Identification

Name
Amphotericin B
Accession Number
DB00681  (APRD00797)
Type
Small Molecule
Groups
Approved, Investigational
Description

Amphotericin B shows a high order of in vitro activity against many species of fungi. Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus are all inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/mL in vitro. While Candida albicans is generally quite susceptible to amphotericin B, non-albicans species may be less susceptible. Pseudallescheria boydii and Fusarium sp. are often resistant to amphotericin B. The antibiotic is without effect on bacteria, rickettsiae, and viruses.

Structure
Thumb
Synonyms
  • Amfotericina B
  • AMPH-b
  • Amphotericin B
  • Amphotéricine B
  • Amphotericinum B
  • C-AmB
  • Liposomal amphotericin b
External IDs
NSC-527017 / RP 17774
Product Ingredients
IngredientUNIICASInChI Key
Amphotericin B Cholesteryl Sulfate Complex774X4698X3120895-52-5Not applicable
CorifunginL26BTK479141610-51-9MTSXPVSZJVNPBE-ALEYTFIZSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AbelcetSuspension5 mgIntravenousLeadiant Biosciences, Inc1997-09-25Not applicableCanada
AmBisomePowder, for solution50 mgIntravenousAstellas Pharma Inc2000-05-29Not applicableCanada
AmBisomeInjection, powder, lyophilized, for solution50 mg/12.5mLIntravenousAstellas Pharma Inc1997-08-11Not applicableUs
AmphotecInjection, lipid complex100 mg/100mgIntravenousKadmon Pharmaceuticals2005-05-202011-05-31Us
AmphotecInjection, lipid complex50 mg/50mgIntravenousKadmon Pharmaceuticals2005-05-202011-05-31Us
Amphotec 100 mgPowder, for suspension100 mgIntravenousThree Rivers Pharmaceuticals Llc2004-06-172013-08-22Canada
Amphotec 50 mgPowder, for suspension50 mgIntravenousThree Rivers Pharmaceuticals Llc2007-02-262013-08-22Canada
Amphotericin B for Injection, USPPowder, for solution50 mgIntravenousSterimax IncNot applicableNot applicableCanada
Fungizone Intravenous Injection 50mgPowder, for solution50 mgIntravenousBristol Myers Squibb1958-12-31Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Amphotericin BInjection, powder, lyophilized, for solution50 mg/10mLIntravenousX Gen Pharmaceuticals, Inc.1992-04-29Not applicableUs
FungizoneInjection, powder, lyophilized, for solution50 mg/10mLIntravenousE.R. Squibb & Sons, L.L.C.1966-03-012005-09-30Us
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
AbelcetAmphotericin B (5 mg/1mL) + DL-dimyristoylphosphatidylcholine (3.4 mg/1mL) + DL-dimyristoylphosphatidylglycerol (1.5 mg/1mL)InjectionIntravenousLeadiant Biosciences, Inc.2010-10-18Not applicableUs
International/Other Brands
Abelect (Cephalon) / Ampho-Moronal (Dermapharm) / Amphocil (Alza) / Amphocin (Pfizer) / Amphotericin (Bristol-Myers Squibb) / Fungilin (Sigma) / Fungisome / Fungizone (Bristol-Myers Squibb) / Fungizone Intravenous (Bristol-Myers Squibb) / Halizon (Fuji Yakuhin)
Categories
UNII
7XU7A7DROE
CAS number
1397-89-3
Weight
Average: 924.079
Monoisotopic: 923.487849915
Chemical Formula
C47H73NO17
InChI Key
APKFDSVGJQXUKY-INPOYWNPSA-N
InChI
InChI=1S/C47H73NO17/c1-27-17-15-13-11-9-7-5-6-8-10-12-14-16-18-34(64-46-44(58)41(48)43(57)30(4)63-46)24-38-40(45(59)60)37(54)26-47(61,65-38)25-33(51)22-36(53)35(52)20-19-31(49)21-32(50)23-39(55)62-29(3)28(2)42(27)56/h5-18,27-38,40-44,46,49-54,56-58,61H,19-26,48H2,1-4H3,(H,59,60)/b6-5+,9-7+,10-8+,13-11+,14-12+,17-15+,18-16+/t27-,28-,29-,30+,31+,32+,33-,34-,35+,36+,37-,38-,40+,41-,42+,43+,44-,46-,47+/m0/s1
IUPAC Name
(1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,35S,36R,37S)-33-{[(2R,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy}-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid
SMILES
[H][C@]12C[C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](N)[C@@H]3O)\C=C\C=C\C=C\C=C\C=C\C=C\C=C\[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]1C(O)=O)O2

Pharmacology

Indication

Used to treat potentially life threatening fungal infections.

