Colchicine

Colchicine is a medication used to prevent and treat gout,<ref>Template:Cite web</ref><ref>Template:Cite web</ref> to treat familial Mediterranean fever<ref>Template:Cite web</ref> and Behçet's disease,<ref>Template:Cite book</ref> and to reduce the risk of myocardial infarction.<ref>Template:Cite web</ref> The American College of Rheumatology recommends colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids in the treatment of gout.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Other uses for colchicine include the management of pericarditis.<ref>Template:Cite book</ref>

Colchicine is taken by mouth.<ref name=AHFS2019>Template:Cite web</ref> The injectable route of administration for colchicine can be toxic. In 2008, the US Food and Drug Administration removed all injectable colchicine from the US market.<ref>Template:Cite web</ref><ref>Template:Cite web</ref>

Colchicine has a narrow therapeutic index, so overdosing is a significant risk. Common side effects of colchicine include gastrointestinal upset, particularly at high doses.<ref name=NPS2010>Template:Cite web</ref> Severe side effects may include pancytopenia (low blood cell counts) and rhabdomyolysis (damage to skeletal muscle), and the medication can be deadly in overdose.<ref name=AHFS2019/> Whether colchicine is safe for use during pregnancy is unclear, but its use during breastfeeding appears to be safe.<ref name=AHFS2019/><ref name=BNF76/> Colchicine works by decreasing inflammation via multiple mechanisms.<ref name=Dal2014>Template:Cite journal</ref>

Colchicine, in the form of the autumn crocus (Colchicum autumnale), was used as early as 1500 BC to treat joint swelling.<ref>Template:Cite book</ref> It was approved for medical use in the United States in 1961.<ref name=Daily2019>Template:Cite web</ref> It is available as a generic medication.<ref name=BNF76>Template:Cite book Template:Cite web Available online in UK only</ref> In 2023, it was the 215th most commonly prescribed medication in the United States, with more than 2Template:Nbspmillion prescriptions.<ref>Template:Cite web</ref><ref>Template:Cite web</ref>

Colchicine is used in plant breeding to induce polyploidy, in which the number of chromosomes in plant cells are doubled. This helps produce larger, hardier, faster-growing, and in general, more desirable plants than the normally diploid parents.<ref name="Griffiths"/>

Medical uses

Gout

Colchicine is an alternative for those unable to tolerate nonsteroidal anti-inflammatory drugs (NSAIDs) when treating gout.<ref name="Review08">Template:Cite journal</ref><ref name="fda-dap">Template:Cite web</ref><ref name="FDA Warning">Template:Cite web</ref><ref name=CFP09>Template:Cite journal</ref> 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.<ref name="McKenzie-2021">Template:Cite journal</ref> At higher doses, side effects (primarily diarrhea, nausea, or vomiting) limit its use.<ref name="McKenzie-2021" />

For treating gout symptoms, colchicine is taken orally, with or without food, as symptoms first appear.<ref name=drugs/> Subsequent doses may be needed if symptoms worsen.<ref name=drugs/>

There is preliminary evidence that daily colchicine may be effective as a long-term prophylaxis when used with allopurinol to reduce the risk of increased uric acid levels and acute gout flares;<ref name="shekelle">Template:Cite journal</ref> adverse gastrointestinal effects may occur,<ref name="qaseem">Template:Cite journal</ref> though overall the risk of serious side effects is low.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Risk of cardiovascular disorders

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 existing cardiovascular diseases.<ref name="drugs-lod">Template:Cite web</ref><ref name="nelson">Template:Cite journal</ref> 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.<ref name=nelson/> Colchicine was most effective in combination therapy with lipid-lowering and anti-inflammatory medications.<ref name=nelson/> The mechanism for this effect of colchicine is unknown.<ref name=drugs-lod/>

Other conditions

Colchicine is also used as an anti-inflammatory agent for long-term treatment of Behçet's disease.<ref name="Cocco">Template:Cite journal</ref> It appears to have limited effect in relapsing polychondritis, as it may only be useful for the treatment of chondritis and mild skin symptoms.<ref>Template:Cite journal</ref> It is a component of therapy for several other conditions, including pericarditis, pulmonary fibrosis, biliary cirrhosis, various vasculitides, pseudogout, spondyloarthropathy, calcinosis, scleroderma, and amyloidosis.<ref name="Cocco" /><ref>Template:Cite journal</ref><ref name="Hoffman-2019">Template:Cite book</ref>

Research regarding the efficacy of colchicine in many of these diseases has not been performed.<ref name="Hoffman-2019" /> It is also used in the treatment of familial Mediterranean fever,<ref name="Cocco" /> in which it reduces attacks and the long-term risk of amyloidosis.<ref>Template:Cite journal</ref>

Colchicine is effective for prevention of atrial fibrillation after cardiac surgery.<ref name="Lennerz_2017">Template:Cite journal</ref> 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.<ref name="Imazio-2020">Template:Cite journal</ref><ref name="Nidorf-2020">Template:Cite journal</ref>

