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Identification
NameDabigatran etexilate
Accession NumberDB06695
TypeSmall Molecule
GroupsApproved
Description

Dabigatran etexilate is an oral prodrug that is metabolized by a serum esterase to dabigatran. It is a synthetic, competitive and reversible direct thrombin inhibitor. Inhibition of thrombin disrupts the coagulation cascade and inhibits the formation of clots. Dabigatran etexilate may be used to decrease the risk of venous thromboembolic events in patients who have undergone total hip or knee replacement surgery, or to prevent stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation therapy is indicated. In contrast to warfarin, because its anticoagulant effects are predictable, lab monitoring is not necessary. FDA approved on October 19, 2010.

Structure
Thumb
Synonyms
SynonymLanguageCode
Dabigatran Not AvailableNot Available
Ethyl 3-[[[4-[[[(hexyloxyl)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino] propanoateNot AvailableINN
PradaxaNot AvailableNot Available
Salts
Name/CAS Structure Properties
Dabigatran etexilate mesilate
Thumb
  • InChI Key: XETBXHPXHHOLOE-UHFFFAOYSA-N
  • Monoisotopic Mass: 723.305032141
  • Average Mass: 723.839
DBSALT000035
Brand names
NameCompany
PradaxBoehringer Ingelheim
PradaxaBoehringer Ingelheim
RendixNot Available
Brand mixturesNot Available
Categories
CAS number211915-06-9
WeightAverage: 627.7332
Monoisotopic: 627.316917457
Chemical FormulaC34H41N7O5
InChI KeyKSGXQBZTULBEEQ-UHFFFAOYSA-N
InChI
InChI=1S/C34H41N7O5/c1-4-6-7-10-21-46-34(44)39-32(35)24-12-15-26(16-13-24)37-23-30-38-27-22-25(14-17-28(27)40(30)3)33(43)41(20-18-31(42)45-5-2)29-11-8-9-19-36-29/h8-9,11-17,19,22,37H,4-7,10,18,20-21,23H2,1-3H3,(H2,35,39,44)
IUPAC Name
ethyl 3-(1-{2-[({4-[amino({[(hexyloxy)carbonyl]imino})methyl]phenyl}amino)methyl]-1-methyl-1H-1,3-benzodiazol-5-yl}-N-(pyridin-2-yl)formamido)propanoate
SMILES
CCCCCCOC(=O)N=C(N)C1=CC=C(NCC2=NC3=C(C=CC(=C3)C(=O)N(CCC(=O)OCC)C3=CC=CC=N3)N2C)C=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzimidazoles
SubclassNot Available
Direct parentBenzimidazoles
Alternative parentsBenzamides; Benzoyl Derivatives; Aminopyridines and Derivatives; Dicarboxylic Acids and Derivatives; N-substituted Imidazoles; Tertiary Carboxylic Acid Amides; Carboxylic Acid Esters; Tertiary Amines; Ethers; Carboxylic Acids; Carboxamidines; Secondary Amines; Polyamines; Enolates
Substituentsbenzoyl; aminopyridine; dicarboxylic acid derivative; pyridine; benzene; n-substituted imidazole; azole; imidazole; tertiary carboxylic acid amide; carboxamide group; tertiary amine; carboxylic acid ester; amidine; ether; polyamine; carboxylic acid; enolate; secondary amine; carboxylic acid amidine; carboxylic acid derivative; amine; organonitrogen compound
Classification descriptionThis compound belongs to the benzimidazoles. These are organic compounds containing a benzene ring fused to an imidazole ring (five member ring containing a nitrogen atom, 4 carbon atoms, and two double bonds).
Pharmacology
IndicationDabigatran is indicated for the prevention of venous thromboembolic events in patients who have undergone elective hip or knee replacement surgery (based on RE-NOVATE, RE-MODEL, and RE-MOBILIZE trials). In 2010, it was approved in the US and Canada for prevention of stroke and systemic embolism in patients with atrial fibrillation (approval based on the RE-LY trial). Contraindications: severe renal impairment (CrCL < 30 ml/min); haemorrhagic manifestations, bleeding diathesis or spontaneous or pharmacologic impairment of haemostasis; lesions at risk of clinically significant bleeding (e.g. extensive cerebral infarction (haemorrhagic or ischemic) in the last 6 months, active peptic ulcer disease); concomitant treatment with P-glycoprotein inhibitors (e.g. oral ketoconazole, verapamil); and those with known hypersensitivity to dabigatran, dabigatran etexilate or any ingredient used in the formulation or component of the container. As of December 2012, dabigatran is contraindicated in patients with mechanical prosthetic heart valves.
PharmacodynamicsDabigatran directly inhibits thrombin in a concentration-dependent, reversible, specific, and competitive manner which results in a prolongation of aPTT (partial thromboplastin time), ECT (Ecarin clotting time), and TT (thrombin time). It may increase INR but this laboratory parameter is relatively insensitive to the activity of dabigatran.
Mechanism of actionDabigatran etexilate is an inactive pro-drug that is converted to dabigatran, the active form, by esterase-catalyzed hydrolysis in the plasma and liver. Dabigatran, the main active principle in plasma, is a rapid-acting competitive and reversible direct inhibitor of thrombin. Thrombin, a serine protease, is responsible for the conversion of fibrinogen to fibrin in the coagulation cascade. Inhibition of thrombin consequently prevents thrombus development. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.
AbsorptionPeak plasma concentrations were achieved in 6 hours in post surgical patients. In healthy patients, maximum concentrations were achieved in 0.5 to 2 hours. The absolute bioavailability of dabigatran in the body after administration of dabigatran etexilate was 6.5%. Food does not affect the bioavailability of dabigatran etexilate, but it delays the time to peak plasma concentrations by 2 hours. Oral bioavailability may increase by up to 75% when pellets are taken out of the hydroxypropylmethylcellulose (HPMC) capsule. Therefore, capsules should not be opened and pellets taken alone. Furthermore, although absorption of dabigatran etexilate is independent of gastrointestinal acidity, coadministration of pantoprazole (proton pump inhibitor) may reduce the bioavailability of dabigatran. Despite this finding, dose adjustment is not required.
Volume of distribution

