''Colchicum'' extract was first described as a treatment for gout in ''De Materia Medica'' by Pedanius Dioscorides
Pedanius Dioscorides ( grc-gre, Πεδάνιος Διοσκουρίδης, ; 40–90 AD), “the father of pharmacognosy”, was a Greek physician, pharmacologist, botanist, and author of '' De materia medica'' (, On Medical Material) —a 5-vo ...
, in the first century AD. Use of the bulb-like corm
A corm, bulbo-tuber, or bulbotuber is a short, vertical, swollen underground plant stem that serves as a storage organ that some plants use to survive winter or other adverse conditions such as summer drought and heat (perennation).
The word ' ...
s 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
Ibn Sina ( fa, ابن سینا; 980 – June 1037 CE), commonly known in the West as Avicenna (), was a Persian polymath who is regarded as one of the most significant physicians, astronomers, philosophers, and writers of the Islamic ...
, and were recommended by Ambroise Paré
Ambroise Paré (c. 1510 – 20 December 1590) was a French barber surgeon who served in that role for kings Henry II, Francis II, Charles IX and Henry III. He is considered one of the fathers of surgery and modern forensic pathology and a pi ...
in the 16th century, and appeared in the ''London Pharmacopoeia
A pharmacopoeia, pharmacopeia, or pharmacopoea (from the obsolete typography ''pharmacopœia'', meaning "drug-making"), in its modern technical sense, is a book containing directions for the identification of compound medicines, and published by ...
'' of 1618. ''Colchicum'' use waned over time, likely due to the severe gastrointestinal side effects preparations caused. In 1763, ''Colchicum'' was recorded as a remedy for dropsy (now called edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...
) among other illnesses. ''Colchicum'' plants were brought to North America by Benjamin Franklin
Benjamin Franklin ( April 17, 1790) was an American polymath who was active as a writer, scientist, inventor, statesman, diplomat, printer, publisher, and political philosopher. Encyclopædia Britannica, Wood, 2021 Among the leading int ...
, who had gout himself and had written humorous doggerel about the disease during his stint as United States Ambassador to France
The United States ambassador to France is the official representative of the president of the United States to the president of France. The United States has maintained diplomatic relations with France since the American Revolution. Relations we ...
.
Colchicine was first isolated in 1820 by French chemists P. S. Pelletier and J. B. Caventou. In 1833, P. L. Geiger purified an active ingredient, which he named colchicine. It quickly became a popular remedy for gout. 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. Its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin.
United States Unapproved Drugs Initiative
An unintended consequence of the 2006 U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) safety program called the Unapproved Drugs Initiative—through which the FDA sought more rigorous testing of efficacy and safety of colchicine and other unapproved drugs—was a price increase of 2000 percent for "a gout remedy so old that the ancient Greeks knew about its effects". Under Unapproved Drugs Initiative small companies such as 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.
Oral colchicine had been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings. On 30 July 2009, the FDA approved colchicine as a monotherapy for the treatment of three different indications (familial Mediterranean fever
Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are sus ...
, acute gout flares, and for the prophylaxis of gout flares[), and gave URL Pharma a three-year marketing exclusivity agreement] 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. Colchicine in combination with probenecid has been FDA-approved before 1982.
On 29 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. 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.
Marketing exclusivity in the United States
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.
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 randomized control trial. Through the Unapproved Drugs Initiative, the FDA sought more rigorous testing of the efficacy and safety of colchicine and other unapproved drugs. In exchange for paying for the costly testing, the FDA gave URL Pharma three years of market exclusivity for its Colcrys brand, under the Hatch-Waxman Act
The Drug Price Competition and Patent Term Restoration Act (Public Law 98-417), informally known as the Hatch-Waxman Act, is a 1984 United States federal law that encourages the manufacture of generic drugs by the pharmaceutical industry and es ...
, based in part on URL-funded research in 2007, including pharmacokinetic
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
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
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the lat ...
, or large insurers to pay for trials themselves. Furthermore, the cost burden of this subsidy falls primarily on patients or their insurers. In September 2010, the FDA ordered a halt to marketing unapproved single-ingredient oral colchicine.
Colchicine patents expire on 10 February 2029.
Orphan drug
URL Pharma also 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
Medicaid in the United States is a federal and state program that helps with healthcare costs for some people with limited income and resources. Medicaid also offers benefits not normally covered by Medicare, including nursing home care and per ...
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
Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications o ...
was approved in 1998 as an orphan drug for leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria '' Mycobacterium leprae'' or '' Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve d ...
and in 2006 for multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, ...
.)
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.
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.
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.
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.
Formulations and dosing
Trade name
A trade name, trading name, or business name, is a pseudonym used by companies that do not operate under their registered company name. The term for this type of alternative name is a "fictitious" business name. Registering the fictitious name w ...
s for colchicine are Colcrys or Mitigare, which are manufactured as a dark– and light-blue capsule having a dose of 0.6 mg. Colchicine is also prepared as a white, yellow, or purple pill (tablet
Tablet may refer to:
Medicine
* Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill"
Computing
* Tablet computer, a mobile computer that is primarily operated by touching the ...
