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Identification
NameTerfenadine
Accession NumberDB00342  (APRD00606)
TypeSmall Molecule
GroupsWithdrawn
Description

In the U.S., Terfenadine was superseded by fexofenadine in the 1990s due to the risk of cardiac arrhythmia caused by QT interval prolongation.

Structure
Thumb
Synonyms
SynonymLanguageCode
(RS)-1-(4-tert-butylphenyl)-4-{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}-butan-1-olNot AvailableIUPAC
TerfenadinNot AvailablePh. Eur. 7
TerfenadinaNot AvailableDCIT
TerfénadineNot AvailableDCF
TerfenadineNot AvailableBP 2011, Ph. Eur. 7, USP 23
TerfenadinumLatinPh. Eur. 7
SaltsNot Available
Brand names
NameCompany
BronalGalenika
DaylertMicro Labs
SeldaneNot Available
ServininNovartis
TeldaneNot Available
TerfedCipla
Terfenadin ALAliud
Terfenadine FLXAccord Healthcare
TerfinInterbat
TernadinDunar
TrexylRanbaxy
TriludanNot Available
Brand mixtures
Brand NameIngredients
RhinofedTerfenadine and Pseudoephedrine
Terfed-DTerfenadine and Pseudoephedrine
TrexydinTerfenadine and Pseudoephedrine
TusantTerfenadine and Dextromethorphan
Categories
CAS number50679-08-8
WeightAverage: 471.6734
Monoisotopic: 471.313729561
Chemical FormulaC32H41NO2
InChI KeyGUGOEEXESWIERI-UHFFFAOYSA-N
InChI
InChI=1S/C32H41NO2/c1-31(2,3)26-18-16-25(17-19-26)30(34)15-10-22-33-23-20-29(21-24-33)32(35,27-11-6-4-7-12-27)28-13-8-5-9-14-28/h4-9,11-14,16-19,29-30,34-35H,10,15,20-24H2,1-3H3
IUPAC Name
1-(4-tert-butylphenyl)-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butan-1-ol
SMILES
CC(C)(C)C1=CC=C(C=C1)C(O)CCCN1CCC(CC1)C(O)(C1=CC=CC=C1)C1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassDiphenylmethanes
Direct parentDiphenylmethanes
Alternative parentsAromatic Monoterpenes; Cumenes; Piperidines; Tertiary Alcohols; Polyols; Tertiary Amines; Secondary Alcohols; Polyamines
Substituentsmonoterpene; aromatic monoterpene; p-cymene; cumene; piperidine; tertiary alcohol; tertiary amine; polyol; secondary alcohol; polyamine; amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Pharmacology
IndicationFor the treatment of allergic rhinitis, hay fever, and allergic skin disorders.
PharmacodynamicsTerfenadine, an H1-receptor antagonist antihistamine, is similar in structure to astemizole and haloperidol, a butyrophenone antipsychotic. The active metabolite of terfenadine is fexofenadine.
Mechanism of actionTerfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier, CNS depression is minimal.
AbsorptionOn the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 70%
Volume of distributionNot Available
Protein binding70%
Metabolism

