Colchicine

Colchicine

Clinical data
Pronunciation	/ˈkɒltʃɪsiːn/ KOL-chiss-een
Trade names	Colcrys, Mitigare, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682711
License data	US DailyMed: Colchicine
Pregnancy category	AU: D
Routes of administration	By mouth
ATC code	M04AC01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only[1] UK: POM (Prescription only) US: ℞-only[2]
Pharmacokinetic data
Bioavailability	45%
Protein binding	35-44%
Metabolism	Metabolism, partly by CYP3A4
Elimination half-life	26.6-31.2 hours
Excretion	Feces (65%)
Identifiers
IUPAC name N-[(7S)-1,2,3,10-Tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide
JSmol)	Interactive image
SMILES CC(=O)N[C@H]1CCC2=CC(=C(C(=C2C3=CC=C(C(=O)C=C13)OC)OC)OC)OC
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 Y Key:IAKHMKGGTNLKSZ-INIZCTEOSA-N Y
(verify)

Colchicine is a

Colchicine has a narrow therapeutic index, so overdosing is a significant risk. Common side effects of colchicine include gastrointestinal upset, particularly at high doses.^[7] Severe side effects may include pancytopenia (low blood cell counts) and rhabdomyolysis, and the medication can be deadly in overdose.^[3] Whether colchicine is safe for use during pregnancy is unclear, but its use during breastfeeding appears to be safe.^[3][8] Colchicine works by decreasing inflammation via multiple mechanisms.^[9]

Colchicine, in the form of the

Colchicine is an alternative for those unable to tolerate NSAIDs when treating gout.[14]^[15][16][17] Low doses (1.2 mg in one hour, followed by 0.6 mg an hour later) appear to be well tolerated and may reduce gout symptoms and pain, perhaps as effectively as NSAIDS.^[18] At higher doses, side effects (primarily diarrhea, nausea, or vomiting) limit its use.^[18]

For treating gout symptoms, colchicine is taken orally, with or without food, as symptoms first appear.^[19] Subsequent doses may be needed if symptoms worsen.^[19]

There is preliminary evidence that daily colchicine (0.6 mg twice daily) may be effective as a long-term

In June 2023, the U.S. FDA approved a low-dose regimen of colchicine (tradename Lodoco) to reduce the risk of further disorders in adults with existing cardiovascular diseases.^[23][24] As an anti-inflammatory drug, Lodoco in a dose of 0.5 mg per day reduced the rate of cardiovascular events by 31% in people with established atherosclerosis and by 23% in people with recent myocardial infarction.^[24] Colchicine was most effective in combination therapy with lipid-lowering and anti-inflammatory medications.^[24] The mechanism for this effect of colchicine is unknown.^[23]

Other conditions

Colchicine is also used as an anti-inflammatory agent for long-term treatment of Behçet's disease.^[25] It appears to have limited effect in relapsing polychondritis, as it may only be useful for the treatment of chondritis and mild skin symptoms.^[26] It is a component of therapy for several other conditions, including pericarditis, pulmonary fibrosis, biliary cirrhosis, various vasculitides, pseudogout, spondyloarthropathy, calcinosis, scleroderma, and amyloidosis.^[25][27][28] Research regarding the efficacy of colchicine in many of these diseases has not been performed.^[28] It is also used in the treatment of familial Mediterranean fever,^[25] in which it reduces attacks and the long-term risk of amyloidosis.^[29]

Colchicine is effective for prevention of

Deaths – both accidental and intentional – have resulted from overdose of colchicine.[19] Typical side effects of moderate doses may include gastrointestinal upset, diarrhea, and neutropenia.^[15] High doses can also damage bone marrow, lead to anemia, and cause hair loss. All of these side effects can result from inhibition of mitosis,^[34] which may include neuromuscular toxicity and rhabdomyolysis.^[19]

Toxicity

According to one review, colchicine poisoning by overdose (range of acute doses of 7 to 26 mg) begins with a gastrointestinal phase occurring 10–24 hours after ingestion, followed by multiple organ dysfunction occurring 24 hours to 7 days after ingestion, after which the affected person either declines into multiple organ failure or recovers over several weeks.^[35]

Colchicine can be toxic when ingested, inhaled, or absorbed in the eyes.

Because colchicine is so toxic, chemists are continuing to try to synthesize derivatives of the molecule that decrease the toxicity. The most important aspect of these derivatives is that they keep the tropolone ring (the ring with the methoxy group and the carbonyl) intact to retain the mechanistic properties of the molecule.[37]

Mechanism of toxicity

With overdoses, colchicine becomes toxic as an extension of its cellular mechanism of action via binding to tubulin.

