Lenalidomide (CED0001905)

Record Information
Version1.0
Creation Date2016-05-22 05:52:22 UTC
Update Date2026-08-18 23:27:02 UTC
Accession NumberCHEM019161
Identification
Common NameLenalidomide
ClassSmall Molecule
Description
Lenalidomide (C13H13N3O3) is an organic compound with an average molecular weight of 259.26 g/mol. Lenalidomide belongs to the isoindolines, a subclass of isoindoles and derivatives within the organic compounds. It functions as a drug (PMC4695140) and an anti-inflammatory agent (PMC3732931). The compound acts as an antagonist, inhibitor, or negative modulator of Protein cereblon (CRBN), Tumor necrosis factor ligand superfamily member 11 (TNFSF11), Prostaglandin G/H synthase 2 (PTGS2), Cadherin-5 (CDH5), and one other protein. Oral exposure is a recorded route for this compound, which is found in sources including healthcare, pharmaceuticals and veterinary products (immunosuppressants), household cleaning and consumer products (non electric simulated smoking devices), food, food processing and cookware (preparation of wine or sparkling wine), and electrical and electronic equipment (antennas, electric hearing aids). Lenalidomide is used in the treatment of anemia (PMC3977019, PMC4706836), B-cell lymphoma (PMC11743790), acute myeloid leukemia (PMC3128214), neuropathy (PMC7109734), and multiple myeloma (PMC10022849, PMC10040899, PMC10184122, PMC10216254, PMC10649824, PMC11172882, PMC11201495, PMC11219377). It has therapeutic effects on fatigue (PMC4408989) and multiple myeloma (PMC3496085, PMC4889030, PMC5217191, PMC5930136, PMC6410697, PMC7368820). Associated health effects include fatigue (PMC11219377, PMC12405678, PMC3674591, PMC3699390, PMC5215577, PMC6290473, PMC8171498, PMC8212249), neutropenia (PMC10230432, PMC10651865, PMC11219377, PMC11404760, PMC12052864, PMC12399965, PMC12405678, PMC12553274, PMC12801173), thrombocytopenia (PMC10651865, PMC12052864, PMC2361627, PMC3670754, PMC3674591, PMC3699390, PMC4232868, PMC4559079), diarrhea (PMC10828760, PMC12405678, PMC12801173, PMC4559079, PMC4753325, PMC6290473, PMC7271593), and thrombosis (PMC10519171, PMC10651865, PMC12946163, PMC13187128, PMC3674591, PMC4753325). Other associations include rash (PMC10230432, PMC10519171, PMC12405678, PMC4436674, PMC5215577, PMC6290473, PMC8171498, PMC8212249), pneumonia (PMC3227886, PMC3699390, PMC5679834, PMC8212249), hypokalemia (PMC5930136, PMC6290473, PMC8212249), bleeding (PMC10230432), neuropathy (PMC11219377), neuropathic pain (PMC4559079), confusion (PMC5930136), hypertension (PMC12946163), congestive heart failure (PMC12946163), cough (PMC8171498), bronchitis (PMC8171498), and renal failure (PMC11554676). The compound is elevated in the blood during renal insufficiency (PMC3673285).
Contaminant Type
  • Human Neurotoxin
Chemical Structure
MOLSDFPDBSMILESInChI
Synonyms
ValueSource
1-oxo-2-(2,6-Dioxopiperidin-3-yl)-4-aminoisoindolineChEBI
3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dioneChEBI
RevlimidChEBI
CC-5013HMDB
CDC 501HMDB
IMiD3HMDB
RevimidMeSH, HMDB
Celgene brand OF lenalidomideMeSH, HMDB
IMiD3 CPDMeSH, HMDB
Chemical FormulaC13H13N3O3
Average Molecular Mass259.261 g/mol
Monoisotopic Mass259.096 g/mol
CAS Registry Number191732-72-6
IUPAC Name3-(4-amino-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione
Traditional Namelenalidomide
SMILESNC1=CC=CC2=C1CN(C1CCC(=O)NC1=O)C2=O
InChI IdentifierInChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)
InChI KeyGOTYRUGSSMKFNF-UHFFFAOYSA-N
Chemical Taxonomy
Description Belongs to the class of organic compounds known as isoindolones. These are aromatic polycyclic compounds that an isoindole bearing a ketone.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassIsoindoles and derivatives
Sub ClassIsoindolines
Direct ParentIsoindolones
Alternative Parents
Substituents
  • Isoindolone
  • Alpha-amino acid or derivatives