Moderate tissue distribution with a Vd of 60-70L.
Accumulation factor, twice daily dosing = 2

Protein bindingRelatively low binding (34-35%) to plasma proteins.
Metabolism

CYP450 enzymes are not involved in the metabolism of dabigatran thus is not expected to interact with drugs metabolized by CYP isoenzymes. Dabigatran is typically metabolised by esterases and microsomal carboxylesterases. Pharmacologically active acylglucoronides are formed via conjugation. Four positional isomers, 1-O, 2-O, 3-O, and 4-O, acylglucuronides exist, each accounting for less than 10% of total plasma dabagatran.

Route of eliminationMainly excreted in urine (85%). Fecal excretion accounts for 6% of the orally administered dose. Dabigatran is primarily eliminated unchanged via the kidneys at a rate of 100 ml/min corresponding to the glomerular filtration rate.
Half life12-14 hours in healthy volunteers. 14-17 hours in patients treated for prevention of venous thromboembolism following hip- or knee-replacement surgery.
ClearanceNot Available
ToxicityThe most common adverse reactions include dyspepsia or gastritis-like symptoms. The approximate lethal dose (LD50) in rats and mice was observed at single oral doses of > 2000 mg/kg. Oral doses of 600 mg/kg did not induce any toxicologically meaningful changes in dogs and Rhesus monkeys. Dabigatran was well-tolerated in rats and Rhesus monkeys during repeat-dose toxicity studies. No evidence of mutagenic potential.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.942
Blood Brain Barrier + 0.8673
Caco-2 permeable - 0.7014
P-glycoprotein substrate Substrate 0.7412
P-glycoprotein inhibitor I Inhibitor 0.7539
P-glycoprotein inhibitor II Inhibitor 0.8443
Renal organic cation transporter Non-inhibitor 0.701
CYP450 2C9 substrate Non-substrate 0.858
CYP450 2D6 substrate Non-substrate 0.837
CYP450 3A4 substrate Substrate 0.6154
CYP450 1A2 substrate Non-inhibitor 0.6906
CYP450 2C9 substrate Non-inhibitor 0.5102
CYP450 2D6 substrate Non-inhibitor 0.8417
CYP450 2C19 substrate Inhibitor 0.5157
CYP450 3A4 substrate Inhibitor 0.781
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5789
Ames test Non AMES toxic 0.6292
Carcinogenicity Non-carcinogens 0.8065
Biodegradation Not ready biodegradable 0.9931
Rat acute toxicity 2.7093 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9047
hERG inhibition (predictor II) Inhibitor 0.6181
Pharmacoeconomics
Manufacturers
  • Boehringer ingelheim
PackagersNot Available
Dosage forms
FormRouteStrength
CapsuleOral110 mg
CapsuleOral150 mg
CapsuleOral75 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States60873802010-10-192018-02-18
United States78664742010-10-192027-08-31
United States79322732010-10-192025-09-07
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point180 +/- 3 (DSC: 10 K min^-1 heating rate)Not Available
water solubility1.8mg/ml, partly soluble MSDS
logP3.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00466ALOGPS
logP5.17ALOGPS
logP4.59ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)17.89ChemAxon
pKa (Strongest Basic)3.87ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area154.03 Å2ChemAxon
Rotatable Bond Count17ChemAxon
Refractivity176.43 m3·mol-1ChemAxon
Polarizability71.11 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Christian Filser, Wolfgang Dersch, Rainer Hamm, Arndt Hausherr, Gunter Koch, Ulrich Scholz, Georg Zerban, “METHOD FOR PRODUCING AN INTERMEDIATE PRODUCT OF DABIGATRAN ETEXILATE.” U.S. Patent US20110118471, issued May 19, 2011.