In the United States, several hundred cases of colchicine toxicity are reported annually, about 10% of which end with serious morbidity or mortality. Many of these cases are intentional overdoses, but others were accidental; for example, if the drug were not dosed appropriately for kidney function. Most cases of colchicine toxicity occur in adults. Many of these adverse events resulted from the use of intravenous colchicine.[28]

Drug interactions

Colchicine interacts with the P-glycoprotein transporter, and the CYP3A4 enzyme involved in drug and toxin metabolism.^[19][35] Fatal drug interactions have occurred when colchicine was taken with other drugs that inhibit P-glycoprotein and CYP3A4, such as erythromycin or clarithromycin.^[19]

People taking

In gout, inflammation in joints results from the precipitation of uric acid as needle-like crystals of monosodium urate in and around synovial fluid and soft tissues of joints.^[9] These crystal deposits cause inflammatory arthritis, which is initiated and sustained by mechanisms involving various proinflammatory mediators, such as cytokines.^[9] Colchicine accumulates in white blood cells and affects them in a variety of ways - decreasing motility, mobilization (especially chemotaxis), and adhesion.^[28]

Under preliminary research are various mechanisms by which colchicine may interfere with gout inflammation:

• Inhibits microtubule polymerization by binding to its constitutive protein, tubulin^[9]
• As availability of tubulin is essential to mitosis, colchicine may inhibit mitosis^[9]
• Inhibits activation and migration of neutrophils to sites of inflammation^[19]
• Interferes with the
  interleukin-1β activation, a component of inflammation^[19]
• Inhibits
  superoxide anion production in response to urate crystals^[9]
• Interrupts mast cell and lysosome degranulation^[9][28]
• Inhibits release of glycoproteins that promote chemotaxis from synovial cells and neutrophils^[28]

Generally, colchicine appears to inhibit multiple proinflammatory mechanisms, while enabling increased levels of anti-inflammatory mediators.^[9] Apart from inhibiting mitosis, colchicine inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect, which has efficacy for inhibiting or preventing gout inflammation.^[9][19]

Pharmacokinetics

Colchicine appears to be a peripherally selective drug with limited brain uptake due to binding to P-glycoprotein.^[39][40][41]

History

The plant source of colchicine, the autumn crocus (

Colchicine was first isolated in 1820 by French chemists P. S. Pelletier and J. B.

Caventou.^[46] In 1833, P. L. Geiger purified an active ingredient, which he named colchicine.^[47] It quickly became a popular remedy for gout.^[28] The determination of colchicine's structure required decades, although in 1945, Michael Dewar made an important contribution when he suggested that, among the molecule's three rings, two were seven-member rings.^[48]

Its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin.

The full synthesis of colchicine was achieved by the Swiss organic chemist Albert Eschenmoser in 1959.^[49]

United States

Unapproved Drugs Initiative

An unintended consequence of the 2006 U.S.

URL Pharma, a Philadelphia drugmaker, were rewarded with licenses for testing of medicines like colchicine. In 2009, the FDA reviewed a New Drug Application

for colchicine submitted by URL Pharma. URL Pharma did the testing, gained FDA formal approval, and was granted rights over colchicine. With this monopoly pricing power, the price of colchicine increased.

In 2012, Asia's biggest drugmaker,

Takeda Pharmaceutical Co., acquired URL Pharma for $800 million including the rights to colchicine (brand name Colcrys) earning $1.2 billion in revenue by raising the price even more.^[51]

Oral colchicine had been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings.[52] In July 2009, the FDA approved colchicine as a monotherapy for the treatment of three different indications (familial Mediterranean fever, acute gout flares, and for the prophylaxis of gout flares^[52]), and gave URL Pharma a three-year marketing exclusivity agreement^[53] in exchange for URL Pharma doing 17 new studies and investing $100 million into the product, of which $45 million went to the FDA for the application fee. URL Pharma raised the price from $0.09 per tablet to $4.85, and the FDA removed the older unapproved colchicine from the market in October 2010, both in oral and intravenous forms, but allowed pharmacies to buy up the older unapproved colchicine.^[54] Colchicine in combination with probenecid has been FDA-approved before 1982.^[53]

In July 2009, colchicine won FDA approval in the United States as a stand-alone drug for the treatment of acute flares of gout and familial Mediterranean fever.^[55][56] 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 (1.2 mg and 0.6 mg) an hour apart were as effective as higher doses in combating the acute flare of gout.^[57]

Marketing exclusivity

As a drug antedating the FDA, colchicine was sold in the United States for many years without having been reviewed by the FDA for safety and efficacy. The FDA reviewed 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 $0.09 to $4.85 per tablet.^[58][59][60]

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

pharmacokinetic

studies and a randomized control trial with 185 patients with acute gout.

