R1 signal transduction pathway.
2001 Mar 1
Thalidomide in multiple myeloma: lack of response of soft-tissue plasmacytomas.
2001 May
Approach to corticosteroid-dependent and corticosteroid-refractory Crohn's disease.
2001 May
Thalidomide and its dermatologic uses.
2001 May
Pilot study using the combination of methotrexate and thalidomide in the treatment of rheumatoid arthritis.
2001 May-Jun
Patents

Sample Use Guides

MM: 200 mg orally once daily. The recommended dose of dexamethasone is 40 mg/day on days 1-4, 9-12, and 17-20 every 28 days. • ENL: 100 to 300 mg/day for an episode of cutaneous ENL. Up to 400 mg/day for severe cutaneous ENL.
Route of Administration: Oral
The minimum dose of thalidomide used (1 uM) inhibited TNF-α production in HTLV-1-infected subjects in vitro.
Name Type Language
THALIDOMIDE
EMA EPAR   HSDB   INN   JAN   MART.   MI   ORANGE BOOK   USAN   USP   USP-RS   VANDF   WHO-DD  
USAN   INN  
Official Name English
K-17
Code English
KEVADON
Brand Name English
THALIDOMIDE [JAN]
Common Name English
THALIDOMIDE [HSDB]
Common Name English
Thalidomide [WHO-DD]
Common Name English
THALIDOMIDE [MART.]
Common Name English
2,6-DIOXO-3-PHTHALIMIDOPIPERIDINE
Systematic Name English
CONTERGAN
Brand Name English
THALIDOMIDE [VANDF]
Common Name English
DISTAVAL
Brand Name English
(±)-N-(2,6-DIOXO-3-PIPERIDYL)PHTHALIMIDE
Systematic Name English
PHARMION
Brand Name English
THALIDOMIDE [USAN]
Common Name English
N-PHTHALYLGLUTAMIC ACID IMIDE
Common Name English
.ALPHA.-PHTHALIMIDOGLUTARIMIDE
Common Name English
NSC-527179
Code English
MYRIN
Brand Name English
NSC-66847
Code English
N-(2,6-Dioxo-3-piperidyl)phthalimide
Systematic Name English
thalidomide [INN]
Common Name English
THALIDOMIDE [USP MONOGRAPH]
Common Name English
THALIDOMIDE [USP-RS]
Common Name English
NEUROSEDYN
Brand Name English
THALIDOMIDE [ORANGE BOOK]
Common Name English
1H-ISOINDOLE-1,3(2H)-DIONE, 2-(2,6-DIOXO-3-PIPERIDINYL)-, (±)-
Systematic Name English
CELGENE
Brand Name English
THALOMID
Brand Name English
2-(2,6-DIOXO-3-PIPERIDINYL)-1H-ISOINDOLE-1,3(2H)-DIONE
Systematic Name English
SOFTENON
Brand Name English
.ALPHA.-(N-PHTHALIMIDO)GLUTARIMIDE
Common Name English
PANTOSEDIV
Brand Name English
THALIDOMIDE [EMA EPAR]
Common Name English
3-PHTHALIMIDOGLUTARIMIDE
Systematic Name English
THALED
Brand Name English
THALIDOMIDE [MI]
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 43890
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 80194
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 30788
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
WHO-ATC L04AX02
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 115598
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 43790
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
NDF-RT N0000008663
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
WHO-VATC QL04AX02
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 90795
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
EU-Orphan Drug EU/3/01/067
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
NDF-RT N0000008663
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 585417
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 110197
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 72092
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
NCI_THESAURUS C129820
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 114998
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
NCI_THESAURUS C1742
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 121898
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 187204
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 94995
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
NCI_THESAURUS C574
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 32188
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
EMA ASSESSMENT REPORTS THALIDOMIDE CELGENE (AUTHORIZED: MUTIPLE MYELOMA)
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
NCI_THESAURUS C54677
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
FDA ORPHAN DRUG 82594
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
LIVERTOX NBK548371
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
Code System Code Type Description
CAS
50-35-1
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
NSC
527179
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
RXCUI
10432
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY RxNorm
DAILYMED
4Z8R6ORS6L
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
EPA CompTox
DTXSID9022524
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
SMS_ID
100000089194
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
RS_ITEM_NUM
1652500
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
FDA UNII
4Z8R6ORS6L
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
CHEBI
74947
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
MESH
D013792
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
PUBCHEM
5426
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
NSC
66847
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
DRUG BANK
DB01041
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
IUPHAR
7327
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
ChEMBL
CHEMBL468
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
WIKIPEDIA
THALIDOMIDE
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
EVMPD
SUB10958MIG
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
CHEBI
9513
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
NCI_THESAURUS
C870
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
ECHA (EC/EINECS)
200-031-1
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
INN
762
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
DRUG CENTRAL
2616
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY
MERCK INDEX
m10673
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY Merck Index
HSDB
3586
Created by admin on Fri Dec 15 16:11:52 UTC 2023 , Edited by admin on Fri Dec 15 16:11:52 UTC 2023
PRIMARY