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Colchicine

Tubulin_with_taxol

Colchicine
 
 
Systematic (IUPAC) name
N-?[(7S)-?1,?2,?3,?10-?tetramethoxy-?9-?oxo-?5,?6,?7,?9-?tetrahydrobenzo?[a]?heptalen-?7-?yl]?acetamide
Clinical data
Drugs.com monograph
MedlinePlus a682711
Pregnancy cat. X
Legal status RX/POM
Routes Oral tablets
Pharmacokinetic data
Half-life 9.3 – 10.6 hours
Excretion Primarily feces, urine 10-20%
Identifiers
CAS number 64-86-8 YesY
ATC code AC01
PubChem CID 6167
IUPHAR ligand 2367
DrugBank DB01394
ChemSpider 5933 YesY
UNII SML2Y3J35T YesY
KEGG D00570 YesY
ChEBI CHEBI:27882 YesY
ChEMBL CHEMBL107 YesY
Chemical data
Formula O6 
Mol. mass 399.437
SMILES

  • O=C(N[C@@H]3C1=CC(=O)C(OC)=C/C=C/1c2c(cc(OC)c(OC)c2OC)CC3)C
InChI

  • InChI=1S/C22H25NO6/c1-12(24)23-16-8-6-13-10-19(27-3)21(28-4)22(29-5)20(13)14-7-9-18(26-2)17(25)11-15(14)16/h7,9-11,16H,6,8H2,1-5H3,(H,23,24)/t16-/m0/s1 YesY
    Key:IAKHMKGGTNLKSZ-INIZCTEOSA-N YesY
 YesY (verify)

Colchicine is a medication that treats gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum (autumn crocus, Colchicum autumnale, also known as “meadow saffron”). It was used originally to treat rheumatic complaints, especially gout, and still finds use for these purposes today despite dosing issues concerning its toxicity.[1] It was also prescribed for its cathartic and emetic effects.

 

Contents

[edit] History

The plant source of colchicine, the [4]

Colchicine was first isolated in 1820 by the tubulin.

[edit] FDA approval

Oral colchicine had been used for many years as an unapproved drug with no prescribing information, dosage recommendations, or drug interaction warnings approved by the U.S. [9]

[edit] Pharmacology

[edit] Mechanism of action

Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules. Availability of tubulin is essential to mitosis, and therefore colchicine effectively functions as a “mitotic poison” or spindle poison.[11]
The karyotype studies.
Apart from inhibiting mitosis (a process heavily dependent on cytoskeletal changes), colchicine also inhibits anti-inflammatory effect.

[edit] Indications

Colchicine has a relatively low [12]

It is also used as an anti-inflammatory agent for long-term treatment of Behçet’s disease.[14]

[edit] Use in cancer treatment

Since one of the defining characteristics of cancer cells is a significantly increased rate of mitosis, this means that cancer cells are significantly more vulnerable to colchicine poisoning than are normal cells. However, the therapeutic value of colchicine against cancer is (as is typical with chemotherapy agents) limited by its toxicity against normal cells.

[edit] Off-label uses

The British drug development company Angiogene is developing a prodrug of a colchicine congener, ZD6126[15] (also known as ANG453) as a treatment for cancer.
Colchicine is also used for constipation-predominant irritable bowel syndrome in women,[17]

[edit] Contraindications

Long-term (prophylactic) regimens of oral colchicine are absolutely contraindicated in patients with advanced renal failure (including those on dialysis). Ten to 20% of a colchicine dose is excreted unchanged by the kidneys. Colchicine is not removed by hemodialysis. Cumulative toxicity is a high probability in this clinical setting. A severe neuromyopathy may result. The presentation includes a progressive onset of proximal weakness, elevated creatine kinase, and sensorimotor polyneuropathy. Colchicine toxicity can be potentiated by the concomitant use of cholesterol-lowering drugs (statins, fibrates). This neuromuscular condition can be irreversible (even after drug discontinuation). Accompanying dementia has been noted in advanced cases. It may culminate in hypercapnic respiratory failure and death. (Minniti-2005)

