Colchicine has a narrowtherapeutic index, so overdosing is a significant risk. Common side effects of colchicine includegastrointestinal upset, particularly at high doses.[14] Severe side effects may includepancytopenia (low blood cell counts) andrhabdomyolysis (damage toskeletal muscle), and the medication can be deadly in overdose.[11] Whether colchicine is safe for use duringpregnancy is unclear, but its use duringbreastfeeding appears to be safe.[11][15] Colchicine works by decreasinginflammation via multiple mechanisms.[16]
Colchicine, in the form of theautumn crocus (Colchicum autumnale), was used as early as 1500 BC to treat joint swelling.[17] It was approved for medical use in the United States in 1961.[2] It is available as ageneric medication.[15] In 2023, it was the 215th most commonly prescribed medication in the United States, with more than 2million prescriptions.[18][19]
Colchicine is used inplant breeding to inducepolyploidy, in which the number ofchromosomes in plant cells are doubled. This helps produce larger, hardier, faster-growing, and in general, more desirable plants than the normallydiploid parents.[20]
Colchicine is an alternative for those unable to toleratenonsteroidal anti-inflammatory drugs (NSAIDs) when treating gout.[21][22][23][24] 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.[25] At higher doses, side effects (primarily diarrhea, nausea, or vomiting) limit its use.[25]
For treating gout symptoms, colchicine is taken orally, with or without food, as symptoms first appear.[26] Subsequent doses may be needed if symptoms worsen.[26]
There is preliminary evidence that daily colchicine may be effective as a long-termprophylaxis when used withallopurinol to reduce the risk of increased uric acid levels and acute gout flares;[27]adverse gastrointestinal effects may occur,[28] though overall the risk of serious side effects is low.[29][30]
In June 2023, the US FDA approved a low-dose regimen of colchicine (brand name Lodoco) to reduce the risk of further disorders in adults with existingcardiovascular diseases.[31][32] 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 establishedatherosclerosis and by 23% in people with recentmyocardial infarction.[32] Colchicine was most effective in combination therapy with lipid-lowering andanti-inflammatory medications.[32] The mechanism for this effect of colchicine is unknown.[31]
Colchicine is also used as an anti-inflammatory agent for long-term treatment ofBehçet's disease.[33] It appears to have limited effect inrelapsing polychondritis, as it may only be useful for the treatment of chondritis and mild skin symptoms.[34] It is a component of therapy for several other conditions, including pericarditis, pulmonary fibrosis, biliary cirrhosis, various vasculitides, pseudogout,spondyloarthropathy, calcinosis, scleroderma, and amyloidosis.[33][35][36]
Research regarding the efficacy of colchicine in many of these diseases has not been performed.[36] It is also used in the treatment offamilial Mediterranean fever,[33] in which it reduces attacks and the long-term risk ofamyloidosis.[37]
Colchicine is effective for prevention ofatrial fibrillation aftercardiac surgery.[38] In people with recent myocardial infarction (recent heart attack), it has been found to reduce risk of future cardiovascular events. Its clinical use may grow to include this indication.[39][40]
Long-term (prophylactic) regimens of oral colchicine are absolutely contraindicated in people with advancedkidney failure (including those ondialysis).[26] About 10–20% of a colchicine dose is excreted unchanged by the kidneys; it is not removed byhemodialysis. Cumulative toxicity is a high probability in this clinical setting, and a severeneuromyopathy may result. The presentation includes a progressive onset of proximal weakness, elevatedcreatine kinase, and sensorimotorpolyneuropathy. Colchicine toxicity can be potentiated by the concomitant use ofcholesterol-lowering drugs.[26]
Deaths – both accidental and intentional – have resulted from overdose of colchicine.[26] Typical side effects of moderate doses may include gastrointestinal upset, diarrhea, andneutropenia.[22] High doses can also damagebone marrow, lead toanemia, and cause hair loss. All of these side effects can result from inhibition ofmitosis,[41] which may include neuromuscular toxicity andrhabdomyolysis.[26]
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.[42]
Colchicine can be toxic when ingested, inhaled, or absorbed in the eyes.[22] It can cause a temporary clouding of thecornea and be absorbed into the body, causing systemic toxicity. Symptoms of colchicine overdose start 2 to 24 hours after the toxic dose has been ingested, and include burning in the mouth and throat,fever,vomiting, diarrhea, andabdominal pain.[26] This can causehypovolemic shock due to extreme vascular damage and fluid loss through thegastrointestinal tract, which can be fatal.[42][43]
No specific antidote for colchicine is known, but supportive care is used in cases of overdose. In the immediate period after an overdose, monitoring for gastrointestinal symptoms, cardiac dysrhythmias, and respiratory depression is appropriate,[41] and may require gastrointestinal decontamination withactivated charcoal orgastric lavage.[42][43]
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.[36] It was used intentionally as a poison in the 2015killing of Mary Yoder.