Hepatic

SubstrateEnzymesProduct
Terfenadine
fexofenadineDetails
Route of eliminationNot Available
Half life3.5 hours
ClearanceNot Available
ToxicityMild (e.g., headache, nausea, confusion), but adverse cardiac events including cardiac arrest, ventricular arrhythmias including torsades de pointes and QT prolongation have been reported. LD50=mg/kg (orally in mice)
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 + 0.9535
Blood Brain Barrier + 0.5319
Caco-2 permeable + 0.6691
P-glycoprotein substrate Substrate 0.8338
P-glycoprotein inhibitor I Inhibitor 0.7145
P-glycoprotein inhibitor II Inhibitor 0.5515
Renal organic cation transporter Inhibitor 0.5731
CYP450 2C9 substrate Non-substrate 0.8286
CYP450 2D6 substrate Substrate 0.7689
CYP450 3A4 substrate Substrate 0.6664
CYP450 1A2 substrate Inhibitor 0.5553
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.8932
CYP450 2C19 substrate Inhibitor 0.5229
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9627
Ames test Non AMES toxic 0.8907
Carcinogenicity Non-carcinogens 0.8443
Biodegradation Not ready biodegradable 0.9683
Rat acute toxicity 2.0063 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.5556
hERG inhibition (predictor II) Inhibitor 0.8014
Pharmacoeconomics
ManufacturersNot Available
Packagers
  • Pharmaceutical Utilization Management Program VA Inc.
  • Pharmedix
  • Veratex Corp.
Dosage forms
FormRouteStrength
TabletOral
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point147 °CPhysProp
water solubility0.0963 mg/L (at 25 °C)MCFARLAND,JW ET AL. (2001)
logP7.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000458ALOGPS
logP5.89ALOGPS
logP6.48ChemAxon
logS-6ALOGPS
pKa (Strongest Acidic)13.2ChemAxon
pKa (Strongest Basic)9.02ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area43.7 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity146.27 m3·mol-1ChemAxon
Polarizability56.45 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
References
Synthesis Reference

Timothy G. Fawcett, Christian T. Goralski, David W. Ziettlow, “Preparation of polymorphically pure terfenadine.” U.S. Patent US4742175, issued April, 1975.