  • Isoindole
  • Piperidinedione
  • Piperidinone
  • Delta-lactam
  • Benzenoid
  • Piperidine
  • Tertiary carboxylic acid amide
  • Carboxylic acid imide, n-unsubstituted
  • Dicarboximide
  • Carboxylic acid imide
  • Lactam
  • Carboxamide group
  • Amino acid or derivatives
  • Azacycle
  • Carboxylic acid derivative
  • Organic nitrogen compound
  • Organic oxygen compound
  • Organopnictogen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginNot Available
Cellular LocationsNot Available
Biofluid LocationsNot Available
Tissue LocationsNot Available
ApplicationsNot Available
Biological Roles
Chemical RolesNot Available
Organoleptic EffectsNot Available
Physical Properties
StateNot Available
AppearanceNot Available
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilityNot Available
Predicted Properties
PropertyValueSource
Water Solubility2.33 g/LALOGPS
logP-0.43ALOGPS
logP-0.71ChemAxon
logS-2ALOGPS
pKa (Strongest Acidic)11.61ChemAxon
pKa (Strongest Basic)2.31ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area92.5 ŲChemAxon
Rotatable Bond Count1ChemAxon
Refractivity68.3 m³·mol⁻¹ChemAxon
Polarizability25.55 ųChemAxon
Number of Rings3ChemAxon
BioavailabilityYesChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrumsplash10-01si-4950000000-d56c036a1d29e5a9442fNot AvailableView Spectrum
Predicted GC-MSPredicted GC-MS SpectrumNot AvailableNot AvailableView Spectrum
Predicted GC-MSPredicted GC-MS SpectrumNot AvailableNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0002-1920000000-c10c48acd9b8123e3505Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0002-1920000000-c10c48acd9b8123e3505Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-03dl-0090000000-2431a4e4063fb866e502Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-03dl-0590000000-3bd8341d78d9f0bb2185Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-0006-5900000000-ede52ce7143fcbe39e3cNot AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-0a4i-0190000000-a51e8a05d578a97d3916Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-0btc-2980000000-9fa6887f8d1dd5044b78Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-000f-9500000000-60ff64f6a1048a417538Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-03dj-0590000000-f93c028e30eeeb33fb07Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-01pk-0970000000-62ad8f815b005ef334f6Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-001j-2900000000-882d6b2043b051c57a33Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-0a4i-0090000000-7a47503a13a4776dc84eNot AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-0a4u-1690000000-9c997f4a738ff527b14aNot AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-0006-6910000000-618785cddde3e646877bNot AvailableView Spectrum
1D NMR13C NMR Spectrum (1D, D2O, predicted)Not AvailableNot AvailableView Spectrum
1D NMR1H NMR Spectrum (1D, D2O, predicted)Not AvailableNot AvailableView Spectrum
Toxicity Profile
Mechanism of ToxicityNot Available
Carcinogenicity (IARC Classification)Not Available
Minimum Risk LevelNot Available
SymptomsNot Available
TreatmentNot Available
Toxicity Values
Toxicity ValueUnitValue RangeOrganismDose DescriptorRoute of ExposurePredicted or ExperimentalReference
2143.0Log mg/kg[1200:3800]RatLD50oralpredictedNot Available
Health Effects
Health EffectRelationshipDirectionReference
hypertensionassociated_withNot AvailablePMC12946163
inflammationhas_therapeutic_effect_onNot AvailablePMC4505747
canceris_treatment_forNot AvailablePMC4084783 , PMC6052860
cancerassociated_withNot AvailablePMC2361627
breast cancerassociated_withNot AvailablePMC10828760
anemiais_treatment_forNot AvailablePMC3977019 , PMC4706836
anemiaassociated_withNot AvailablePMC4436674 , PMC4753325 , PMC6290473
anemiahas_therapeutic_effect_onNot AvailablePMC4979191
insomniaassociated_withNot AvailablePMC3674591 , PMC3674591
renal failureassociated_withNot AvailablePMC11554676