Associated Conditions
Pharmacodynamics

Amphotericin B shows a high order of in vitro activity against many species of fungi. Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus are all inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/mL in vitro. While Candida albicans is generally quite susceptible to amphotericin B, non-albicans species may be less susceptible. Pseudallescheria boydii and Fusarium sp. are often resistant to amphotericin B. The antibiotic is without effect on bacteria, rickettsiae, and viruses.

Mechanism of action

Amphotericin B is fungistatic or fungicidal depending on the concentration obtained in body fluids and the susceptibility of the fungus. The drug acts by binding to sterols (ergosterol) in the cell membrane of susceptible fungi. This creates a transmembrane channel, and the resultant change in membrane permeability allowing leakage of intracellular components. Ergosterol, the principal sterol in the fungal cytoplasmic membrane, is the target site of action of amphotericin B and the azoles. Amphotericin B, a polyene, binds irreversibly to ergosterol, resulting in disruption of membrane integrity and ultimately cell death.

TargetActionsOrganism
AErgosterol
binder
Candida albicans
Absorption

Bioavailability is 100% for intravenous infusion.

Volume of distribution
Not Available
Protein binding

Highly bound (>90%) to plasma proteins.

Metabolism

Exclusively renal

Route of elimination
Not Available
Half life

An elimination half-life of approximately 15 days follows an initial plasma half-life of about 24 hours.

Clearance
  • 39 +/- 22 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day at Day 1]
  • 17 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day 3-20 days later]
  • 51 +/- 44 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day at Day 1]
  • 22 +/- 15 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day 3-20 days later]
  • 21 +/- 14 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day at Day 1]
  • 11 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day 3-20 days later]
Toxicity

Oral, rat: LD50 = >5 gm/kg. Amphotericin B overdoses can result in cardio-respiratory arrest.

Affected organisms
  • Various Fungus Species
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Amphotericin B.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Amphotericin B.
3-isobutyl-1-methyl-7H-xanthineThe metabolism of 3-isobutyl-1-methyl-7H-xanthine can be decreased when combined with Amphotericin B.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Amphotericin B.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Amphotericin B.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Amphotericin B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Amphotericin B.
7-DeazaguanineThe metabolism of 7-Deazaguanine can be decreased when combined with Amphotericin B.
7,9-DimethylguanineThe metabolism of 7,9-Dimethylguanine can be decreased when combined with Amphotericin B.
8-azaguanineThe metabolism of 8-azaguanine can be decreased when combined with Amphotericin B.
Food Interactions
Not Available

References

Synthesis Reference

Frank Sipos, "Process for producing the methyl ester of amphotericin B." U.S. Patent US4035567, issued March, 1976.

