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Record Information
Version2.0
Creation Date2009-07-15 20:49:10 UTC
Update Date2014-12-24 20:25:49 UTC
Accession NumberT3D2680
Identification
Common NameRosuvastatin
ClassSmall Molecule
DescriptionRosuvastatin is an antilipemic agent that competitively inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reducuase catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step in cholesterol biosynthesis. Rosuvastatin belongs to a class of medications called statins and is used to reduce plasma cholesterol levels and prevent cardiovascular disease.
Compound Type
  • Amide
  • Anticholesteremic Agent
  • Drug
  • Hydroxymethylglutaryl-CoA Reductase Inhibitor
  • Metabolite
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(3R,5S,6e)-7-(4-(4-Fluorophenyl)-6-(1-methylethyl)-2-(ethyl(methylsulfonyl)amino)-5-pyrimidinyl)-3,5-dihydroxy-6-heptenoic acid
(3R,5S,6e)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3,5-dihydroxyhept-6-enoic acid
Astende
Cirantan
Cresadex
Crestor
Provisacor
Razel
Rosedex
Rosimol
Rosumed
Rosustatin
Rosuvas
Rosuvast
Rosuvastatin calcium
Rosvel
Rovartal
Simestat
Sinlip
Visacor
Vivacor
ZD-4522
Chemical FormulaC22H28FN3O6S
Average Molecular Mass481.538 g/mol
Monoisotopic Mass481.168 g/mol
CAS Registry Number287714-41-4
IUPAC Name(3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid
Traditional Namerosuvastatin
SMILES[H]C(=C([H])[C@@]([H])(O)C[C@@]([H])(O)CC(O)=O)C1=C(N=C(N=C1C1=CC=C(F)C=C1)N(C)S(C)(=O)=O)C(C)C
InChI IdentifierInChI=1S/C22H28FN3O6S/c1-13(2)20-18(10-9-16(27)11-17(28)12-19(29)30)21(14-5-7-15(23)8-6-14)25-22(24-20)26(3)33(4,31)32/h5-10,13,16-17,27-28H,11-12H2,1-4H3,(H,29,30)/b10-9+/t16-,17-/m1/s1
InChI KeyInChIKey=BPRHUIZQVSMCRT-VEUZHWNKSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenylpyrimidines. These are polycyclic aromatic compounds containing a benzene ring linked to a pyrimidine ring through a CC or CN bond. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazines
Sub ClassPyrimidines and pyrimidine derivatives
Direct ParentPhenylpyrimidines
Alternative Parents
Substituents
  • 4-phenylpyrimidine
  • 5-phenylpyrimidine
  • Medium-chain hydroxy acid
  • Medium-chain fatty acid
  • Beta-hydroxy acid
  • Fluorobenzene
  • Halobenzene
  • Halogenated fatty acid
  • Heterocyclic fatty acid
  • Hydroxy fatty acid
  • Unsaturated fatty acid
  • Organosulfonic acid amide
  • Organic sulfonic acid amide
  • Fatty acyl
  • Fatty acid
  • Benzenoid
  • Aryl fluoride
  • Aryl halide
  • Monocyclic benzene moiety
  • Hydroxy acid
  • Aminosulfonyl compound
  • Heteroaromatic compound
  • Sulfonyl
  • Organosulfonic acid or derivatives
  • Organic sulfonic acid or derivatives
  • Secondary alcohol
  • Azacycle
  • Carboxylic acid derivative
  • Carboxylic acid
  • Monocarboxylic acid or derivatives
  • Organofluoride
  • Organonitrogen compound
  • Organooxygen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Carbonyl group
  • Organosulfur compound
  • Organic oxygen compound
  • Organohalogen compound
  • Alcohol
  • Organic nitrogen compound
  • Organopnictogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceSolid (1).
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilitySparingly soluble in water
LogP0.13
Predicted Properties
PropertyValueSource
Water Solubility0.089 g/LALOGPS
logP1.47ALOGPS
logP1.92ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)4ChemAxon
pKa (Strongest Basic)-2.8ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area140.92 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity121.44 m³·mol⁻¹ChemAxon
Polarizability48.55 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-03dl-4024900000-6da5a329db1ec51e7329JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-001i-3000019000-fe48b7ae5cb710394f30JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03dj-0000900000-ffe3f70c801ef1fe024bJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-000i-2009600000-06a41807156bb026dc0aJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-007c-8239500000-8f10bc31f645273fc135JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-2001900000-9b3574916dc9d66a08d4JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-057i-9204500000-6690570c98256ed46990JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0bvi-7309000000-e1540b16a54c6fe4499bJSpectraViewer
Toxicity Profile
Route of ExposureInhalation. Bioavailability is approximately 20%. Peak plasma concentrations were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to CRESTOR dose. Food has no effect on the AUC of rosuvastatin.