[edit] Side-effects

Side-effects include gastrointestinal upset and citation needed]
A main side-effect associated with all mitotic inhibitors is peripheral neuropathy, which is a numbness or tingling in the hands and feet due to peripheral nerve damage that can become so severe that reduction in dosage or complete cessation of the drug may be required. Microtubules are involved in vesicular transport. Peripheral nerves are among the longest in the body. Brownian motion is not significant enough in these peripheral nerves to allow vesicles to reach their destination. Thus, they are susceptible to microtubule toxins.[citation needed]

[edit] Toxicity

Colchicine poisoning has been compared to respiratory failure. Recovery may begin within six to eight days.
There is no specific antidote for colchicine, though various treatments exist.[1]

[edit] Biosynthesis

Several experiments show that the biosynthesis of colchicine involves the amino acids phenylalanine and tyrosine as precursors. Indeed, the feeding of Colchicum autumnale with radioactive amino acid, tyrosine-2-C14, caused the latter to partially incorporate in the ring system of colchicine. The induced absorption of radioactive phenylalanine-2-C14 by Colchicum byzantinum, another plant of the Colchicaceae family, resulted in its efficient absorption by colchicine.[21]
 

[edit] Botanical use

Since tetraploid instead of diploid). While this would be fatal in animal cells, in plant cells it is not only usually well tolerated but in fact frequently results in plants that are larger, hardier, faster-growing, and in general more desirable than the normally diploid parents; for this reason, this type of genetic manipulation is frequently used in breeding plants commercially.
When such a tetraploid plant is crossed with a diploid plant, the cross-pollination with a diploid parent to induce fruit production.
Colchicine’s ability to induce polyploidy can be also exploited to render infertile hybrids fertile, for example in breeding hexaploid triticale.
When used to induce polyploidy in plants, colchicine cream is usually applied to a growth point of the plant, such as an apical tip, shoot, or sucker. Also, seeds can be presoaked in a colchicine solution before planting. Another way to induce polyploidy is to chop off the tops of plants and carefully examine the regenerating lateral shoots and suckers to see if any look different.[22] If no visual difference is evident, flow cytometry can be used for analysis.
Doubling of plant chromosome numbers also occurs spontaneously in nature, with many familiar plants being fertile octoploid.

[edit] Marketing exclusivity in the United States

As a drug predating the FDA, colchicine was sold in the [25]
Numerous consensus guidelines, and previous randomized controlled trials, had concluded that colchicine is effective for acute flares of gouty arthritis. However, as of 2006, the drug was not formally approved by the FDA, owing to the lack of a conclusive [28]
In April 2010, in an editorial in the [29]
In September 2010, the FDA ordered a halt to marketing unapproved single-ingredient oral colchicine.[30]