US4742175
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00521
KEGG CompoundC07463
PubChem Compound5405
PubChem Substance46507007
ChemSpider5212
BindingDB50017376
Therapeutic Targets DatabaseDAP000102
PharmGKBPA451619
IUPHAR2608
Guide to Pharmacology2608
Drug Product Database1913395
RxListhttp://www.rxlist.com/cgi/generic/terfen.htm
Drugs.comhttp://www.drugs.com/mtm/terfenadine.html
WikipediaTerfenadine
ATC CodesR06AX12
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(72.9 KB)
Interactions
Drug Interactions
Drug
AcetophenazineIncreased risk of cardiotoxicity and arrhythmias
AlimemazineIncreased risk of cardiotoxicity and arrhythmias
AmiodaroneIncreased risk of cardiotoxicity and arrhythmias
AmitriptylineIncreased risk of cardiotoxicity and arrhythmias
AmoxapineIncreased risk of cardiotoxicity and arrhythmias
AmprenavirIncreased risk of cardiotoxicity and arrhythmias
AprepitantIncreased risk of cardiotoxicity and arrhythmias
BepridilIncreased risk of cardiotoxicity and arrhythmias
ChlorpromazineIncreased risk of cardiotoxicity and arrhythmias
CimetidineIncreased risk of cardiotoxicity and arrhythmias
CisaprideIncreased risk of cardiotoxicity and arrhythmias
ClarithromycinIncreased risk of cardiotoxicity and arrhythmias
ClomipramineIncreased risk of cardiotoxicity and arrhythmias
DelavirdineIncreased risk of cardiotoxicity and arrhythmias
DesipramineIncreased risk of cardiotoxicity and arrhythmias
DiltiazemIncreased risk of cardiotoxicity and arrhythmias
DisopyramideIncreased risk of cardiotoxicity and arrhythmias
DoxepinIncreased risk of cardiotoxicity and arrhythmias
EfavirenzIncreased risk of cardiotoxicity and arrhythmias
ErythromycinIncreased risk of cardiotoxicity and arrhythmias
FlecainideIncreased risk of cardiotoxicity and arrhythmias
FluconazoleIncreased risk of cardiotoxicity and arrhythmias
FluoxetineIncreased risk of cardiotoxicity and arrhythmias
FluphenazineIncreased risk of cardiotoxicity and arrhythmias
FluvoxamineIncreased risk of cardiotoxicity and arrhythmias
FosamprenavirIncreased risk of cardiotoxicity and arrhythmias
GrepafloxacinIncreased risk of cardiotoxicity and arrhythmias
ImipramineIncreased risk of cardiotoxicity and arrhythmias
IndinavirIncreased risk of cardiotoxicity and arrhythmias
ItraconazoleIncreased risk of cardiotoxicity and arrhythmias
JosamycinIncreased risk of cardiotoxicity and arrhythmias
KetoconazoleIncreased risk of cardiotoxicity and arrhythmias
MesoridazineIncreased risk of cardiotoxicity and arrhythmias
MethdilazineIncreased risk of cardiotoxicity and arrhythmias
MethotrimeprazineIncreased risk of cardiotoxicity and arrhythmias
MexiletineIncreased risk of cardiotoxicity and arrhythmias
MibefradilIncreased risk of cardiotoxicity and arrhythmias
NefazodoneIncreased risk of cardiotoxicity and arrhythmias
NelfinavirIncreased risk of cardiotoxicity and arrhythmias
NicardipineIncreased risk of cardiotoxicity and arrhythmias
NortriptylineIncreased risk of cardiotoxicity and arrhythmias
PerphenazineIncreased risk of cardiotoxicity and arrhythmias
PosaconazoleContraindicated co-administration
ProcainamideIncreased risk of cardiotoxicity and arrhythmias
ProchlorperazineIncreased risk of cardiotoxicity and arrhythmias
PromazineIncreased risk of cardiotoxicity and arrhythmias
PromethazineIncreased risk of cardiotoxicity and arrhythmias
PropafenoneIncreased risk of cardiotoxicity and arrhythmias.
PropericiazineIncreased risk of cardiotoxicity and arrhythmias
PropiomazineIncreased risk of cardiotoxicity and arrhythmias
ProtriptylineIncreased risk of cardiotoxicity and arrhythmias
QuinidineIncreased risk of cardiotoxicity and arrhythmias
QuinineIncreased risk of cardiotoxicity and arrhythmias
QuinupristinThis combination presents an increased risk of toxicity
RitonavirIncreased risk of cardiotoxicity and arrhythmias
SaquinavirIncreased risk of cardiotoxicity and arrhythmias
SotalolIncreased risk of cardiotoxicity and arrhythmias
SparfloxacinIncreased risk of cardiotoxicity and arrhythmias
TelavancinAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
TelithromycinIncreased risk of cardiotoxicity and arrhythmias
ThiethylperazineIncreased risk of cardiotoxicity and arrhythmias
ThioridazineIncreased risk of cardiotoxicity and arrhythmias
TipranavirTipranavir, co-administered with Ritonavir, may increase the plasma concentration of Terfenadine. Concomitant therapy is contraindicated.
TocainideIncreased risk of cardiotoxicity and arrhythmias
TrifluoperazineIncreased risk of cardiotoxicity and arrhythmias
TriflupromazineIncreased risk of cardiotoxicity and arrhythmias
TrimipramineIncreased risk of cardiotoxicity and arrhythmias
TroleandomycinIncreased risk of cardiotoxicity and arrhythmias
VerapamilIncreased risk of cardiotoxicity and arrhythmias
VoriconazoleIncreased risk of cardiotoxicity and arrhythmias
Food InteractionsNot Available

Targets

1. Histamine H1 receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Histamine H1 receptor P35367 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Kishimoto W, Hiroi T, Sakai K, Funae Y, Igarashi T: Metabolism of epinastine, a histamine H1 receptor antagonist, in human liver microsomes in comparison with that of terfenadine. Res Commun Mol Pathol Pharmacol. 1997 Dec;98(3):273-92. Pubmed
  3. Salata JJ, Jurkiewicz NK, Wallace AA, Stupienski RF 3rd, Guinosso PJ Jr, Lynch JJ Jr: Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine. Circ Res. 1995 Jan;76(1):110-9. Pubmed
  4. Wood-Baker R, Smith R, Holgate ST: A double-blind, placebo controlled study of the effect of the specific histamine H1-receptor antagonist, terfenadine, in chronic severe asthma. Br J Clin Pharmacol. 1995 Jun;39(6):671-5. Pubmed
  5. Phillips GD, Polosa R, Holgate ST: The effect of histamine-H1 receptor antagonism with terfenadine on concentration-related AMP-induced bronchoconstriction in asthma. Clin Exp Allergy. 1989 Jul;19(4):405-9. Pubmed
  6. Rafferty P, Holgate ST: Terfenadine (Seldane) is a potent and selective histamine H1 receptor antagonist in asthmatic airways. Am Rev Respir Dis. 1987 Jan;135(1):181-4. Pubmed