) having a dose of 0.6 mg.[
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.][ With an oral dose of 0.6 mg, peak blood levels occur within one to two hours.][ 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.][ It has a narrow therapeutic window, requiring monitoring of the subject for potential toxicity.][ Colchicine is not a general pain-relief drug, and is not used to treat pain in other disorders.][
]
Biosynthesis
According to laboratory research, the biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecul ...
of colchicine involves the amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amin ...
and tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...
as precursor
Precursor or Precursors may refer to:
* Precursor (religion), a forerunner, predecessor
** The Precursor, John the Baptist
Science and technology
* Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of u ...
s. Giving radioactive phenylalanine-2-14C to ''C. byzantinum'', another plant of the family Colchicaceae, resulted in its incorporation into colchicine. However, the tropolone ring of colchicine resulted from the expansion of the tyrosine ring. Radioactive
Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration, or nuclear disintegration) is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is consi ...
feeding experiments of ''C. autumnale'' revealed that colchicine can be synthesized biosynthetically from ''(S)''-autumnaline. That biosynthesic pathway occurs primarily through a phenolic coupling reaction A coupling reaction in organic chemistry is a general term for a variety of reactions where two fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (R = ...
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.
:
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.
Botanical use
Colchicine is widely used in plant breeding
Plant breeding is the science of changing the traits of plants in order to produce desired characteristics. It has been used to improve the quality of nutrition in products for humans and animals. The goals of plant breeding are to produce cr ...
by inducing polyploidy in plant cells to produce new or improved varieties, strains, and cultivars. 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
Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segrega ...
is driven by microtubules, colchicine alters cellular division by inhibiting chromosome segregation during meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately ...
; half the resulting gamete
A gamete (; , ultimately ) is a haploid cell that fuses with another haploid cell during fertilization in organisms that reproduce sexually. Gametes are an organism's reproductive cells, also referred to as sex cells. In species that produce ...
s, therefore, contains no chromosomes, while the other half contains double the usual number of chromosomes (i.e., diploid
Ploidy () is the number of complete sets of chromosomes in a cell, and hence the number of possible alleles for autosomal and pseudoautosomal genes. Sets of chromosomes refer to the number of maternal and paternal chromosome copies, respectiv ...
instead of haploid
Ploidy () is the number of complete sets of chromosomes in a cell, and hence the number of possible alleles for autosomal and pseudoautosomal genes. Sets of chromosomes refer to the number of maternal and paternal chromosome copies, respective ...
, 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 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.][
When such a tetraploid plant is crossed with a diploid plant, the triploid offspring are usually ]sterile
Sterile or sterility may refer to:
*Asepsis
Asepsis is the state of being free from disease-causing micro-organisms (such as pathogenic bacteria, viruses, pathogenic fungi, and parasites). There are two categories of asepsis: medical and surgi ...
(unable to produce fertile
Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Fertili ...
seeds or spore
In biology, a spore is a unit of sexual or asexual reproduction that may be adapted for dispersal and for survival, often for extended periods of time, in unfavourable conditions. Spores form part of the life cycles of many plants, algae, ...
s), 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 shrub
A shrub (often also called a bush) is a small-to-medium-sized perennial woody plant. Unlike herbaceous plants, shrubs have persistent woody stems above the ground. Shrubs can be either deciduous or evergreen. They are distinguished from tree ...
s, are becoming increasingly valued in horticulture
Horticulture is the branch of agriculture that deals with the art, science, technology, and business of plant cultivation. It includes the cultivation of fruits, vegetables, nuts, seeds, herbs, sprouts, mushrooms, algae, flowers, seaweeds and no ...
and landscaping
Landscaping refers to any activity that modifies the visible features of an area of land, including the following:
# Living elements, such as flora or fauna; or what is commonly called gardening, the art and craft of growing plants with a goal ...
because they do not become invasive species
An invasive species otherwise known as an alien is an introduced organism that becomes overpopulated and harms its new environment. Although most introduced species are neutral or beneficial with respect to other species, invasive species adv ...
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
Pollination is the transfer of pollen from an anther of a plant to the stigma of a plant, later enabling fertilisation and the production of seeds, most often by an animal or by wind. Pollinating agents can be animals such as insects, bird ...
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
Polyploidy is a condition in which the cells of an organism have more than one pair of ( homologous) chromosomes. Most species whose cells have nuclei ( eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set conta ...
triticale.
Research
COVID-19
Colchicine was researched for potential benefit in treating COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quick ...
following hypotheses at the start of the pandemic that it may be an applicable medication. No good evidence of benefit was found.
References
Further reading
*
External links
*
*
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