colchicine

Colchicine

Systematic (IUPAC) name
N-​[(7S)-​1,​2,​3,​10-​tetramethoxy-​9-​oxo-​5,​6,​7,​9-​tetrahydrobenzo​[a]​heptalen-​7-​yl]​acetamide
Identifiers
CAS number	64-86-8
ATC code	M04AC01
PubChem	6167
ChemSpider	5933
Chemical data
Formula	C22H25NO6
Mol. mass	399.437
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	9.3 - 10.6 hours
Excretion	Primarily feces, urine 10-20%
Therapeutic considerations
Pregnancy cat.	X
Legal status	RX/POM
Routes	Oral tablets
Y(what is this?)  (verify)

Colchicine 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. It was also prescribed for its cathartic and emetic effects. Colchicine's present medicinal use is in the treatment of gout and familial Mediterranean fever; it can also be used as initial treatment for pericarditis and preventing recurrences of the condition. It is also being investigated for its use as an anti-cancer drug. In neurons, axoplasmic transport is disrupted by colchicine.

History

Colchicum extract was first described as a treatment for gout in De Materia Medica by Pedanius Dioscorides in the first century CE. Colchicine, an alkaloid, was first isolated in 1820 by the two French chemists P.S. Pelletier and J. Caventon.^[1] The alkaloid was later identified as a tricyclic alkaloid, and its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin.

Pharmacology

Biological function

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.^[2] 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.

Apart from inhibiting mitosis (a process heavily dependent on cytoskeletal changes), colchicine also inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect. Colchicine also inhibits the deposition of uric acid (urate) crystals. Since the formation of such crystals is enhanced by a low pH in the tissues, it is surmised that colchicine raises the tissue pH by inhibiting the oxidation of glucose, thereby reducing the production of lactic acid in leukocytes. The inhibition of uric acid crystals is a vital aspect of the mechanism of gout treatment.

Colchicine as medicine

In August 2009, colchicine won Food and Drug Administration (FDA) approval in the United States as a stand-alone drug for the treatment of acute flares of gout and familial Mediterranean fever.^[3] It had previously been approved as an ingredient in an FDA-approved combination product for gout. The approval was based on a study in which two doses an hour apart were effective at combating the condition.^[3]

It is also used as an anti-inflammatory agent for long-term treatment of Behçet's disease.^{[citation needed]}

The Australian biotechnology company Giaconda has developed a combination therapy to treat constipation-predominant irritable bowel syndrome which combines colchicine with the anti-inflammatory drug olsalazine.

The British drug development company Angiogene is developing a prodrug of colchicine, ZD6126^[4] (also known as ANG453) as a treatment for cancer.

Colchicine has a relatively low therapeutic index.

Long term (prophylactic) regimens of oral colchicine are absolutely contraindicated in patients with advanced renal failure (including those on dialysis). 10-20% 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)

Colchicine is "used widely" off-label by naturopaths for a number of treatments, including the treatment of back pain.^[5]

Side effects

Side effects include gastro-intestinal upset and neutropenia. High doses can also damage bone marrow and lead to anemia. Note that all of these side effects can result from hyper-inhibition of mitosis.

Toxicity

Colchicine poisoning has been compared to arsenic poisoning: symptoms start 2 to 5 hours after the toxic dose has been ingested and include burning in the mouth and throat, fever, vomiting, diarrhea, abdominal pain and kidney failure. These symptoms may set in as many as 24 hours after the exposure. Onset of multiple-system organ failure may occur within 24 to 72 hours. This includes hypovolemic shock due to extreme vascular damage and fluid loss through the GI tract, which may result in death. Additionally, sufferers may experience kidney damage resulting in low urine output and bloody urine; low white blood cell counts (persisting for several days); anemia; muscular weakness; and respiratory failure. Recovery may begin within 6 to 8 days. There is no specific antidote for colchicine, although various treatments do exist.^[6]

Biosynthesis

Several experiments have shown that the biosynthesis of colchicine involves the amino acids precursors phenylalanine and tyrosine. Indeed, the feeding of Colchicum autumnale with radioactive amino acid, tyrosine-2-C14, caused the latter to be partially incorporated 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.^[7] However, it was proven that the tropolone ring of colchicine resulted essentially from the expansion of the tyrosine ring. Further radioactive feeding experiments of Colchicum autumnale revealed that Colchicine can be synthesized biosynthetically from (S)-Autumnaline. That biosynthesic pathway occurs primarily through a para-para phenolic coupling reaction involving the intermediate isoandrocymbine. The resulting molecule undergoes O-methylation directed by S-Adenosylmethionine (SAM). Two oxidation steps followed by the cleavage of the cyclopropane ring leads to the formation of the tropolone ring contained by N-formyldemecolcine. N-formyldemecolcine hydrolyzes then to generate the molecule demecolcine which also goes through an oxidative demethylation that generates deacetylcolchicine. The molecule of colchicine appears finally after addition of acetyl-Coenzyme A to deacetylcolchicine.^[8],^[9]

Botanical use

Since chromosome segregation is driven by microtubules, colchicine is also used for inducing polyploidy in plant cells during cellular division by inhibiting chromosome segregation during meiosis; half the resulting gametes therefore contain no chromosomes, while the other half contain double the usual number of chromosomes (i.e., diploid instead of haploid as gametes usually are), and lead to embryos with double the usual number of chromosomes (i.e. 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 which 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. In addition, when such a tetraploid plant is crossed with a diploid plant, the triploid offspring will be sterile, which may be commercially useful in itself by requiring growers to buy seed from the supplier, but also can often be induced to create a "seedless" fruit if pollinated (usually the triploid will also not produce pollen, therefore a diploid parent is needed to provide the pollen). This is the method used to create seedless watermelons, for instance. On the other hand, colchicine's ability to induce polyploidy can be exploited to render infertile hybrids fertile, as is done when breeding triticale from wheat and rye. Wheat is typically tetraploid and rye diploid, with the triploid hybrid infertile. Treatment with colchicine of triploid triticale gives fertile hexaploid triticale.

When used to induce polyploidy in plants, colchicine is usually applied to the plant as a cream. It has to be applied to a growth point of the plant, such as an apical tip, shoot or sucker. Seeds can be presoaked in a colchicine solution before planting. As colchicine is so dangerous, it is worth noting that doubling of chromosome numbers can occur spontaneously in nature, and not infrequently. The best place to look is in regenerating tissue. One way to induce it is to chop off the tops of plants and carefully examine the lateral shoots and suckers to see if any look different.^[10] If there is no visual difference flow cytometry can be used for analysis.

References

External links

• Feature on colchicine, by Matthew J. Dowd at vcu.edu
• NIOSH Emergency Response Database
• Eugene E. Van Tamelen, Thomas A. Spencer Jr., Duff S. Allen Jr., Roy L. Orvis (1959). "The Total Synthesis of Colchicine". J. Am. Chem. Soc. 81 (23): 6341–6342. doi:10.1021/ja01532a070. 
• Cerquaglia C, Diaco M, Nucera G, La Regina M, Montalto M, Manna R (February 2005). "Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update". Current drug targets. Inflammation and allergy 4 (1): 117–24. PMID 15720245. http://www.bentham-direct.org/pages/content.php?CDTIA/2005/00000004/00000001/0019L.SGM.