US20110118471
General Reference
  1. Bauer KA: New oral anticoagulants in development: potential for improved safety profiles. Rev Neurol Dis. 2010;7(1):1-8. Pubmed
  2. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. Epub 2009 Aug 30. Pubmed
  3. Wolowacz SE, Roskell NS, Plumb JM, Caprini JA, Eriksson BI: Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis. Thromb Haemost. 2009 Jan;101(1):77-85. Pubmed
  4. Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH, Lieberman JR, Muntz JE, Raskob GE, Clements ML, Hantel S, Schnee JM, Caprini JA: Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009 Jan;24(1):1-9. Epub 2008 Apr 14. Pubmed
  5. Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, Kalebo P, Reilly P: A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost. 2005 Jan;3(1):103-11. Pubmed
  6. Di Nisio M, Middeldorp S, Buller HR: Direct thrombin inhibitors. N Engl J Med. 2005 Sep 8;353(10):1028-40. Pubmed
  7. Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G, Stahle H, Rathgen K, Svard R: Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol. 2005 May;45(5):555-63. Pubmed
  8. Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-Azad K, Pedersen KE, Lionetti DA, Stangier J, Wallentin L: Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol. 2007 Nov 1;100(9):1419-26. Epub 2007 Aug 17. Pubmed
  9. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kalebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Buller HR: Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007 Nov;5(11):2178-85. Pubmed
  10. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Buller HR: Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007 Sep 15;370(9591):949-56. Pubmed
  11. European Medicines Agency
  12. Abrams P and Marzella N: Dabigatran (Rendix): A Promising New Oral Direct Thrombin Inhibitor. Drug Forecast. 2007;32(5):271-5. pharmscope
  13. Scaglione F: New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013 Feb;52(2):69-82. doi: 10.1007/s40262-012-0030-9. Pubmed
External Links
ResourceLink
KEGG DrugD07144
PubChem Compound6445226
PubChem Substance99443249
ChemSpider4948999
ChEBI70746
ChEMBLCHEMBL539697
PharmGKBPA165958369
RxListhttp://www.rxlist.com/pradaxa-drug.htm
Drugs.comhttp://www.drugs.com/cdi/dabigatran.html
PDRhealthhttp://www.pdrhealth.com/drugs/pradaxa
WikipediaDabigatran
ATC CodesB01AE07
AHFS Codes
  • 20:12.04.12
PDB EntriesNot Available
FDA labelshow(431 KB)
MSDSshow(99.2 KB)
Interactions
Drug Interactions
Drug
AmiodaroneAmiodarone may increase the serum concentration of dabigatran etexilate, resulting in increased risk of bleeding. Consider modifying therapy.
ApixabanConcomitant therapy with another anticoagulant may increase bleed risk. Monitor closely for adverse effects.
CarbamazepineP-Glycoprotein inducers such as carbamazepine may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
DexamethasoneP-Glycoprotein inducers such as dexamethasone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
DoxorubicinP-Glycoprotein inducers such as doxorubicin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
DronedaroneDronedarone inhibits P-glycoprotein transporter thus increasing serum concentrations of dabigatran 1.1-1.9-fold.
EptifibatideMonitor therapy due to increased bleeding.
Ginkgo bilobaAdditive anticoagulant/antiplatelet effects of gingko may increase bleed risk for patients on dabigatran. Concomitant therapy should be avoided.
KetoconazoleCoadministration with a strong p-glycoprotein inhibitor may increase the level or effect of dabigatran. Monitor closely for adverse effects.
LomitapideDabigatran is a p-glycoprotien (P-gp) substrate. Levels of dabigatran may increase if coadministered with lomipatide, which is a P-gp inhibitor. Thus, it is recommended to dose reduce P-gp substrates (such as ambrisentan, aliskiren, colchicine, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) with the concomitant use of lomipatide.
MifepristoneMay lead to excessive post-abortion bleeding in patients on anticoagulant therapy. Concomitant therapy is contraindicated.
NefazodoneP-Glycoprotein inducers such as nefazodone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
PantoprazoleProton pump inhibitors may decrease the bioavailability of dabigatran by 28% and increase inter-patient pharmacokinetic variability, especially in females. However, dose adjustment is not required.
PrazosinP-Glycoprotein inducers such as prazosin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
QuinidineQuinidine may increase the serum concentration of dabigatran etexilate, resulting in increased bleeding. Consider modification of therapy.
RifampicinP-Glycoprotein inducers such as rifampin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
RivaroxabanUsing additional anticoagulants such as dabigatran can increase the anticoagulant effect of rivaroxaban. Avoid concurrent use of rivaroxaban with other anticoagulants whenever possible, other than during transition periods, due to the possible increased for bleeding.
TipranavirP-Glycoprotein inducers such as tipranavir may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
TrazodoneP-Glycoprotein inducers such as trazodone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
VerapamilVerapamil may increase serum concentrations of the active metabolite(s) of dabigatran etexilate, resulting in an increased risk of bleeding. It is also a strong p-glycoprotein inhibitor. Therapy modification should be considered.
VinblastineP-Glycoprotein inducers such as vinblastine may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
Food Interactions
  • St. John's Wort

