Identification

Name
Etacrynic acid
Accession Number
DB00903  (APRD00251)
Type
Small Molecule
Groups
Approved, Investigational
Description

A compound that inhibits symport of sodium, potassium, and chloride primarily in the ascending limb of Henle, but also in the proximal and distal tubules. This pharmacological action results in excretion of these ions, increased urinary output, and reduction in extracellular fluid. This compound has been classified as a loop or high ceiling diuretic.

Structure
Thumb
Synonyms
  • (2,3-Dichloro-4-(2-methylene-1-oxobutyl)phenoxy)acetic acid
  • acide étacrynique
  • ácido etacrínico
  • acidum etacrynicum
  • Etacrinic acid
  • Etakrinic acid
  • Ethacryinic Acid
  • Ethacrynate
  • Ethacrynic acid
  • Methylenebutyrylphenoxyacetic acid
External IDs
MK-595 / NSC-85791
Product Ingredients
IngredientUNIICASInChI Key
Ethacrynate sodiumK41MYV7MPM6500-81-8CWCSCNSKBSCYCS-UHFFFAOYSA-M
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EdecrinTablet25 mg/1OralAton Pharma, Inc.1967-01-102014-12-31Us
EdecrinTablet25 mg/1OralKAISER FOUNDATION HOSPITALS2013-01-102019-02-28Us25010 0215 15 nlmimage10 a93ad486
EdecrinTablet25 mgOralValeant Canada Lp Valeant Canada S.E.C.2004-10-15Not applicableCanada
EdecrinTablet25 mg/1OralAvera McKennan Hospital2015-10-02Not applicableUs69189 037120180907 15195 1g80pdi
EdecrinTablet25 mg/1OralAton Pharma, Inc.1967-01-10Not applicableUs
EdecrinTablet25 mg/1OralMerck Sharp & Dohme Limited1967-01-102009-01-31Us
Edecrin SodiumInjection, powder, lyophilized, for solution50 mg/50mLIntravenousMerck Sharp & Dohme Limited1967-01-102007-10-31Us
Edecrin Tab 50mgTablet50 mgOralMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1968-12-312004-03-04Canada
Ethacrynate Sodium for Injection USPPowder, for solution50 mgIntravenousSterimax Inc2018-03-29Not applicableCanada
Sodium EdecrinPowder, for solution50 mg/50mLIntravenousAton Pharma, Inc.1967-01-10Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Ethacrynate SodiumInjection, powder, lyophilized, for solution50 mg/50mLIntravenousZydus Pharmaceuticals Usa, Inc.2018-01-24Not applicableUs
Ethacrynate SodiumInjection, powder, for solution50 mg/50mLIntravenousPar Pharmaceutical, Inc.2015-07-30Not applicableUs
Ethacrynate SodiumInjection, powder, lyophilized, for solution50 mg/50mLIntravenousCadila Pharnmaceuticals2018-01-24Not applicableUs
Ethacrynic acidTablet25 mg/1OralAlvogen, Inc.2018-07-24Not applicableUs
Ethacrynic AcidTablet25 mg/1OralEdenbridge Pharmaceuticals Llc2016-07-05Not applicableUs
Ethacrynic AcidTablet25 mg/1OralPar Pharmaceutical2017-07-21Not applicableUs
Ethacrynic AcidTablet25 mg/1OralIngenus Pharmaceuticals Nj, Llc2016-07-052018-05-07Us
Ethacrynic AcidTablet25 mg/1OralAmneal Pharmaceuticals2018-05-14Not applicableUs
Ethacrynic AcidTablet25 mg/1OralGolden State Medical Supply, Inc.2017-05-04Not applicableUs
Ethacrynic AcidTablet25 mg/1OralWest-Ward Pharmaceuticals Corp.2017-02-24Not applicableUs
International/Other Brands
Crinuryl (Assia) / Edecril (Merck) / Edecrina / Endecril / Hidromedin / Hydromedin (Merck) / Mingit / Otacril / Reomax (Bioindustria) / Taladren (Malesci) / Uregit
Categories
UNII
M5DP350VZV
CAS number
58-54-8
Weight
Average: 303.138
Monoisotopic: 302.011264286
Chemical Formula
C13H12Cl2O4
InChI Key
AVOLMBLBETYQHX-UHFFFAOYSA-N
InChI
InChI=1S/C13H12Cl2O4/c1-3-7(2)13(18)8-4-5-9(12(15)11(8)14)19-6-10(16)17/h4-5H,2-3,6H2,1H3,(H,16,17)
IUPAC Name
2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid
SMILES
CCC(=C)C(=O)C1=C(Cl)C(Cl)=C(OCC(O)=O)C=C1

Pharmacology

Indication

For the treatment of high blood pressure and edema caused by diseases like congestive heart failure, liver failure, and kidney failure.

