Memantine (T3D2967)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (8)XML
Targets (8)
Record Information
Version2.0
Creation Date2009-07-21 20:28:14 UTC
Update Date2014-12-24 20:25:54 UTC
Accession NumberT3D2967
Identification
Common NameMemantine
ClassSmall Molecule
DescriptionMemantine is an amantadine derivative with low to moderate-affinity for NMDA receptors. It is a noncompetitive NMDA receptor antagonist that binds preferentially to NMDA receptor-operated cation channels. It blocks the effects of excessive levels of glutamate that may lead to neuronal dysfunction. It is under investigation for the treatment of Alzheimer's disease, but there has been no clinical support for the prevention or slowing of disease progression.
Compound Type
  • Amine
  • Antidyskinetic
  • Antiparkinson Agent
  • Central Nervous System Agent
  • Dopamine Agent
  • Drug
  • Excitatory Amino Acid Antagonist
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
1,3-Dimethyl-5-adamantanamine
1-Amino-3,5-dimethyladamantane
3,5-Dimethyl-1-adamantanamine
3,5-Dimethyl-1-aminoadamantane
3,5-Dimethyltricyclo(3.3.1.1(3,7))decan-1-amine
Abixa
Akatinol
Axura
Ebixa
Memantina
Memantinum
Memox
Namenda
Chemical FormulaC12H21N
Average Molecular Mass179.302 g/mol
Monoisotopic Mass179.167 g/mol
CAS Registry Number19982-08-2
IUPAC Name3,5-dimethyladamantan-1-amine
Traditional Namememantine
SMILESCC12CC3CC(C)(C1)CC(N)(C3)C2
InChI IdentifierInChI=1/C12H21N/c1-10-3-9-4-11(2,6-10)8-12(13,5-9)7-10/h9H,3-8,13H2,1-2H3
InChI KeyInChIKey=BUGYDGFZZOZRHP-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as monoalkylamines. These are organic compounds containing an primary aliphatic amine group.
KingdomOrganic compounds
Super ClassOrganic nitrogen compounds
ClassOrganonitrogen compounds
Sub ClassAmines
Direct ParentMonoalkylamines
Alternative Parents
Substituents
  • Organopnictogen compound
  • Hydrocarbon derivative
  • Primary aliphatic amine
  • Aliphatic homopolycyclic compound
Molecular FrameworkAliphatic homopolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point258°C
Boiling PointNot Available
Solubility35 mg/mL (HCl salt), 0.9 mg/mL for free base
LogP3.28
Predicted Properties
PropertyValueSource
Water Solubility0.046 g/LALOGPS
logP3.31ALOGPS
logP2.07ChemAxon
logS-3.6ALOGPS
pKa (Strongest Basic)10.7ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area26.02 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity54.49 m³·mol⁻¹ChemAxon
Polarizability21.82 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-03fr-0900000000-4db94b4b87705e834d5d2017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03e9-0900000000-65172d14e0f6b9102d732017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03di-0900000000-ce475f103d528ff4d3422017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03di-0900000000-1c9199c5cf1c902223ae2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-08fr-0900000000-1bac817f714e7eec74882017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0a4i-2900000000-eb58e236084a93a3d37b2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0a4i-4900000000-5a87d54400c3e9720ad02017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-052f-9500000000-95eb2b63a2392449ec4a2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0006-9100000000-608b372857aacd60eb612017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00kf-9000000000-f283a81168372575c2aa2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03di-0900000000-bbf1127413d0f995a0002017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 20V, Positivesplash10-08fr-1900000000-af0d7a2139a4f01010292021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 120V, Positivesplash10-052f-9500000000-7d8b0b05d4e422cf43ff2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 90V, Positivesplash10-0a4i-4900000000-c38a0c0bf1d2218762552021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-052f-9400000000-b9b0845988ac96d136552021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 150V, Positivesplash10-0006-9100000000-c0a9196c8aea3bbc9ba52021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 50V, Positivesplash10-044i-0900000000-dbaa35eb2bd2e8a926ee2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-03di-0900000000-fe3a10c3c4ef737f63172021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-08fr-0900000000-31518410ee334d4b0e502021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 10V, Positivesplash10-03e9-0900000000-d6a33792b66ebc7fcaa52021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-01q9-0900000000-d5fdfd99bc401e75f44d2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-01q9-0900000000-8e06cea62d1b5b2287fd2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-03di-0900000000-07e8313e47d270feab022016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0900000000-8a0b61ba65a9638329fb2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-0900000000-242508d651dfd0b38ea82016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-01t9-0900000000-710a53b2a03cd1789d692016-08-03View Spectrum
Toxicity Profile
Route of ExposureWell absorbed orally with a bioavailability of approximately 100%. Peak plasma concentrations are reached in 3-7 hours. Food has no effect on absorption.
