Colchicine

Colchicine

Colchicine 2D structure
Colchicine 3D structure
Systematic (IUPAC) name
N-​[(7S)-​1,​2,​3,​10-​tetramethoxy-​9-​oxo-​5,​6,​7,​9-​tetrahydrobenzo​[a]​heptalen-​7-​yl]​acetamide
Clinical data
Pregnancy category	X
Routes of administration	Oral tablets
Legal status
Legal status	RX/POM
Pharmacokinetic data
Biological half-life	9.3 - 10.6 hours
Excretion	Primarily feces, urine 10-20%
Identifiers
CAS Number	64-86-8
ATC code	M04AC01 (WHO)
PubChem	CID 6167
IUPHAR/BPS	2367
ChemSpider	5933
Chemical data
Formula	C22H25NO6
Molar mass	399.437[[]]
(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 despite dosing issues concerning its toxicity. 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 anticancer drug. In neurons, axoplasmic transport is disrupted by colchicine.

Oral colchicine has been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings. On July 29, 2009 U.S. Food and Drug Administration (FDA) approved colchicine as a monotherapy, and gave 7-year marketing exclusivity to URL Pharma, in exchange for URL Pharma doing 2 new studies. URL Pharma raised the price from $0.09 per pill to $4.85, and sued to remove other versions from market. Colchicine in combination with probenecid has been FDA approved prior to 1982.

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. 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.

The precursor of colchicine Colchicum was described for treatment of rheumatism and swelling in the Ebers Papyrus, ca. 1500 B.C. The use of Colchicum corm for gout probably traces back to ca. 550 A.D., as the "hermodactyl" recommended by Alexander of Tralles. Colchicum corm was used by ibn Sina Persian physician and other Islamic physicians, was recommended by Ambroise Pare in the sixteenth century, and appeared in the London Pharmacopoeia of 1618. In 1833 P.L. Geiger purified an active ingredient, which he named colchicine. Colchicum was brought to America by Benjamin Franklin; Franklin suffered from gout himself and had written humorous doggerel about the disease during his stint as Envoy to France.

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. 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. 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.

It is also used as an anti-inflammatory agent for long-term treatment of Behçet's disease.

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 a colchicine congener, ZD6126 (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.

Side effects

Side effects include gastrointestinal upset and neutropenia. High doses can also damage bone marrow and lead to anemia. Note that all of these side effects can result from hyperinhibition 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.

Certain common inhibitors of CYP3A4 and/or P-gp, including grapefruit juice, may increase the risk of colchicine toxicity.

Biosynthesis

Several experiments have shown 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 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. 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.,

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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. If there is no visual difference flow cytometry can be used for analysis.

Marketing exclusivity

As a drug predating the FDA, colchicine was sold as a generic in the United States for many years. In 2009, the FDA approved colchicine for gout flares, awarding Colcrys a three-year term of market exclusivity, prohibiting generic sales, and increasing the price of the drug from $9 to $485 per bottle.

Numerous consensus guidelines, and previous randomized controlled trials, concluded colchicine is effective for acute flares of gouty arthritis. But the FDA gave URL Pharma 3 years market exclusivity for its Colcrys brand, under the Waxman-Hatch Act, based on 2007 pharmacokinetic studies and RCT with 185 patients with acute gout. URL Pharma also got 7 years market exclusivity for Colcrys in treatment of familial Mediterranean fever, under the orphan drug act. URL Pharma raised the price from $0.09 per pill to $4.85, and sued to remove other versions from market. This will increase costs to state Medicaid programs from $1 million to $50 million. (Similarly, thalidomide approved in 1998 as an orphan drug for leprosy and in 2006 for multiple myeloma.)

In a critical editorial in the New England Journal of Medicine, Kesselheim and Solomon said that the rewards of this legislation are not calibrated to the quality or value of information produced. There is no evidence of meaningful improvement to public health. It would be much less expensive for the FDA or NIH to pay for trials themselves on widely available drugs such as colchicine. The burden falls primarily on patients or their insurers.

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. CS1 maint: Multiple names: authors list (link)

ar:كولشيسين zh:秋水仙素