Mechanism of ToxicityRosuvastatin is a competitive inhibitor of HMG-CoA reductase. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Rosuvastatin acts primarily in the liver. Decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Rosuvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL. In vitro and in vivo animal studies also demonstrate that rosuvastatin exerts vasculoprotective effects independent of its lipid-lowering properties. Rosuvastatin exerts an anti-inflammatory effect on rat mesenteric microvascular endothelium by attenuating leukocyte rolling, adherence and transmigration (7). The drug also modulates nitric oxide synthase (NOS) expression and reduces ischemic-reperfusion injuries in rat hearts (8). Rosuvastatin increases the bioavailability of nitric oxide (7) by upregulating NOS (10) and by increasing the stability of NOS through post-transcriptional polyadenylation (11). It is unclear as to how rosuvastatin brings about these effects though they may be due to decreased concentrations of mevalonic acid.
MetabolismNot extensively metabolized. Only ~10% is excreted as metabolite. Cytochrome P450 (CYP) 2C9 is primarily responsible for the formation of rosuvastatin's major metabolite, N-desmethylrosuvastatin. N-desmethylrosuvastatin has approximately 50% of the pharmacological activity of its parent compound in vitro. Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin accounts for greater than 90% of the pharmacologic action. Inhibitors of CYP2C9 increase the AUC by less than 2-fold. This interaction does not appear to be clinically significant. Route of Elimination: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. Half Life: 19 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesUsed as an adjunct to dietary therapy to treat primary hyperlipidemia (heterozygous familial and nonfamilial), mixed dyslipidemia and hypertriglyceridemia. Also indicated for homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies or when other such therapies are not available. Furthermore, it is used to slow the progression of atherosclerosis and for primary prevention of cardiovascular disease.
Minimum Risk LevelNot Available
Health EffectsHealth effects include abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities (1).
SymptomsGenerally well-tolerated. Side effects may include myalgia, constipation, asthenia, abdominal pain, and nausea. Other possible side effects include myotoxicity (myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid toxicity in Asian patients, lower doses should be considered. Pharmacokinetic studies show an approximately two-fold increase in peak plasma concentration and AUC in Asian patients (Philippino, Chinese, Japanese, Korean, Vietnamese, or Asian-Indian descent) compared to Caucasians patients.
TreatmentAfter ingestion exposure, administer charcoal as a slurry. In case of Rhabdomyolosis, administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. (16)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01098
HMDB IDHMDB15230
PubChem Compound ID446157
ChEMBL IDCHEMBL1496
ChemSpider ID393589
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID38545
BioCyc IDNot Available
CTD IDNot Available
Stitch IDRosuvastatin
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkRosuvastatin
References
Synthesis Reference

Valerie Niddam-Hildesheim, Greta Sterimbaum, “Process for preparation of rosuvastatin calcium.” U.S. Patent US20050080134, issued April 14, 2005.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A, Schneck D, Smith G, Warwick M: Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol. 2001 Mar 8;87(5A):28B-32B. [11256847 ]
  3. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM: Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006 Apr 5;295(13):1556-65. Epub 2006 Mar 13. [16533939 ]
  4. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW: Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003 Jul 15;92(2):152-60. [12860216 ]
  5. The statin wars: why AstraZeneca must retreat. Lancet. 2003 Oct 25;362(9393):1341. [14585629 ]
  6. McKillop T: The statin wars. Lancet. 2003 Nov 1;362(9394):1498. [14602449 ]
  7. Stalker TJ, Lefer AM, Scalia R: A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid. Br J Pharmacol. 2001 Jun;133(3):406-12. [11375257 ]
  8. Di Napoli P, Taccardi AA, Grilli A, De Lutiis MA, Barsotti A, Felaco M, De Caterina R: Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts. Cardiovasc Res. 2005 Jun 1;66(3):462-71. Epub 2005 Mar 2. [15914111 ]
  9. Laufs U, Gertz K, Dirnagl U, Bohm M, Nickenig G, Endres M: Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res. 2002 Jun 28;942(1-2):23-30. [12031849 ]
  10. Jones SP, Gibson MF, Rimmer DM 3rd, Gibson TM, Sharp BR, Lefer DJ: Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor. J Am Coll Cardiol. 2002 Sep 18;40(6):1172-8. [12354446 ]
  11. Kosmidou I, Moore JP, Weber M, Searles CD: Statin treatment and 3' polyadenylation of eNOS mRNA. Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2642-9. Epub 2007 Oct 4. [17916773 ]
  12. Everett BM, Glynn RJ, MacFadyen JG, Ridker PM: Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein: justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Circulation. 2010 Jan 5;121(1):143-50. doi: 10.1161/CIRCULATIONAHA.109.874834. Epub 2009 Dec 21. [20026779 ]
  13. Kilic E, Kilic U, Matter CM, Luscher TF, Bassetti CL, Hermann DM: Aggravation of focal cerebral ischemia by tissue plasminogen activator is reversed by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor but does not depend on endothelial NO synthase. Stroke. 2005 Feb;36(2):332-6. Epub 2004 Dec 29. [15625301 ]
  14. Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, Kim RB: Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006 May;130(6):1793-806. Epub 2006 Mar 6. [16697742 ]
  15. FDA label
  16. Wikipedia. Tramadol. Last Updated 8 August 2009. [Link]
  17. Drugs.com [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Nadph binding
Specific Function:
Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins.