[edit] References

  1. ^ http://www.nps.org.au/health_professionals/publications/nps_radar/2010/may_2010/brief_item_colchicine. Retrieved 14 May 2010.
  2. http://ard.bmj.com/content/12/1/16.full.pdf.
  3. ^ Edward F. Hartung (1954). “History of the Use of Colchicum and related Medicaments in Gout”. Ann Rheum Dis 13 (3): 190–200. doi:10.1136/ard.13.3.190. http://ard.bmj.com/content/13/3/190.full.pdf. (free BMJ registration required)
  4. http://books.google.com/?id=CMJKgfhCKzIC&pg=PA275&lpg=PA275.
  5. “Examen chimique des plusieurs végétaux de la famille des colchicées, et du principe actif qu’ils renferment. [Cévadille (veratrum sabadilla) ; hellébore blanc (veratrum album) ; colchique commun (colchicum autumnale)“] (Chemical examination of several plants of the meadow saffron family, and of the active principle that they contain.) Annales de Chimie et de Physique, 14 : 69-81.
  6. “Ueber einige neue giftige organische Alkalien” (On some new poisonous organic alkalies) Annalen der Pharmacie, 7 (3) : 269-280; colchicine is discussed on pages 274-276.
  7. ^ Dewar, Michael J.S. (February 3, 1945) “Letters to Editor: Structure of colchicine,” Nature 155 : 141-142. Note: Dewar did not prove the structure of colchicine; he merely suggested that it contained two 7-membered rings. Colchicine’s structure was determined by X-ray crystallography in 1952 [Murray Vernon King, J. L. de Vries, and Ray Pepinsky (July 1952) “An x-ray diffraction determination of the chemical structure of colchicine,” Acta Crystallographica, 5 : 437-440]. Its total synthesis was first accomplished in 1959 [Albert Eschenmoser (1959) “Synthese des Colchicins,” Angewandte Chemie, 71 : 637-640.]
  8. ^ http://www.medscape.com/viewarticle/706814.
  9. ^ [1] FDA Orange Book; search for colchicine
  10. ^ Questions and Answers for Patients and Healthcare Providers Regarding Single-ingredient Oral Colchicine Products
  11. ^ Cyberbotanica: Colchicine
  12. ^ MedPage Today
  13. http://www.bentham-direct.org/pages/content.php?CDTIA/2005/00000004/00000001/0019L.SGM.
  14. 21111934.
  15. ^ Description of ZD6126 on US National Cancer Institute website retrieved 26th April 2008
  16. ^ Verne, GN; Davis et al (May 1998). “Treatment of chronic constipation with colchicine: randomized, double-blind, placebo-controlled, crossover trial.”. Am J Gastroenterology 98 (5): 1112–6.
  17. ^ Porter, S; Scully (June 2005). “Aphthous Ulcers (recurrent)”. Clin Evid 13: 1687–1694.
  18. ^ Colchicine. National Institute for Occupational Safety and Health. Emergency Response Safety and Health Database, August 22, 2008. Retrieved December 23, 2008.
  19. ^ Leete, E. The biosynthesis of the alkaloids of Colchicum: The incorporation of phenylalaline-2-C14 into colchicine and demecolcine. J. Am. Chem. Soc. 1963, 85, 3666-3669.
  20. ^ Dewick, P. M.(2009).Medicinal Natural Products: A biosynthetic Approach. Wiley. p.360-362.
  21. ^ Maier, U. H.; Meinhart, H. Z. Colchicine is formed by para para phenol-coupling from autumnaline. Tetrahedron Lett. 1997, 38, 7357-7360.
  22. ^ Deppe, Carol (1993). Breed Your own Vegetable Varieties. Little, Brown & Company. p.150-151. ISBN 0-316-18104-8
  23. ^ Kurt R. Karst (2009-10-21). “California Court Denies Preliminary Injunction in Lanham Act Case Concerning Unapproved Colchicine Drugs”. http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2009/10/california-court-denies-preliminary-injunction-in-lanham-act-case-concerning-unapproved-colchicine-d.html.
  24. ^ Harris Meyer (2009-12-29). “The High Price of FDA Approval”. Kaiser Health News and the Philadelphia Inquirer. http://www.kaiserhealthnews.org/Stories/2009/December/29/FDA-approval.aspx.
  25. ^ Colcrys vs. Unapproved Colchicine Statement from URL Pharma
  26. ^ “FDA Unapproved Drugs Initiative”. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/ucm118990.htm.
  27. ^ “About Colcrys”. Colcrys. URL Pharma. http://www.colcrys.com/about-colcrys.htm. Retrieved 11 September 2011.
  28. ^ http://content.nejm.org/cgi/content/short/362/22/2045.
  29. ^ Response from URL Pharma
  30. ^ “FDA orders halt to marketing of unapproved single-ingredient oral colchicine”. 30 Sept 2010. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm227796.htm.

[edit] External links

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Source: Wikipedia