bronchitisassociated_withNot AvailablePMC8171498
colorectal cancerhas_therapeutic_effect_onNot AvailablePMC11029172
fatigueassociated_withNot AvailablePMC11219377 , PMC11219377 , PMC12405678 , PMC12405678 , PMC3674591 , PMC3699390 , PMC5215577 , PMC6290473 , PMC8171498 , PMC8212249
fatiguehas_therapeutic_effect_onNot AvailablePMC4408989
multiple myelomais_treatment_forNot AvailablePMC10022849 , PMC10040899 , PMC10040899 , PMC10184122 , PMC10216254 , PMC10649824 , PMC11172882 , PMC11172882 , PMC11201495 , PMC11219377
multiple myelomahas_therapeutic_effect_onNot AvailablePMC3496085 , PMC4889030 , PMC5217191 , PMC5930136 , PMC6410697 , PMC7368820
multiple myelomaassociated_withNot AvailablePMC12405678 , PMC2361627 , PMC2776067 , PMC4370362
diarrheaassociated_withNot AvailablePMC10828760 , PMC12405678 , PMC12801173 , PMC4559079 , PMC4753325 , PMC4753325 , PMC6290473 , PMC7271593 , PMC7271593 , PMC7271593
neutropeniaassociated_withNot AvailablePMC10230432 , PMC10651865 , PMC10651865 , PMC11219377 , PMC11404760 , PMC12052864 , PMC12399965 , PMC12405678 , PMC12553274 , PMC12801173
thrombocytopeniaassociated_withNot AvailablePMC10651865 , PMC12052864 , PMC2361627 , PMC2361627 , PMC3670754 , PMC3674591 , PMC3699390 , PMC4232868 , PMC4232868 , PMC4559079
thrombocytopeniaassociated_withincreasePMC4753325
neuropathic painassociated_withNot AvailablePMC4559079
feverassociated_withNot AvailablePMC10230432
bleedingassociated_withNot AvailablePMC10230432 , PMC6593978
painhas_therapeutic_effect_onNot AvailablePMC7271593
headacheassociated_withNot AvailablePMC8212249
Prostate cancerassociated_withNot AvailablePMC10828760 , PMC4370362
congestive heart failureassociated_withNot AvailablePMC12946163
melanomaassociated_withNot AvailablePMC4370362
melanomahas_therapeutic_effect_onNot AvailablePMC5730367
coughassociated_withNot AvailablePMC8171498
leukemiahas_therapeutic_effect_onNot AvailablePMC11780777
leukemiais_treatment_forNot AvailablePMC4182694
gastroenteritisassociated_withNot AvailablePMC12014722
hypothyroidismassociated_withNot AvailablePMC4684154
lymphomahas_therapeutic_effect_onNot AvailablePMC12917533
lymphomais_treatment_forNot AvailablePMC12052864 , PMC12405678 , PMC12983746 , PMC6033275 , PMC9323819
nauseaassociated_withincreasePMC4753325 , PMC6290473
vomitingassociated_withNot AvailablePMC3674591 , PMC4753325 , PMC6290473
edemaassociated_withNot AvailablePMC4436674
hyperuricemiaassociated_withNot AvailablePMC6290473
rashassociated_withNot AvailablePMC10230432 , PMC10519171 , PMC12405678 , PMC12405678 , PMC4436674 , PMC5215577 , PMC6290473 , PMC8171498 , PMC8171498 , PMC8212249
hypokalemiaassociated_withNot AvailablePMC5930136 , PMC6290473 , PMC8212249
pneumoniaassociated_withNot AvailablePMC3227886 , PMC3699390 , PMC3699390 , PMC5679834 , PMC8212249
neuropathyis_treatment_forNot AvailablePMC7109734
neuropathyassociated_withNot AvailablePMC11219377
thrombosisassociated_withNot AvailablePMC10519171 , PMC10651865 , PMC12946163 , PMC13187128 , PMC3674591 , PMC4753325
thrombosisassociated_withincreasePMC4753325
acute renal failureassociated_withNot AvailablePMC11554676
proteinuriais_treatment_forNot AvailablePMC6355407
proteinuriahas_therapeutic_effect_onNot AvailablePMC6355407
renal insufficiencyelevated_in_blood_inincreasePMC3673285
atrial fibrillationassociated_withNot AvailablePMC8212249
acute myeloid leukemiais_treatment_forNot AvailablePMC3128214
acute myeloid leukemiahas_therapeutic_effect_onNot AvailablePMC4684154
non-Hodgkin lymphomais_treatment_forNot AvailablePMC7581128
non-Hodgkin lymphomahas_therapeutic_effect_onNot AvailablePMC8212249
dyspneahas_therapeutic_effect_onNot AvailablePMC7581128
vertigoassociated_withNot AvailablePMC10230432
B-cell lymphomais_treatment_forNot AvailablePMC11743790
B-cell lymphomahas_therapeutic_effect_onNot AvailablePMC7705367
confusionassociated_withNot AvailablePMC5930136