In April 2010, an editorial in the

New England Journal of Medicine said that the rewards of this legislation are not calibrated to the quality or value of the information produced, that no evidence of meaningful improvement to public health was seen, and that it would be less expensive for the FDA, the National Institutes of Health, or large insurers to pay for trials themselves. Furthermore, the cost burden of this subsidy falls primarily on patients or their insurers.^[62] In September 2010, the FDA ordered a halt to marketing unapproved single-ingredient oral colchicine.^[63]

Colchicine patents expire in February 2029.[64]

Price increase as orphan drug

URL Pharma received seven years of market exclusivity for Colcrys in the treatment of familial Mediterranean fever, under the Orphan Drug Law. URL Pharma then raised the price per tablet from $0.09 to $4.85 and sued to remove other versions from the market, increasing annual costs for the drug to U.S. state Medicaid programs from $1 million to $50 million. Medicare also paid significantly higher costs, making this a direct money-loser for the government. (In a similar case, thalidomide was approved in 1998 as an orphan drug for leprosy and in 2006 for multiple myeloma.)^[62]

Sources and uses

Physical properties

Colchicine has a melting point of 142-150 °C. It has a molecular weight of 399.4 grams per mole.^[65]

Structure

Colchicine has one stereocenter located at carbon 7. The natural configuration of this stereocenter is S. The molecule also contains one chiral axis - the single bond between rings A and C. The natural configuration of this axis is aS. Although colchicine has four stereoisomers, the only one found in nature is the aS,7s configuration.^[66]

Light sensitivity

Colchicine is a light-sensitive compound, so needs to be stored in a dark bottle. Upon exposure to light, colchicine undergoes photoisomerization and transforms into structural isomers, called lumicolchicine. After this transformation, colchicine is no longer effective in its mechanistic binding to tubulin, so is not effective as a drug.^[67]

Regulation

It is classified as an

extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002) and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.^[68]

Formulations and dosing

pill (tablet) having a dose of 0.6 mg.^[69]

Colchicine is typically prescribed to mitigate or prevent the onset of gout, or its continuing symptoms and pain, using a low-dose prescription of 0.6 to 1.2 mg per day, or a high-dose amount of up to 4.8 mg in the first 6 hours of a gout episode.^[7][19] With an oral dose of 0.6 mg, peak blood levels occur within one to two hours.^[43] For treating gout, the initial effects of colchicine occur in a window of 12 to 24 hours, with a peak within 48 to 72 hours.^[19] It has a narrow therapeutic window, requiring monitoring of the subject for potential toxicity.^[19] Colchicine is not a general pain-relief drug, and is not used to treat pain in other disorders.^[19]

Biosynthesis

According to laboratory research, the

Radioactive feeding experiments of C. autumnale revealed that colchicine can be synthesized biosynthetically from (S)-autumnaline. That biosynthetic pathway occurs primarily through a phenolic coupling reaction involving the intermediate isoandrocymbine. The resulting molecule undergoes O-methylation directed by S-adenosylmethionine. Two oxidation steps followed by the cleavage of the cyclopropane ring lead 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.^[71][72]

Purification

Colchicine may be purified from Colchicum autumnale (autumn crocus) or Gloriosa superba (glory lily). Concentrations of colchicine in C. autumnale peak in the summer, and range from 0.1% in the flower to 0.8% in the bulb and seeds.^[28]

Botanical use

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Colchicine is widely used in

tetraploid instead of diploid).^[13] While this would be fatal in most higher animal cells, in plant cells, it is not only usually well-tolerated, but also frequently results in larger, hardier, faster-growing, and in general more desirable plants than the normally diploid parents. For this reason, this type of genetic manipulation is frequently used in breeding plants commercially.^[13]

When such a tetraploid plant is crossed with a diploid plant, the

triploid offspring are usually sterile (unable to produce fertile seeds or spores), although many triploids can be propagated vegetatively. Growers of annual triploid plants not readily propagated vegetatively cannot produce a second-generation crop from the seeds (if any) of the triploid crop and need to buy triploid seed from a supplier each year. Many sterile triploid plants, including some trees and shrubs, are becoming increasingly valued in horticulture and landscaping because they do not become invasive species and do not drop undesirable fruit and seed litter. In certain species, colchicine-induced triploidy has been used to create "seedless" fruit, such as seedless watermelons (Citrullus lanatus). Since most triploids do not produce pollen themselves, such plants usually require cross-pollination

with a diploid parent to induce seedless fruit production.

The ability of colchicine to induce polyploidy can be also exploited to render infertile hybrids fertile, for example in breeding

hexaploid triticale.^[73]

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External links

Wikimedia Commons has media related to Colchicine.

• "Colchicine : Biotoxin". Emergency Response Safety and Health Database. 8 November 2017.