2. Potassium voltage-gated channel subfamily H member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Potassium voltage-gated channel subfamily H member 2 Q12809 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Gessner G, Zacharias M, Bechstedt S, Schonherr R, Heinemann SH: Molecular determinants for high-affinity block of human EAG potassium channels by antiarrhythmic agents. Mol Pharmacol. 2004 May;65(5):1120-9. Pubmed
  3. Testai L, Cecchetti V, Sabatini S, Martelli A, Breschi MC, Calderone V: Effects of K openers on the QT prolongation induced by HERG-blocking drugs in guinea-pigs. J Pharm Pharmacol. 2010 Jul;62(7):924-30. Pubmed

3. Muscarinic acetylcholine receptor M3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M3 P20309 Details

References:

  1. Yasuda SU, Yasuda RP: Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes. Pharmacotherapy. 1999 Apr;19(4):447-51. Pubmed

4. Muscarinic acetylcholine receptor M1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: binder

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M1 P11229 Details

References:

  1. Yasuda SU, Yasuda RP: Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes. Pharmacotherapy. 1999 Apr;19(4):447-51. Pubmed

5. Muscarinic acetylcholine receptor M5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: binder

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M5 P08912 Details

References:

  1. Yasuda SU, Yasuda RP: Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes. Pharmacotherapy. 1999 Apr;19(4):447-51. Pubmed

6. Muscarinic acetylcholine receptor M4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: binder

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M4 P08173 Details

References:

  1. Yasuda SU, Yasuda RP: Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes. Pharmacotherapy. 1999 Apr;19(4):447-51. Pubmed

7. Muscarinic acetylcholine receptor M2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: binder

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M2 P08172 Details

References:

  1. Yasuda SU, Yasuda RP: Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes. Pharmacotherapy. 1999 Apr;19(4):447-51. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Wang RW, Newton DJ, Liu N, Atkins WM, Lu AY: Human cytochrome P-450 3A4: in vitro drug-drug interaction patterns are substrate-dependent. Drug Metab Dispos. 2000 Mar;28(3):360-6. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  4. Kishimoto W, Hiroi T, Sakai K, Funae Y, Igarashi T: Metabolism of epinastine, a histamine H1 receptor antagonist, in human liver microsomes in comparison with that of terfenadine. Res Commun Mol Pathol Pharmacol. 1997 Dec;98(3):273-92. Pubmed
  5. Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry. 1996 Mar;153(3):311-20. Pubmed

2. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  2. Kishimoto W, Hiroi T, Sakai K, Funae Y, Igarashi T: Metabolism of epinastine, a histamine H1 receptor antagonist, in human liver microsomes in comparison with that of terfenadine. Res Commun Mol Pathol Pharmacol. 1997 Dec;98(3):273-92. Pubmed

4. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

6. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed.

7. Cytochrome P450 2J2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2J2 P51589 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. Pubmed
  2. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. Pubmed
  3. Hait WN, Gesmonde JF, Murren JR, Yang JM, Chen HX, Reiss M: Terfenadine (Seldane): a new drug for restoring sensitivity to multidrug resistant cancer cells. Biochem Pharmacol. 1993 Jan 26;45(2):401-6. Pubmed
  4. Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, Roden MM, Belas F, Chaudhary AK, Roden DM, Wood AJ, Wilkinson GR: Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res. 1999 Mar;16(3):408-14. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on March 19, 2014 18:39