squamous cell carcinomaassociated_withNot AvailablePMC10828760
basal cell carcinomaassociated_withNot AvailablePMC10230432 , PMC10828760
chest painassociated_withNot AvailablePMC4436674 , PMC8639956
leukopeniaassociated_withNot AvailablePMC6290473
Burkitt lymphomahas_therapeutic_effect_onNot AvailablePMC4505747
pulmonary embolismassociated_withNot AvailablePMC10651865
pulmonary hypertensionis_treatment_forNot AvailablePMC7705367
pulmonary hypertensionhas_therapeutic_effect_onNot AvailablePMC7705367
chronic lymphocytic leukemiais_treatment_forNot AvailablePMC6400263
chronic lymphocytic leukemiahas_therapeutic_effect_onNot AvailablePMC4182694 , PMC4505747
hematologic cancerassociated_withNot AvailablePMC3653900 , PMC3653900 , PMC3653900 , PMC3653900
plasma cell leukemiahas_therapeutic_effect_onNot AvailablePMC4044724
mantle cell lymphomais_treatment_forNot AvailablePMC12000610 , PMC4725701 , PMC4725701
mantle cell lymphomahas_therapeutic_effect_onNot AvailablePMC4370362
follicular lymphomais_treatment_forNot AvailablePMC11743790 , PMC12000610 , PMC12405678 , PMC9198921 , PMC9262142 , PMC9553375
follicular lymphomahas_therapeutic_effect_onNot AvailablePMC7705367
marginal zone lymphomais_treatment_forNot AvailablePMC12000610 , PMC13096082
myelodysplastic syndromeis_treatment_forNot AvailablePMC3128214 , PMC5350610
myelodysplastic syndromehas_therapeutic_effect_onNot AvailablePMC3496085
lung adenocarcinomaassociated_withNot AvailablePMC10828760
myelofibrosishas_therapeutic_effect_onNot AvailablePMC4408989
leprosyis_treatment_forNot AvailablePMC10216254
POEMS syndromeis_treatment_forNot AvailablePMC6067145 , PMC7238582 , PMC7654174 , PMC9387014 , PMC9387014
POEMS syndromehas_therapeutic_effect_onNot AvailablePMC6928515
lymphopeniaassociated_withincreasePMC10651865 , PMC9262142 , PMC9262142
lymph node diseasehas_therapeutic_effect_onNot AvailablePMC4436674
diffuse large B-cell lymphomais_treatment_forNot AvailablePMC10828760 , PMC10879405 , PMC11936473 , PMC11936473 , PMC12917533 , PMC12983746 , PMC8639956 , PMC9519642
diffuse large B-cell lymphomahas_therapeutic_effect_onNot AvailablePMC4370362 , PMC4505747
pancreatitisassociated_withNot AvailablePMC8212249
thrombocytosisassociated_withNot AvailablePMC2361627
plasmablastic lymphomais_treatment_forNot AvailablePMC9323819
smoldering myelomais_treatment_forNot AvailablePMC11404760 , PMC11404760
anaplastic large cell lymphomais_treatment_forNot AvailablePMC7598776
relapsed/refractory diffuse large B-cell lymphomais_treatment_forNot AvailablePMC10020798
amyloidosisis_treatment_forNot AvailablePMC3789465
paronychiaassociated_withNot AvailablePMC10519171
thrombotic thrombocytopenic purpuraassociated_withNot AvailablePMC6290473
Exposure Sources
Source IDSourceSectorReference
362ImmunosuppressantsHealthcare, pharmaceuticals & veterinary productsNot Available
506AntennasElectrical & Electronic EquipmentNot Available
516Electric Hearing AidsElectrical & Electronic EquipmentNot Available
549Preparation Of Wine Or Sparkling WineFood, food processing & cookwareNot Available
559Non Electric Simulated Smoking DevicesHousehold cleaning & consumer productsNot Available
Pathways
2 pathways
Lenalidomide Drug Metabolism Action Pathway
Lenalidomide Drug Metabolism Action Pathway
Lenalidomide Predicted Metabolism Pathway
Lenalidomide Predicted Metabolism Pathway
Targets
StructureProteinUniProt IDOrganismRelationshipDetails
Protein cereblon structureClick to view 3D structureProtein cereblonQ96SW2HumansPredicted (SEA)0.0778492
Tumor necrosis factor structureClick to view 3D structureTumor necrosis factorP01375HumansPredicted (SEA)0.0778492
Interleukin-1 beta structureClick to view 3D structureInterleukin-1 betaP01584HumansPredicted (SEA)0.0778492
Click to view 3D structureGlyceraldehyde-3-phosphate dehydrogenase, cytosolicQ01558Leishmania mexicanaPredicted (SEA)0.0778492