Targets

1. Prothrombin

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Prothrombin P00734 Details

References:

  1. Squizzato A, Dentali F, Steidl L, Ageno W: New direct thrombin inhibitors. Intern Emerg Med. 2009 Dec;4(6):479-84. Epub 2009 Sep 15. Pubmed
  2. Liesenfeld KH, Schafer HG, Troconiz IF, Tillmann C, Eriksson BI, Stangier J: Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol. 2006 Nov;62(5):527-37. Pubmed
  3. Karthikeyan G, Eikelboom JW, Hirsh J.:Dabigatran: ready for prime time?Pol Arch Med Wewn. 2010 Apr;120(4):137-42. Pubmed

Enzymes

1. Liver carboxylesterase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Liver carboxylesterase 1 P23141 Details

References:

  1. Hu ZY, Parker RB, Herring VL, Laizure SC: Conventional liquid chromatography/triple quadrupole mass spectrometry based metabolite identification and semi-quantitative estimation approach in the investigation of in vitro dabigatran etexilate metabolism. Anal Bioanal Chem. 2013 Feb;405(5):1695-704. doi: 10.1007/s00216-012-6576-4. Epub 2012 Dec 14. Pubmed

2. Cocaine esterase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cocaine esterase O00748 Details

References:

  1. Hu ZY, Parker RB, Herring VL, Laizure SC: Conventional liquid chromatography/triple quadrupole mass spectrometry based metabolite identification and semi-quantitative estimation approach in the investigation of in vitro dabigatran etexilate metabolism. Anal Bioanal Chem. 2013 Feb;405(5):1695-704. doi: 10.1007/s00216-012-6576-4. Epub 2012 Dec 14. Pubmed

3. UDP-glucuronosyltransferase 1-9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-9 O60656 Details

References:

  1. Ebner T, Wagner K, Wienen W: Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010 Sep;38(9):1567-75. doi: 10.1124/dmd.110.033696. Epub 2010 Jun 15. Pubmed

4. UDP-glucuronosyltransferase 2B7

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 2B7 P16662 Details

References:

  1. Ebner T, Wagner K, Wienen W: Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010 Sep;38(9):1567-75. doi: 10.1124/dmd.110.033696. Epub 2010 Jun 15. Pubmed

5. UDP-glucuronosyltransferase 2B15

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 2B15 P54855 Details

References:

  1. Ebner T, Wagner K, Wienen W: Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010 Sep;38(9):1567-75. doi: 10.1124/dmd.110.033696. Epub 2010 Jun 15. Pubmed

6. Ribosyldihydronicotinamide dehydrogenase [quinone]

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Ribosyldihydronicotinamide dehydrogenase [quinone] P16083 Details

References:

  1. Michaelis S, Marais A, Schrey AK, Graebner OY, Schaudt C, Sefkow M, Kroll F, Dreger M, Glinski M, Koester H, Metternich R, Fischer JJ: Dabigatran and dabigatran ethyl ester: potent inhibitors of ribosyldihydronicotinamide dehydrogenase (NQO2). J Med Chem. 2012 Apr 26;55(8):3934-44. doi: 10.1021/jm3001339. Epub 2012 Apr 17. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Galanis T, Thomson L, Palladino M, Merli GJ: New oral anticoagulants. J Thromb Thrombolysis. 2011 Apr;31(3):310-20. Pubmed
  2. Scaglione F: New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013 Feb;52(2):69-82. doi: 10.1007/s40262-012-0030-9. Pubmed

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Drug created on May 03, 2010 12:25 / Updated on September 16, 2013 18:04