In gout, inflammation injoints results from the precipitation ofuric acid as needle-likecrystals of monosodium urate in and aroundsynovial fluid andsoft tissues of joints.[16] These crystal deposits cause inflammatory arthritis, which is initiated and sustained by mechanisms involving various proinflammatory mediators, such ascytokines.[16] Colchicine accumulates in white blood cells and affects them in a variety of ways - decreasing motility, mobilization (especiallychemotaxis), and adhesion.[36]
Under preliminary research are various mechanisms by which colchicine may interfere with gout inflammation:
Inhibitsmicrotubule polymerization by binding to its constitutive protein, tubulin[16]
As availability of tubulin is essential tomitosis, colchicine may inhibit mitosis[16]
Inhibits activation and migration ofneutrophils to sites of inflammation[26]
Inhibits release of glycoproteins that promote chemotaxis fromsynovial cells and neutrophils[36]
Generally, colchicine appears to inhibit multiple proinflammatory mechanisms, while enabling increased levels ofanti-inflammatory mediators.[16] 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.[16][26]
Colchicine was first isolated in 1820 by French chemists P. S. Pelletier and J. B.Caventou.[52] In 1833, P. L. Geiger purified an active ingredient, which he named colchicine.[53] It quickly became a popular remedy for gout.[36] 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.[54] 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 chemistAlbert Eschenmoser in 1959.[55]
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.[57]
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.[58]
Trade names for colchicine are Colcrys or Mitigare, which are manufactured as a dark– and light-bluecapsule having a dose of 0.6 mg.[26][60] Colchicine is also prepared as a white, yellow, or purplepill (tablet) having a dose of 0.6 mg.[60]
Colchicine is typically prescribed to mitigate or prevent the onset of gout, or its continuing symptoms and pain, using a low-doseprescription 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.[14][26] With an oral dose of 0.6 mg, peak blood levels occur within one to two hours.[49] 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.[26] It has a narrow therapeutic window, requiring monitoring of the subject for potential toxicity.[26] Colchicine is not a general pain-relief drug, and is not used to treat pain in other disorders.[26]
According to laboratory research, thebiosynthesis of colchicine involves theamino acidsphenylalanine andtyrosine asprecursors. Giving radioactive phenylalanine-2-14C toC. byzantinum, another plant of the family Colchicaceae, resulted in its incorporation into colchicine.[61] However, thetropolone ring of colchicine resulted from the expansion of the tyrosine ring.Radioactive feeding experiments ofC. autumnale revealed that colchicine can be synthesized biosynthetically from(S)-autumnaline. That biosynthetic pathway occurs primarily through a phenoliccoupling reaction involving the intermediate isoandrocymbine. The resulting molecule undergoesO-methylation directed by S-adenosylmethionine. Two oxidation steps followed by the cleavage of the cyclopropane ring lead to the formation of thetropolone ring contained byN-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 the addition of acetyl-coenzyme A to deacetylcolchicine.[62][63]
Colchicine may be purified fromColchicum autumnale (autumn crocus) orGloriosa superba (glory lily). Concentrations of colchicine inC. autumnale peak in the summer, and range from 0.1% in the flower to 0.8% in the bulb and seeds.[36]
Colchicine is used inplant breeding by inducingpolyploidy in plant cells to produce new or improved varieties, strains, and cultivars.[20] 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. Seeds can be presoaked in a colchicine solution before planting. Sincechromosome segregation is driven by microtubules, colchicine alterscellular division by inhibiting chromosome segregation duringmitosis; half the resulting daughter cells, therefore, contain no chromosomes, while the other half contains double the usual number of chromosomes (i.e.,tetraploid instead ofdiploid), and lead to cell nuclei with double the usual number of chromosomes (i.e.,tetraploid instead of diploid).[20] 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.[20]
When such a tetraploid plant is crossed with a diploid plant, thetriploid offspring are usuallysterile (unable to producefertile seeds orspores), although many triploids can bepropagated vegetatively. Growers ofannual 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 andshrubs, are becoming increasingly valued inhorticulture andlandscaping because they do not becomeinvasive 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 seedlesswatermelons (Citrullus lanatus). Since most triploids do not produce pollen themselves, such plants usually requirecross-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 breedingtriticale (×Triticosecale) fromwheat (Triticum spp.) andrye (Secale cereale). Wheat is typically tetraploid and rye diploid, with their triploid hybrid infertile; treatment of triploid triticale with colchicine gives fertilehexaploid triticale.[64]
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