Dicoumarol
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| MedlinePlus | a605015 |
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| Protein binding | plasmatic proteins |
| Metabolism | hepatic |
| Excretion | faeces, urine |
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| ECHA InfoCard | 100.000.575 |
| Chemical and physical data | |
| Formula | C19H12O6 |
| Molar mass | 336.299 g·mol−1 |
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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 Dicoumarol itself, for a short time, was employed as a medicinal anticoagulant drug, but since the mid-1950s has been replaced by its simpler derivative warfarin, and other 4-hydroxycoumarin drugs.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
[edit]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
[edit]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
[edit]Overdose results in serious, sometimes fatal uncontrolled hemorrhage.[2]
History
[edit]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]
See also
[edit]References
[edit]- ^ Kresge N, Simoni RD, Hill RL (February 2005). "Hemorrhagic sweet clover disease, dicumarol, and warfarin: the work of Karl Paul Link". Journal of Biological Chemistry. 280 (8): e6–e7. doi:10.1016/S0021-9258(19)62862-0.
- ^ Duff IF, Shull WH (March 1949). "Fatal hemorrhage in dicumarol poisoning; with report of necropsy". Journal of the American Medical Association. 139 (12): 762–766. doi:10.1001/jama.1949.02900290008003. PMID 18112552.
- ^ a b Wardrop D, Keeling D (June 2008). "The story of the discovery of heparin and warfarin". British Journal of Haematology. 141 (6): 757–763. doi:10.1111/j.1365-2141.2008.07119.x. PMID 18355382.
Further reading
[edit] | This article includes a list of general references, but it lacks sufficient corresponding inline citations. (September 2011) |
- Cullen JJ, Hinkhouse MM, Grady M, Gaut AW, Liu J, Zhang YP, et al. (September 2003). "Dicumarol inhibition of NADPH:quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism". Cancer Research. 63 (17): 5513–5520. PMID 14500388.
- Mironov AA, Colanzi A, Polishchuk RS, Beznoussenko GV, Mironov AA, Fusella A, et al. (July 2004). "Dicumarol, an inhibitor of ADP-ribosylation of CtBP3/BARS, fragments golgi non-compact tubular zones and inhibits intra-golgi transport". European Journal of Cell Biology. 83 (6): 263–279. doi:10.1078/0171-9335-00377. PMID 15511084.
- Abdelmohsen K, Stuhlmann D, Daubrawa F, Klotz LO (February 2005). "Dicumarol is a potent reversible inhibitor of gap junctional intercellular communication". Archives of Biochemistry and Biophysics. 434 (2): 241–247. doi:10.1016/j.abb.2004.11.002. PMID 15639223.
- Thanos CG, Liu Z, Reineke J, Edwards E, Mathiowitz E (July 2003). "Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride". Pharmaceutical Research. 20 (7): 1093–1100. doi:10.1023/A:1024474609667. PMID 12880296. S2CID 448086.]
External links
[edit]- Diseases Database (DDB): 30166