Mechanism of ToxicityMemantine exerts its action through uncompetitive NMDA receptor antagonism, binding preferentially to the NMDA receptor-operated cation channels. Prolonged increased levels of glutamate in the brain of demented patients are sufficient to counter the voltage-dependent block of NMDA receptors by Mg2+ ions and allow continuous influx of Ca2+ ions into cells, ultimately resulting in neuronal degeneration. Studies suggest that memantine binds more effectively than Mg2+ ions at the NMDA receptor, and thereby effectively blocks this prolonged influx of Ca2+ ions through the NMDA channel whilst preserving the transient physiological activation of the channels by higher concentrations of synaptically released glutamate. Thus memantine protects against chronically elevated concentrations of glutamate. Memantine also has antagonistic activity at the type 3 serotonergic (5-HT3) receptor with a potency that is similar to that at the NMDA receptor, and lower antagonistic activity at the nicotinic acetylcholine receptor. This drug has no affinity for gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels.
MetabolismExcreted largely unchanged. About 20% is metabolized to 1-amino-3-hydroxymethyl-5-methyl-adamantane and 3-amino-1-hydroxy-5,7-dimethyl-adamantane. Route of Elimination: Memantine undergoes partial hepatic metabolism. About 48% of administered drug is excreted unchanged in urine; the remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. It is excreted predominantly in the urine, unchanged. Half Life: 60-100 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of moderate to severe dementia of the Alzheimer's type.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSide effects include pain, abnormal crying, leg pain, fever, increased apetite. Adverse drug reactions include: dizziness, confusion, headache, hallucinations, tiredness. Less common side effects include: vomiting, anxiety, hypertonia, cystitis, and increased libido. Doses of up to 400 mg have been tolerated.
TreatmentAs in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine. (7)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01043
HMDB IDHMDB15177
PubChem Compound ID4054
ChEMBL IDCHEMBL807
ChemSpider ID3914
KEGG IDC13736
UniProt IDNot Available
OMIM ID
ChEBI ID64312
BioCyc IDNot Available
CTD IDNot Available
Stitch IDMemantine
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkMemantine
References
Synthesis Reference

DrugSyn.org

MSDSLink
General References
  1. Cacabelos R, Takeda M, Winblad B: The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease. Int J Geriatr Psychiatry. 1999 Jan;14(1):3-47. [10029935 ]
  2. Rogawski MA, Wenk GL: The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease. CNS Drug Rev. 2003 Fall;9(3):275-308. [14530799 ]
  3. Robinson DM, Keating GM: Memantine: a review of its use in Alzheimer's disease. Drugs. 2006;66(11):1515-34. [16906789 ]
  4. Rogawski MA: Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents--toward an understanding of their favorable tolerability. Amino Acids. 2000;19(1):133-49. [11026482 ]
  5. Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, Parsons CG: The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett. 2001 Jun 22;306(1-2):81-4. [11403963 ]
  6. Drugs.com [Link]
  7. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Glutamate receptor ionotropic, NMDA 2A
General Function:
Zinc ion binding
Specific Function:
NMDA receptor subtype of glutamate-gated ion channels possesses high calcium permeability and voltage-dependent sensitivity to magnesium. Activation requires binding of agonist to both types of subunits.
Gene Name:
GRIN2A
Uniprot ID:
Q12879
Molecular Weight:
165281.215 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC505.6 uMNot AvailableBindingDB 50062599
References
  1. Chen HS, Lipton SA: Pharmacological implications of two distinct mechanisms of interaction of memantine with N-methyl-D-aspartate-gated channels. J Pharmacol Exp Ther. 2005 Sep;314(3):961-71. Epub 2005 May 18. [15901795 ]
  2. Maler JM, Esselmann H, Wiltfang J, Kunz N, Lewczuk P, Reulbach U, Bleich S, Ruther E, Kornhuber J: Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons. Brain Res. 2005 Aug 9;1052(2):156-62. [16009352 ]
  3. Bresink I, Benke TA, Collett VJ, Seal AJ, Parsons CG, Henley JM, Collingridge GL: Effects of memantine on recombinant rat NMDA receptors expressed in HEK 293 cells. Br J Pharmacol. 1996 Sep;119(2):195-204. [8886398 ]
  4. Blanpied TA, Boeckman FA, Aizenman E, Johnson JW: Trapping channel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol. 1997 Jan;77(1):309-23. [9120573 ]
  5. Rook Y, Schmidtke KU, Gaube F, Schepmann D, Wunsch B, Heilmann J, Lehmann J, Winckler T: Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents. J Med Chem. 2010 May 13;53(9):3611-7. doi: 10.1021/jm1000024. [20361801 ]
Target Details
2. Glutamate receptor ionotropic, NMDA 2B
General Function:
Zinc ion binding
Specific Function:
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. In concert with DAPK1 at extrasynaptic sites, acts as a central mediator for stroke damage. Its phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity inducing injurious Ca2+ influx through them, resulting in an irreversible neuronal death (By similarity).