Associated Conditions
Pharmacodynamics

Ethacrynic acid is a monosulfonamyl loop or high ceiling diuretic. Ethacrynic acid acts on the ascending limb of the loop of Henle and on the proximal and distal tubules. Urinary output is usually dose dependent and related to the magnitude of fluid accumulation. Water and electrolyte excretion may be increased several times over that observed with thiazide diuretics, since ethacrynic acid inhibits reabsorption of a much greater proportion of filtered sodium than most other diuretic agents. Therefore, ethacrynic acid is effective in many patients who have significant degrees of renal insufficiency. Ethacrynic acid has little or no effect on glomerular filtration or on renal blood flow, except following pronounced reductions in plasma volume when associated with rapid diuresis.

Mechanism of action

Ethacrynic acid inhibits symport of sodium, potassium, and chloride primarily in the ascending limb of Henle, but also in the proximal and distal tubules. This pharmacological action results in excretion of these ions, increased urinary output, and reduction in extracellular fluid. Diuretics also lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases, explaining its antihypertensive action. Eventually, cardiac output returns to normal with an accompanying decrease in peripheral resistance. Its mode of action does not involve carbonic anhydrase inhibition.

TargetActionsOrganism
ASodium/potassium-transporting ATPase subunit alpha-1
inhibitor
Human
ASolute carrier family 12 member 1
inhibitor
Human
ULymphoid enhancer-binding factor 1Not AvailableHuman
UGlutathione S-transferase P
inhibitor
Human
Absorption

Onset of action is rapid, usually within 30 minutes after an oral dose of ethacrynic acid or within 5 minutes after an intravenous injection of ethacrynic acid.

Volume of distribution
Not Available
Protein binding

> 98%

Metabolism

Hepatic.

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Overdosage may lead to excessive diuresis with electrolyte depletion.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Ethacrynic Acid Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe protein binding of (R)-warfarin can be decreased when combined with Etacrynic acid.
(S)-WarfarinThe protein binding of (S)-Warfarin can be decreased when combined with Etacrynic acid.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidEtacrynic acid may increase the hypotensive activities of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Etacrynic acid.
4-hydroxycoumarinThe protein binding of 4-hydroxycoumarin can be decreased when combined with Etacrynic acid.
AbediterolThe risk or severity of hyperkalemia can be increased when Abediterol is combined with Etacrynic acid.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Etacrynic acid.
AcebutololThe risk or severity of adverse effects can be increased when Etacrynic acid is combined with Acebutolol.
AceclofenacThe therapeutic efficacy of Etacrynic acid can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Etacrynic acid can be decreased when used in combination with Acemetacin.
Food Interactions
  • Take with food to reduce irritation.

References

Synthesis Reference

Schultz, E.M. and Sprague, J.M.; U.S. Patent 3,255,241; June 7, 1966; assigned to Merck & co., Inc.

General References
Not Available
External Links
Human Metabolome Database
HMDB0015039
KEGG Drug
D00313
PubChem Compound
3278
PubChem Substance
46507562
ChemSpider
3163
BindingDB
50186231
ChEBI
4876
ChEMBL
CHEMBL456
Therapeutic Targets Database
DAP000748
PharmGKB
PA449518
HET
EAA
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ethacrynic_acid
ATC Codes
C03CC01 — Etacrynic acid
AHFS Codes
  • 40:28.08 — Loop Diuretics
PDB Entries
11gs / 1gse / 1gsf / 2gss / 3dgq / 3gss / 3hjo / 3km6 / 3kmo / 3n9j
FDA label
Download (75.2 KB)
MSDS
Download (74 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentBladder Cancers1
1, 2CompletedOtherGlaucoma1
3CompletedTreatmentFluid Overload1