Contraindications

Long-term (prophylactic) regimens of oral colchicine are absolutely contraindicated in people with advanced kidney failure (including those on dialysis).<ref name=drugs/> About 10–20% of a colchicine dose is excreted unchanged by the kidneys; it is not removed by hemodialysis. Cumulative toxicity is a high probability in this clinical setting, and 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.<ref name=drugs/>

Adverse effects

Deaths – both accidental and intentional – have resulted from overdose of colchicine.<ref name=drugs/> Typical side effects of moderate doses may include gastrointestinal upset, diarrhea, and neutropenia.<ref name=fda-dap/> 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,<ref name="CDC">Template:Cite web</ref> which may include neuromuscular toxicity and rhabdomyolysis.<ref name=drugs/>

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.<ref name=ct/>

Colchicine can be toxic when ingested, inhaled, or absorbed in the eyes.<ref name=fda-dap/> It can cause a temporary clouding of the cornea 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, and abdominal pain.<ref name=drugs/> This can cause hypovolemic shock due to extreme vascular damage and fluid loss through the gastrointestinal tract, which can be fatal.<ref name=ct/><ref name="doogue">Template:Cite web</ref>

If the affected persons survive the gastrointestinal phase of toxicity, they may experience multiple organ failure and critical illness. This includes kidney damage, which causes low urine output and bloody urine; low white blood cell counts that can last for several days; anemia; muscular weakness; liver failure; hepatomegaly; bone marrow suppression; thrombocytopenia; and ascending paralysis leading to potentially fatal respiratory failure. Neurologic symptoms are also evident, including seizures, confusion, and delirium; children may experience hallucinations. Recovery may begin within six to eight days and begins with rebound leukocytosis and alopecia as organ functions return to normal.<ref name="CDC" /><ref name=ct/>

Long-term exposure to colchicine can lead to toxicity, particularly of the bone marrow, kidney, and nerves. Effects of long-term colchicine toxicity include agranulocytosis, thrombocytopenia, low white blood cell counts, aplastic anemia, alopecia, rash, purpura, vesicular dermatitis, kidney damage, anuria, peripheral neuropathy, and myopathy.<ref name="CDC" />

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,<ref name="CDC" /> and may require gastrointestinal decontamination with activated charcoal or gastric lavage.<ref name=ct/><ref name=doogue/>

Mechanism of toxicity

With overdoses, colchicine becomes toxic as an extension of its cellular mechanism of action via binding to tubulin.<ref name=ct/> Cells so affected undergo impaired protein assembly with reduced endocytosis, exocytosis, cellular motility, and interrupted function of heart cells, culminating in multiple organ failure.<ref name=Dal2014/><ref name=ct/>

Epidemiology

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.<ref name="Hoffman-2019" /> It was used intentionally as a poison in the 2015 killing of Mary Yoder.

Drug interactions

Colchicine interacts with the P-glycoprotein transporter, and the CYP3A4 enzyme involved in drug and toxin metabolism.<ref name=drugs/><ref name="ct">Template:Cite journal</ref> Fatal drug interactions have occurred when colchicine was taken with other drugs that inhibit P-glycoprotein and CYP3A4, such as erythromycin or clarithromycin.<ref name=drugs/>

People taking macrolide antibiotics, ketoconazole, or cyclosporine, or those who have liver or kidney disease, should not take colchicine, as these drugs and conditions may interfere with colchicine metabolism and raise its blood levels, potentially increasing its toxicity abruptly.<ref name=drugs/><ref name=ct/> Symptoms of toxicity include gastrointestinal upset, fever, muscle pain, low blood cell counts, and organ failure.<ref name=fda-dap/><ref name=drugs/> People with HIV/AIDS taking atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir may experience colchicine toxicity.<ref name=drugs/> Grapefruit juice and statins can also increase colchicine concentrations.<ref name=drugs/><ref name="schwier">Template:Cite journal</ref>

Pharmacology

Mechanism of action

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.<ref name=Dal2014/> These crystal deposits cause inflammatory arthritis, which is initiated and sustained by mechanisms involving various proinflammatory mediators, such as cytokines.<ref name=Dal2014/> Colchicine accumulates in white blood cells and affects them in a variety of ways - decreasing motility, mobilization (especially chemotaxis), and adhesion.<ref name="Hoffman-2019" />

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

• Inhibits microtubule polymerization by binding to its constitutive protein, tubulin<ref name=Dal2014/>
• As availability of tubulin is essential to mitosis, colchicine may inhibit mitosis<ref name=Dal2014/>
• Inhibits activation and migration of neutrophils to sites of inflammation<ref name=drugs/>
• Interferes with the inflammasome complex found in neutrophils and monocytes that mediate interleukin-1β activation, a component of inflammation<ref name=drugs/>
• Inhibits superoxide anion production in response to urate crystals<ref name=Dal2014/>
• Interrupts mast cell and lysosome degranulation<ref name=Dal2014/><ref name="Hoffman-2019" />
• Inhibits release of glycoproteins that promote chemotaxis from synovial cells and neutrophils<ref name="Hoffman-2019" />