Gene Name:
HMGCR
Uniprot ID:
P04035
Molecular Weight:
97475.155 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.0009 uMNot AvailableBindingDB 18372
Inhibitory71 uMNot AvailableBindingDB 18372
IC500.0031 uMNot AvailableBindingDB 18372
IC500.005 uMNot AvailableBindingDB 18372
IC500.0054 uMNot AvailableBindingDB 18372
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A, Schneck D, Smith G, Warwick M: Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol. 2001 Mar 8;87(5A):28B-32B. [11256847 ]
  3. Hanefeld M: Clinical rationale for rosuvastatin, a potent new HMG-CoA reductase inhibitor. Int J Clin Pract. 2001 Jul-Aug;55(6):399-405. [11501230 ]
  4. Davidson MH: Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia. Expert Opin Investig Drugs. 2002 Jan;11(1):125-41. [11772327 ]
  5. Olsson AG, McTaggart F, Raza A: Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev. 2002 Winter;20(4):303-28. [12481202 ]
  6. Chapman MJ, Caslake M, Packard C, McTaggart F: New dimension of statin action on ApoB atherogenicity. Clin Cardiol. 2003 Jan;26(1 Suppl 1):I7-10. [12539816 ]
  7. Pfefferkorn JA, Song Y, Sun KL, Miller SR, Trivedi BK, Choi C, Sorenson RJ, Bratton LD, Unangst PC, Larsen SD, Poel TJ, Cheng XM, Lee C, Erasga N, Auerbach B, Askew V, Dillon L, Hanselman JC, Lin Z, Lu G, Robertson A, Olsen K, Mertz T, Sekerke C, Pavlovsky A, Harris MS, Bainbridge G, Caspers N, Chen H, Eberstadt M: Design and synthesis of hepatoselective, pyrrole-based HMG-CoA reductase inhibitors. Bioorg Med Chem Lett. 2007 Aug 15;17(16):4538-44. Epub 2007 Jun 6. [17574412 ]
  8. Thilagavathi R, Kumar R, Aparna V, Sobhia ME, Gopalakrishnan B, Chakraborti AK: Three-dimensional quantitative structure (3-D QSAR) activity relationship studies on imidazolyl and N-pyrrolyl heptenoates as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitors by comparative molecular similarity indices analysis (CoMSIA). Bioorg Med Chem Lett. 2005 Feb 15;15(4):1027-32. [15686906 ]
  9. Medina-Franco JL, Lopez-Vallejo F, Rodriguez-Morales S, Castillo R, Chamorro G, Tamariz J: Molecular docking of the highly hypolipidemic agent alpha-asarone with the catalytic portion of HMG-CoA reductase. Bioorg Med Chem Lett. 2005 Feb 15;15(4):989-94. [15686898 ]
General Function:
Tetrahydrobiopterin binding
Specific Function:
Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.
Gene Name:
NOS3
Uniprot ID:
P29474
Molecular Weight:
133287.62 Da
References
  1. Stalker TJ, Lefer AM, Scalia R: A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid. Br J Pharmacol. 2001 Jun;133(3):406-12. [11375257 ]
  2. Laufs U, Gertz K, Dirnagl U, Bohm M, Nickenig G, Endres M: Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res. 2002 Jun 28;942(1-2):23-30. [12031849 ]
  3. Jones SP, Gibson MF, Rimmer DM 3rd, Gibson TM, Sharp BR, Lefer DJ: Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor. J Am Coll Cardiol. 2002 Sep 18;40(6):1172-8. [12354446 ]
  4. Kilic E, Kilic U, Matter CM, Luscher TF, Bassetti CL, Hermann DM: Aggravation of focal cerebral ischemia by tissue plasminogen activator is reversed by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor but does not depend on endothelial NO synthase. Stroke. 2005 Feb;36(2):332-6. Epub 2004 Dec 29. [15625301 ]
  5. Di Napoli P, Taccardi AA, Grilli A, De Lutiis MA, Barsotti A, Felaco M, De Caterina R: Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts. Cardiovasc Res. 2005 Jun 1;66(3):462-71. Epub 2005 Mar 2. [15914111 ]
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin.
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
References
  1. Huang L, Wang Y, Grimm S: ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein. Drug Metab Dispos. 2006 May;34(5):738-42. Epub 2006 Jan 13. [16415124 ]
  2. Zhang W, Yu BN, He YJ, Fan L, Li Q, Liu ZQ, Wang A, Liu YL, Tan ZR, Fen-Jiang, Huang YF, Zhou HH: Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta. 2006 Nov;373(1-2):99-103. Epub 2006 May 13. [16784736 ]