Pharmacoeconomics

Manufacturers
  • Aton pharma inc
Packagers
  • Aton Pharma Inc.
  • Ben Venue Laboratories Inc.
  • Draxis Specialty Pharmaceuticals Inc.
  • DSM Corp.
  • Kaiser Foundation Hospital
  • Merck & Co.
  • Professional Co.
Dosage forms
FormRouteStrength
TabletOral25 mg/1
TabletOral25 mg
Injection, powder, lyophilized, for solutionIntravenous50 mg/50mL
TabletOral50 mg
Injection, powder, for solutionIntravenous50 mg/50mL
Powder, for solutionIntravenous50 mg/50mL
Powder, for solutionIntravenous50 mg
Prices
Unit descriptionCostUnit
Sodium edecrin 50 mg vial527.4USD vial
Edecrin sodium 50 mg vial114.0USD vial
Ethacrynic acid 100% powder26.4USD g
Edecrin 25 mg tablet3.19USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)118.5-120.5Schultz, E.M. and Sprague, J.M.; U.S. Patent 3,255,241; June 7, 1966; assigned to Merck & co., Inc.
logP3.3Not Available
pKa3.5MERCK INDEX (2001)
Predicted Properties
PropertyValueSource
Water Solubility0.0194 mg/mLALOGPS
logP3.42ALOGPS
logP3.66ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)2.8ChemAxon
pKa (Strongest Basic)-5ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area63.6 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity72.22 m3·mol-1ChemAxon
Polarizability28.57 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9591
Blood Brain Barrier-0.6921
Caco-2 permeable+0.5597
P-glycoprotein substrateSubstrate0.54
P-glycoprotein inhibitor INon-inhibitor0.5574
P-glycoprotein inhibitor IINon-inhibitor0.9828
Renal organic cation transporterNon-inhibitor0.9052
CYP450 2C9 substrateNon-substrate0.8508
CYP450 2D6 substrateNon-substrate0.8947
CYP450 3A4 substrateNon-substrate0.5262
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorInhibitor0.8949
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.831
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8384
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8344
BiodegradationReady biodegradable0.6545
Rat acute toxicity2.4505 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9228
hERG inhibition (predictor II)Non-inhibitor0.9044
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0690000000-f598b8bee69a6b62e817
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0fb9-2930000000-143e32f52c12761e81dd