Click to view 3D structureZinc finger protein AiolosQ9UKT9HumansPredicted (SEA)0.0778492
Click to view 3D structureCereblon isoform 4A4TVL0Magnetospirillum gryphiswaldensePredicted (SEA)0.0778492
Bromodomain-containing protein 4 structureClick to view 3D structureBromodomain-containing protein 4O60885HumansPredicted (SEA)41.2601
Zinc finger protein Helios structureClick to view 3D structureZinc finger protein HeliosQ9UKS7HumansPredicted (SEA)0.155698
DNA-binding protein Ikaros structureClick to view 3D structureDNA-binding protein IkarosQ13422HumansPredicted (SEA)0.311397
Click to view 3D structureProtein Aster-AQ96CP6HumansPredicted (SEA)0.700643
Eukaryotic peptide chain release factor GTP-binding subunit ERF3A structureClick to view 3D structureEukaryotic peptide chain release factor GTP-binding subunit ERF3AP15170HumansPredicted (SEA)0.233548
Voltage-gated inwardly rectifying potassium channel KCNH2 structureClick to view 3D structureVoltage-gated inwardly rectifying potassium channel KCNH2Q12809HumansPredicted (SEA)1603.3
Cytochrome P450 2C19 structureClick to view 3D structureCytochrome P450 2C19P33261HumansPredicted (SEA)726.178
Signal transducer and activator of transcription 2 structureClick to view 3D structureSignal transducer and activator of transcription 2P52630HumansPredicted (SEA)2.17978
Cytochrome P450 3A4 structureClick to view 3D structureCytochrome P450 3A4P08684HumansPredicted (SEA)2852.47
Cytochrome P450 2C9 structureClick to view 3D structureCytochrome P450 2C9P11712HumansPredicted (SEA)2438.47
Cytochrome P450 1A2 structureClick to view 3D structureCytochrome P450 1A2P05177HumansPredicted (SEA)1677.18
Click to view 3D structureSignal transducer and activator of transcription 4Q14765HumansPredicted (SEA)1.94623
Cytochrome P450 2D6 structureClick to view 3D structureCytochrome P450 2D6P10635HumansPredicted (SEA)2706.19
Cytochrome P450 2B6 structureClick to view 3D structureCytochrome P450 2B6P20813HumansPredicted (SEA)144.177
Casein kinase I isoform alpha structureClick to view 3D structureCasein kinase I isoform alphaP48729HumansPredicted (SEA)2292.35
Click to view 3D structureSigma intracellular receptor 2Q5BJF2HumansPredicted (SEA)1414.6
Receptor-type tyrosine-protein kinase FLT3 structureClick to view 3D structureReceptor-type tyrosine-protein kinase FLT3P36888HumansPredicted (SEA)3931.62
Histone deacetylase 1 structureClick to view 3D structureHistone deacetylase 1Q13547HumansPredicted (SEA)2809.11
Click to view 3D structureProstaglandin G/H synthase 1P05979Ovis ariesPredicted (SEA)615.865
Concentrations
Not Available
External Links
DrugBank IDDB00480
HMDB IDHMDB0259413
FooDB IDNot Available
Phenol Explorer IDNot Available
KNApSAcK IDNot Available
BiGG IDNot Available
BioCyc IDNot Available
METLIN IDNot Available
PDB IDNot Available
Wikipedia LinkLenalidomide
Chemspider ID187515
ChEBI ID63791
PubChem Compound IDNot Available
Kegg Compound IDNot Available
YMDB IDNot Available
ECMDB IDNot Available
References
Synthesis ReferenceNot Available
MSDSNot Available
General References
1. https://www.ncbi.nlm.nih.gov/pubmed/?term=21533608
2. https://www.ncbi.nlm.nih.gov/pubmed/?term=21823830
3. https://www.ncbi.nlm.nih.gov/pubmed/?term=21835953
4. https://www.ncbi.nlm.nih.gov/pubmed/?term=22001752
5. https://www.ncbi.nlm.nih.gov/pubmed/?term=22066855
6. https://www.ncbi.nlm.nih.gov/pubmed/?term=22107129
7. https://www.ncbi.nlm.nih.gov/pubmed/?term=22143062
8. https://www.ncbi.nlm.nih.gov/pubmed/?term=22211836
9. https://www.ncbi.nlm.nih.gov/pubmed/?term=22241792
10. https://www.ncbi.nlm.nih.gov/pubmed/?term=22245427
11. https://www.ncbi.nlm.nih.gov/pubmed/?term=22245805
12. https://www.ncbi.nlm.nih.gov/pubmed/?term=22245806
13. https://www.ncbi.nlm.nih.gov/pubmed/?term=22246035
14. https://www.ncbi.nlm.nih.gov/pubmed/?term=22253550
15. https://www.ncbi.nlm.nih.gov/pubmed/?term=22261445