US4035567
General References
Not Available
External Links
Human Metabolome Database
HMDB0014819
KEGG Drug
D00203
KEGG Compound
C06573
PubChem Compound
5280965
PubChem Substance
46505473
ChemSpider
10237579
ChEBI
2682
ChEMBL
CHEMBL267345
Therapeutic Targets Database
DAP001322
PharmGKB
PA448415
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Amphotericin_B
ATC Codes
J02AA01 — Amphotericin bG01AA03 — Amphotericin bA01AB04 — Amphotericin bA07AA07 — Amphotericin b
AHFS Codes
  • 08:14.28 — Polyenes
FDA label
Download (1.02 MB)
MSDS
Download (73.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableInfection NOS1
1CompletedNot AvailableNormal Healthy Subjects1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal1
1RecruitingTreatmentVisceral Leishmaniasis1
1, 2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal1
1, 2WithdrawnTreatmentEffects of Immunotherapy / Leishmaniasis1
2Active Not RecruitingTreatmentAspergillosis, Allergic Bronchopulmonary1
2CompletedPreventionAcute Myelogenous Leukaemia (AML) / Myelodysplastic Syndrome1
2CompletedPreventionFungus Diseases1
2CompletedTreatmentAspergillosis1
2CompletedTreatmentFevers / Neutropenias1
2CompletedTreatmentFungus Diseases / Hematopoietic Stem Cell Transplantation (HSCT)1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal2
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Oral Candidiasis1
2CompletedTreatmentLeukaemia, Lymphoblastic / Myeloblastic Leukemia / Pulmonary Invasive Aspergillosis1
2CompletedTreatmentMeningitis, Cryptococcal1
2CompletedTreatmentMucormycosis1
2CompletedTreatmentPrimary Visceral Leishmaniasis1
2CompletedTreatmentVisceral Leishmaniasis1
2CompletedTreatmentZygomycosis1
2RecruitingTreatmentChronic Mucocutaneous Candidiasis (CMC)1
2RecruitingTreatmentHuman Immunodeficiency Virus (HIV) / Meningitis / Meningitis streptococcal / Meningoencephalitis1
2RecruitingTreatmentPKDL - Post-Kala-Azar Dermal Leishmanioid1
2SuspendedPreventionLung Transplant Recipients1
2TerminatedTreatmentAspergillosis1
2TerminatedTreatmentMeningitis, Cryptococcal1
2TerminatedTreatmentVisceral Leishmaniasis1
2Unknown StatusPreventionLeukemia Acute Myeloid Leukemia (AML)1
3Active Not RecruitingTreatmentVisceral Leishmaniasis1
3CompletedDiagnosticAspergillosis1
3CompletedPreventionInfections, Fungal / Transplantation, Lung2
3CompletedPreventionInvasive Fungal Disease1
3CompletedPreventionMycoses / Transplantation, Liver1
3CompletedSupportive CareInfection NOS1
3CompletedSupportive CareMalignancies2
3CompletedTreatmentAcquired Immune Deficiency Syndrome (AIDS) / Aspergillosis / Human Immunodeficiency Virus (HIV) Infections / Immunologic Deficiency Syndromes / Neutropenias1
3CompletedTreatmentBlastomycosis / Histoplasmosis / Human Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentChronic Rhinosinusitis1
3CompletedTreatmentDisseminated Leishmaniasis1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Mycoses1
3CompletedTreatmentInvasive Aspergillosis / Other Fungal Infections1
3CompletedTreatmentInvasive Fungal Infections / Malignancies, Hematologic1
3CompletedTreatmentVisceral Leishmaniasis6
3CompletedTreatmentCandidiasis infection1
3TerminatedTreatmentChronic Lung Diseases / Transplantation, Lung1
3TerminatedTreatmentCandidiasis infection1
3Unknown StatusPreventionPediatric Acute Leukemia Induction1
3Unknown StatusTreatmentBacterial Vaginosis (BV) / Candidiasis infection1
4CompletedPreventionLeukemias1
4CompletedPreventionCandidiasis infection1
4CompletedTreatmentCandidemia / Candidiasis, Invasive1
4CompletedTreatmentCentral Line Fungal Infections1
4CompletedTreatmentInfections, Fungal / Liver Diseases1
4CompletedTreatmentInvasive Aspergillosis1
4CompletedTreatmentPost-kala-azar Dermal Leishmaniasis1
4CompletedTreatmentVisceral Leishmaniasis1
4Not Yet RecruitingTreatmentMeningitis, Cryptococcal1
4Not Yet RecruitingTreatmentVisceral Leishmaniasis1
4RecruitingOtherObesity, Morbid1
4SuspendedTreatmentBlastomycosis1
4TerminatedPreventionInfections, Fungal1
4TerminatedPreventionTransplantation, Liver1
4TerminatedTreatmentDuration of Neutropenia Following Chemotherapy > 10 Days / Malignant Hemopathies1
4TerminatedTreatmentNeutropenia, Febrile1
4TerminatedTreatmentVisceral Leishmaniasis1
4Unknown StatusPreventionPulmonary Invasive Aspergillosis1
4Unknown StatusPreventionProphylaxis of Candida Infections / Sepsis1
Not AvailableActive Not RecruitingNot AvailableSystemic Fungal Infections1
Not AvailableCompletedTreatmentEsophageal Candidiasis / Human Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal7
Not AvailableUnknown StatusTreatmentMeningitis, Cryptococcal1