Taxonomy

Description
This compound belongs to the class of organic compounds known as chlorophenoxyacetates. These are compounds containing a phenoxyacetate that carries one or more chlorine atoms on the benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenoxyacetic acid derivatives
Direct Parent
Chlorophenoxyacetates
Alternative Parents
Butyrophenones / Aryl ketones / Benzoyl derivatives / Dichlorobenzenes / Phenol ethers / Phenoxy compounds / Alkyl aryl ethers / Alpha-branched alpha,beta-unsaturated ketones / Aryl chlorides / Enones
show 7 more
Substituents
Chlorophenoxyacetate / Butyrophenone / 1,2-dichlorobenzene / Phenoxy compound / Benzoyl / Phenol ether / Aryl ketone / Halobenzene / Chlorobenzene / Alkyl aryl ether
show 20 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
aromatic ether, monocarboxylic acid, dichlorobenzene, aromatic ketone (CHEBI:4876)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Steroid hormone binding
Specific Function
This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates th...
Gene Name
ATP1A1
Uniprot ID
P05023
Uniprot Name
Sodium/potassium-transporting ATPase subunit alpha-1
Molecular Weight
112895.01 Da
References
  1. Ronquist G, Agren GK: A Mg2+- and Ca2+-stimulated adenosine triphosphatase at the outer surface of Ehrlich ascites tumor cells. Cancer Res. 1975 Jun;35(6):1402-6. [PubMed:124205]
  2. Proverbio F, Condrescu-Guidi M, Whittembury G: Ouabain-insensitive Na+ stimulation of an Mg-2+ -dependent ATPase in kidney tissue. Biochim Biophys Acta. 1975 Jun 25;394(2):281-92. [PubMed:124600]
  3. Valdes RM, Huff MO, El-Masri MA, El-Mallakh RS: Effect of ethacrynic acid on sodium pump alpha isoforms in SH-SY5Y cells. Bipolar Disord. 2003 Apr;5(2):123-8. [PubMed:12680902]
  4. Kiil F, Sejersted OM: Analysis of energy metabolism and mechanism of loop diuretics in the thick ascending limb of Henle's loop in dog kidneys. Acta Physiol Scand. 2003 May;178(1):73-82. [PubMed:12713517]
  5. Schurek HJ, Aulbert E, Ebel H, Muller-Suur C: Influence of ouabain and ethacrynic acid on sodium transport and NaK-ATPase activity in the isolated perfused rat kidney. Curr Probl Clin Biochem. 1975;4:162-8. [PubMed:127690]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Sodium:potassium:chloride symporter activity
Specific Function
Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume.
Gene Name
SLC12A1
Uniprot ID
Q13621
Uniprot Name
Solute carrier family 12 member 1
Molecular Weight
121449.13 Da
References
  1. Bowes TJ, Gupta RS: Induction of mitochondrial fusion by cysteine-alkylators ethacrynic acid and N-ethylmaleimide. J Cell Physiol. 2005 Mar;202(3):796-804. [PubMed:15389563]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Participates in the Wnt signaling pathway. Activates transcription of target genes in the presence of CTNNB1 and EP300. May play a role in hair cell differentiation and follicle morphogenesis. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by LEF1 and CTNNB1. Regulates T-cell receptor alpha enhancer function. Binds DNA in a sequence-specific manner. PIAG antagonizes both Wnt-dependent and Wnt-independent activation by LEF1 (By similarity). Isoform 3 lacks the CTNNB1 interaction domain and may be an antagonist for Wnt signaling. Isoform 5 transcriptionally activates the fibronectin promoter, binds to and represses transcription from the E-cadherin promoter in a CTNNB1-independent manner, and is involved in reducing cellular aggregation and increasing cell migration of pancreatic cancer cells. Isoform 1 transcriptionally activates MYC and CCND1 expression and enhances proliferation of pancreatic tumor cells.
Specific Function
Armadillo repeat domain binding
Gene Name
LEF1
Uniprot ID
Q9UJU2
Uniprot Name
Lymphoid enhancer-binding factor 1
Molecular Weight
44200.41 Da
References
  1. Lu D, Liu JX, Endo T, Zhou H, Yao S, Willert K, Schmidt-Wolf IG, Kipps TJ, Carson DA: Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway. PLoS One. 2009 Dec 14;4(12):e8294. doi: 10.1371/journal.pone.0008294. [PubMed:20011538]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
irreversible inhibitor
General Function
S-nitrosoglutathione binding
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name
GSTP1
Uniprot ID
P09211
Uniprot Name
Glutathione S-transferase P
Molecular Weight
23355.625 Da
References
  1. van Iersel ML, Ploemen JP, Lo Bello M, Federici G, van Bladeren PJ: Interactions of alpha, beta-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1. Chem Biol Interact. 1997 Dec 12;108(1-2):67-78. [PubMed:9463521]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Glutathione transferase activity
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Gene Name
GSTA2
Uniprot ID
P09210
Uniprot Name
Glutathione S-transferase A2
Molecular Weight
25663.675 Da
References
  1. Depeille P, Cuq P, Passagne I, Evrard A, Vian L: Combined effects of GSTP1 and MRP1 in melanoma drug resistance. Br J Cancer. 2005 Jul 25;93(2):216-23. [PubMed:15999103]
  2. Awasthi S, Srivastava SK, Ahmad F, Ahmad H, Ansari GA: Interactions of glutathione S-transferase-pi with ethacrynic acid and its glutathione conjugate. Biochim Biophys Acta. 1993 Jul 10;1164(2):173-8. [PubMed:8329448]
  3. Iersel ML, Ploemen JP, Struik I, van Amersfoort C, Keyzer AE, Schefferlie JG, van Bladeren PJ: Inhibition of glutathione S-transferase activity in human melanoma cells by alpha,beta-unsaturated carbonyl derivatives. Effects of acrolein, cinnamaldehyde, citral, crotonaldehyde, curcumin, ethacrynic acid, and trans-2-hexenal. Chem Biol Interact. 1996 Oct 21;102(2):117-32. [PubMed:8950226]
  4. van Iersel ML, Ploemen JP, Lo Bello M, Federici G, van Bladeren PJ: Interactions of alpha, beta-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1. Chem Biol Interact. 1997 Dec 12;108(1-2):67-78. [PubMed:9463521]
  5. Morrow CS, Smitherman PK, Townsend AJ: Combined expression of multidrug resistance protein (MRP) and glutathione S-transferase P1-1 (GSTP1-1) in MCF7 cells and high level resistance to the cytotoxicities of ethacrynic acid but not oxazaphosphorines or cisplatin. Biochem Pharmacol. 1998 Oct 15;56(8):1013-21. [PubMed:9776312]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Bertucci C, Nanni B, Raffaelli A, Salvadori P: Chemical modification of human albumin at cys34 by ethacrynic acid: structural characterisation and binding properties. J Pharm Biomed Anal. 1998 Oct;18(1-2):127-36. [PubMed:9863950]
  2. Bertucci C, Wainer IW: Improved chromatographic performance of a modified human albumin based stationary phase. Chirality. 1997;9(4):335-40. [PubMed:9275312]
  3. Fehske KJ, Muller WE: High-affinity binding of ethacrynic acid is mediated by the two most important drug binding sites of human serum albumin. Pharmacology. 1986;32(4):208-13. [PubMed:3714803]
  4. Lebedev AA, Samokrutova OV: [Study of the binding of diuretics by serum proteins according to changes in tryptophan fluorescence]. Farmakol Toksikol. 1989 May-Jun;52(3):40-3. [PubMed:2792351]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H: Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem. 1997 Jul 25;272(30):18526-9. [PubMed:9228014]

Drug created on June 13, 2005 07:24 / Updated on December 12, 2018 03:40