Generally, colchicine appears to inhibit multiple proinflammatory mechanisms, while enabling increased levels of anti-inflammatory mediators.<ref name=Dal2014/> 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.<ref name=Dal2014/><ref name=drugs/>

Pharmacokinetics

Colchicine appears to be a peripherally selective drug with limited brain uptake due to binding to P-glycoprotein.<ref name="pmid17067838">Template:Cite journal</ref><ref name="pmid8858954">Template:Cite journal</ref><ref name="pmid14620515">Template:Cite journal</ref>

History

The plant source of colchicine, the autumn crocus (Colchicum autumnale), was described for treatment of rheumatism and swelling in the Ebers Papyrus (circa 1500 BC), an Egyptian medical text.<ref>Template:Cite journal</ref> It is a toxic alkaloid and secondary metabolite.<ref name=fda-dap/><ref name="cder">Template:Cite web</ref><ref name="drugs">Template:Cite web</ref> Colchicum extract was first described as a treatment for gout in De Materia Medica by Pedanius Dioscorides, in the first century AD. Use of the bulb-like corms of Colchicum to treat gout probably dates to around 550 AD, as the "hermodactyl" recommended by Alexander of Tralles. Colchicum corms were used by the Persian physician Avicenna, and were recommended by Ambroise Paré in the 16th century, and appeared in the London Pharmacopoeia of 1618.<ref>Template:Cite journal (free BMJ registration required)</ref><ref name="Hoffman-2019" /> Colchicum use waned over time, likely dueTemplate:Proveit to the severe gastrointestinal side effects preparations caused. In 1763, Colchicum was recorded as a remedy for dropsy (now called edema) among other illnesses.<ref name="Hoffman-2019" /> Colchicum plants were brought to North America by Benjamin Franklin, who had gout himself and had written humorous doggerel about the disease during his stint as United States Ambassador to France.<ref>Template:Cite book</ref>

Colchicine was first isolated in 1820 by French chemists P. S. Pelletier and J. B. Caventou.<ref>Template:Cite journal</ref> In 1833, P. L. Geiger purified an active ingredient, which he named colchicine.<ref>Template:Cite journal; colchicine is discussed on pages 274-276 </ref> It quickly became a popular remedy for gout.<ref name="Hoffman-2019" /> 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.<ref>Template:Cite journal Dewar did not prove the structure of colchicine; he merely suggested that it contained two seven-membered rings. Colchicine's structure was determined by X-ray crystallography in 1952 Template:Cite journal Its total synthesis was first accomplished in 1959 Template:Cite journal</ref> 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.<ref>Albert Eschenmoser The Franklin Institute. fi.edu. Accessed 24 September 2023.</ref>

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.<ref>Template:Cite web</ref>

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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

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.<ref name="Right_to_Know_List">Template:Cite web</ref>

Formulations and dosing

Trade names for colchicine are Colcrys or Mitigare, which are manufactured as a dark– and light-blue capsule having a dose of 0.6 mg.<ref name=drugs/><ref name="drugs-images">Template:Cite web</ref> Colchicine is also prepared as a white, yellow, or purple pill (tablet) having a dose of 0.6 mg.<ref name=drugs-images/>

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.<ref name=NPS2010/><ref name=drugs/> With an oral dose of 0.6 mg, peak blood levels occur within one to two hours.<ref name=cder/> 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.<ref name=drugs/> It has a narrow therapeutic window, requiring monitoring of the subject for potential toxicity.<ref name=drugs/> Colchicine is not a general pain-relief drug, and is not used to treat pain in other disorders.<ref name=drugs/>

Biosynthesis

According to laboratory research, the biosynthesis of colchicine involves the amino acids phenylalanine and tyrosine as precursors. Giving radioactive phenylalanine-2-¹⁴C to C. byzantinum, another plant of the family Colchicaceae, resulted in its incorporation into colchicine.<ref>Template:Cite journal</ref> However, the tropolone ring of colchicine resulted from the expansion of the tyrosine ring. 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 the addition of acetyl-coenzyme A to deacetylcolchicine.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref>

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.<ref name="Hoffman-2019" />

Botanical use and seedless fruit

Template:More citations needed section Colchicine is used in plant breeding by inducing polyploidy in plant cells to produce new or improved varieties, strains, and cultivars.<ref name="Griffiths">Template:Cite journal</ref> 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. Since chromosome segregation is driven by microtubules, colchicine alters cellular division by inhibiting chromosome segregation during mitosis; half the resulting daughter cells, therefore, contain no chromosomes, while the other half contains double the usual number of chromosomes (i.e., tetraploid instead of diploid), and lead to cell nuclei with double the usual number of chromosomes (i.e., tetraploid instead of diploid).<ref name=Griffiths/> 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.<ref name=Griffiths/>

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 triticale (× Triticosecale) from wheat (Triticum spp.) and rye (Secale cereale). Wheat is typically tetraploid and rye diploid, with their triploid hybrid infertile; treatment of triploid triticale with colchicine gives fertile hexaploid triticale.<ref>Template:Cite web</ref>

External links

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