Pharmacoeconomics

Manufacturers
  • Apothecon inc div bristol myers squibb
  • Sigma tau pharmaceuticals inc
  • Three rivers pharmaceuticals llc
  • Astellas pharma us inc
  • Abbott laboratories
  • Abraxis pharmaceutical products
  • Teva parenteral medicines inc
  • X gen pharmaceuticals inc
  • Bristol myers squibb co
Packagers
  • Astellas Pharma Inc.
  • Ben Venue Laboratories Inc.
  • Bristol-Myers Squibb Co.
  • Cardinal Health
  • DSM Corp.
  • E.R. Squibb and Sons LLC
  • Enzon Inc.
  • Gilead Sciences Inc.
  • Medisca Inc.
  • Oso Biopharmaceuticals Manufacturing LLC
  • Pharmacia Inc.
  • Sigma-Tau Pharmaceuticals Inc.
  • Teva Pharmaceutical Industries Ltd.
  • Three Rivers Pharmaceuticals LLC
  • X-Gen Pharmaceuticals
Dosage forms
FormRouteStrength
InjectionIntravenous
SuspensionIntravenous5 mg
Injection, powder, lyophilized, for solutionIntravenous50 mg/12.5mL
Powder, for solutionIntravenous50 mg
Injection, lipid complexIntravenous100 mg/100mg
Injection, lipid complexIntravenous50 mg/50mg
Powder, for suspensionIntravenous100 mg
Powder, for suspensionIntravenous50 mg
Injection, powder, lyophilized, for solutionIntravenous50 mg/10mL
Prices
Unit descriptionCostUnit
Ambisome 50 mg vial188.4USD vial
Amphotec 100 mg vial160.0USD vial
Amphotec 50 mg vial93.33USD vial
Fungizone Iv 50 mg/vial72.5USD vial
Amphotericin b powder29.99USD g
Amphotericin b 50 mg vial24.5USD vial
Abelcet 5 mg/ml vial p-f12.0USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA1339008No1997-03-252014-03-25Canada
CA1336890No1995-09-052012-09-05Canada
US6406713No1999-06-182019-06-18Us
US5874104No1996-02-232016-02-23Us
US5965156No1996-10-122016-10-12Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)170.0 °CNot Available
water solubility750 mg/L (at 28 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP0.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0819 mg/mLALOGPS
logP-0.66ALOGPS
logP-2.3ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)3.58ChemAxon
pKa (Strongest Basic)9.11ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count17ChemAxon
Hydrogen Donor Count12ChemAxon
Polar Surface Area319.61 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity244.67 m3·mol-1ChemAxon
Polarizability99.45 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9308
Blood Brain Barrier-0.9659
Caco-2 permeable-0.7539
P-glycoprotein substrateSubstrate0.6404
P-glycoprotein inhibitor INon-inhibitor0.7322
P-glycoprotein inhibitor IINon-inhibitor0.5977
Renal organic cation transporterNon-inhibitor0.9491
CYP450 2C9 substrateNon-substrate0.7992
CYP450 2D6 substrateNon-substrate0.8785
CYP450 3A4 substrateSubstrate0.5496
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.941
CYP450 2D6 inhibitorNon-inhibitor0.9444
CYP450 2C19 inhibitorNon-inhibitor0.921
CYP450 3A4 inhibitorNon-inhibitor0.9381
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.984
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9682
BiodegradationNot ready biodegradable0.9414
Rat acute toxicity2.2357 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9777
hERG inhibition (predictor II)Non-inhibitor0.7887
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as aminoglycosides. These are molecules or a portion of a molecule composed of amino-modified sugars.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbohydrates and carbohydrate conjugates
Direct Parent
Aminoglycosides
Alternative Parents
Macrolides and analogues / Hexoses / O-glycosyl compounds / Beta hydroxy acids and derivatives / Oxanes / Dicarboxylic acids and derivatives / Secondary alcohols / 1,2-aminoalcohols / Amino acids / Lactones
show 11 more
Substituents
Aminoglycoside core / Macrolide / Hexose monosaccharide / O-glycosyl compound / Glycosyl compound / Beta-hydroxy acid / Dicarboxylic acid or derivatives / Oxane / Hydroxy acid / Monosaccharide
show 24 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
antibiotic antifungal drug, macrolide antibiotic, polyene antibiotic (CHEBI:2682) / Plyenes (C06573) / Polyenes (LMPK06000002)

Targets

1. Ergosterol
Kind
Small molecule
Organism
Candida albicans
Pharmacological action
Yes
Actions
Binder
References
  1. Laniado-Laborin R, Cabrales-Vargas MN: Amphotericin B: side effects and toxicity. Rev Iberoam Micol. 2009 Dec 31;26(4):223-7. doi: 10.1016/j.riam.2009.06.003. [PubMed:19836985]
  2. Baginski M, Czub J: Amphotericin B and its new derivatives - mode of action. Curr Drug Metab. 2009 Jun;10(5):459-69. [PubMed:19689243]
  3. Baginski M, Sternal K, Czub J, Borowski E: Molecular modelling of membrane activity of amphotericin B, a polyene macrolide antifungal antibiotic. Acta Biochim Pol. 2005;52(3):655-8. Epub 2005 Aug 5. [PubMed:16086075]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Kuper JI, D'Aprile M: Drug-Drug interactions of clinical significance in the treatment of patients with Mycobacterium avium complex disease. Clin Pharmacokinet. 2000 Sep;39(3):203-14. [PubMed:11020135]

Drug created on June 13, 2005 07:24 / Updated on November 14, 2018 12:44