Dicoumarol

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Not to be confused with Coumadin or coumarin.
Dicoumarol
Dicumarol.svg
Clinical data
MedlinePlusa605015
ATC code
Legal status
Legal status
  • US: Withdrawn from market
Pharmacokinetic data
Protein bindingplasmatic proteins
Metabolismhepatic
Excretionfaeces, urine
Identifiers
  • 3,3'-Methylenebis(4-hydroxy-2H-chromen-2-one)
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.000.575 Edit this at Wikidata
Chemical and physical data
FormulaC19H12O6
Molar mass336.299 g·mol−1
3D model (JSmol)
  • O=C1Oc2ccccc2C(O)=C1CC3=C(O)c4ccccc4OC3=O
  • InChI=1S/C19H12O6/c20-16-10-5-1-3-7-14(10)24-18(22)12(16)9-13-17(21)11-6-2-4-8-15(11)25-19(13)23/h1-8,20-21H,9H2 checkY
  • Key:DOBMPNYZJYQDGZ-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  

Dicoumarol (INN) or dicumarol (USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases.

Dicoumarol is a natural chemical substance of combined plant and fungal origin. It is a derivative of coumarin, a bitter-tasting but sweet-smelling substance made by plants that does not itself affect coagulation, but which is (classically) transformed in mouldy feeds or silages by a number of species of fungi, into active dicoumarol. Dicoumarol does affect coagulation, and was discovered in mouldy wet sweet-clover hay, as the cause of a naturally occurring bleeding disease in cattle.[1] See warfarin for a more detailed discovery history.

Identified in 1940, dicoumarol became the prototype of the 4-hydroxycoumarin anticoagulant drug class. Dicoumarol itself, for a short time, was employed as a medicinal anticoagulant drug, but since the mid-1950s has been replaced by its simpler derivative warfarin, and other 4-hydroxycoumarin drugs.

It is given orally, and it acts within two days.

Uses[]

Dicoumarol was used, along with heparin, for the treatment of deep venous thrombosis. Unlike heparin, this class of drugs may be used for months or years.

Mechanism of action[]

Like all 4-hydroxycoumarin drugs it is a competitive inhibitor of vitamin K epoxide reductase, an enzyme that recycles vitamin K, thus causing depletion of active vitamin K in blood. This prevents the formation of the active form of prothrombin and several other coagulant enzymes. These compounds are not antagonists of Vitamin K directly—as they are in pharmaceutical uses—but rather promote depletion of vitamin K in bodily tissues allowing vitamin K's mechanism of action as a potent medication for dicoumarol toxicity. The mechanism of action of Vitamin K along with the toxicity of dicoumarol are measured with the prothrombin time (PT) blood test.

Poisoning[]

Overdose results in serious, sometimes fatal uncontrolled hemorrhage.[2]

History[]

Dicoumarol was isolated by Karl Link's laboratory at University of Wisconsin, six years after a farmer had brought a dead cow and a milk can full of uncoagulated blood to an agricultural extension station of the university. The cow had died of internal bleeding after eating moldy sweet clover; an outbreak of such deaths had begun in the 1920s during The Great Depression as farmers could not afford to waste hay that had gone bad.[3] Link's work led to the development of the rat poison warfarin and then to the anticoagulants still in clinical use today.[3]

Footnotes[]

  1. ^ Nicole Kresge; Robert D. Simoni; Robert L. Hill (2005-02-25). "Sweet clover disease and warfarin review". Journal of Biological Chemistry. 280 (8): e5. Retrieved 2012-09-26.
  2. ^ Duff, I. F.; Shull, W. H. (1949). "Fatal Hemorrhage in Dicumarol® Poisoning". Journal of the American Medical Association. 139 (12): 762–6. doi:10.1001/jama.1949.02900290008003. PMID 18112552.
  3. ^ a b Wardrop, Douglas; Keeling, David (2008). "The story of the discovery of heparin and warfarin" (PDF). British Journal of Haematology. 141 (6): 757–763. doi:10.1111/j.1365-2141.2008.07119.x. PMID 18355382.

See also[]

References[]

  • Cullen J, Hinkhouse M, Grady M, Gaut A, Liu J, Zhang Y, Weydert C, Domann F, Oberley L (2003). "Dicumarol inhibition of NADPH: quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism". Cancer Res. 63 (17): 5513–20. PMID 14500388.
  • Mironov A, Colanzi A, Polishchuk R, Beznoussenko G, Mironov A, Fusella A, Di Tullio G, Silletta M, Corda D, De Matteis M, Luini A (2004). "Dicumarol, an inhibitor of ADP-ribosylation of CtBP3/BARS, fragments golgi non-compact tubular zones and inhibits intra-golgi transport". Eur J Cell Biol. 83 (6): 263–79. doi:10.1078/0171-9335-00377. PMID 15511084.
  • Abdelmohsen K, Stuhlmann D, Daubrawa F, Klotz L (2005). "Dicumarol is a potent reversible inhibitor of gap junctional intercellular communication". Arch Biochem Biophys. 434 (2): 241–7. doi:10.1016/j.abb.2004.11.002. PMID 15639223.
  • Thanos C, Liu Z, Reineke J, Edwards E, Mathiowitz E (2003). "Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride". Pharm Res. 20 (7): 1093–100. doi:10.1023/A:1024474609667. PMID 12880296.]

External links[]

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