Gene Name:
GRIN2B
Uniprot ID:
Q13224
Molecular Weight:
166365.885 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC505.5 uMNot AvailableBindingDB 50062599
References
  1. Maler JM, Esselmann H, Wiltfang J, Kunz N, Lewczuk P, Reulbach U, Bleich S, Ruther E, Kornhuber J: Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons. Brain Res. 2005 Aug 9;1052(2):156-62. [16009352 ]
  2. Blanpied TA, Boeckman FA, Aizenman E, Johnson JW: Trapping channel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol. 1997 Jan;77(1):309-23. [9120573 ]
  3. Kashiwagi K, Masuko T, Nguyen CD, Kuno T, Tanaka I, Igarashi K, Williams K: Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore. Mol Pharmacol. 2002 Mar;61(3):533-45. [11854433 ]
  4. Nakazato E, Kato A, Watanabe S: Brain but not spinal NR2B receptor is responsible for the anti-allodynic effect of an NR2B subunit-selective antagonist CP-101,606 in a rat chronic constriction injury model. Pharmacology. 2005 Jan;73(1):8-14. Epub 2004 Sep 27. [15452358 ]
  5. Rook Y, Schmidtke KU, Gaube F, Schepmann D, Wunsch B, Heilmann J, Lehmann J, Winckler T: Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents. J Med Chem. 2010 May 13;53(9):3611-7. doi: 10.1021/jm1000024. [20361801 ]
Target Details
3. Glutamate receptor ionotropic, NMDA 3A
General Function:
Protein phosphatase 2a binding
Specific Function:
NMDA receptor subtype of glutamate-gated ion channels with reduced single-channel conductance, low calcium permeability and low voltage-dependent sensitivity to magnesium. Mediated by glycine. May play a role in the development of dendritic spines. May play a role in PPP2CB-NMDAR mediated signaling mechanism (By similarity).
Gene Name:
GRIN3A
Uniprot ID:
Q8TCU5
Molecular Weight:
125464.07 Da
References
  1. Smothers CT, Woodward JJ: Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-D-aspartate NR1 and NR3 subunits. J Pharmacol Exp Ther. 2007 Aug;322(2):739-48. Epub 2007 May 14. [17502428 ]
  2. Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D: Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature. 2002 Feb 14;415(6873):793-8. Epub 2002 Jan 30. [11823786 ]
  3. Schrattenholz A, Soskic V: NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling. Curr Top Med Chem. 2006;6(7):663-86. [16719808 ]
Target Details
4. Glutamate receptor ionotropic, NMDA 1
General Function:
Voltage-gated cation channel activity
Specific Function:
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors (By similarity).
Gene Name:
GRIN1
Uniprot ID:
Q05586
Molecular Weight:
105371.945 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC509.52 uMNot AvailableBindingDB 50062599
References
  1. Kotermanski SE, Wood JT, Johnson JW: Memantine binding to a superficial site on NMDA receptors contributes to partial trapping. J Physiol. 2009 Oct 1;587(Pt 19):4589-604. doi: 10.1113/jphysiol.2009.176297. Epub 2009 Aug 17. [19687120 ]
  2. Rosini M, Simoni E, Bartolini M, Cavalli A, Ceccarini L, Pascu N, McClymont DW, Tarozzi A, Bolognesi ML, Minarini A, Tumiatti V, Andrisano V, Mellor IR, Melchiorre C: Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer's disease: a promising direction for the multi-target-directed ligands gold rush. J Med Chem. 2008 Aug 14;51(15):4381-4. doi: 10.1021/jm800577j. Epub 2008 Jul 8. [18605718 ]
Target Details
5. 5-hydroxytryptamine receptor 3A
General Function:
Voltage-gated potassium channel activity
Specific Function:
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel.
Gene Name:
HTR3A
Uniprot ID:
P46098
Molecular Weight:
55279.835 Da
References
  1. Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, Parsons CG: The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett. 2001 Jun 22;306(1-2):81-4. [11403963 ]
Target Details
6. Alpha-7 nicotinic cholinergic receptor subunit
General Function:
Not Available
Specific Function:
Not Available
Gene Name:
CHRNA7
Uniprot ID:
Q693P7
Molecular Weight:
2987.635 Da
References
  1. Aracava Y, Pereira EF, Maelicke A, Albuquerque EX: Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther. 2005 Mar;312(3):1195-205. Epub 2004 Nov 2. [15522999 ]
Target Details
7. D(2) dopamine receptor
General Function:
Potassium channel regulator activity
Specific Function:
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name:
DRD2
Uniprot ID:
P14416
Molecular Weight:
50618.91 Da
References
  1. Seeman P, Caruso C, Lasaga M: Memantine agonist action at dopamine D2High receptors. Synapse. 2008 Feb;62(2):149-53. [18000814 ]
Target Details
8. Solute carrier family 22 member 1
General Function:
Secondary active organic cation transmembrane transporter activity
Specific Function:
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin-dependent kinase II and LCK tyrosine kinase.
Gene Name:
SLC22A1
Uniprot ID:
O15245
Molecular Weight:
61153.345 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5027.2 uMNot AvailableBindingDB 50062599
References
  1. Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergstrom CA, Artursson P: Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1. J Med Chem. 2008 Oct 9;51(19):5932-42. doi: 10.1021/jm8003152. Epub 2008 Sep 13. [18788725 ]